Bio

Clinical Focus


  • Neonatology
  • Neonatal-Perinatal Medicine

Administrative Appointments


  • Chief, Division of Neonatal and Developmental Medicine, Stanford University School of Medicine (1989 - 2007)
  • Program Director, Training in Developmental and Neonatal Biology, Stanford University School of Medicine (1989 - 2015)
  • Harold K. Faber Professor of Pediatrics, Stanford University School of Medicine (1992 - Present)
  • Associate Program Director, General Clinical Research Center; Head, Pediatric Component, Stanford University School of Medicine (1993 - 2008)
  • Director, Charles B. and Ann L. Johnson Center for Pregnancy and Newborn Services, Lucile Packard Children's Hospital at Stanford (1997 - 2017)
  • Senior Associate Dean for Academic Affairs, Stanford University School of Medicine (2001 - 2013)
  • Vice Dean, Stanford University School of Medicine (2006 - 2013)
  • Co-Director, Stanford Center for Clinical and Translational Education and Research (2008 - 2018)
  • Co-Leader, Stanford Clinical and Translational Unit (CTRU) (2008 - 2018)
  • Leader, Spectrum Child Health (2008 - 2018)
  • Senior Associate Dean for Maternal & Child Health, Stanford University School of Medicine (2014 - Present)

Honors & Awards


  • Kaiser Award for Outstanding and Innovative Contributions to Medical Education, The Henry J. Kaiser Family Foundation (1983)
  • Ross Young Investigator Award, Western Society for Pediatric Research (1990)
  • American Academy of Pediatrics Award for Excellence in Pediatric Research, American Academy of Pediatrics (1991)
  • The Duane Alexander Award for Academic Leadership in Perinatal Medicine, The National Institute of Child Health and Human Development (2003)
  • Advisor of Highest Distinction for Exemplary Contributions to Undergraduate Education, Stanford University (2004)
  • MENTOR Award for Excellence in Research Training, The National Institute of Child Health and Human Development (2004)
  • The Neonatal Education Award in Perinatal Pediatrics, American Academy of Pediatrics (2004)
  • Virginia Apgar Award in Perinatal Pediatrics, American Academy of Pediatrics (2006)
  • Albion Walter Hewlett Award, Stanford University School of Medicine (2009)
  • Alwin C. Rambar-James B.D. Mark Award for Excellence in Patient Care, Stanford University School of Medicine (2009)
  • Joseph W. St. Geme, Jr. Education Award, Western Society for Pediatric Research (2009)
  • Jonas Salk Award for Leadership in Prematurity Prevention, March of Dimes Foundation (2011)
  • Maureen Andrew Mentor Award, Society for Pediatric Research (2011)
  • Member, Institute of Medicine, National Academy of Sciences (2012)
  • William A. Silverman Lectureship, American Academy of Pediatrics (2013)
  • James L (Scooter) Haywood Memorial Lecture, University of Alabama (2014)
  • Member, National Academy of Medicine, 2015, National Academy of Medicine (2015)
  • Gladys J. Fashena Lecture, University of Texas Southwestern Medical Center (2016)
  • Joseph W. St. Geme, Jr. Leadership Award, Federation of Pediatric Organizations (2016)
  • Robert B. Cotton Lecture, Vanderbilt University School of Medicine (2016)
  • Stanley Wright Memorial Lecture, Western Society for Pediatric Research (2016)
  • 23rd Annual Kurt Benirschke Lecture, University of California San Diego, School of Medicine (2017)
  • 9th Gregor Stoddard Lecture, University of Colorado (2017)
  • Frank H. Morriss, Jr. Leadership Award, University of Iowa Carver College of Medicine (2017)
  • Medical Staff Distinguished Service Award, LPCH (2018)

Boards, Advisory Committees, Professional Organizations


  • Secretary-Treasurer, Western Society for Pediatric Research (1986 - 1990)
  • Committee on Awards for Excellence in Pediatric Research, American Academy of Pediatrics (1987 - 1991)
  • Member, Ross Laboratory Seminars on Perinatal Medicine Advisory Board (1987 - 1995)
  • Neonatal-Perinatal Examination Committee, American Board of Pediatrics (1990 - 1996)
  • Member, American Academy of Pediatrics Executive Committee, Section on Perinatal Pediatrics (1991 - 1998)
  • Chair, American Academy of Pediatrics Executive Committee, Section on Perinatal Pediatrics (1994 - 1996)
  • Member, March of Dimes Basil O’Connor Advisory Committee (1995 - 2002)
  • President, Western Society for Pediatric Research (1996 - 1997)
  • Liaison Member for Section on Perinatal Pediatrics, Committee on Fetus and Newborn (COFN), American Academy of Pediatrics (1997 - 1998)
  • Chair, Western Conference for Perinatal Research, (Mead Johnson Nutritionals) (1997 - 2002)
  • Member, Sub-Board of Neonatal-Perinatal Medicine (1997 - 2002)
  • Member, Council of the American Pediatric Society (1997 - 2007)
  • President, California Association of Neonatologists (CAN) (1999 - 2000)
  • Chair, Sub-Board of Neonatal-Perinatal Medicine, American Board of Pediatrics (2000 - 2002)
  • Program Chair, Pediatric Academic Societies Annual Meeting (2000 - 2003)
  • Vice President/President-Elect, American Pediatric Society (2004 - 2005)
  • Board of Directors, American Board of Pediatrics (2004 - 2009)
  • President, American Pediatric Society (2005 - 2006)
  • Board of Directors, Children’s Health Council (2005 - 2008)
  • Scientific Advisory Board, Faculty of Pharmacy, University of Lisboa, Portugal (2007 - Present)
  • Chair, Long Range Planning Committee, American Board of Pediatrics (2009 - 2013)
  • Task Force on Subspecialty Training and Certification, American Board of Pediatrics (2010 - 2013)
  • Maureen Andrew Mentor Award Selection Committee, Society for Pediatric Research (2011 - 2013)
  • Affiliated Faculty Member, Woods Institute (2011 - Present)
  • Chair, Maureen Andrew Mentor Award Selection Committee, Society for Pediatric Research (2013 - 2013)
  • Transdisciplinary Centers (TDC) Advisory Committee, Ex Officio Member, March of Dimes (2013 - Present)
  • Guest Professor, Juntendo University, Tokyo, Japan (2015 - Present)

Professional Education


  • Board Certification: Neonatal-Perinatal Medicine, American Board of Pediatrics (1979)
  • Board Certification: Pediatrics, American Board of Pediatrics (1979)
  • Fellowship:Stanford University Medical Center (1979) CA
  • Residency:University of Washington School of Medicine (1977) WA
  • Internship:University of Washington School of Medicine (1976) WA
  • Medical Education:University of Washington School of Medicine (1975) WA
  • B.A., Stanford University, Philosophy (1971)
  • M.D., University of Washington School of Medicine, Medicine (1975)

Research & Scholarship

Current Research and Scholarly Interests


Our research is focused on the study of the ontogeny and control of heme catabolism and bilirubin production in the developing neonate. A better understanding of the role of increased bilirubin production in neonatal jaundice and the prevention of hemolytic jaundice has remained an overall objective of our program. To this end, we are actively investigating a more targeted, preventive approach to the diagnosis and treatment of newborns, who are high producers of the pigment and/or unable to efficiently eliminate bilirubin, thus leading to an accumulation of the pigment in circulation and tissues, which may lead to irreversible neurologic injury. Control of bilirubin production is a logical strategy, but has unexplored consequences for the immature mammal. Thus, we are studying the pivotal role of heme oxygenase (HO), the rate-limiting enzyme in the production of bilirubin, under a variety of commonly encountered pathological conditions, such as infection and hypoxia-ischemia, as well as in anti-oxidant defense, immune response and the regulation of hematopoiesis. In support of the above interests, studies are in progress, which are designed to screen a variety of metalloporphyrins and other compounds for maximum in vitro and in vivo efficacy with minimal side effects; to determine the ontogeny of the HO enzyme system in various murine tissues, focusing on perturbations resulting from treatment with HO inhibitors; and further to develop and test new technologies for noninvasive or minimally-invasive measurements of in vivo metabolism that could be used for diagnostic and monitoring purposes.

Clinical Trials


  • Vitamin E for Extremely Preterm Infants Recruiting

    The purpose of this pilot trial is to test the safety and efficacy of administering one dose of vitamin E, via a tube into the stomach, to extremely preterm infants (less than 27 weeks gestation and less than 1000 grams birth weight). This pilot will examine whether a single dose of vitamin E will be absorbed into the infants' bloodstreams with resulting serum α-tocopherol level in the target range of 1-3 mg/dl.

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  • Laparotomy vs. Drainage for Infants With Necrotizing Enterocolitis Not Recruiting

    This trial will compare the effectiveness of two surgical procedures -laparotomy versus drainage - commonly used to treat necrotizing enterocolitis (NEC) or isolated intestinal perforations (IP) in extremely low birth weight infants (≤1,000 g). Infants diagnosed with NEC or IP requiring surgical intervention, will be recruited. Subjects will be randomized to receive either a laparotomy or peritoneal drainage. Primary outcome is impairment-free survival at 18-22 months corrected age.

    Stanford is currently not accepting patients for this trial. For more information, please contact M. Bethany Ball, (650) 725 - 8342.

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  • Late Hypothermia for Hypoxic-Ischemic Encephalopathy Not Recruiting

    This study is a randomized, placebo-controlled, clinical trial to evaluate whether induced whole-body hypothermia initiated between 6-24 hours of age and continued for 96 hours in infants ≥ 36 weeks gestational age with hypoxic-ischemic encephalopathy will reduce the incidence of death or disability at 18-22 months of age. The study will enroll 168 infants with signs of hypoxic-ischemic encephalopathy at 16 NICHD Neonatal Research Network sites, and randomly assign them to either receive hypothermia or participate in a non-cooled control group.

    Stanford is currently not accepting patients for this trial. For more information, please contact Bethany Ball, (650) 735 - 8342.

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  • Optimizing (Longer, Deeper) Cooling for Neonatal Hypoxic-Ischemic Encephalopathy(HIE) Not Recruiting

    The Optimizing Cooling trial will compare four whole-body cooling treatments for infants born at 36 weeks gestational age or later with hypoxic-ischemic encephalopathy: (1) cooling for 72 hours to 33.5°C; (2) cooling for 120 hours to 33.5°C; (3) cooling for 72 hours to 32.0°C; and (4) cooling for 120 hours to 32.0°C. The objective of this study is to evaluate whether whole-body cooling initiated at less than 6 hours of age and continued for 120 hours and/or a depth at 32.0°C in will reduce death and disability at 18-22 months corrected age.

    Stanford is currently not accepting patients for this trial. For more information, please contact M Bethany Ball, (650) 725 - 8342.

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  • Cycled Phototherapy: A Safer Effective Treatment for Small Premature Infants? Recruiting

    Cycled (intermittent) phototherapy will be compared to continuous (uninterrupted) phototherapy in the treatment of hyperbilirubinemia (newborn jaundice) in extremely low birth weight newborns in a pilot randomized controlled trial. Hypothesis: Cycled phototherapy (PT) will provide the same benefits as continuous phototherapy in extremely low birth weight (ELBW) infants without the risks that have been associated with continuous phototherapy.

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  • Benchmarking Initiative to Reduce Bronchopulmonary Dysplasia Not Recruiting

    This study tested whether Neonatal Intensive Care Unit (NICU) teams trained in benchmarking -- comparing care practices between different NICUs to see which practices prevent bronchopulmonary dysplasia (BPD) -- and quality improvement would change practices and improve rates of survival without BPD in inborn neonates with birth weights of <1250 grams. Benchmarking is a method involving detailed comparisons of processes between similar organizations. For this study, three NRN centers with the lowest rates of BPD have been identified as Benchmark centers. During a 6-month pre-intervention period, details of care practices and management style at these centers were carefully assessed. Based on practices at these Benchmarking sites, we developed a quality improvement program. For this study, 14 other NRN sites were randomized to either implement the benchmarking intervention (intervention sites) or continue with their usual care practices (control sites). After the 1-year intervention period, we compared changes in the rate of survival without BPD at 36 weeks corrected age between the intervention and control sites.

    Stanford is currently not accepting patients for this trial.

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  • Dexamethasone Therapy in VLBW Infants at Risk of CLD Not Recruiting

    Infants who are on breathing support are often treated with steroids (dexamethasone); however, the best timing of therapy is not known. This trial looked at the benefits and hazards of starting dexamethasone therapy at two weeks of age and four weeks of age in premature infants.

    Stanford is currently not accepting patients for this trial.

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  • Growth Observational Study Not Recruiting

    This study was a multicenter, prospective cohort study to define postnatal longitudinal growth for very low birth weight (VLBW) infants. The objectives were: 1) to develop postnatal growth curves for VLBW preterm infants that would permit an assessment of growth velocity; 2) to relate growth velocity and nutritional practices (duration of parenteral nutrition, age at first enteral feeding, and age at full enteral feeding); 3) to compare growth velocity in infants who are small-for-gestational age (SGA) with infants who are appropriate-for-gestational age (AGA); and 4) to relate growth velocity to several common, major morbidities, including chronic lung disease (CLD), nosocomial infection (or late-onset infection) and necrotizing enterocolitis (NEC). These growth data may be useful in identifying preterm infants who are growing slowly despite current nutritional support and in designing and performing clinical trials of nutritional interventions.

    Stanford is currently not accepting patients for this trial.

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  • Supplemental Therapeutic Oxygen for Prethreshold Retinopathy of Prematurity Not Recruiting

    The purpose of this trial was to determine the efficacy and safety of supplemental therapeutic oxygen for infants with prethreshold retinopathy of prematurity (ROP) to reduce the probability of progression to threshold ROP and the need for peripheral retinal ablation.

    Stanford is currently not accepting patients for this trial.

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  • Persistent Pulmonary Hypertension of the Newborn (PPHN) Observational Study Not Recruiting

    This study was an observational study to estimate the prevalence of Persistent pulmonary hypertension of the newborn (PPHN) among term or near-term infants with severe respiratory disease.

    Stanford is currently not accepting patients for this trial.

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  • In Utero Magnesium Sulfate Exposure: Effects on Extremely-Low-Birth-Weight Infants Not Recruiting

    This study examined the effect of magnesium sulfate (MgSO4) exposure on adverse outcome in extremely low birth weight (ELBW) infants. For infants included in the NICHD Neonatal Research Network Generic Database whose mothers were given prenatal MgSO4, data were prospectively collected on maternal/infant conditions and magnesium exposure (including indications, timing and duration of exposure).

    Stanford is currently not accepting patients for this trial.

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  • Prediction of Jaundice in Term Infants Not Recruiting

    The objective of this study was to describe total bilirubin production in healthy term infants as a means of understanding the differences in jaundice pigment production associated with various common clinical circumstances.

    Stanford is currently not accepting patients for this trial.

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  • Early Blood Pressure Management in Extremely Premature Infants Not Recruiting

    This trial tests the feasibility of enrolling 60 extremely preterm infants in a randomized, double-blinded study of blood pressure management within 12 months. Eligible infants will receive an infusion drug (dopamine or a dextrose placebo) and a syringe drug (hydrocortisone or a normal saline placebo). Enrolled infants will be randomized to receive one of the following drug pairs: - dopamine and hydrocortisone - dopamine and normal saline - dextrose and hydrocortisone - dextrose and normal saline. In addition to the intervention above, the NRN is conducting a 6-month time-limited prospective observational study of all infants born at an NRN center between 23 and 26 weeks gestational age. All clinical decisions made for these babies will be at the discretion of the attending neonatologist/infant care team according to standard practice at each institution. Data on blood pressure management in the first 24 postnatal hours collected for each infant.

    Stanford is currently not accepting patients for this trial. For more information, please contact M Bethany Ball, (650) 725 - 8342.

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  • Observational Study of Surgical Treatment of Necrotizing Enterocolotis Not Recruiting

    The purposes of this study were: 1) to compare mortality and postoperative morbidities in extremely low birth weight (ELBW) infants who underwent initial laparotomy or drainage for necrotizing enterocolitis (NEC) or isolated intestinal perforation (IP); 2) to determine the ability to distinguish NEC from IP preoperatively and the importance of this distinction on outcome measures; and 3) to evaluate the association between extent of intestinal disease determined at operation and outcome measures. All ELBW infants born at participating NRN centers were screened for the presence of NEC or IP that was thought by the pediatric surgeon and neonatologist to require surgical intervention. Data were collected enrolled infants, including: intraoperative findings recorded by the surgeon and specific post-operative complications. Neurodevelopmental examinations were conducted on surviving infants at 18-22 months corrected age.

    Stanford is currently not accepting patients for this trial.

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  • Glutamine Supplementation to Prevent Death or Infection in Extremely Premature Infants Not Recruiting

    This large multicenter double-masked clinical trial tested whether supplementation of standard neonatal parenteral nutrition with glutamine would reduce the risk of death or late-onset sepsis in extremely-low-birth-weight (ELBW, less than or equal to 1000 gm) infants. Neonates with birth weights of 401-1000gm were randomized to standard TrophAmine or TrophAmine supplemented with glutamine before 72 hours and continued until the infants are tolerating full enteral feedings.

    Stanford is currently not accepting patients for this trial.

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  • Inflammatory Cytokines Associated With Perinatal Brain Injury Not Recruiting

    This observational study assessed whether measurements of certain pro-inflammatory and anti-inflammatory cytokines in the blood (either singly or in combination) at birth and/or up to day of life 21 can predict cerebral palsy at 18-22 months corrected age.

    Stanford is currently not accepting patients for this trial.

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  • Minimal Breathing Support and Early Steroids to Prevent Chronic Lung Disease in Extremely Premature Infants (SAVE) Not Recruiting

    This multicenter clinical trial tested whether minimal ventilation decreases death or BPD. Infants with birth weight 501g to 1000g and mechanically ventilated before 12 hours were randomly assigned to minimal ventilation (partial pressure of carbon dioxide [PCO(2)] target >52 mm Hg) or routine ventilation (PCO(2) target <48 mm Hg) and a tapered dexamethasone course or saline placebo for 10 days, using a 2 x 2 factorial design. The primary outcome was death or BPD at 36 weeks' postmenstrual age. Blood gases, ventilator settings, and FiO2 were recorded for 10 days; complications and outcomes were monitored to discharge. The infants' neurodevelopment was evaluated at 18-22 months corrected age.

    Stanford is currently not accepting patients for this trial.

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  • Inhaled Nitric Oxide Study for Respiratory Failure in Newborns Not Recruiting

    Respiratory failure in term newborns is associated with increased rates of death and long-term neurodevelopmental problems. This large international multicenter trial randomized newborns who had failed to respond to intensive care, including high levels of ventilator support, to receive either inhaled nitric oxide (iNO) or 100 percent oxygen to test whether iNO would decrease their risk of dying or requiring temporary lung bypass. Infants were followed during their initial hospitalization; their outcome was assessed at 18 to 24 mos of age.

    Stanford is currently not accepting patients for this trial.

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  • Antenatal Phenobarbital to Prevent Neonatal Intracranial Hemorrhage Not Recruiting

    This large randomized trial tested whether phenobarbital given to a pregnant woman about to deliver a premature infant would prevent brain injuries in their newborns. Women with 24 to 32 week fetuses who were in preterm labor and were expected to deliver within 24 hrs were randomized to phenobarbital or usual care. They were treated until they deliver or the fetus reaches 33 wks gestation. Babies were followed until discharge and evaluated at 18-22 mos corrected age for neurodevelopmental outcome.

    Stanford is currently not accepting patients for this trial.

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  • Exosurf Neonatal and Survanta for Treatment of Respiratory Distress Syndrome Not Recruiting

    The purpose of this study is to compare the efficacy of two surfactants, Exosurf Neonatal (Burroughs Wellcome Co.) and Survanta (Ross Laboratories), for the treatment of neonatal respiratory distress syndrome.

    Stanford is currently not accepting patients for this trial.

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  • Development of Standards for the New Ballard Maturation Score Not Recruiting

    The primary purpose of this study was to evaluate the accuracy of gestational age (GA) estimates by using the New Ballard Score (NBS) in newborns 24 to 27 weeks GA with accurate obstetric estimates of GA. Secondary purposes were: (1) to compare the accuracy of GA estimates derived from the NBS, the original Ballard score, and the physical items of the original Ballard score and (2) to compare these measures of GA and best obstetric estimates of GA as predictors of survival, morbidity, and hospital stay among infants <28 weeks' gestation and among very low birth weight infants in general.

    Stanford is currently not accepting patients for this trial.

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  • Vitamin A Supplementation for Extremely-Low-Birth-Weight Infants Not Recruiting

    This multi-site, randomized trial was conducted to determine the safety and effectiveness of a higher dose of vitamin A and determine if this would increase the rate of survival without bronchopulmonary dysplasia (BPD) and reduce the risk of sepsis. Infants with birth weights from 401-1000g and who were on mechanical ventilation or supplemental oxygen at 24-96 hours of age were enrolled. Subjects were randomized to either the Vitamin A or a control group. Infants in the Vitamin A group were given a dose of 5000 IU (0.1 ml) intramuscularly on Mondays, Wednesdays, and Fridays for four weeks. Control infants received a sham procedure rather than placebo injections.

    Stanford is currently not accepting patients for this trial.

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  • Trial of Indomethacin Prophylaxis in Preterm Infants (TIPP) Not Recruiting

    This trial was to determine whether giving low-dose indomethacin to infants weight 500 to 999 grams (approximately 1 to 2 pounds) at birth improves their survival without cerebral palsy or developmental problems at 18 to 22 months of age.

    Stanford is currently not accepting patients for this trial.

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  • Early Surfactant to Reduce Use of Mechanical Breathing in Low Birth Weight Infants Not Recruiting

    Mechanical ventilation (MV) of preterm infants with respiratory distress syndrome (RDS) is associated with lung injury and nosocomial infection. Moderately premature infants with mild respiratory distress do not routinely receive artificial surfactant early in their course of treatment. This multi-center, randomized trial tested whether early surfactant therapy and nasal continuous positive airway pressure (CPAP) in infants 1,250-2,000g with RDS reduced mechanical ventilation usage without added complications. Infants with mild to moderate respiratory distress syndrome were enrolled in the trial and given either early administration of surfactant followed by extubation within 30 minutes and the use of CPAP, or standard practice (surfactant according to current center practice, only after initiation of mechanical ventilation), to see whether the experimental method would reduce the need for subsequent mechanical ventilation.

    Stanford is currently not accepting patients for this trial.

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  • Inhaled PGE1 in Neonatal Hypoxemic Respiratory Failure Not Recruiting

    This pilot study was a randomized, placebo-controlled, clinical trial to test the safety of using the intravenous form of Prostaglandin E1 (PGE1) in an inhaled form for treatment of hypoxemic respiratory failure in term newborns. The study planned to enroll 50 infants diagnosed with hypoxemic respiratory failure at nine NICHD Neonatal Research Network sites, and randomly assign them to receive one dose over a 72-hour period of either high concentration PGE1 (300 ng/kg/min), low concentration PGE1 (150 ng/kg/min), or placebo (normal saline, the diluent for the drug). In addition to determining the safety, optimal dose, and duration of the therapy, this pilot trial planned to evaluate the feasibility of conducting a larger, multi-center randomized, blinded placebo-controlled trial.

    Stanford is currently not accepting patients for this trial. For more information, please contact Bethany Ball, (650) 725 - 8342.

    View full details

Teaching

2017-18 Courses


Stanford Advisees


Publications

All Publications


  • Stillbirth and Live Birth at Periviable Gestational Age: A Comparison of Prevalence and Risk Factors. American journal of perinatology Carmichael, S. L., Blumenfeld, Y. J., Mayo, J. A., Profit, J., Shaw, G. M., Hintz, S. R., Stevenson, D. K. 2018

    Abstract

    OBJECTIVE: We compared the prevalence of and risk factors for stillbirth and live birth at periviable gestational age (20-25 weeks).STUDY DESIGN: This is a cohort study of 2.5 million singleton births in California from 2007 to 2011. We estimated racial-ethnic prevalence ratios and used multivariable logistic regression for risk factor comparisons.RESULTS: In this study, 42% of deliveries at 20 to 25 weeks' gestation were stillbirths, and 22% were live births who died within 24 hours. The prevalence of delivery at periviable gestation was 3.4 per 1,000 deliveries among whites, 10.9 for blacks, 3.5 for Asians, and 4.4 for Hispanics. Nonwhite race-ethnicity, lower education, uninsured status, being U.S. born, older age, obesity, smoking, pre-pregnancy hypertension, nulliparity, interpregnancy interval, and prior preterm birth or stillbirth were all associated with increased risk of both stillbirth and live birth at 20 to 25 weeks' gestation, compared with delivery of a live birth at 37 to 41 weeks.CONCLUSION: Inclusion of stillbirths and live births in studies of deliveries at periviable gestations is important.

    View details for DOI 10.1055/s-0038-1670633

    View details for PubMedID 30208499

  • Epigenetic immune cell counting in human blood samples for immunodiagnostics SCIENCE TRANSLATIONAL MEDICINE Baron, U., Werner, J., Schildknecht, K., Schulze, J. J., Mulu, A., Liebert, U., Sack, U., Speckmann, C., Gossen, M., Wong, R. J., Stevenson, D. K., Babel, N., Schuermann, D., Baldinger, T., Bacchetta, R., Gruetzkau, A., Borte, S., Olek, S. 2018; 10 (452)

    Abstract

    Immune cell profiles provide valuable diagnostic information for hematologic and immunologic diseases. Although it is the most widely applied analytical approach, flow cytometry is limited to liquid blood. Moreover, either analysis must be performed with fresh samples or cell integrity needs to be guaranteed during storage and transport. We developed epigenetic real-time quantitative polymerase chain reaction (qPCR) assays for analysis of human leukocyte subpopulations. After method establishment, whole blood from 25 healthy donors and 97 HIV+ patients as well as dried spots from 250 healthy newborns and 24 newborns with primary immunodeficiencies were analyzed. Concordance between flow cytometric and epigenetic data for neutrophils and B, natural killer, CD3+ T, CD8+ T, CD4+ T, and FOXP3+ regulatory T cells was evaluated, demonstrating substantial equivalence between epigenetic qPCR analysis and flow cytometry. Epigenetic qPCR achieves both relative and absolute quantifications. Applied to dried blood spots, epigenetic immune cell quantification was shown to identify newborns suffering from various primary immunodeficiencies. Using epigenetic qPCR not only provides a precise means for immune cell counting in fresh-frozen blood but also extends applicability to dried blood spots. This method could expand the ability for screening immune defects and facilitates diagnostics of unobservantly collected samples, for example, in underdeveloped areas, where logistics are major barriers to screening.

    View details for DOI 10.1126/scitranslmed.aan3508

    View details for Web of Science ID 000440494900001

    View details for PubMedID 30068569

  • Prethreshold retinopathy of prematurity: VEGF inhibition without VEGF inhibitors. Journal of perinatology : official journal of the California Perinatal Association Gaynon, M. W., Wong, R. J., Stevenson, D. K., Sunshine, P. 2018

    Abstract

    The risk of developing treatment-warranted Type 1 retinopathy of prematurity (ROP) might be reduced in preterm infants by modifying certain systemic factors. There are steps that can be taken both early and late in the course of retinal vascular maturation that may potentially reduce an infant's risk of developing Type 1 ROP. In prethreshold stage 2-3 ROP without plus disease, a combination of supplemental oxygen, correction of severe anemia, and light adaptation to reduce rod photoreceptor oxygen consumption helped us to reduce ROP severity, and encouraged a return to a more physiologic retinal vascular maturation pattern. Thus, it may be possible to reduce the risk of developing Type 1 ROP by making adjustments in certain systemic parameters aimed at reducing retinal hypoxia, thereby gently lowering pathologically elevated levels of vascular endothelial growth factor (VEGF) within the eye.

    View details for DOI 10.1038/s41372-018-0177-9

    View details for PubMedID 30046180

  • Bilirubin binding in jaundiced newborns: from bench to bedside? Pediatric research Ahlfors, C. E., Bhutani, V. K., Wong, R. J., Stevenson, D. K. 2018

    Abstract

    BACKGROUND: Bilirubin-induced neurologic dysfunction (BIND) is a spectrum of preventable neurological sequelae in jaundiced newborns. Current total plasma bilirubin (BT) concentration thresholds for phototherapy and/or exchange transfusion poorly predict BIND.METHODS: The unbound (free) bilirubin (Bf) measured at these BT thresholds provides additional information about the risk for BIND. Bf can be readily adapted to clinical use by determining Bf population parameters at current BT thresholds. These parameters can be established using a plasma bilirubin binding panel (BBP) consisting of BT, Bf, and two empiric constants, the maximum BT (BTmax) and the corresponding equilibrium association bilirubin constant (K).RESULTS: BTmax and K provide the variables needed to accurately estimate Bf at BT

    View details for DOI 10.1038/s41390-018-0010-3

    View details for PubMedID 29967530

  • Residential agricultural pesticide exposures and risks of preeclampsia. Environmental research Shaw, G. M., Yang, W., Roberts, E. M., Aghaeepour, N., Mayo, J. A., Weber, K. A., Maric, I., Carmichael, S. L., Winn, V. D., Stevenson, D. K., English, P. B. 2018; 164: 546–55

    Abstract

    We investigated risks of preeclampsia phenotypes from potential residential pesticide exposures, including 543 individual chemicals and 69 physicochemical groupings that were applied in the San Joaquin Valley of California during the study period, 1998-2011. The study population was derived from birth certificate data linked with Office of Statewide Health Planning and Development maternal and infant hospital discharge data. The following numbers of women with preeclampsia phenotypes were identified: 1045 with superimposed (pre-existing hypertension with preeclampsia) preeclampsia (265 with gestational weeks 20-31 and 780 with gestational weeks 32-36); 3471 with severe preeclampsia (824 with gestational weeks 20-31 and 2647 with gestational weeks 32-36); and 2780 with mild preeclampsia (207 with gestational weeks 20-31 and 2573 with gestational weeks 32-36). The reference population for these groups was 197,461 women who did not have diabetes (gestational or pre-existing), did not have any hypertensive disorder, and who delivered at 37 weeks or later. The frequency of any exposure was lower or about the same in each preeclampsia case group (further delineated by gestational age), and month time period, relative to the frequency in reference population controls. Nearly all odds ratios were below 1.0 for these any vs no exposure comparisons. This study showed a general lack of increased risks between a range of agriculture pesticide exposures near women's residences and various preeclampsia phenotypes.

    View details for DOI 10.1016/j.envres.2018.03.020

    View details for PubMedID 29614386

  • Hypoxia regulates placental angiogenesis via alternatively activated macrophages. American journal of reproductive immunology (New York, N.Y. : 1989) Zhao, H., Kalish, F. S., Wong, R. J., Stevenson, D. K. 2018: e12989

    Abstract

    PROBLEM: Uterine and placental macrophages play critical roles in maintaining a normal pregnancy. The majority of these macrophages are believed to be alternatively activated macrophages (M2).METHOD OF STUDY: Mouse bone marrow cells were differentiated into macrophages and polarized to M2 in vitro by treatment with IL-4 [M2a] or IL-10 [M2c] and M1 with LPS/IFN-gamma as controls. Macrophage subtypes were confirmed by surface markers and characterized by gene expression profiles.RESULTS: Compared to M1, M2 showed strong pro-angiogenic activity by expressing higher mRNA for angiogenic-associated factors (Cxcl12, Vegfa, PlGF, Mmp2). M2c produced the highest levels of PlGF, Mmp2, and Cxcr4. To mimic the normal placental microenvironment, M2 were exposed to hypoxia and sex hormones (progesterone, estrogen). In both M2c and M2a, severe hypoxic (1%-3% O2 ) exposure significantly suppressed PlGF, Cxcl12, and Mmp2 mRNA, but not Vegfa, compared to normoxia (21% O2 ) or physiological hypoxia (5% O2 ). mRNA expression returned to normal when hypoxic cells were returned to normoxia. Hypoxia (1%) reduced antioxidant levels in M2 and re-exposure to normoxia significantly increased superoxide dismutase (Sod1, Sod2) and heme oxygenase-1 (HO-1) levels in M2a, and only glutathione peroxidase (Gpx1, Gpx3, Gpx4) in M2c. However, progesterone and estrogen treatment had minimal effects on angiogenic factor expression in M2.CONCLUSION: M2, particularly M2c, displayed strong pro-angiogenic potential, which decreased under severe hypoxia such as in early pregnancy. Thus, conditions that alter the placental oxygen microenvironment or macrophage response in early pregnancy might cause aberrant angiogenesis and vascular remodeling, and lead to abnormal placental vascular development.

    View details for DOI 10.1111/aji.12989

    View details for PubMedID 29932269

  • Natural Selection Has Differentiated the Progesterone Receptor among Human Populations. American journal of human genetics Li, J., Hong, X., Mesiano, S., Muglia, L. J., Wang, X., Snyder, M., Stevenson, D. K., Shaw, G. M. 2018

    Abstract

    The progesterone receptor (PGR) plays a central role in maintaining pregnancy and is significantly associated with medical conditions such as preterm birth that affects 12.6% of all the births in U.S. PGR has been evolving rapidly since the common ancestor of human and chimpanzee, and we herein investigated evolutionary dynamics of PGR during recent human migration and population differentiation. Our study revealed substantial population differentiation at the PGR locus driven by natural selection, where very recent positive selection in East Asians has substantially decreased its genetic diversity by nearly fixing evolutionarily novel alleles. On the contrary, in European populations, the PGR locus has been promoted to a highly polymorphic state likely due to balancing selection. Integrating transcriptome data across multiple tissue types together with large-scale genome-wide association data for preterm birth, our study demonstrated the consequence of the selection event in East Asians on remodeling PGR expression specifically in the ovary and determined a significant association of early spontaneous preterm birth with the evolutionarily selected variants. To reconstruct its evolutionary trajectory on the human lineage, we observed substantial differentiation between modern and archaic humans at the PGR locus, including fixation of a deleterious missense allele in the Neanderthal genome that was later introgressed in modern human populations. Taken together, our study revealed substantial evolutionary innovation in PGR even during very recent human evolution, and its different forms among human populations likely result in differential susceptibility to progesterone-associated disease conditions including preterm birth.

    View details for DOI 10.1016/j.ajhg.2018.05.009

    View details for PubMedID 29937092

  • Noninvasive blood tests for fetal development predict gestational age and preterm delivery SCIENCE Ngo, T. M., Moufarrej, M. N., Rasmussen, M. H., Camunas-Soler, J., Pan, W., Okamoto, J., Neff, N. F., Liu, K., Wong, R. J., Downes, K., Tibshirani, R., Shaw, G. M., Skotte, L., Stevenson, D. K., Biggio, J. R., Elovitz, M. A., Melbye, M., Quake, S. R. 2018; 360 (6393): 1133–36

    Abstract

    Noninvasive blood tests that provide information about fetal development and gestational age could potentially improve prenatal care. Ultrasound, the current gold standard, is not always affordable in low-resource settings and does not predict spontaneous preterm birth, a leading cause of infant death. In a pilot study of 31 healthy pregnant women, we found that measurement of nine cell-free RNA (cfRNA) transcripts in maternal blood predicted gestational age with comparable accuracy to ultrasound but at substantially lower cost. In a related study of 38 women (23 full-term and 15 preterm deliveries), all at elevated risk of delivering preterm, we identified seven cfRNA transcripts that accurately classified women who delivered preterm up to 2 months in advance of labor. These tests hold promise for prenatal care in both the developed and developing worlds, although they require validation in larger, blinded clinical trials.

    View details for DOI 10.1126/science.aar3819

    View details for Web of Science ID 000434635500050

    View details for PubMedID 29880692

  • Heme oxygenase-1 deficiency promotes severity of sepsis in a non-surgical preterm mouse model. Pediatric research Fujioka, K., Kalish, F., Zhao, H., Wong, R. J., Stevenson, D. K. 2018

    Abstract

    BACKGROUND: Sepsis in preterm infants is associated with systemic inflammatory responses. The stress-response protein heme oxygenase-1 (HO-1) has protective anti-inflammatory properties. Recently, we reported a protective role of HO-1 using our non-surgical cecal slurry (CS) model in wild-type (WT) mouse pups. Here, we extend these findings to investigate the association of HO-1 deficiency with sepsis severity.METHODS: Adapting the Wynn model, we induced sepsis in 4-day-old HO-1-deficient (HO-1+/-, Het) pups to determine if HO-1 deficiency affected survival rates at the LD40 (2.0mg/g) of WT pups. To see if HO-1 induction affected sepsis severity, we gave 30-mumol heme/kg subcutaneously to 3-day-old mice 24h prior to sepsis induction.RESULTS: Post-sepsis induction, Het pups had a mortality of 85.0% (n=20) and increased expression of the pro-inflammatory gene in the livers and affected hematologic profiles. Heme treatment 24h prior to sepsis induction significantly increased liver HO activity, reduced mortality to 24.5% (n=17), attenuated inflammatory responses, reduced spleen bacterial counts, and significantly increased peripheral neutrophils.CONCLUSIONS: A partial deficiency in HO-1 increased the progression and mortality in sepsis. Furthermore, induction of HO-1 significantly reduced the mortality even in Het pups. Thus, we conclude that HO-1 plays an important role in the protection against preterm sepsis.

    View details for DOI 10.1038/s41390-018-0028-6

    View details for PubMedID 29795214

  • Neuro-inflammatory effects of photodegradative products of bilirubin SCIENTIFIC REPORTS Jasprova, J., Dal Ben, M., Hurny, D., Hwang, S., Zizalova, K., Kotek, J., Wong, R. J., Stevenson, D. K., Gazzin, S., Tiribelli, C., Vitek, L. 2018; 8: 7444

    Abstract

    Phototherapy was introduced in the early 1950's, and is the primary treatment of severe neonatal jaundice or Crigler-Najjar syndrome. Nevertheless, the potential biological effects of the products generated from the photodegradation of bilirubin during phototherapy remain unknown. This is very relevant in light of recent clinical observations demonstrating that the use of aggressive phototherapy can increase morbidity or even mortality, in extremely low birthweight (ELBW) infants. The aim of our study was to investigate the effects of bilirubin, lumirubin (LR, its major photo-oxidative product), and BOX A and B (its monopyrrolic oxidative products) on the central nervous system (CNS) using in vitro and ex vivo experimental models. The effects of bilirubin photoproducts on cell viability and expression of selected genes were tested in human fibroblasts, three human CNS cell lines (neuroblastoma SH-SY5Y, microglial HMC3, and glioblastoma U-87 cell lines), and organotypic rat hippocampal slices. Neither bilirubin nor its photo-oxidative products affected cell viability in any of our models. In contrast, LR in biologically-relevant concentrations (25 μM) significantly increased gene expression of several pro-inflammatory genes as well as production of TNF-α in organotypic rat hippocampal slices. These findings might underlie the adverse outcomes observed in ELBW infants undergoing aggressive phototherapy.

    View details for DOI 10.1038/s41598-018-25684-2

    View details for Web of Science ID 000431762200004

    View details for PubMedID 29748620

    View details for PubMedCentralID PMC5945592

  • Heme oxygenase-1 deficiency results in splenic T-cell dysregulation in offspring of mothers exposed to late gestational inflammation AMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY Ozen, M., Zhao, H., Kalish, F., Yang, Y., Folkins, A., Burd, I., Wong, R. J., Stevenson, D. K. 2018; 79 (5): e12829

    Abstract

    Infection during pregnancy can disrupt regulatory/effector immune system balance, resulting in adverse pregnancy and fetal-neonatal outcomes. Heme oxygenase-1 (HO-1) is a major regulatory enzyme in the immune system. We observed maternal immune response dysregulation during late gestational inflammation (LGI), which may be mediated by HO-1. Here, we extend these studies to examine the immune response of offspring.Pregnant wild-type (Wt) and HO-1 heterozygote (Het) dams were treated with lipopolysaccharide (LPS) or vehicle at E15.5. Pups' splenic immune cells were characterized using flow cytometry.CD3+ CD4+ CD25+ (Tregs) and CD3+ CD8+ (Teffs) T cells in Wt and Het were similar in control neonates and increased with age. We showed not only age- but also genotype-specific and long-lasting T-cell dysregulation in pups after maternal LGI. The persistent immune dysregulation, mediated by HO-1 deficiency, was reflected as a decrease in Treg FoxP3 and CD3+ CD8+ T cells, and an increase in CD4+ /CD8+ T-cell and Treg/Teff ratios in Hets compared with Wt juvenile mice after maternal exposure to LGI.Maternal exposure to LGI can result in dysregulation of splenic T cells in offspring, especially in those with HO-1 deficiency. We speculate that these immune alterations are the basis of adverse outcomes in neonates from mothers exposed to low-grade (subclinical) infections.

    View details for DOI 10.1111/aji.12829

    View details for Web of Science ID 000430386400008

    View details for PubMedID 29484761

  • Identification of risk for neonatal haemolysis. Acta paediatrica (Oslo, Norway : 1992) Bhutani, V. K., Maisels, M. J., Schutzman, D. L., Castillo Cuadrado, M. E., Aby, J. L., Bogen, D. L., Christensen, R. D., Watchko, J. F., Wong, R. J., Stevenson, D. K. 2018

    Abstract

    AIM: To identify neonates at risk of haemolytic hyperbilirubinaemia through near-concurrent measurements of total serum/plasma bilirubin (TB) or transcutaneous bilirubin (TcB) and end-tidal breath carbon monoxide (CO), corrected for ambient CO (ETCOc), an index of bilirubin production and haemolysis.METHODS: Paired TB/TcB (mg/dL) and ETCOc (ppm) measurements were obtained in newborns (n = 283) at 20 to <60 hours of age in five nurseries. TB/TcB values were assigned TB/TcB percentile risk values using the Bhutani hour-specific nomogram. In infants having two serial TB/TcB measurements (n = 76), TB rate of rise (ROR, mg/dL/h) was calculated.RESULTS: For the entire cohort (n = 283), 67.1% and 32.9% had TB/TcB<75th and ≥75th percentile, respectively. TB/TcB (5.79 ± 1.84 vs 9.14 ± 2.25 mg/dL) and ETCOc (1.61 ± 0.45 vs 2.02 ± 1.35 ppm, p = 0.0002) were different between the groups. About 36.6% of infants with TB/TcB ≥75th percentile had ETCOc ≥ 2.0 ppm. In the subcohort of infants with serial TB/TcB measurements (n = 76), 44.7% and 55.3% had TB/TcB<75th and ≥75th percentile, respectively. TB/TcB (5.28 ± 1.97 vs 9.53 ± 2.78 mg/dL), ETCOc (1.72 ± 0.48 vs 2.38 ± 1.89 ppm, p = 0.05) and TB ROR (0.011 ± 0.440 vs 0.172 ± 0.471 mg/dL/h) were different between the groups.CONCLUSION: The combined use of TB/TcB percentile risk assessments and ETCOc measurements can identify infants with haemolytic hyperbilirubinaemia. The addition of TB ROR can identify those infants with elimination disorders.

    View details for DOI 10.1111/apa.14316

    View details for PubMedID 29532503

  • Divergent Patterns of Mitochondrial and Nuclear Ancestry Are Associated with the Risk for Preterm Birth JOURNAL OF PEDIATRICS Crawford, N., Prendergast, D., Oehlert, J. W., Shaw, G. M., Stevenson, D. K., Rappaport, N., Sirota, M., Tishkoff, S. A., Sondheimer, N. 2018; 194: 40-+

    Abstract

    To examine linkages between mitochondrial genetics and preterm birth by assessing the risk for preterm birth associated with the inheritance of nuclear haplotypes that are ancestrally distinct from mitochondrial haplogroup.Genome-wide genotyping studies of cohorts of preterm and term individuals were evaluated. We determined the mitochondrial haplogroup and nuclear ancestry for individuals and developed a scoring for the degree to which mitochondrial ancestry is divergent from nuclear ancestry.Infants with higher degrees of divergent mitochondrial ancestry were at increased risk for preterm birth (0.124 for preterm vs 0.105 for term infants; P< .05). This finding was validated in 1 of 2 replication cohorts. We also observed that greater degrees of divergent ancestry correlated with earlier delivery within the primary study population, but this finding was not replicated in secondary cohorts born preterm.Individuals with divergent patterns of mitochondrial and nuclear ancestry are at increased risk for preterm birth. These findings may in part explain the higher rates of preterm birth in African Americans and in individuals with a matrilineal family history of preterm birth.

    View details for DOI 10.1016/j.jpeds.2017.10.052

    View details for Web of Science ID 000426440700011

    View details for PubMedID 29249523

  • A genome-wide association study identifies only two ancestry specific variants associated with spontaneous preterm birth SCIENTIFIC REPORTS Rappoport, N., Toung, J., Hadley, D., Wong, R. J., Fujioka, K., Reuter, J., Abbott, C. W., Oh, S., Hu, D., Eng, C., Huntsman, S., Bodian, D. L., Niederhuber, J. E., Hong, X., Zhang, G., Sikora-Wohfeld, W., Gignoux, C. R., Wang, H., Oehlert, J., Jelliffe-Pawlowski, L. L., Gould, J. B., Darmstadt, G. L., Wang, X., Bustamante, C. D., Snyder, M. P., Ziv, E., Patsopoulos, N. A., Muglia, L. J., Burchard, E., Shaw, G. M., O'Brodovich, H. M., Stevenson, D. K., Butte, A. J., Sirota, M. 2018; 8: 226

    Abstract

    Preterm birth (PTB), or the delivery prior to 37 weeks of gestation, is a significant cause of infant morbidity and mortality. Although twin studies estimate that maternal genetic contributions account for approximately 30% of the incidence of PTB, and other studies reported fetal gene polymorphism association, to date no consistent associations have been identified. In this study, we performed the largest reported genome-wide association study analysis on 1,349 cases of PTB and 12,595 ancestry-matched controls from the focusing on genomic fetal signals. We tested over 2 million single nucleotide polymorphisms (SNPs) for associations with PTB across five subpopulations: African (AFR), the Americas (AMR), European, South Asian, and East Asian. We identified only two intergenic loci associated with PTB at a genome-wide level of significance: rs17591250 (P = 4.55E-09) on chromosome 1 in the AFR population and rs1979081 (P = 3.72E-08) on chromosome 8 in the AMR group. We have queried several existing replication cohorts and found no support of these associations. We conclude that the fetal genetic contribution to PTB is unlikely due to single common genetic variant, but could be explained by interactions of multiple common variants, or of rare variants affected by environmental influences, all not detectable using a GWAS alone.

    View details for DOI 10.1038/s41598-017-18246-5

    View details for Web of Science ID 000419659800061

    View details for PubMedID 29317701

    View details for PubMedCentralID PMC5760643

  • Point-of-Care Fecal Calprotectin Monitoring in Preterm Infants at Risk for Necrotizing Enterocolitis. The Journal of pediatrics Nakayuenyongsuk, W., Christofferson, M., Stevenson, D. K., Sylvester, K., Lee, H. C., Park, K. T. 2018

    Abstract

    To establish baseline trends in fecal calprotectin, a protein excreted into the stool when there is neutrophilic inflammation in the bowel, in infants at risk for necrotizing enterocolitis (NEC).We performed a prospective observational cohort study in infants with a birth weight of <1500 g without existing bowel disease at a level IV neonatal intensive care unit from October 2015 to September 2016. Stools were collected once daily for 30 days or until 32 weeks postmenstrual age and processed using the Fecal Calprotectin High Range Quantitative Quantum Blue assay.In 64 preterm infants, during the first week after birth, 62% of infants had an initial stool sample with high baseline calprotectin levels (≥200 µg/g). In assessment of maternal and neonatal risk factors, maternal etiology for preterm birth (ie, eclamplsia or preeclampsia) was the only significant factor associated with high baseline calprotectin level. Two patients in the cohort developed NEC. Calprotectin levels for the entire cohort fluctuated during the observed period but generally increased in the third and fourth weeks after birth.At-risk infants had highly variable fecal calprotectin levels, with maternal causes for preterm birth associated with higher baseline levels. More longitudinal data in infants with NEC are necessary to determine whether acute rises in fecal calprotectin levels prior to clinical diagnosis can be confirmed as a diagnostic or prognostic biomarker.

    View details for DOI 10.1016/j.jpeds.2017.12.069

    View details for PubMedID 29519542

  • Prediction of cognitive and motor development in preterm children using exhaustive feature selection and cross-validation of near-term white matter microstructure NEUROIMAGE-CLINICAL Schadl, K., Vassar, R., Cahill-Rowley, K., Yeom, K. W., Stevenson, D. K., Rose, J. 2018; 17: 667–79
  • Simultaneously Monitoring Immune Response and Microbial Infections during Pregnancy through Plasma cfRNA Sequencing CLINICAL CHEMISTRY Pan, W., Ngo, T. M., Camunas-Soler, J., Song, C., Kowarsky, M., Blumenfeld, Y. J., Wong, R. J., Shaw, G. M., Stevenson, D. K., Quake, S. R. 2017; 63 (11): 1695–1704

    Abstract

    Plasma cell-free RNA (cfRNA) encompasses a broad spectrum of RNA species that can be derived from both human cells and microbes. Because cfRNA is fragmented and of low concentration, it has been challenging to profile its transcriptome using standard RNA-seq methods.We assessed several recently developed RNA-seq methods on cfRNA samples. We then analyzed the dynamic changes of both the human transcriptome and the microbiome of plasma during pregnancy from 60 women.cfRNA reflects a well-orchestrated immune modulation during pregnancy: an up-regulation of antiinflammatory genes and an increased abundance of antimicrobial genes. We observed that the plasma microbiome remained relatively stable during pregnancy. The bacteria Ureaplasma shows an increased prevalence and increased abundance at postpartum, which is likely to be associated with postpartum infection. We demonstrated that cfRNA-seq can be used to monitor viral infections. We detected a number of human pathogens in our patients, including an undiagnosed patient with a high load of human parvovirus B19 virus (B19V), which is known to be a potential cause of complications in pregnancy.Plasma cfRNA-seq demonstrates the potential to simultaneously monitor immune response and microbial infections during pregnancy.

    View details for DOI 10.1373/clinchem.2017.273888

    View details for Web of Science ID 000414042600008

    View details for PubMedID 28904056

  • Numerous uncharacterized and highly divergent microbes which colonize humans are revealed by circulating cell-free DNA PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Kowarsky, M., Camunas-Soler, J., Kertesz, M., De Vlaminck, I., Koh, W., Pan, W., Martin, L., Neff, N. F., Okamoto, J., Wong, R. J., Kharbanda, S., El-Sayed, Y., Blumenfeld, Y., Stevenson, D. K., Shaw, G. M., Wolfe, N. D., Quake, S. R. 2017; 114 (36): 9623–28

    Abstract

    Blood circulates throughout the human body and contains molecules drawn from virtually every tissue, including the microbes and viruses which colonize the body. Through massive shotgun sequencing of circulating cell-free DNA from the blood, we identified hundreds of new bacteria and viruses which represent previously unidentified members of the human microbiome. Analyzing cumulative sequence data from 1,351 blood samples collected from 188 patients enabled us to assemble 7,190 contiguous regions (contigs) larger than 1 kbp, of which 3,761 are novel with little or no sequence homology in any existing databases. The vast majority of these novel contigs possess coding sequences, and we have validated their existence both by finding their presence in independent experiments and by performing direct PCR amplification. When their nearest neighbors are located in the tree of life, many of the organisms represent entirely novel taxa, showing that microbial diversity within the human body is substantially broader than previously appreciated.

    View details for DOI 10.1073/pnas.1707009114

    View details for Web of Science ID 000409182200053

    View details for PubMedID 28830999

    View details for PubMedCentralID PMC5594678

  • Heme oxygenase-1 promoter polymorphisms: do they modulate neonatal hyperbilirubinemia? JOURNAL OF PERINATOLOGY Kaplan, M., Wong, R. J., Stevenson, D. K. 2017; 37 (8): 901–5

    Abstract

    The role of genetic factors in the modulation of serum bilirubin levels and the pathophysiology of neonatal hyperbilirubinemia is being increasingly recognized. Heme oxygenase-1 (HO-1) is the rate-limiting enzyme by which heme is catabolized to biliverdin and thence to bilirubin, with the simultaneous release of equimolar quantities of ferrous iron (Fe3+) and carbon monoxide. Polymorphisms of the HO-1 gene promoter may modulate transcriptional activity, thereby augmenting or attenuating HO-1 expression with resultant modulation of the production of bilirubin. Few studies have related these polymorphisms to neonatal bilirubin metabolism and have reported conflicting results. In this clinical review, we surveyed the role of HO-1 gene promoter polymorphisms in the control of bilirubin production and further considered their role, if any, in the pathophysiology of neonatal hyperbilirubinemia.

    View details for DOI 10.1038/jp.2017.6

    View details for Web of Science ID 000408784400002

    View details for PubMedID 28206992

  • Interpregnancy Interval and Adverse Pregnancy Outcomes: An Analysis of Successive Pregnancies and Interpregnancy Interval and Pregnancy Outcomes: Causal or Not? OBSTETRICS AND GYNECOLOGY Mayo, J. A., Shachar, B., Stevenson, D. K., Shaw, G. M. 2017; 130 (2): 463

    View details for DOI 10.1097/AOG.0000000000002171

    View details for Web of Science ID 000406240500039

    View details for PubMedID 28742651

  • . journal of maternal-fetal & neonatal medicine Shachar, B. Z., Mayo, J. A., Lyell, D. J., Stevenson, D. K., Shaw, G. M., Blumenfeld, Y. J. 2017: 1-7

    Abstract

    Approximately 10% of US couples are inter-racial/ethnic. Substantial variation in preterm birth (PTB) rates is seen when stratified by race/ethnicity, although most studies focused solely on maternal racial/ethnic demographics. Our aims were to analyze the contribution of paternal in addition to maternal race/ethnicity, and to evaluate risk of spontaneous PTB for previously understudied inter-racial/ethnic couples.California singleton live births from 2007 to 2010 were included. Race/ethnicity was determined based on self-report, obtained from birth certificates and defined as African American (AA), Hispanic, Asian, and White. Logistic regression was used to estimate odds ratios of spontaneous PTB at 20-23, 24-31, 32-36 and <37 weeks of gestation, with White-White couples as reference. Results were stratified by previous PTB, pre-gestational and gestational diabetes and hypertension. To investigate the paternal contribution to the risk for any given maternal race/ethnicity we assessed the rates of PTB among inter-racial/ethnic couples compared to the respective same-race couple. Odds ratios were adjusted for maternal age, parity, BMI, prenatal care, payor status, education and smoking.Among 1,664,939 live births, 13% (n = 216,417) were born to inter-racial/ethnic couples. Compared to White-White couples, risk for spontaneous PTB was increased across all inter-racial/ethnic couples with a non-White mother, except when the father was Asian. Patterns of association were similar after stratification by previous PTB, hypertension and diabetes. Paternal race/ethnicity was also a significant risk factor for PTB.Increased risks for spontaneous PTB were seen in most inter-racial/ethnic couple groupings. In addition to maternal race/ethnicity, paternal race/ethnicity was a significant risk factor in many inter-racial/ethnic couplings. Identifying such different risk profiles based on both maternal and paternal race/ethnicity may offer new lines of research inquiry for the underlying etiologies of PTB.

    View details for DOI 10.1080/14767058.2017.1293029

    View details for PubMedID 28399669

  • Fetal de novo mutations and preterm birth. PLoS genetics Li, J., Oehlert, J., Snyder, M., Stevenson, D. K., Shaw, G. M. 2017; 13 (4)

    Abstract

    Preterm birth (PTB) affects ~12% of pregnancies in the US. Despite its high mortality and morbidity, the molecular etiology underlying PTB has been unclear. Numerous studies have been devoted to identifying genetic factors in maternal and fetal genomes, but so far few genomic loci have been associated with PTB. By analyzing whole-genome sequencing data from 816 trio families, for the first time, we observed the role of fetal de novo mutations in PTB. We observed a significant increase in de novo mutation burden in PTB fetal genomes. Our genomic analyses further revealed that affected genes by PTB de novo mutations were dosage sensitive, intolerant to genomic deletions, and their mouse orthologs were likely developmentally essential. These genes were significantly involved in early fetal brain development, which was further supported by our analysis of copy number variants identified from an independent PTB cohort. Our study indicates a new mechanism in PTB occurrence independently contributed from fetal genomes, and thus opens a new avenue for future PTB research.

    View details for DOI 10.1371/journal.pgen.1006689

    View details for PubMedID 28388617

  • Multicenter Systems Analysis of Human Blood Reveals Immature Neutrophils in Males and During Pregnancy. Journal of immunology Blazkova, J., Gupta, S., Liu, Y., Gaudilliere, B., Ganio, E. A., Bolen, C. R., Saar-Dover, R., Fragiadakis, G. K., Angst, M. S., Hasni, S., Aghaeepour, N., Stevenson, D., Baldwin, N., Anguiano, E., Chaussabel, D., Altman, M. C., Kaplan, M. J., Davis, M. M., Furman, D. 2017; 198 (6): 2479-2488

    Abstract

    Despite clear differences in immune system responses and in the prevalence of autoimmune diseases between males and females, there is little understanding of the processes involved. In this study, we identified a gene signature of immature-like neutrophils, characterized by the overexpression of genes encoding for several granule-containing proteins, which was found at higher levels (up to 3-fold) in young (20-30 y old) but not older (60 to >89 y old) males compared with females. Functional and phenotypic characterization of peripheral blood neutrophils revealed more mature and responsive neutrophils in young females, which also exhibited an elevated capacity in neutrophil extracellular trap formation at baseline and upon microbial or sterile autoimmune stimuli. The expression levels of the immature-like neutrophil signature increased linearly with pregnancy, an immune state of increased susceptibility to certain infections. Using mass cytometry, we also find increased frequencies of immature forms of neutrophils in the blood of women during late pregnancy. Thus, our findings show novel sex differences in innate immunity and identify a common neutrophil signature in males and in pregnant women.

    View details for DOI 10.4049/jimmunol.1601855

    View details for PubMedID 28179497

  • INDUCTION OF HEME OXYGENASE-1 ATTENUATES THE SEVERITY OF SEPSIS IN A NON-SURGICAL PRETERM MOUSE MODEL SHOCK Fujioka, K., Kalish, F., Zhao, H., Lu, S., Wong, S., Wong, R. J., Stevenson, D. K. 2017; 47 (2): 242-250

    Abstract

    Preterm sepsis is characterized by systemic bacterial invasion and inflammatory response. Its pathogenesis is unclear due to lack of proper animal models. Heme oxygenase-1 (HO-1) can affect physiologic and pathologic conditions through its anti-inflammatory, antioxidative, and anti-apoptotic properties. Since HO-1 is developmentally regulated, it may play a role in the pathogenesis of preterm sepsis. For this study, sepsis was induced using the non-surgical "cecal slurry" (CS) model. CS was given intraperitoneally at various doses to 4-day-old newborn mice to determine dose-dependent effects. The LD40 was then given and changes in bodyweight, bacterial colonization of organs, hematology, serum biochemistry, and immunomodulatory gene expression were determined. We found a dose-dependent mortality with an LD40 of 2.0 mg/g. Significant bacterial colonization and hematological changes (leukocytopenia, thrombocytopenia, and lymphocytopenia) and increased gene expression of pro-inflammatory cytokines, pattern-recognition receptors, and other genes related to immune responses were also observed. Twenty-four hours post-sepsis induction, bodyweight loss was associated with mortality and organ damage. Finally, to elucidate a protective role of HO-1, 30-μmol heme/kg was given subcutaneously 24 h pre-sepsis induction. HO activity in livers and spleens significantly increased 64% and 50% over age-matched controls 24 h post-heme administration. Importantly, heme significantly reduced mortality from 40.9% to 6.3% (P <0.005) and gene expression of pro-inflammatory cytokines (Ccl5, Cxcl10, IL-1b, and Ifng). We conclude that the CS model can be used as a model to study preterm sepsis. Because induction of HO-1 significantly reduced mortality, we speculate that HO-1 may confer protection against sepsis in preterm infants.

    View details for DOI 10.1097/SHK.0000000000000689

    View details for Web of Science ID 000392813300016

    View details for PubMedID 27454382

  • Acylcarnitine Profiles Reflect Metabolic Vulnerability for Necrotizing Enterocolitis in Newborns Born Premature. journal of pediatrics Sylvester, K. G., Kastenberg, Z. J., Moss, R. L., Enns, G. M., Cowan, T. M., Shaw, G. M., Stevenson, D. K., Sinclair, T. J., Scharfe, C., Ryckman, K. K., Jelliffe-Pawlowski, L. L. 2017; 181: 80-85 e1

    Abstract

    To evaluate the association between newborn acylcarnitine profiles and the subsequent development of necrotizing enterocolitis (NEC) with the use of routinely collected newborn screening data in infants born preterm.A retrospective cohort study was conducted with the use of discharge records for infants born preterm admitted to neonatal intensive care units in California from 2005 to 2009 who had linked state newborn screening results. A model-development cohort of 94 110 preterm births from 2005 to 2008 was used to develop a risk-stratification model that was then applied to a validation cohort of 22 992 births from 2009.Fourteen acylcarnitine levels and acylcarnitine ratios were associated with increased risk of developing NEC. Each log unit increase in C5 and free carnitine /(C16 + 18:1) was associated with a 78% and a 76% increased risk for developing NEC, respectively (OR 1.78, 95% CI 1.53-2.02, and OR 1.76, 95% CI 1.51-2.06). Six acylcarnitine levels, along with birth weight and total parenteral nutrition, identified 89.8% of newborns with NEC in the model-development cohort (area under the curve 0.898, 95% CI 0.889-0.907) and 90.8% of the newborns with NEC in the validation cohort (area under the curve 0.908, 95% CI 0.901-0.930).Abnormal fatty acid metabolism was associated with prematurity and the development of NEC. Metabolic profiling through newborn screening may serve as an objective biologic surrogate of risk for the development of disease and thus facilitate disease-prevention strategies.

    View details for DOI 10.1016/j.jpeds.2016.10.019

    View details for PubMedID 27836286

  • Infiltration of myeloid cells in the pregnant uterus is affected by heme oxygenase-1 JOURNAL OF LEUKOCYTE BIOLOGY Zhao, H., Kalish, F., Wong, R. J., Stevenson, D. K. 2017; 101 (1): 217-226

    Abstract

    Infiltrating myeloid cells in pregnant uteri play critical roles in the establishment of the placenta and maintenance of normal pregnancies. Their recruitment and proliferation are primarily mediated by the interactions of cytokines and chemokines secreted locally with their corresponding receptors. Heme oxygenase-1 (HO-1) has various physiologic properties that contribute to placental vascular development, with deficiencies in HO-1 associated with pregnancy disorders. Here, we investigated the effect of HO-1 on myeloid cell infiltration into pregnant uteri using a partial HO-1-deficient (Het, HO-1(+/-)) mouse model. With the use of flow cytometry, HO-1 was found predominantly expressed in circulating and uterine myeloid cells, specifically neutrophils and monocytes/macrophages. In pregnant Het uteri, the numbers of neutrophils and monocytes/macrophages were significantly reduced compared with pregnant wild-type (WT; HO-1(+/+)) uteri. With the use of BrdU in vivo assays, HO-1 deficiency did not affect cell proliferation or blood cell populations. With the use of PCR arrays, gene expression of cytokines (Csf1, Csf3), chemokines (Ccl1, Ccl2, Ccl6, Ccl8, Ccl11, Ccl12, Cxcl4, Cxcl9, Cxcl12), and their receptors (Ccr1, Ccr2, Ccr3, Ccr5) were also reduced significantly in Het compared with pregnant WT uteri. Moreover, with the use of flow cytometry, myeloid CSF1R and CCR2 expression in blood and uteri from both pregnant and nonpregnant mice was characterized, and a deficiency in HO-1 significantly reduced CCR2 expression in infiltrating uterine monocytes/macrophages and dendritic cells (DCs). These data reveal that HO-1 regulates not only cytokine/chemokine production in pregnant uteri but also myeloid cell receptor numbers, suggesting a role of HO-1 in the recruitment and maintenance of myeloid cells in pregnant uteri and subsequent effects on placental vascular formation.

    View details for DOI 10.1189/jlb.1A0116-020RR

    View details for Web of Science ID 000392148500020

    View details for PubMedID 27468759

  • An immune clock of human pregnancy. Science immunology Aghaeepour, N., Ganio, E. A., Mcilwain, D., Tsai, A. S., Tingle, M., Van Gassen, S., Gaudilliere, D. K., Baca, Q., McNeil, L., Okada, R., Ghaemi, M. S., Furman, D., Wong, R. J., Winn, V. D., Druzin, M. L., El-Sayed, Y. Y., Quaintance, C., Gibbs, R., Darmstadt, G. L., Shaw, G. M., Stevenson, D. K., Tibshirani, R., Nolan, G. P., Lewis, D. B., Angst, M. S., Gaudilliere, B. 2017; 2 (15)

    Abstract

    The maintenance of pregnancy relies on finely tuned immune adaptations. We demonstrate that these adaptations are precisely timed, reflecting an immune clock of pregnancy in women delivering at term. Using mass cytometry, the abundance and functional responses of all major immune cell subsets were quantified in serial blood samples collected throughout pregnancy. Cell signaling-based Elastic Net, a regularized regression method adapted from the elastic net algorithm, was developed to infer and prospectively validate a predictive model of interrelated immune events that accurately captures the chronology of pregnancy. Model components highlighted existing knowledge and revealed previously unreported biology, including a critical role for the interleukin-2-dependent STAT5ab signaling pathway in modulating T cell function during pregnancy. These findings unravel the precise timing of immunological events occurring during a term pregnancy and provide the analytical framework to identify immunological deviations implicated in pregnancy-related pathologies.

    View details for DOI 10.1126/sciimmunol.aan2946

    View details for PubMedID 28864494

  • Heme Oxygenase Activity and Heme Binding in a Neonatal Mouse Model NEONATOLOGY Kourula, S., Ang, J., Zhao, H., Kalish, F., Vandenabeele, P., Sylvester, K. G., Wong, R. J., Stevenson, D. K. 2017; 112 (4): 376–83

    Abstract

    Severe hemolytic disease of the newborn leads to the release of pro-oxidative free heme (FH). Heme oxygenase (HO) is primarily responsible for detoxifying FH.To investigate the protective effects of HO in a model of heme overload.For in vitro studies, NIH3T3 HO-1-luc cells were incubated with 10, 30, or 60 µM FH or methemalbumin (MHA). HO-1 promoter activity was assessed 3, 6, and 24 h after treatment. Cell survival was indexed by viability assays. For in vivo studies, 1- and 5-week-old wild-type (Wt) or HO-1-heterozygous (Het, HO-1+/-) mice were given 60 µmol FH or MHA/kg intraperitoneally. After 24 h, plasma aspartate aminotransferease (AST)/alanine transaminase (ALT) and hemopexin, liver HO activity, and lipid peroxidation (LP) were determined.In HO-1-luc cells, HO-1 promoter activity peaked 6 h after incubation with 30 µM FH (1.6-fold) or 60 µM MHA (2.1-fold) over baseline. Twenty-four hours after exposure to 60 µM FH, a decrease in viability of 80% was found, compared with no decrease after exposure to 60 µM MHA. In 1-week-old Wt and HO-1 Het pups given 60 µmol FH/kg, HO activity significantly increased 3.5- and 3.1-fold, respectively. No changes in LP or AST/ALT levels were observed. In adult Wt and HO-1 Het mice, HO activity increased (3.0- and 2.6-fold, respectively). LP and AST levels significantly increased 28.4- and 2.7-fold, respectively, in adult HO-1 Het mice. Hemopexin levels at baseline were higher in adults compared with newborns for both Wt and Het mice. In addition, FH induced hemopexin levels in both adults and newborns, but to a lesser degree in newborns.FH is highly toxic in vitro, but its toxicity is abolished when bound to albumin. Newborns appear to be protected from the pro-oxidative effects of FH, which may be mediated by heme binding and a higher absolute HO activity at baseline and after FH-mediated induction.

    View details for DOI 10.1159/000479493

    View details for Web of Science ID 000414355900011

    View details for PubMedID 28926834

  • Risky Business: Meeting the Structural Needs of Transdisciplinary Science. The Journal of pediatrics Wise, P. H., Shaw, G. M., Druzin, M. L., Darmstadt, G. L., Quaintance, C., Mäkinen, E., Relman, D. A., Quake, S. R., Butte, A. J., Angst, M. S., Muglia, L. J., Macones, G., Driscoll, D., Ober, C., Simpson, J. L., Katz, M., Howse, J., Stevenson, D. K. 2017; 191: 255–58

    View details for DOI 10.1016/j.jpeds.2017.08.072

    View details for PubMedID 29173314

  • A Proteomic Clock of Human Pregnancy. American journal of obstetrics and gynecology Aghaeepour, N., Lehallier, B., Baca, Q., Ganio, E. A., Wong, R. J., Ghaemi, M. S., Culos, A., El-Sayed, Y. Y., Blumenfeld, Y. J., Druzin, M. L., Winn, V. D., Gibbs, R. S., Tibshirani, R., Shaw, G. M., Stevenson, D. K., Gaudilliere, B., Angst, M. S. 2017

    Abstract

    Early detection of maladaptive processes underlying pregnancy-related pathologies is desirable, as it will enable targeted interventions ahead of clinical manifestations. The quantitative analysis of plasma proteins features prominently among molecular approaches used to detect deviations from normal pregnancy. However, derivation of proteomic signatures sufficiently predictive of pregnancy-related outcomes has been challenging. An important obstacle hindering such efforts were limitations in assay technology, which prevented the broad examination of the plasma proteome.The recent availability of a highly-multiplexed platform affording the simultaneous measurement of 1,310 plasma proteins opens the door for a more explorative approach. The major aim of this study was to examine whether analysis of plasma collected during gestation of term pregnancy would allow identifying a set of proteins that tightly track gestational age. Establishing precisely-timed plasma proteomic changes during term pregnancy is a critical step in identifying deviations from regular patterns due to fetal and maternal maladaptations. A second aim was to gain insight into functional attributes of identified proteins, and link such attributes to relevant immunological changes.Pregnant women participated in this longitudinal study. In two subsequent subsets of 21 (training cohort) and 10 (validation cohort) women, specific blood specimens were collected during the first (7-14 wks), second (15-20 wks), and third (24-32 wks) trimesters, and 6 wks post-partum for analysis with a highly-multiplexed aptamer-based platform. An elastic net algorithm was applied to infer a proteomic model predicting gestational age. A bootstrapping procedure and piece-wise regression analysis was used to extract the minimum number of proteins required for predicting gestational age without compromising predictive power. Gene ontology analysis was applied to infer enrichment of molecular functions among proteins included in the proteomic model. Changes in abundance of proteins with such functions were linked to immune features predictive of gestational age at the time of sampling in pregnancies delivering at term.An independently validated model consisting of 74 proteins strongly predicted gestational age (p = 3.8x10-14, R = 0.97). The model could be reduced to eight proteins without losing its predictive power (p = 1.7x10-3, R = 0.91). The three top ranked proteins were glypican 3, chorionic somatomammotropin hormone, and granulins. Proteins activating the Janus kinase (JAK) and signal transducer and activator of transcription (STAT) pathway were enriched in the proteomic model, chorionic somatomammotropin hormone being the top ranked protein. Abundance of chorionic somatomammotropin hormone strongly correlated with STAT5 signaling activity in CD4 T cells, the endogenous cell-signaling event most predictive of gestational age.Results indicate that precisely timed changes in the plasma proteome during term pregnancy mirror a "proteomic clock". Importantly, the combined use of several plasma proteins was required for accurate prediction. The exciting promise of such a "clock" is that deviations from its regular chronological profile may assist in the early diagnoses of pregnancy-relate pathologies and point to underlying pathophysiology. Functional analysis of the proteomic model generated the novel hypothesis that somatomammotropin hormone may critically regulate T-cell function during pregnancy.

    View details for DOI 10.1016/j.ajog.2017.12.208

    View details for PubMedID 29277631

  • The Importance of Hemolysis and Its Clinical Detection in Neonates with Hyperbilirubinemia. Current pediatric reviews Wong, R. J., Bhutani, V. K., Stevenson, D. K. 2017; 13 (3): 193–98

    Abstract

    BACKGROUND: Hyperbilirubinemia is a benign transitional phenomenon that occurs in 60% to 80% of all term infants. The degree of hyperbilirubinemia and hence risk for developing bilirubin-induced neurologic dysfunction or BIND is dependent upon two major processes: (i) bilirubin production and its elimination.OBJECTIVE: The aim of this review is to address the importance of hemolysis and its clinical detection in neonates with hyperbilirubinemia.RESULTS: In newborns, an increased bilirubin production rate due to hemolysis is often the primary cause of hyperbilirubinemia during the first week of life. If undiagnosed or untreated, it may lead to an increased risk for BIND. Therefore, the ability to identify infants with hemolytic disease is important in assessing those at risk for developing BIND. In addition, an infant's genetic profile and bilirubin binding status can also affect their overall capacity to cope with the resultant tissue bilirubin load and affect risk and guide appropriate management strategies.CONCLUSION: Therefore, the determination of a newborn's bilirubin production rate is critical to the assessment of a newborn's risk for developing unpredictable extreme hyperbilirubinemia and preventing BIND.

    View details for DOI 10.2174/1573396313666170807121444

    View details for PubMedID 28782473

  • Replication and refinement of a vaginal microbial signature of preterm birth in two racially distinct cohorts of US women. Proceedings of the National Academy of Sciences of the United States of America Callahan, B. J., DiGiulio, D. B., Goltsman, D. S., Sun, C. L., Costello, E. K., Jeganathan, P., Biggio, J. R., Wong, R. J., Druzin, M. L., Shaw, G. M., Stevenson, D. K., Holmes, S. P., Relman, D. A. 2017

    Abstract

    Preterm birth (PTB) is the leading cause of neonatal morbidity and mortality. Previous studies have suggested that the maternal vaginal microbiota contributes to the pathophysiology of PTB, but conflicting results in recent years have raised doubts. We conducted a study of PTB compared with term birth in two cohorts of pregnant women: one predominantly Caucasian (n = 39) at low risk for PTB, the second predominantly African American and at high-risk (n = 96). We profiled the taxonomic composition of 2,179 vaginal swabs collected prospectively and weekly during gestation using 16S rRNA gene sequencing. Previously proposed associations between PTB and lower Lactobacillus and higher Gardnerella abundances replicated in the low-risk cohort, but not in the high-risk cohort. High-resolution bioinformatics enabled taxonomic assignment to the species and subspecies levels, revealing that Lactobacillus crispatus was associated with low risk of PTB in both cohorts, while Lactobacillus iners was not, and that a subspecies clade of Gardnerella vaginalis explained the genus association with PTB. Patterns of cooccurrence between L. crispatus and Gardnerella were highly exclusive, while Gardnerella and L. iners often coexisted at high frequencies. We argue that the vaginal microbiota is better represented by the quantitative frequencies of these key taxa than by classifying communities into five community state types. Our findings extend and corroborate the association between the vaginal microbiota and PTB, demonstrate the benefits of high-resolution statistical bioinformatics in clinical microbiome studies, and suggest that previous conflicting results may reflect the different risk profile of women of black race.

    View details for DOI 10.1073/pnas.1705899114

    View details for PubMedID 28847941

  • Women's prepregnancy underweight as a risk factor for preterm birth: a retrospective study. bjog-an international journal of obstetrics and gynaecology Girsen, A. I., Mayo, J. A., Carmichael, S. L., Phibbs, C. S., Shachar, B. Z., Stevenson, D. K., Lyell, D. J., Shaw, G. M., Gould, J. B. 2016; 123 (12): 2001-2007

    Abstract

    To investigate the distribution of known factors for preterm birth (PTB) by severity of maternal underweight; to investigate the risk-adjusted relation between severity of underweight and PTB, and to assess whether the relation differed by gestational age.Retrospective cohort study.State of California, USA.Maternally linked hospital and birth certificate records of 950 356 California deliveries in 2007-2010 were analysed. Singleton live births of women whose prepregnancy body mass index (BMI) was underweight (<18.5 kg/m(2) ) or normal (18.50-24.99 kg/m(2) ) were analysed. Underweight BMI was further categorised as: severe (<16.00), moderate (16.00-16.99) or mild (17.00-18.49). PTB was grouped as 22-27, 28-31, 32-36 or <37 weeks (compared with 37-41 weeks). Adjusted multivariable Poisson regression modeling was used to estimate relative risk for PTB.Risk of PTB.About 72 686 (7.6%) women were underweight. Increasing severity of underweight was associated with increasing percent PTB: 7.8% (n = 4421) in mild, 9.0% (n = 1001) in moderate and 10.2% (475) in severe underweight. The adjusted relative risk of PTB also significantly increased: adjusted relative risk (aRR) = 1.22 (95% CI 1.19-1.26) in mild, aRR = 1.41 (95% CI 1.32-1.50) in moderate and aRR = 1.61 (95% CI 1.47-1.76) in severe underweight. These findings were similar in spontaneous PTB, medically indicated PTB, and the gestational age groupings.Increasing severity of maternal prepregnancy underweight BMI was associated with increasing risk-adjusted PTB at <37 weeks. This increasing risk was of similar magnitude in spontaneous and medically indicated births and in preterm delivery at 28-31 and at 32-36 weeks of gestation.Increasing severity of maternal underweight BMI was associated with increasing risk of preterm birth.

    View details for DOI 10.1111/1471-0528.14027

    View details for PubMedID 27172996

    View details for PubMedCentralID PMC5069076

  • Leading by Example and Design: The Joseph St Geme Jr Leadership Award, 2016 PEDIATRICS Stevenson, D. K. 2016; 138 (5)
  • Interpregnancy interval after live birth or pregnancy termination and estimated risk of preterm birth: a retrospective cohort study. bjog-an international journal of obstetrics and gynaecology Shachar, B. Z., Mayo, J. A., Lyell, D. J., Baer, R. J., Jeliffe-Pawlowski, L. L., Stevenson, D. K., Shaw, G. M. 2016; 123 (12): 2009-2017

    Abstract

    We assessed whether interpregnancy interval (IPI) length after live birth and after pregnancy termination was associated with preterm birth (PTB).Multiyear birth cohort.Fetal death, birth and infant death certificates in California merged with Office of Statewide Health Planning and Development.One million California live births (2007-10) after live birth and after pregnancy termination.Logistic regression was used to estimate odds ratios (ORs) of PTB of 20-36 weeks of gestation and its subcategories for IPIs after a live birth and after a pregnancy termination. We used conditional logistic regression (two IPIs/mother) to investigate associations within mothers.PTB relative to gestations of ≥ 37 weeks.Analyses included 971 211 women with IPI after live birth, and 138 405 women with IPI after pregnancy termination with 30.6% and 74.6% having intervals of <18 months, respectively. IPIs of <6 months or 6-11 months after live birth showed increased odds of PTB adjusted ORs for PTB of 1.71 (95% CI 1.65-1.78) and 1.20 (95% CI 1.16-1.24), respectively compared with intervals of 18-23 months. An IPI >36 months (versus 18-23 months) was associated with increased odds for PTB. Short IPI after pregnancy termination showed a decreased OR of 0.87 (95% CI 0.81-0.94). The within-mother analysis showed the association of increased odds of PTB for short IPI, but not for long IPI.Women with IPI <1 or >3 years after a live birth were at increased odds of PTB-an important group for intervention to reduce PTB. Short IPI after pregnancy termination was associated with reduced odds for PTB and needs to be further explored.Short and long IPI after live birth, but not after pregnancy termination, showed increased odds for PTB.

    View details for DOI 10.1111/1471-0528.14165

    View details for PubMedID 27405702

  • Mapping the Fetomaternal Peripheral Immune System at Term Pregnancy. Journal of immunology Fragiadakis, G. K., Baca, Q. J., Gherardini, P. F., Ganio, E. A., Gaudilliere, D. K., Tingle, M., Lancero, H. L., McNeil, L. S., Spitzer, M. H., Wong, R. J., Shaw, G. M., Darmstadt, G. L., Sylvester, K. G., Winn, V. D., Carvalho, B., Lewis, D. B., Stevenson, D. K., Nolan, G. P., Aghaeepour, N., Angst, M. S., Gaudilliere, B. L. 2016

    Abstract

    Preterm labor and infections are the leading causes of neonatal deaths worldwide. During pregnancy, immunological cross talk between the mother and her fetus is critical for the maintenance of pregnancy and the delivery of an immunocompetent neonate. A precise understanding of healthy fetomaternal immunity is the important first step to identifying dysregulated immune mechanisms driving adverse maternal or neonatal outcomes. This study combined single-cell mass cytometry of paired peripheral and umbilical cord blood samples from mothers and their neonates with a graphical approach developed for the visualization of high-dimensional data to provide a high-resolution reference map of the cellular composition and functional organization of the healthy fetal and maternal immune systems at birth. The approach enabled mapping of known phenotypical and functional characteristics of fetal immunity (including the functional hyperresponsiveness of CD4(+) and CD8(+) T cells and the global blunting of innate immune responses). It also allowed discovery of new properties that distinguish the fetal and maternal immune systems. For example, examination of paired samples revealed differences in endogenous signaling tone that are unique to a mother and her offspring, including increased ERK1/2, MAPK-activated protein kinase 2, rpS6, and CREB phosphorylation in fetal Tbet(+)CD4(+) T cells, CD8(+) T cells, B cells, and CD56(lo)CD16(+) NK cells and decreased ERK1/2, MAPK-activated protein kinase 2, and STAT1 phosphorylation in fetal intermediate and nonclassical monocytes. This highly interactive functional map of healthy fetomaternal immunity builds the core reference for a growing data repository that will allow inferring deviations from normal associated with adverse maternal and neonatal outcomes.

    View details for PubMedID 27793998

    View details for PubMedCentralID PMC5125527

  • Identification of neonatal haemolysis: an approach to predischarge management of neonatal hyperbilirubinemia. Acta paediatrica (Oslo, Norway : 1992) Bhutani, V. K., Srinivas, S., Castillo Cuadrado, M. E., Aby, J. L., Wong, R. J., Stevenson, D. K. 2016; 105 (5): e189-94

    Abstract

    Relative contributions of increased production [by end-tidal carbon monoxide concentrations (ETCOc)] and decreased elimination of bilirubin to predischarge hour-specific total bilirubin (TB) levels were assessed in healthy late-preterm and term newborns. Secondly, we report predischarge ETCOc ranges to guide clinical management of hyperbilirubinemia.TB and ETCOc (≤3 timepoints) determinations of newborns aged between six hours and <6 days (n = 79) were stratified by postnatal age epochs. Hyperbilirubinemia risk was assessed by plotting TB values as a function of ETCOc.Stratifications of ETCOc (in ppm, mean, median and interquartile ranges) by postnatal age epochs (0-24, 24-48 and 48-72) were as follows: 2.0, 1.9, 1.8-2.2 (n = 11); 1.6, 1.5, 1.1-2.0 (n = 58); and 2.0, 1.8, 1.6-2.3 (n = 9), respectively. Infants with ETCOc ≥ 2.5 were at high risk, between 1.5 and 2.5 at moderate risk and ≤1.5 were at low risk. Risk due to haemolysis alone was not independent (p < 0.01). For infants with TB >75th percentile (n = 31), 23% had ETCO ≤1.5, and 77% had ETCOc > 1.5 (p < 0.00003).Near-simultaneous ETCOc and TB measurements in infants with TB >75th percentile accurately identify haemolytic hyperbilirubinemia.

    View details for DOI 10.1111/apa.13341

    View details for PubMedID 26802319

  • Inhibition of heme oxygenase activity using a microparticle formulation of zinc protoporphyrin in an acute hemolytic newborn mouse model PEDIATRIC RESEARCH Fujioka, K., Kalish, F., Wong, R. J., Stevenson, D. K. 2016; 79 (2): 251-257

    Abstract

    Increased bilirubin production due to hemolysis can lead to neonatal hyperbilirubinemia. Inhibition of heme oxygenase (HO), the rate-limiting enzyme in heme catabolism, by metalloporphyrins (Mps) may be an ideal preventive strategy for neonatal hemolytic disease. Zinc protoporphyrin (ZnPP) is a naturally occurring Mp, potent, not phototoxic, with minimal HO-1 upregulation, but is not orally absorbed. Recently, we designed a lipid-based ZnPP formulation (ZnPP-Lipid), which is orally absorbed by newborn mice. Here, we evaluated the efficacy of ZnPP-Lipid in heme-loaded newborn mice, a model analogous to hemolytic infants.After 24 h of heme administration (30 µmol/kg s.c.), 4-d-old mice were given 30 µmol ZnPP-Lipid/kg via intragastric injections. After 3 h, liver and brain HO activity were measured. HO-1 upregulation was assessed by determinations of HO-1 protein, promoter activity, and mRNA by Western blot, in vivo bioluminescence imaging, and RT-PCR, respectively.After heme loading, liver HO activity significantly increased ~1.6-fold, which was inhibited in a dose-dependent manner by ZnPP-Lipid. A dose of 30 µmol/kg returned activity to control levels. Brain HO activity was not inhibited. No significant increases in liver and brain HO-1 protein, promoter activity, and mRNA were observed.ZnPP-Lipid is effective and thus has potential for treating neonatal hyperbilirubinemia due to hemolysis.

    View details for DOI 10.1038/pr.2015.207

    View details for Web of Science ID 000372377200003

  • Neonatal Biomarkers of Inflammation: Correlates of Early Neurodevelopment and Gait in Very-Low-Birth-Weight Preterm Children AMERICAN JOURNAL OF PERINATOLOGY Rose, J., Vassar, R., Cahill-Rowley, K., Hintz, S. R., Stevenson, D. K. 2016; 33 (1): 71-78

    Abstract

    Neonatal biomarkers of inflammation were examined in relation to early neurodevelopment and gait in very-low-birth-weight (VLBW) preterm children. We hypothesized that preterm infants exposed to higher levels of neonatal inflammation would demonstrate lower scores on Bayley Scales of Infant Toddler Development, 3rd ed. (BSID-III) and slower gait velocity at 18 to 22 months adjusted age.A total of 102 VLBW preterm infants (birthweight [BW] ≤ 1,500 g, gestational age [GA] ≤ 32 weeks) admitted to neonatal intensive care unit [NICU] were recruited. Neonatal risk factors examined were GA at birth, BW, bronchopulmonary dysplasia, necrotizing enterocolitis, retinopathy of prematurity, sepsis, and serum C-reactive protein (CRP), albumin, and total bilirubin over first 2 postnatal weeks. At 18 to 22 months, neurodevelopment was assessed with BSID-III and gait was assessed with an instrumented mat.Children with neonatal CRP ≥ 0.20 mg/dL (n = 52) versus < 0.20 mg/dL (n = 37) had significantly lower BSID-III composite cognitive (92.0 ± 13.1 vs. 100.1 ± 9.6, p = 0.002), language (83.9 ± 16.0 vs. 95.8 ± 14.2, p < 0.001), and motor scores (90.0 ± 13.2 vs. 98.8 ± 10.1, p = 0.002), and slower gait velocity (84.9 ± 19.0 vs. 98.0 ± 22.4 cm/s, p = 0.004). Higher neonatal CRP correlated with lower cognitive (rho =  - 0.327, p = 0.002), language (rho =  - 0.285, p = 0.007), and motor scores (rho =  - 0.257, p = 0.015), and slower gait (rho =  - 0.298, p = 0.008). Multivariate analysis demonstrated neonatal CRP ≥ 0.20 mg/dL significantly predicted BSID-III cognitive (adjusted R(2) = 0.104, p = 0.008), language (adjusted R(2) = 0.124, p = 0.001), and motor scores (adjusted R(2) = 0.122, p = 0.004).Associations between low-level neonatal inflammation and neurodevelopment suggest early biomarkers that may inform neuroprotective treatment for preterm children.

    View details for DOI 10.1055/s-0035-1557106

    View details for Web of Science ID 000367556500010

  • Heme Oxygenase-1 Expression Affects Murine Abdominal Aortic Aneurysm Progression. PloS one Azuma, J., Wong, R. J., Morisawa, T., Hsu, M., Maegdefessel, L., Zhao, H., Kalish, F., Kayama, Y., Wallenstein, M. B., Deng, A. C., Spin, J. M., Stevenson, D. K., Dalman, R. L., Tsao, P. S. 2016; 11 (2)

    Abstract

    Heme oxygenase-1 (HO-1), the rate-limiting enzyme in heme degradation, is a cytoprotective enzyme upregulated in the vasculature by increased flow and inflammatory stimuli. Human genetic data suggest that a diminished HO-1 expression may predispose one to abdominal aortic aneurysm (AAA) development. In addition, heme is known to strongly induce HO-1 expression. Utilizing the porcine pancreatic elastase (PPE) model of AAA induction in HO-1 heterozygous (HO-1+/-, HO-1 Het) mice, we found that a deficiency in HO-1 leads to augmented AAA development. Peritoneal macrophages from HO-1+/- mice showed increased gene expression of pro-inflammatory cytokines, including MCP-1, TNF-alpha, IL-1-beta, and IL-6, but decreased expression of anti-inflammatory cytokines IL-10 and TGF-beta. Furthermore, treatment with heme returned AAA progression in HO-1 Het mice to a wild-type profile. Using a second murine AAA model (Ang II-ApoE-/-), we showed that low doses of the HMG-CoA reductase inhibitor rosuvastatin can induce HO-1 expression in aortic tissue and suppress AAA progression in the absence of lipid lowering. Our results support those studies that suggest that pleiotropic statin effects might be beneficial in AAA, possibly through the upregulation of HO-1. Specific targeted therapies designed to induce HO-1 could become an adjunctive therapeutic strategy for the prevention of AAA disease.

    View details for DOI 10.1371/journal.pone.0149288

    View details for PubMedID 26894432

    View details for PubMedCentralID PMC4760983

  • A Randomized Trial of Phototherapy with Filtered Sunlight in African Neonates. New England journal of medicine Slusher, T. M., Olusanya, B. O., Vreman, H. J., Brearley, A. M., Vaucher, Y. E., Lund, T. C., Wong, R. J., Emokpae, A. A., Stevenson, D. K. 2015; 373 (12): 1115-1124

    Abstract

    Sequelae of severe neonatal hyperbilirubinemia constitute a substantial disease burden in areas where effective conventional phototherapy is unavailable. We previously found that the use of filtered sunlight for the purpose of phototherapy is a safe and efficacious method for reducing total bilirubin. However, its relative safety and efficacy as compared with conventional phototherapy are unknown.We conducted a randomized, controlled noninferiority trial in which filtered sunlight was compared with conventional phototherapy for the treatment of hyperbilirubinemia in term and late-preterm neonates in a large, urban Nigerian maternity hospital. The primary end point was efficacy, which was defined as a rate of increase in total serum bilirubin of less than 0.2 mg per deciliter per hour for infants up to 72 hours of age or a decrease in total serum bilirubin for infants older than 72 hours of age who received at least 5 hours of phototherapy; we prespecified a noninferiority margin of 10% for the difference in efficacy rates between groups. The need for an exchange transfusion was a secondary end point. We also assessed safety, which was defined as the absence of the need to withdraw therapy because of hyperthermia, hypothermia, dehydration, or sunburn.We enrolled 447 infants and randomly assigned 224 to filtered sunlight and 223 to conventional phototherapy. Filtered sunlight was efficacious on 93% of treatment days that could be evaluated, as compared with 90% for conventional phototherapy, and had a higher mean level of irradiance (40 vs. 17 μW per square centimeter per nanometer, P<0.001). Temperatures higher than 38.0°C occurred in 5% of the infants receiving filtered sunlight and in 1% of those receiving conventional phototherapy (P<0.001), but no infant met the criteria for withdrawal from the study for reasons of safety or required an exchange transfusion.Filtered sunlight was noninferior to conventional phototherapy for the treatment of neonatal hyperbilirubinemia and did not result in any study withdrawals for reasons of safety. (Funded by the Thrasher Research Fund, Salt Lake City, and the National Center for Advancing Translational Sciences of the National Institutes of Health; Clinical Trials.gov number, NCT01434810.).

    View details for DOI 10.1056/NEJMoa1501074

    View details for PubMedID 26376136

  • Temporal and spatial variation of the human microbiota during pregnancy PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA DiGiulio, D. B., Callahan, B. J., McMurdie, P. J., Costello, E. K., Lyell, D. J., Robaczewska, A., Sun, C. L., Goltsman, D. S., Wong, R. J., Shaw, G., Stevenson, D. K., Holmes, S. P., Relman, D. A. 2015; 112 (35): 11060-11065

    Abstract

    Despite the critical role of the human microbiota in health, our understanding of microbiota compositional dynamics during and after pregnancy is incomplete. We conducted a case-control study of 49 pregnant women, 15 of whom delivered preterm. From 40 of these women, we analyzed bacterial taxonomic composition of 3,767 specimens collected prospectively and weekly during gestation and monthly after delivery from the vagina, distal gut, saliva, and tooth/gum. Linear mixed-effects modeling, medoid-based clustering, and Markov chain modeling were used to analyze community temporal trends, community structure, and vaginal community state transitions. Microbiota community taxonomic composition and diversity remained remarkably stable at all four body sites during pregnancy (P > 0.05 for trends over time). Prevalence of a Lactobacillus-poor vaginal community state type (CST 4) was inversely correlated with gestational age at delivery (P = 0.0039). Risk for preterm birth was more pronounced for subjects with CST 4 accompanied by elevated Gardnerella or Ureaplasma abundances. This finding was validated with a set of 246 vaginal specimens from nine women (four of whom delivered preterm). Most women experienced a postdelivery disturbance in the vaginal community characterized by a decrease in Lactobacillus species and an increase in diverse anaerobes such as Peptoniphilus, Prevotella, and Anaerococcus species. This disturbance was unrelated to gestational age at delivery and persisted for up to 1 y. These findings have important implications for predicting premature labor, a major global health problem, and for understanding the potential impact of a persistent, altered postpartum microbiota on maternal health, including outcomes of pregnancies following short interpregnancy intervals.

    View details for DOI 10.1073/pnas.1502875112

    View details for Web of Science ID 000360383200068

  • Heme oxygenase-1 promoter polymorphisms and risk of spina bifida. Birth defects research. Part A, Clinical and molecular teratology Fujioka, K., Yang, W., Wallenstein, M. B., Zhao, H., Wong, R. J., Stevenson, D. K., Shaw, G. M. 2015; 103 (9): 741-746

    Abstract

    Spina bifida is the most common form of neural tube defects (NTDs). Etiologies of NTDs are multifactorial, and oxidative stress is believed to play a key role in NTD development. Heme oxygenase (HO), the rate-limiting enzyme in heme degradation, has multiple protective properties including mediating antioxidant processes, making it an ideal candidate for study. The inducible HO isoform (HO-1) has two functional genetic polymorphisms: (GT)n dinucleotide repeats and A(-413)T SNP (rs2071746), both of which can affect its promoter activity. However, no study has investigated a possible association between HO-1 genetic polymorphisms and risk of NTDs.This case-control study included 152 spina bifida cases (all myelomeningoceles) and 148 nonmalformed controls obtained from the California Birth Defects Monitoring Program reflecting births during 1990 to 1999. Genetic polymorphisms were determined by polymerase chain reaction and amplified fragment length polymorphisms/restriction fragment length polymorphisms using genomic DNA extracted from archived newborn blood spots. Genotype and haplotype frequencies of two HO-1 promoter polymorphisms between cases and controls were compared.For (GT)n dinucleotide repeat lengths and the A(-413)T SNP, no significant differences in allele frequencies or genotypes were found. Linkage disequilibrium was observed between the HO-1 polymorphisms (D': 0.833); however, haplotype analyses did not show increased risk of spina bifida overall or by race/ethnicity.Although, an association was not found between HO-1 polymorphisms and risk of spina bifida, we speculate that the combined effect of low HO-1 expression and exposures to known environmental oxidative stressors (low folate status or diabetes), may overwhelm antioxidant defenses and increase risk of NTDs and warrants further study. Birth Defects Research (Part A), 2014. © 2014 Wiley Periodicals, Inc.

    View details for DOI 10.1002/bdra.23343

    View details for PubMedID 26173399

  • Bilirubin production and hour-specific bilirubin levels. Journal of perinatology Bhutani, V. K., Wong, R. J., Vreman, H. J., Stevenson, D. K. 2015; 35 (9): 735-738

    Abstract

    We assessed the relative contributions of increased bilirubin production (indexed by end-tidal carbon monoxide (CO) concentrations, corrected for ambient CO (ETCOc)) to hour-specific total bilirubin (TB) levels in healthy late preterm and term newborns.Post hoc analyses of concurrent ETCOc and TB (at 30±6 h of age) and follow-up TB levels at age 96±12 h and up to 168 h after birth were performed in a cohort of 641 term and late preterm infants.Increased bilirubin production (hour-specific ETCOc ⩾1.7 p.p.m. at age 30±6 h) was noted in ~80%, 42% and 32% of infants in the high-, intermediate- and low-risk TB zones, respectively. One infant with TB <40th percentile and ETCOc <1.7 p.p.m. developed TB ⩾95th percentile at age 168 h, probably due to decreased bilirubin elimination.Infants in the high-risk quartile of the hour-specific bilirubin nomogram have a higher mean bilirubin production. Infants with TB levels ⩾95th percentile without increased bilirubin production have impaired bilirubin elimination.

    View details for DOI 10.1038/jp.2015.32

    View details for PubMedID 25880796

  • Implementing Mass Cytometry at the Bedside to Study the Immunological Basis of Human Diseases: Distinctive Immune Features in Patients with a History of Term or Preterm Birth. Cytometry. Part A : the journal of the International Society for Analytical Cytology Gaudillière, B., Ganio, E. A., Tingle, M., Lancero, H. L., Fragiadakis, G. K., Baca, Q. J., Aghaeepour, N., Wong, R. J., Quaintance, C., El-Sayed, Y. Y., Shaw, G. M., Lewis, D. B., Stevenson, D. K., Nolan, G. P., Angst, M. S. 2015; 87 (9): 817-829

    Abstract

    Single-cell technologies have immense potential to shed light on molecular and biological processes that drive human diseases. Mass cytometry (or Cytometry by Time Of Flight mass spectrometry, CyTOF) has already been employed in clinical studies to comprehensively survey patients' circulating immune system. As interest in the "bedside" application of mass cytometry is growing, the delineation of relevant methodological issues is called for. This report uses a newly generated dataset to discuss important methodological considerations when mass cytometry is implemented in a clinical study. Specifically, the use of whole blood samples versus peripheral blood mononuclear cells (PBMCs), design of mass-tagged antibody panels, technical and analytical implications of sample barcoding, and application of traditional and unsupervised approaches to analyze high-dimensional mass cytometry datasets are discussed. A mass cytometry assay was implemented in a cross-sectional study of 19 women with a history of term or preterm birth to determine whether immune traits in peripheral blood differentiate the two groups in the absence of pregnancy. Twenty-seven phenotypic and 11 intracellular markers were simultaneously analyzed in whole blood samples stimulated with lipopolysaccharide (LPS at 0, 0.1, 1, 10, and 100 ng mL(-1) ) to examine dose-dependent signaling responses within the toll-like receptor 4 (TLR4) pathway. Complementary analyses, grounded in traditional or unsupervised gating strategies of immune cell subsets, indicated that the prpS6 and pMAPKAPK2 responses in classical monocytes are accentuated in women with a history of preterm birth (FDR<1%). The results suggest that women predisposed to preterm birth may be prone to mount an exacerbated TLR4 response during the course of pregnancy. This important hypothesis-generating finding points to the power of single-cell mass cytometry to detect biologically important differences in a relatively small patient cohort. © 2015 International Society for Advancement of Cytometry.

    View details for DOI 10.1002/cyto.a.22720

    View details for PubMedID 26190063

  • Implementing Mass Cytometry at the Bedside to Study the Immunological Basis of Human Diseases: Distinctive Immune Features in Patients with a History of Term or Preterm Birth CYTOMETRY PART A Gaudilliere, B., Ganio, E. A., Tingle, M., Lancero, H. L., Fragiadakis, G. K., Baca, Q. J., Aghaeepour, N., Wong, R. J., Quaintance, C., El-Sayed, Y. Y., Shaw, G. M., Lewis, D. B., Stevenson, D. K., Nolan, G. P., Angst, M. S. 2015; 87A (9): 817-829

    Abstract

    Single-cell technologies have immense potential to shed light on molecular and biological processes that drive human diseases. Mass cytometry (or Cytometry by Time Of Flight mass spectrometry, CyTOF) has already been employed in clinical studies to comprehensively survey patients' circulating immune system. As interest in the "bedside" application of mass cytometry is growing, the delineation of relevant methodological issues is called for. This report uses a newly generated dataset to discuss important methodological considerations when mass cytometry is implemented in a clinical study. Specifically, the use of whole blood samples versus peripheral blood mononuclear cells (PBMCs), design of mass-tagged antibody panels, technical and analytical implications of sample barcoding, and application of traditional and unsupervised approaches to analyze high-dimensional mass cytometry datasets are discussed. A mass cytometry assay was implemented in a cross-sectional study of 19 women with a history of term or preterm birth to determine whether immune traits in peripheral blood differentiate the two groups in the absence of pregnancy. Twenty-seven phenotypic and 11 intracellular markers were simultaneously analyzed in whole blood samples stimulated with lipopolysaccharide (LPS at 0, 0.1, 1, 10, and 100 ng mL(-1) ) to examine dose-dependent signaling responses within the toll-like receptor 4 (TLR4) pathway. Complementary analyses, grounded in traditional or unsupervised gating strategies of immune cell subsets, indicated that the prpS6 and pMAPKAPK2 responses in classical monocytes are accentuated in women with a history of preterm birth (FDR<1%). The results suggest that women predisposed to preterm birth may be prone to mount an exacerbated TLR4 response during the course of pregnancy. This important hypothesis-generating finding points to the power of single-cell mass cytometry to detect biologically important differences in a relatively small patient cohort. © 2015 International Society for Advancement of Cytometry.

    View details for DOI 10.1002/cyto.a.22720

    View details for Web of Science ID 000360590500009

  • Evaluation of a new end-tidal carbon monoxide monitor from the bench to the bedside. Acta paediatrica (Oslo, Norway : 1992) Castillo Cuadrado, M. E., Bhutani, V. K., Aby, J. L., Vreman, H. J., Wong, R. J., Stevenson, D. K. 2015; 104 (6): e279-82

    View details for DOI 10.1111/apa.12938

    View details for PubMedID 25640053

  • Heme oxygenase-1 confers protection and alters T-cell populations in a mouse model of neonatal intestinal inflammation PEDIATRIC RESEARCH Schulz, S., Chisholm, K. M., Zhao, H., Kalish, F., Yang, Y., Wong, R. J., Stevenson, D. K. 2015; 77 (5): 640-648

    Abstract

    Necrotizing enterocolitis (NEC), an intestinal inflammatory disease affecting premature infants, is associated with low regulatory T (Treg) to effector T (Teff) cell ratios. We recently demonstrated that heme oxygenase-1 (HO-1) deficiency leads to increased NEC development. Here, we investigated the effects of HO-1 on T-cell proportions in a murine NEC-like injury model.Intestinal injury was induced in 7-d-old wild-type (WT) or HO-1 heterozygous (HO-1 Het) pups by formula-feeding every 4 h for 24-78 h by oral gavage and exposures to 5%O2. Controls remained breastfed. HO-1 was induced in WT pups by administering heme preinjury induction. Lamina propria T cells were identified by flow cytometry. For adoptive transfer studies, WT splenic/thymic Tregs were injected intraperitoneally into HO-1 Het pups 12-24 h preinduction.Het mice showed increased intestinal injury and decreased Treg/Teff ratios. Genes for pattern recognition (Toll-like receptor-4, C-reactive protein, MyD88) and neutrophil recruitment increased in Het pups after NEC induction. Inducing intestinal HO-1 decreased NEC scores and incidence, and increased Treg/Teff ratios. Moreover, adoptive transfer of Tregs from WT to HO-1 Het pups decreased NEC scores and incidence and restored Treg/Teff ratios.HO-1 can change Treg proportions in the lamina propria of young mice under inflammatory conditions, which might, in part, confer intestinal protection.

    View details for DOI 10.1038/pr.2015.22

    View details for Web of Science ID 000353085100006

    View details for PubMedID 25665053

  • Neonatal bilirubin binding capacity discerns risk of neurological dysfunction. Pediatric research Lamola, A. A., Bhutani, V. K., Du, L., Castillo Cuadrado, M., Chen, L., Shen, Z., Wong, R. J., Stevenson, D. K. 2015; 77 (2): 334-339

    View details for DOI 10.1038/pr.2014.191

    View details for PubMedID 25420178

  • Copy Number Variation in Bronchopulmonary Dysplasia AMERICAN JOURNAL OF MEDICAL GENETICS PART A Hoffmann, T. J., Shaw, G. M., Stevenson, D. K., Wang, H., Quaintance, C. C., Oehlert, J., Jelliffe-Pawlowski, L. L., Gould, J. B., Witte, J. S., O'Brodovich, H. M. 2014; 164 (10): 2672–75

    View details for DOI 10.1002/ajmg.a.36659

    View details for Web of Science ID 000342279600041

    View details for PubMedID 24975634

    View details for PubMedCentralID PMC4167221

  • Swedish and American studies show that initiatives to decrease maternal obesity could play a key role in reducing preterm birth. Acta paediatrica (Oslo, Norway : 1992) Gould, J. B., Mayo, J., Shaw, G. M., Stevenson, D. K. 2014; 103 (6): 586-591

    Abstract

    Maternal obesity is a major source of preventable perinatal morbidity, but studies of the relationship between obesity and preterm birth have been inconsistent. This review looks at two major studies covering just under 3.5 million births, from California, USA, and Sweden.Inconsistent findings in previous studies appear to stem from the complex relationship between obesity and preterm birth. Initiatives to decrease maternal obesity represent an important strategy in reducing preterm birth.

    View details for DOI 10.1111/apa.12616

    View details for PubMedID 24575829

  • Effects of light on metalloporphyrin-treated newborn mice. Acta paediatrica Wong, R. J., Schulz, S., Espadas, C., Vreman, H. J., Rajadas, J., Stevenson, D. K. 2014; 103 (5): 474-479

    Abstract

    Zinc protoporphyrin (ZnPP) is a promising metalloporphyrin with sufficient potency, but has poor solubility and is not absorbed well orally. Intragastric administration of ZnPP microparticles (30 μmol/kg) to 3-day-old mice resulted in a twofold increase in potency and no signs of phototoxicity.The use of polymeric particulate delivery systems can improve the stability and enhance intestinal absorption of ZnPP, while retaining HO inhibitory potency without photosensitising effects, and thus is potentially useful in treating neonatal hyperbilirubinemia.

    View details for DOI 10.1111/apa.12554

    View details for PubMedID 24417721

  • Population-Level Correlates of Preterm Delivery among Black and White Women in the U.S. PloS one Carmichael, S. L., Cullen, M. R., Mayo, J. A., Gould, J. B., Loftus, P., Stevenson, D. K., Wise, P. H., Shaw, G. M. 2014; 9 (4)

    View details for DOI 10.1371/journal.pone.0094153

    View details for PubMedID 24740117

  • Risks and benefits of comparative effectiveness research in preterm infants: SUPPORT. Journal of comparative effectiveness research Stevenson, D. K., Wong, R. J., Tyson, J. E. 2014; 3 (1): 17-21

    View details for DOI 10.2217/cer.13.85

    View details for PubMedID 24345253

  • Heme oxygenase-1 in pregnancy and cancer: similarities in cellular invasion, cytoprotection, angiogenesis, and immunomodulation. Frontiers in pharmacology Zhao, H., Ozen, M., Wong, R. J., Stevenson, D. K. 2014; 5: 295-?

    Abstract

    Pregnancy can be defined as a "permissible" process, where a semi-allogeneic fetus and placenta are allowed to grow and survive within the mother. Similarly, in tumor growth, antigen-specific malignant cells proliferate and evade into normal tissues of the host. The microenvironments of the placenta and tumors are amazingly comparable, sharing similar mechanisms exploited by fetal or cancer cells with regard to surviving in a hypoxic microenvironment, invading tissues via degradation and vasculogenesis, and escaping host attack through immune privilege. Heme oxygease-1 (HO-1) is a stress-response protein that has antioxidative, anti-apoptotic, pro-angiogenic, and anti-inflammatory properties. Although a large volume of research has been published in recent years investigating the possible role(s) of HO-1 in pregnancy and in cancer development, the molecular mechanisms that regulate these "yin-yang" processes have still not been fully elucidated. Here, we summarize and compare pregnancy and cancer development, focusing primarily on the function of HO-1 in cellular invasion, cytoprotection, angiogenesis, and immunomodulation. Due to the similarities of both processes, a thorough understanding of the molecular mechanisms of each process may reveal and guide the development of new approaches to prevent not only pregnancy disorders; but also, to study cancer.

    View details for DOI 10.3389/fphar.2014.00295

    View details for PubMedID 25642189

    View details for PubMedCentralID PMC4294126

  • Population-level correlates of preterm delivery among black and white women in the U.S. PloS one Carmichael, S. L., Cullen, M. R., Mayo, J. A., Gould, J. B., Loftus, P., Stevenson, D. K., Wise, P. H., Shaw, G. M. 2014; 9 (4)

    Abstract

    This study examined the ability of social, demographic, environmental and health-related factors to explain geographic variability in preterm delivery among black and white women in the US and whether these factors explain black-white disparities in preterm delivery.We examined county-level prevalence of preterm delivery (20-31 or 32-36 weeks gestation) among singletons born 1998-2002. We conducted multivariable linear regression analysis to estimate the association of selected variables with preterm delivery separately for each preterm/race-ethnicity group.The prevalence of preterm delivery varied two- to three-fold across U.S. counties, and the distributions were strikingly distinct for blacks and whites. Among births to blacks, regression models explained 46% of the variability in county-level risk of delivery at 20-31 weeks and 55% for delivery at 32-36 weeks (based on R-squared values). Respective percentages for whites were 67% and 71%. Models included socio-environmental/demographic and health-related variables and explained similar amounts of variability overall.Much of the geographic variability in preterm delivery in the US can be explained by socioeconomic, demographic and health-related characteristics of the population, but less so for blacks than whites.

    View details for DOI 10.1371/journal.pone.0094153

    View details for PubMedID 24740117

    View details for PubMedCentralID PMC3989227

  • Heme Oxygenase-1 Promoter Polymorphisms and Neonatal Jaundice NEONATOLOGY Kaplan, M., Renbaum, P., Hamrnernnan, C., Vreman, H. J., Wong, R. J., Stevenson, D. K. 2014; 106 (4): 323-329

    Abstract

    Heme oxygenase (HO) is the initial, rate-limiting enzyme in the conversion of heme to bilirubin. Dinucleotide (GT)n repeat length in the promoter region of the encoding gene modulates transcription: shorter alleles, in contrast with longer allele counterparts, are associated with greater gene expression and should result in increased heme catabolism.We compared the rates of heme catabolism and plasma total bilirubin (TB) between HO-1 promoter genotypes of varying (GT)n repeat lengths in glucose-6-phosphate dehydrogenase (G6PD)-normal and -deficient neonates.HO-1 promoter length was determined from genomic DNA from previous studies by size discrimination of fluorescently-labeled PCR products with capillary electrophoresis. Sizing was confirmed by sequencing homozygote samples. Alleles were categorized as: short (≤24 GT repeats), medium (25-33 GT repeats), and long (≥34 GT repeats). Previously determined values for blood carboxyhemoglobin, corrected for inspired carbon monoxide (COHbc), and TB were used to determine the rate of heme catabolism and 3rd day TB values for each HO-1 promoter length genotype, respectively. G6PD Mediterranean was determined by PCR analysis.Neither COHbc nor TB values were significantly different between various HO-1 promoter genotypes for either G6PD-normal or -deficient neonates.In the steady state, HO-1 promoter genotypes, based on the length of (GT)n repeats, do not modulate heme catabolism or 3rd day TB values in either G6PD-normal or -deficient neonates.

    View details for DOI 10.1159/000365744

    View details for Web of Science ID 000344445400007

  • Heme oxygenase-1 deficiency promotes the development of necrotizing enterocolitis-like intestinal injury in a newborn mouse model. American journal of physiology. Gastrointestinal and liver physiology Schulz, S., Wong, R. J., Jang, K. Y., Kalish, F., Chisholm, K. M., Zhao, H., Vreman, H. J., Sylvester, K. G., Stevenson, D. K. 2013; 304 (11): G991-G1001

    Abstract

    Necrotizing enterocolitis (NEC) is typified by mucosal destruction, which subsequently can lead to intestinal necrosis. Prematurity, enteral feeding, and bacterial colonization are the main risk factors and, combined with other stressors, can cause increased intestinal permeability, injury, and an exaggerated inflammatory response. Heme oxygenase-1 (HO-1) mediates intestinal protection due to anti-inflammatory, antioxidative, and antiapoptotic effects of its products carbon monoxide, biliverdin, and bilirubin. This study investigates a possible role of HO-1 in the pathogenesis of NEC using a newborn mouse model. We induced NEC-like intestinal injury in 7-day-old HO-1 heterozygous (HO-1 Het, Hmox1(+/-)) and wild-type (Wt, Hmox1(+/+)) mice by gavage feeding and hypoxic exposures. Control (Con) pups of both genotypes were dam-fed. Intestines of HO-1 Het Con pups appeared predisposed to injury, with higher histological damage scores, more TUNEL-positive cells, and a significant reduction in muscularis externa thickness compared with Wt Con pups. The increase in HO activity after HO-1 induction by the substrate heme or by hypoxic stress was significantly impaired in HO-1 Het pups. After induction of intestinal injury, HO-1 Het pups displayed significantly higher NEC incidence (78 vs. 43%), mortality (83 vs. 54%), and median scores (2.5 vs. 1.5) than Wt NEC pups. PCR array analyses revealed increased expressions of IL-1β, P-selectin, matrix metallopeptidase 2, collagen type XVIII-α1, serpine 1, and others in NEC-induced HO-1 Het ileal and jejunal tissues. We conclude that a partial HO-1 deficiency promotes experimental NEC-like intestinal injury, possibly mediated by exaggerated inflammation and disruption in tissue repair.

    View details for DOI 10.1152/ajpgi.00363.2012

    View details for PubMedID 23578787

    View details for PubMedCentralID PMC3680684

  • Transdisciplinary translational science and the case of preterm birth JOURNAL OF PERINATOLOGY Stevenson, D. K., Shaw, G. M., Wise, P. H., Norton, M. E., Druzin, M. L., Valantine, H. A., McFarland, D. A. 2013; 33 (4): 251-258

    Abstract

    Medical researchers have called for new forms of translational science that can solve complex medical problems. Mainstream science has made complementary calls for heterogeneous teams of collaborators who conduct transdisciplinary research so as to solve complex social problems. Is transdisciplinary translational science what the medical community needs? What challenges must the medical community overcome to successfully implement this new form of translational science? This article makes several contributions. First, it clarifies the concept of transdisciplinary research and distinguishes it from other forms of collaboration. Second, it presents an example of a complex medical problem and a concrete effort to solve it through transdisciplinary collaboration: for example, the problem of preterm birth and the March of Dimes effort to form a transdisciplinary research center that synthesizes knowledge on it. The presentation of this example grounds discussion on new medical research models and reveals potential means by which they can be judged and evaluated. Third, this article identifies the challenges to forming transdisciplines and the practices that overcome them. Departments, universities and disciplines tend to form intellectual silos and adopt reductionist approaches. Forming a more integrated (or 'constructionist'), problem-based science reflective of transdisciplinary research requires the adoption of novel practices to overcome these obstacles.

    View details for DOI 10.1038/jp.2012.133

    View details for Web of Science ID 000316833300001

    View details for PubMedID 23079774

    View details for PubMedCentralID PMC3613736

  • Predischarge Screening for Severe Neonatal Hyperbilirubinemia Identifies Infants Who Need Phototherapy JOURNAL OF PEDIATRICS Bhutani, V. K., Stark, A. R., Lazzeroni, L. C., Poland, R., Gourley, G. R., Kazmierczak, S., Meloy, L., Burgos, A. E., Hall, J. Y., Stevenson, D. K. 2013; 162 (3): 477-?

    Abstract

    To test whether the combined use of total plasma/serum bilirubin (TSB) levels and clinical risk factors more accurately identifies infants who receive phototherapy than does the use of either method alone.We recruited healthy infants of ≥35 weeks' gestation at 6 centers that practiced universal predischarge TSB screening. Transcutaneous bilirubin (TcB) was measured at 24 hours, with TSB at 24-60 hours and at 3- to 5- and 7- to 14-day follow-up visits. Clinical risk factors were identified systematically.Of 1157 infants, 1060 (92%) completed follow-up, and 982 (85%) had complete datasets for analysis. Infant characteristics included 25% were nonwhite and 55% were Hispanic/Latino; >90% were breastfed. During the first week, jaundice was documented in 84% of subjects. Predischarge TSB identified the 41 (4.2%) and 34 (3.5%) infants who received phototherapy before and after discharge, respectively. Prediction of postdischarge phototherapy was similar for combined clinical risk factors (earlier gestational age [GA], bruising, positive direct antiglobulin test, Asian race, exclusive breastfeeding, blood type incompatibility, jaundice extent) and age-adjusted TSB (area under the curve [AUC] = .86 vs .87), but combined screening was better (AUC = .95). TcB/TSB combined with GA alone was equally predictive (AUC = .95; 95% CI .93-.97).Jaundice is present in 4 of 5 (84%) healthy newborns. Predischarge TcB/TSB (adjusted for postnatal age) combined with specific clinical factors (especially GA) best predicts subsequent phototherapy use. Universal implementation of this strategy in the US should improve outcomes of healthy newborns discharged early.

    View details for DOI 10.1016/j.jpeds.2012.08.022

    View details for Web of Science ID 000315790100010

    View details for PubMedID 23043681

  • Neurodevelopmental Outcomes in the Early CPAP and Pulse Oximetry Trial NEW ENGLAND JOURNAL OF MEDICINE Vaucher, Y. E., Peralta-Carcelen, M., Finer, N. N., Carlo, W. A., Gantz, M. G., Walsh, M. C., Laptook, A. R., Yoder, B. A., Faix, R. G., Das, A., Schibler, K., Rich, W., Newman, N. S., Vohr, B. R., Yolton, K., Heyne, R. J., Wilson-Costello, D. E., Evans, P. W., Goldstein, R. F., Acarregui, M. J., Adams-Chapman, I., Pappas, A., Hintz, S. R., Poindexter, B., Dusick, A. M., McGowan, E. C., Ehrenkranz, R. A., Bodnar, A., Bauer, C. R., Fuller, J., O'Shea, T. M., Myers, G. J., Higgins, R. D. 2012; 367 (26): 2495-2504

    Abstract

    Previous results from our trial of early treatment with continuous positive airway pressure (CPAP) versus early surfactant treatment in infants showed no significant difference in the outcome of death or bronchopulmonary dysplasia. A lower (vs. higher) target range of oxygen saturation was associated with a lower rate of severe retinopathy but higher mortality. We now report longer-term results from our prespecified hypotheses.Using a 2-by-2 factorial design, we randomly assigned infants born between 24 weeks 0 days and 27 weeks 6 days of gestation to early CPAP with a limited ventilation strategy or early surfactant administration and to lower or higher target ranges of oxygen saturation (85 to 89% or 91 to 95%). The primary composite outcome for the longer-term analysis was death before assessment at 18 to 22 months or neurodevelopmental impairment at 18 to 22 months of corrected age.The primary outcome was determined for 1234 of 1316 enrolled infants (93.8%); 990 of the 1058 surviving infants (93.6%) were evaluated at 18 to 22 months of corrected age. Death or neurodevelopmental impairment occurred in 27.9% of the infants in the CPAP group (173 of 621 infants), versus 29.9% of those in the surfactant group (183 of 613) (relative risk, 0.93; 95% confidence interval [CI], 0.78 to 1.10; P=0.38), and in 30.2% of the infants in the lower-oxygen-saturation group (185 of 612), versus 27.5% of those in the higher-oxygen-saturation group (171 of 622) (relative risk, 1.12; 95% CI, 0.94 to 1.32; P=0.21). Mortality was increased with the lower-oxygen-saturation target (22.1%, vs. 18.2% with the higher-oxygen-saturation target; relative risk, 1.25; 95% CI, 1.00 to 1.55; P=0.046).We found no significant differences in the composite outcome of death or neurodevelopmental impairment among extremely premature infants randomly assigned to early CPAP or early surfactant administration and to a lower or higher target range of oxygen saturation. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Heart, Lung, and Blood Institute; SUPPORT ClinicalTrials.gov number, NCT00233324.).

    View details for DOI 10.1056/NEJMoa1208506

    View details for Web of Science ID 000312714200007

    View details for PubMedID 23268664

  • An approach to the management of hyperbilirubinemia in the preterm infant less than 35 weeks of gestation JOURNAL OF PERINATOLOGY Maisels, M. J., Watchko, J. F., Bhutani, V. K., Stevenson, D. K. 2012; 32 (9): 660–64

    Abstract

    We provide an approach to the use of phototherapy and exchange transfusion in the management of hyperbilirubinemia in preterm infants of <35 weeks of gestation. Because there are limited data for evidence-based recommendations, these recommendations are, of necessity, consensus-based. The recommended treatment levels are based on operational thresholds for bilirubin levels and represent those levels beyond which it is assumed that treatment will likely do more good than harm. Long-term follow-up of a large population will be needed to evaluate whether or not these recommendations should be modified.

    View details for DOI 10.1038/jp.2012.71

    View details for Web of Science ID 000308278000003

    View details for PubMedID 22678141

  • Effect of light exposure on metalloporphyrin-treated newborn mice PEDIATRIC RESEARCH Schulz, S., Wong, R. J., Kalish, F. S., Zhao, H., Jang, K. Y., Vreman, H. J., Stevenson, D. K. 2012; 72 (2): 161-168

    Abstract

    Neonatal hyperbilirubinemia arises from increased bilirubin production and decreased bilirubin elimination. Although phototherapy safely and effectively reduces bilirubin levels, recent evidence shows that it has adverse effects. Therefore, alternative treatments are warranted. Metalloporphyrins, competitive inhibitors of heme oxygenase (HO), the rate-limiting enzyme in bilirubin production, effectively reduce bilirubin formation; however, many are photoreactive. Here, we investigated possible photosensitizing effects of chromium mesoporphyrin (CrMP) and zinc deuteroporphyrin bis-glycol (ZnBG).Administration of CrMP or ZnBG to 3-d-old mouse pups (3.75-30.0 μmol/kg intraperitoneally) and exposure to cool white (F20T12CW) and blue (TL20W/52) fluorescent lights (+L) for 3 h, resulted in a dose-dependent mortality (50% lethal dose (LD50) = 21.5 and 19.5 μmol/kg, respectively). In contrast to ZnBG, there was no significant difference in survival between the CrMP+L and CrMP groups. Following 30 μmol/kg ZnBG+L, we found significant weight loss, decreased liver antioxidant capacities, and increased aspartate aminotransaminase levels. At 6-d post-light exposure, ZnBG+L-treated pups showed gross and histologic skin changes at doses >7.5 μmol/kg. No lethality was observed following treatment with 30 μmol ZnBG/kg plus exposure to blue light-emitting diodes. Phototoxicity of ZnBG was dependent on light source, emission spectrum, and irradiance.Low doses of ZnBG (<3.75 μmol/kg) retained maximal HO inhibitory potency without photosensitizing effects, and therefore are potentially useful in treating neonatal hyperbilirubinemia.

    View details for DOI 10.1038/pr.2012.62

    View details for Web of Science ID 000306862000007

    View details for PubMedID 22580722

  • A deficiency in haem oxygenase-1 induces foetal growth restriction by placental vasculature defects ACTA PAEDIATRICA Wong, R. J., Zhao, H., Stevenson, D. K. 2012; 101 (8): 827-834

    Abstract

    Haem oxygenase-1 (HO-1), the rate-limiting enzyme in haem degradation, plays a role in angiogenesis and vasculogenesis and is highly expressed in the placenta. Deficiencies in HO-1 are associated with several pregnancy disorders, such as recurrent miscarriages and pre-eclampsia. The unique combination of tissue protective, smooth muscle relaxing and angiogenesis regulatory properties makes HO-1 a key player in the maintenance of a healthy pregnancy through a direct effect on placental structural and vascular development, thus affecting foetal development. Conclusion:  Therefore, we conclude that HO-1 plays an important role in placental vasculature development and a deficiency in HO-1 may contribute to pregnancy complications, such as pre-eclampsia, spontaneous abortions and premature births.

    View details for DOI 10.1111/j.1651-2227.2012.02729.x

    View details for Web of Science ID 000306398200025

    View details for PubMedID 22594519

  • Metalloporphyrins - an update. Frontiers in pharmacology Schulz, S., Wong, R. J., Vreman, H. J., Stevenson, D. K. 2012; 3: 68-?

    Abstract

    Metalloporphyrins are structural analogs of heme and their potential use in the management of neonatal hyperbilirubinemia has been the subject of considerable research for more than three decades. The pharmacological basis for using this class of compounds to control bilirubin levels is the targeted blockade of bilirubin production through the competitive inhibition of heme oxygenase (HO), the rate-limiting enzyme in the bilirubin production pathway. Ongoing research continues in the pursuit of identifying ideal metalloporphyrins, which are safe and effective, by defining therapeutic windows and targeted interventions for the treatment of excessive neonatal hyperbilirubinemia.

    View details for DOI 10.3389/fphar.2012.00068

    View details for PubMedID 22557967

  • Maternal Heme Oxygenase 1 Regulates Placental Vasculature Development via Angiogenic Factors in Mice BIOLOGY OF REPRODUCTION Zhao, H., Azuma, J., Kalish, F., Wong, R. J., Stevenson, D. K. 2011; 85 (5): 1005-1012

    Abstract

    The placental vasculature is critical for nutrient, gas, and waste exchange between the maternal and fetal systems. Its development depends on the proper expression and interaction of angiogenesis and associated growth factors. Heme oxygenase (HMOX), the enzyme for heme degradation, plays a role in angiogenesis and is highly expressed in the placenta. To evaluate the role of maternal HMOX1, the inducible HMOX isozyme, on placental vasculature formation, mice with a partial deficiency in Hmox1 (Hmox1(+/-)) were used. Three-dimensional images of placental vasculatures as well as spiral arteries from Hmox1(+/+) or Hmox1(+/-) placentas were created by vascular corrosion casting technique and imaged by micro-computerized tomography (microCT). The structures and morphologies of fetomaternal interfaces were observed by histological staining and the ultrastructure of uterine natural killer (uNK) cells, a major regulator in spiral artery remodeling, was analyzed by transmission electron microscopy. A group of growth factors and angiogenic factors from the decidua/mesometrial lymphoid aggregate of pregnancy (MLAp) as well as labyrinth regions were quantified using an angiogenesis PCR array kit and compared between Hmox1(+/+) or Hmox1(+/-) placentas. In conclusion, a partial deficiency of maternal Hmox1 resulted in the malformation of fetomaternal interface, insufficiency of spiral artery remodeling, and alteration of uNK cell differentiation and maturation. These changes were independent of the fetal genotype, but relied on the maternal HMOX1 level, which determined the balance of expression levels of pro- and antiangiogenic factors in the decidua/MLAp region. These results implied that Hmox1 polymorphisms among the human population might contribute to some unexplained cases of pregnancy disorders, such as fetal growth retardation and preeclampsia.

    View details for DOI 10.1095/biolreprod.111.093039

    View details for Web of Science ID 000296580000014

    View details for PubMedID 21778140

    View details for PubMedCentralID PMC3197918

  • Effects of Zinc Deuteroporphyrin Bis Glycol on Newborn Mice After Heme Loading PEDIATRIC RESEARCH He, C. X., Campbell, C. M., Zhao, H., Kalish, F. S., Schulz, S., Vreman, H. J., Wong, R. J., Stevenson, D. K. 2011; 70 (5): 467-472

    Abstract

    Infants with hemolytic diseases frequently develop hyperbilirubinemia and are treated with phototherapy, which only eliminates bilirubin after its production. A better strategy might be to directly inhibit heme oxygenase (HO), the rate-limiting enzyme in bilirubin production. Metalloporphyrins (Mps) are heme analogs that competitively inhibit HO activity in vitro and in vivo and suppress plasma bilirubin levels in vivo. A promising Mp, zinc deuteroporphyrin bis glycol (ZnBG), is orally absorbed and effectively inhibits HO activity at relatively low doses. We determined the I(50) (the dose needed to inhibit HO activity by 50%) of orally administered ZnBG in vivo and then evaluated ZnBG's effects on in vivo bilirubin production, HO activity, HO protein levels, and HO-1 gene expression in newborn mice after heme loading, a model analogous to a hemolytic infant. The I(50) of ZnBG was found to be 4.0 μmol/kg body weight (BW). At a dose of 15 μmol/kg BW, ZnBG reduced in vivo bilirubin production, inhibited heme-induced liver HO activity and spleen HO activity to and below baseline, respectively, transiently induced liver and spleen HO-1 gene transcription, and induced liver and spleen HO-1 protein levels. We conclude that ZnBG may be an attractive compound for treating severe neonatal hyperbilirubinemia caused by hemolytic disease.

    View details for Web of Science ID 000296121100005

    View details for PubMedID 21785387

    View details for PubMedCentralID PMC3189293

  • Is phototherapy exposure associated with better or worse outcomes in 501-to 1000-g-birth-weight infants? ACTA PAEDIATRICA Hintz, S. R., Stevenson, D. K., Yao, Q., Wong, R. J., Das, A., Van Meurs, K. P., Morris, B. H., Tyson, J. E., Oh, W., Poole, W. K., Phelps, D. L., McDavid, G. E., Grisby, C., Higgins, R. D. 2011; 100 (7): 960-965

    Abstract

     To compare risk-adjusted outcomes at 18- to 22-month-corrected age for extremely low birth weight (ELBW) infants who never received phototherapy (NoPTx) to those who received any phototherapy (PTx) in the NICHD Neonatal Research Network randomized trial of Aggressive vs. Conservative Phototherapy.Outcomes at 18 to 22-month-corrected age included death, neurodevelopmental impairment (NDI) and Bayley Scales Mental Developmental Index (MDI). Regression models evaluated the independent association of PTx with adverse outcomes controlling for centre and other potentially confounding variables.Of 1972 infants, 216 were NoPTx and 1756 were PTx. For the entire 501- to 1000-g-BW cohort, PTx was not independently associated with death or NDI (OR 0.85, 95% CI: 0.60-1.20), death or adverse neurodevelopmental endpoints. However, among infants 501-750 g BW, the rate of significant developmental impairment with MDI < 50 was significantly higher for NoPTx (29%) than PTx (12%) (p = 0.004).Phototherapy did not appear to be independently associated with death or NDI for the overall ELBW group. Whether PTx increases mortality could not be excluded because of bias from deaths before reaching conservative treatment threshold. The higher rate of MDI < 50 in the 501- to 750-g-BW NoPTx group is concerning and consistent with NRN Trial results.

    View details for DOI 10.1111/j.1651-2227.2011.02175.x

    View details for Web of Science ID 000291224200021

    View details for PubMedID 21272067

    View details for PubMedCentralID PMC3505994

  • Bilirubin Production and the Risk of Bilirubin Neurotoxicity SEMINARS IN PERINATOLOGY Stevenson, D. K., Vreman, H. J., Wong, R. J. 2011; 35 (3): 121-126

    Abstract

    Neonatal jaundice usually occurs in the transitional period after birth, presenting as an elevation of circulating bilirubin. Bilirubin neurotoxicity can occur if the levels of bilirubin become excessive (hyperbilirubinemia). This pathologic phenotype of newborn jaundice can develop because of excessive bilirubin production or impaired conjugation, with the risk for developing bilirubin-induced neurologic dysfunction, depending on the degree of the resultant bilirubin load. The plasma bilirubin level thus can be used to assess an infant's risk for developing bilirubin neurotoxicity relative to an infant's age in hours. Because all infants have an impaired conjugation ability, infants at greatest risk are those who have increased bilirubin production rates, because of hemolysis, for example. Therefore, developing potential preventive strategies as well as noninvasive technologies to treat and to identify infants with increased bilirubin production rates, respectively, are tantamount to reducing the incidence of bilirubin-induced neurologic dysfunction.

    View details for DOI 10.1053/j.semperi.2011.02.005

    View details for Web of Science ID 000292057900004

    View details for PubMedID 21641484

  • Panhematin provides a therapeutic benefit in experimental pancreatitis GUT Habtezion, A., Kwan, R., Akhtar, E., Wanaski, S. P., Collins, S. D., Wong, R. J., Stevenson, D. K., Butcher, E. C., Omary, M. B. 2011; 60 (5): 671-679

    Abstract

    Acute pancreatitis (AP) can result in pancreatic necrosis and inflammation, with subsequent multi-organ failure. AP is associated with increased neutrophil recruitment and a rise in pro-inflammatory cytokines such as TNFα. Pretreatment with haemin, results in recruitment of haem-oxygenase-1 (HO-1)(+) macrophages and protects against experimental pancreatitis. It is not clear whether modulation of HO-1 after onset of disease has a protective role. In this study, we tested the utility of Panhematin, a water-soluble haemin formulation, in activating and inducing pancreatic HO-1, and as a therapeutic agent in treating mouse acute pancreatitis.We defined the distribution of radiolabelled haemin, then used in vivo HO-1-luciferase bioluminescence imaging and the CO-release assay to test Panhematin-induced upregulation of HO-1 transcription and activity, respectively. Using two well-defined AP murine models, we tested the therapeutic benefit of Panhematin, and quantified cytokine release using a luminex assay.Intravenously administered Panhematin induces rapid recruitment of HO-1(+) cells to the pancreas within 2 h and de novo splenic HO-1 transcription by 12 h. Despite high baseline spleen HO-1 activity, the pancreas is particularly responsive to Panhematin-mediated HO-1 induction. Panhematin-treated mice, at various time points after AP induction had significant reduction in mortality, pancreatic injury, together with upregulation of HO-1 and downregulation of pro-inflammatory cytokines and CXCL1, a potent neutrophil chemoattractant.Despite AP-associated mortality and morbidity, no effective treatment other than supportive care exists. We demonstrate that Panhematin leads to: (i) rapid induction and activation of pancreatic HO-1 with recruitment of HO-1(+) cells to the pancreas, (ii) amelioration of AP even when given late during the course of disease, and (iii) a decrease in leucocyte infiltration and pro-inflammatory cytokines including CXCL1. The utility of Panhematin at modest doses as a therapeutic in experimental pancreatitis, coupled with its current use and safety in humans, raises the potential of its applicability to human pancreatitis.

    View details for DOI 10.1136/gut.2010.217208

    View details for Web of Science ID 000289076700015

    View details for PubMedID 21159893

    View details for PubMedCentralID PMC3580958

  • In vitro inhibition of heme oxygenase isoenzymes by metalloporphyrins JOURNAL OF PERINATOLOGY Wong, R. J., Vreman, H. J., Schulz, S., Kalish, F. S., Pierce, N. W., Stevenson, D. K. 2011; 31: S35-S41

    Abstract

    Neonatal jaundice results from an increased bilirubin production and decreased hepatic bilirubin conjugation and excretion. Severe hyperbilirubinemia is currently treated with phototherapy or exchange transfusion; however, its prevention by inhibiting bilirubin formation is a more logical strategy. Heme oxygenase (HO), with inducible (HO-1) and constitutive (HO-2) isoenzymes, is the rate-limiting enzyme in heme catabolism, producing equimolar amounts of bilirubin and carbon monoxide (CO). Metalloporphyrins (Mps) are heme derivatives that competitively inhibit HO and thereby suppress hyperbilirubinemia. No systematic studies have been reported evaluating whether the HO isoenzymes are inhibited differentially by various Mps. Identification of Mps that selectively inhibit the inducible HO-1 without affecting the 'housekeeping' HO-2 isoenzyme might be desirable in the clinical setting of hemolytic disease, in which the Hmox1 gene is greatly induced. Although bilirubin production is due to the activity of both HO-1 and HO-2, the inhibition of HO-1 with a relative sparing of HO-2 activity might provide the most selective approach for the treatment of hemolytic disease.We determined for the deutero-, proto-, meso- and bis-glycol porphyrins with zinc, tin and chromium as central atoms, respectively, the concentration needed for 50% inhibition (I(50)) of HO-1 and HO-2 activities in rat spleen and brain tissue.For a given Mp, HO-1 activity was less inhibited than that of HO-2. The order of inhibitor potency of each Mp was nearly identical for both isoenzymes. Tin mesoporphyrin was the most potent inhibitor for both isoenzymes. HO-2 selectivity was greatest for tin protoporphyrin. Conversely, the Zn compounds were least inhibitory toward HO-2. No Mp preferentially inhibited HO-1.Mps that produce a less inhibitory effect on HO-2, while limiting the response of the inducible HO-1, such as ZnPP, may be a useful clinical tool.

    View details for DOI 10.1038/jp.2010.173

    View details for Web of Science ID 000289236900006

    View details for PubMedID 21448202

  • Phil Sunshine: Apgar Award recipient. Journal of perinatology Stevenson, D. K. 2011; 31: S2-5

    View details for DOI 10.1038/jp.2010.171

    View details for PubMedID 21448198

  • Metalloporphyrins in the management of neonatal hyperbilirubinemia SEMINARS IN FETAL & NEONATAL MEDICINE Stevenson, D. K., Wong, R. J. 2010; 15 (3): 164-168

    Abstract

    Neonatal jaundice in the first week of life is a common problem in newborns. It is due to an imbalance of bilirubin production and its elimination, which can lead to significantly elevated levels of circulating bilirubin or hyperbilirubinemia. Use of phototherapy and/or exchange transfusion are the current modes for treating neonatal hyperbilirubinemia and preventing any neurologic damage. These strategies, however, only remove bilirubin that has already been formed. Preventing the production of excess bilirubin may be a more logical approach. Synthetic heme analogs, metalloporphyrins, are competitive inhibitors of heme oxygenase, the rate-limiting enzyme in bilirubin production, and their use has been proposed as an attractive alternative strategy for preventing or treating severe hyperbilirubinemia.

    View details for DOI 10.1016/j.siny.2009.11.004

    View details for Web of Science ID 000278039100008

    View details for PubMedID 20006567

    View details for PubMedCentralID PMC2859976

  • Understanding Neonatal Jaundice: A Perspective on Causation PEDIATRICS AND NEONATOLOGY Cohen, R. S., Wong, R. J., Stevenson, D. K. 2010; 51 (3): 143-148

    Abstract

    Neonatal jaundice can be best understood as a balance between the production and elimination of bilirubin, with a multitude of factors and conditions affecting each of these processes. When an imbalance results because of an increase in circulating bilirubin (or the bilirubin load) to significantly high levels (severe hyperbilirubinemia), it may cause permanent neurologic sequelae (kernicterus). In most infants, an increase in bilirubin production (e.g., due to hemolysis) is the primary cause of severe hyperbilirubinemia, and thus reducing bilirubin production is a rational approach for its management. The situation can become critical in infants with an associated impaired bilirubin elimination mechanism as a result of a genetic deficiency and/or polymorphism. Combining information about bilirubin production and genetic information about bilirubin elimination with the tracking of bilirubin levels means that a relative assessment of jaundice risk might be feasible. Information on the level of bilirubin production and its rate of elimination may help to guide the clinical management of neonatal jaundice.

    View details for Web of Science ID 000278799200002

    View details for PubMedID 20675237

  • Effect of Heme Oxygenase-1 Deficiency on Placental Development PLACENTA Zhao, H., Wong, R. J., Kalish, F. S., Nayak, N. R., Stevenson, D. K. 2009; 30 (10): 861-868

    Abstract

    Heme oxygenase (HO) is the rate-limiting enzyme in the heme catabolic pathway and highly expressed in the placenta. Deficiencies in HO-1, the inducible isoform, have been associated with pregnancy disorders, such as recurrent miscarriages, intrauterine growth retardation, and pre-eclampsia. The aim of this study was to identify if a deficiency in HO-1 affects placental development using a mouse model. When HO-1 heterozygote (Het, HO-1(+/-)) mice were cross-bred, an extremely low birth rate in homozygote (Mut, HO-1(-/-)) offspring (2.4%) and small litter sizes were observed. Placentas and fetuses from Het cross-breedings were relatively smaller and weighed less than those from wild-type (WT) cross-breedings at E12.5 and E15.5. Furthermore, Het placentas had significantly less HO-1 mRNA and protein levels than WT placentas, but no significant differences in placental HO activity. Interestingly, HO-2, the constituitive HO isoform, as well as iNOS and eNOS expression were significantly upregulated in Het placentas. Histological examination showed that the junctional zone (JZ) of Het placentas were markedly thinner than those of WT placentas and appeared to be due to an increase in apoptosis. Immunohistochemistry revealed that HO-1-expressing cells were located primarily in the JZ of Het placentas, specifically in the spongiotrophoblast layer. In addition, diastolic blood pressures and plasma soluble VEGFR-1 (sFlt-1) levels were significantly elevated in pregnant Het mice. We conclude that a partial deficiency in HO-1 is associated with morphological changes in the placenta and elevations in maternal diastolic blood pressure and plasma sFlt-1 levels, despite a compensatory increase in HO-2 expression.

    View details for DOI 10.1016/j.placenta.2009.07.012

    View details for Web of Science ID 000270706300006

    View details for PubMedID 19699520

    View details for PubMedCentralID PMC2771543

  • Molecular mechanism and functional consequences of lansoprazole-mediated heme oxygenase-1 induction WORLD JOURNAL OF GASTROENTEROLOGY Schulz-Geske, S., Erdmann, K., Wong, R. J., Stevenson, D. K., Schroeder, H., Grosser, N. 2009; 15 (35): 4392-4401

    Abstract

    To investigate the molecular mechanism and functional consequences of heme oxygenase-1 (HO-1) activation by lansoprazole in endothelial cells and macrophages.Expression of HO-1 mRNA was analyzed by Northern blotting. Western blotting was used to determine the HO-1 and ferritin protein levels. NADPH-dependent reactive oxygen species (ROS) formation was measured with lucigenin-enhanced chemiluminescence. HO-1 promoter activity in mouse fibroblasts, stably transfected with a 15-kb HO-1 gene that drives expression of the reporter gene luciferase, was assessed using in vivo bioluminescence imaging.Lansoprazole increased HO-1 mRNA levels in endothelial cells and HO-1 protein levels in macrophages. In addition, lansoprazole-induced ferritin protein levels in both cell systems. Moreover, induction of the antioxidant proteins HO-1 and ferritin by lansoprazole was followed by a decrease in NADPH-mediated ROS formation. The radical scavenging properties of lansoprazole were diminished in the presence of the HO inhibitor, chromium mesoporphyrin IX. Induction of HO-1 gene expression by lansoprazole was not related to oxidative stress or to the activation of the mitogen-activated protein kinase pathway. However, the phosphatidylinositol 3-kinase inhibitor LY294002 showed a concentration-dependent inhibition of HO-1 mRNA and promoter activity.Activation of HO-1 and ferritin may account for the gastric protection of lansoprazole and is dependent on a pathway blocked by LY294002.

    View details for DOI 10.3748/wjg.15.4392

    View details for Web of Science ID 000270080500007

    View details for PubMedID 19764090

    View details for PubMedCentralID PMC2747059

  • Dermal Carbon Monoxide Excretion in Neonatal Rats During Light Exposure PEDIATRIC RESEARCH Vreman, H. J., Knauer, Y., Wong, R. J., Chan, M., Stevenson, D. K. 2009; 66 (1): 66-69

    Abstract

    Total body, head, and trunk carbon monoxide (CO) excretion rates were measured separately by gas chromatography in 1- to 7-d-old Wistar rat pups exposed to the dark and to mixed blue (one Special Blue-F20T12/BB) and white (two Cool White-F20T12/CW) fluorescent light or blue light emitting diode (LED) sources. During 48-min cycled exposures to the dark and to either light source, total body CO excretion rapidly increased 1.9- and 1.4-fold, respectively, over dark control levels. When CO excretion rates from the head and trunk were measured separately during exposure to either light source, CO excretion from the head did not change significantly; however, a large mean 4.4-fold increase in CO excretion from the trunk was observed. When light intensity delivered by the blue LED source was varied, we found that trunk CO excretion increased with increasing light intensities. In the presence of riboflavin (10 micromol/kg), total body CO excretion increased 2.8- and 2.1-fold during exposure to the mixed fluorescent light and blue LED sources, respectively. We conclude that light-induced elevations in total body CO excretion may be caused by transdermally excreted CO, which is most likely produced through endogenous photosensitizer-mediated photooxidation of dermal biomolecules.

    View details for Web of Science ID 000267249300013

    View details for PubMedID 19342986

    View details for PubMedCentralID PMC2714864

  • Effects of sample dilution, peroxidise concentration, and chloride ion on the measurement of unbound bilirubin in premature newborns (vol 40, pg 261, 2007) CLINICAL BIOCHEMISTRY Ahlfors, C. E., Vreman, H. J., Wong, R. J., Bender, G., Oh, W., Morris, B. H., Stevenson, D. K. 2009; 42 (6): 547
  • Gastric protection by lansoprazole and the impact of heme oxygenase-1 and ferritin. World J Gastroenterol Schulz-Geske S, Erdmann K, Wong RJ, Stevenson DK, Schröder H, Grosser N. 2009; 15: 4392-401
  • Photoisomers ? Obfuscating factors in clinical peroxidase measurements of unbound bilirubin? Pediatrics McDonagh AF, Vreman HJ, Wong RJ, Stevenson DK 2009; 123: 67-76
  • Heme oxygenase-1 deficiency leads to disrupted response to acute stress in stem cells and progenitors BLOOD Cao, Y., Wagers, A. J., Karsunky, H., Zhao, H., Reeves, R., Wong, R. J., Stevenson, D. K., Weissman, I. L., Contag, C. H. 2008; 112 (12): 4494-4502

    Abstract

    An effective response to extreme hematopoietic stress requires an extreme elevation in hematopoiesis and preservation of hematopoietic stem cells (HSCs). These diametrically opposed processes are likely to be regulated by genes that mediate cellular adaptation to physiologic stress. Herein, we show that heme oxygenase-1 (HO-1), the inducible isozyme of heme degradation, is a key regulator of these processes. Mice lacking one allele of HO-1 (HO-1(+/-)) showed accelerated hematopoietic recovery from myelotoxic injury, and HO-1(+/-) HSCs repopulated lethally irradiated recipients with more rapid kinetics. However, HO-1(+/-) HSCs were ineffective in radioprotection and serial repopulation of myeloablated recipients. Perturbations in key stem cell regulators were observed in HO-1(+/-) HSCs and hematopoietic progenitors (HPCs), which may explain the disrupted response of HO-1(+/-) HPCs and HPCs to acute stress. Control of stem cell stress response by HO-1 presents opportunities for metabolic manipulation of stem cell-based therapies.

    View details for DOI 10.1182/blood-2007-12-127621

    View details for Web of Science ID 000261217000024

    View details for PubMedID 18509090

    View details for PubMedCentralID PMC2597124

  • Aggressive vs. conservative phototherapy for infants with extremely low birth weight NEW ENGLAND JOURNAL OF MEDICINE Morris, B. H., Oh, W., Tyson, J. E., Stevenson, D. K., Phelps, D. L., O'Shea, T. M., McDavid, G. E., Perritt, R. L., Van Meurs, K. P., Vohr, B. R., Grisby, C., Yao, Q., Pedroza, C., Das, A., Poole, W. K., Carlo, W. A., Duara, S., Laptook, A. R., Salhab, W. A., Shankaran, S., Poindexter, B. B., Fanaroff, A. A., Walsh, M. C., Rasmussen, M. R., Stoll, B. J., Cotten, C. M., Donovan, E. F., Ehrenkranz, R. A., Guillet, R., Higgins, R. D. 2008; 359 (18): 1885-1896

    Abstract

    It is unclear whether aggressive phototherapy to prevent neurotoxic effects of bilirubin benefits or harms infants with extremely low birth weight (1000 g or less).We randomly assigned 1974 infants with extremely low birth weight at 12 to 36 hours of age to undergo either aggressive or conservative phototherapy. The primary outcome was a composite of death or neurodevelopmental impairment determined for 91% of the infants by investigators who were unaware of the treatment assignments.Aggressive phototherapy, as compared with conservative phototherapy, significantly reduced the mean peak serum bilirubin level (7.0 vs. 9.8 mg per deciliter [120 vs. 168 micromol per liter], P<0.01) but not the rate of the primary outcome (52% vs. 55%; relative risk, 0.94; 95% confidence interval [CI], 0.87 to 1.02; P=0.15). Aggressive phototherapy did reduce rates of neurodevelopmental impairment (26%, vs. 30% for conservative phototherapy; relative risk, 0.86; 95% CI, 0.74 to 0.99). Rates of death in the aggressive-phototherapy and conservative-phototherapy groups were 24% and 23%, respectively (relative risk, 1.05; 95% CI, 0.90 to 1.22). In preplanned subgroup analyses, the rates of death were 13% with aggressive phototherapy and 14% with conservative phototherapy for infants with a birth weight of 751 to 1000 g and 39% and 34%, respectively (relative risk, 1.13; 95% CI, 0.96 to 1.34), for infants with a birth weight of 501 to 750 g.Aggressive phototherapy did not significantly reduce the rate of death or neurodevelopmental impairment. The rate of neurodevelopmental impairment alone was significantly reduced with aggressive phototherapy. This reduction may be offset by an increase in mortality among infants weighing 501 to 750 g at birth. (ClinicalTrials.gov number, NCT00114543.)

    View details for Web of Science ID 000260454500005

    View details for PubMedID 18971491

    View details for PubMedCentralID PMC2821221

  • Inhibition of heme oxygenase activity in newborn mice by azalanstat CANADIAN JOURNAL OF PHYSIOLOGY AND PHARMACOLOGY Morisawa, T., Wong, R. J., Bhutani, V. K., Vreman, H. J., Stevenson, D. K. 2008; 86 (10): 651-659

    Abstract

    Inhibition of heme oxygenase (HO), the rate-limiting enzyme in heme catabolism, may be an ideal strategy for preventing neonatal jaundice. Although natural and synthetic heme analogs, called metalloporphyrins (Mps), have been extensively investigated for this purpose, some Mps are phototoxic, affect the activity of other enzymes, or induce HO-1 transcription-properties that may limit their clinical use. Another class of compounds, imidazole-dioxolanes, has been shown to selectively inhibit the inducible isozyme HO-1. Therefore, we investigated the efficacy of azalanstat (AZA), an imidazole-dioxolane, towards inhibiting HO activity in 7-day-old mice. We found that a single dose of AZA at 500 micromol.kg(-1) body mass (BM) administered i.p. significantly inhibited HO activity and reduced in vivo bilirubin production. In the spleen, HO inhibition (>50%) was observed within 0.25-3 h after administration. After 24 h, however, spleen HO activity, HO-1 protein, and HO-1 mRNA levels significantly increased 1.2-, 2.4-, and 4.0-fold, respectively. We conclude that AZA effectively inhibits in vivo HO activity only at a high dose and that it also induces spleen HO-1 gene transcription. Therefore, other imidazole-dioxolanes should be evaluated to determine whether they are more potent than AZA for use in treating neonatal jaundice.

    View details for DOI 10.1139/Y08-069

    View details for Web of Science ID 000260168100001

    View details for PubMedID 18841169

  • Regulation of maternal and fetal hemodynamics by heme oxygenase in mice BIOLOGY OF REPRODUCTION Zhao, H., Wong, R. J., Doyle, T. C., Nayak, N., Vreman, H. J., Contag, C. H., Stevenson, D. K. 2008; 78 (4): 744-751

    Abstract

    Heme oxygenase (HMOX) regulates vascular tone and blood pressure through the production of carbon monoxide (CO), a vasodilator derived from the heme degradation pathway. During pregnancy, the maternal circulation undergoes significant adaptations to accommodate the hemodynamic demands of the developing fetus. Our objective was to investigate the role of HMOX on maternal and fetal hemodynamics during pregnancy in a mouse model. We measured and compared maternal tissue and placental HMOX activity and endogenous CO production, represented by excreted CO and carboxyhemoglobin levels, during pregnancy (Embryonic Days 12.5-15.5) to nonpregnant controls. Micro-ultrasound was used to monitor maternal abdominal aorta diameters as well as blood flow velocities and diameters of fetal umbilical arteries. Tin mesoporphyrin, a potent HMOX inhibitor, was used to inhibit HMOX activity. Changes in maternal vascular tone were monitored by tail cuff blood pressure measurements. Effects of HMOX inhibition on placental structures were assessed by histology. We showed that maternal tissue and placental HMOX activity and CO production were significantly elevated during pregnancy. When HMOX in the placenta was inhibited, maternal and fetal hemodynamics underwent significant changes, with maternal blood pressures increasing. We concluded that increases in maternal tissue and placental HMOX activity contribute to the regulation of peripheral vascular resistance and therefore are important for the maintenance of normal maternal vascular tone and fetal hemodynamic functions during pregnancy.

    View details for DOI 10.1095/biolreprod.107.064899

    View details for Web of Science ID 000254217500020

    View details for PubMedID 18094356

  • Management of jaundice and prevention of severe neonatal hyperbilirubinemia in infants >= 35 weeks gestation NEONATOLOGY Bhutani, V. K., Maisels, M. J., Stark, A. R., Buonocore, G. 2008; 94 (1): 63-67

    Abstract

    Kernicterus is still occurring but should be largely preventable if health care personnel follow the recommendations listed in this guideline. These recommendations emphasize the importance of universal, systematic assessment of the risk of severe hyperbilirubinemia, lactation support, close follow-up, and prompt intervention when necessary. A systems-based approach to prevent severe neonatal hyperbilirubinemia should be implemented at all birthing facilities and coordinated with continuing ambulatory care. Translational research is needed to better understand the mechanisms of bilirubin neurotoxicity and potential therapeutic interventions.

    View details for DOI 10.1159/000113463

    View details for Web of Science ID 000256573000011

    View details for PubMedID 18204221

  • Statin treatment increases formation of carbon monoxide and bilirubin in mice: a novel mechanism of in vivo antioxidant protection CANADIAN JOURNAL OF PHYSIOLOGY AND PHARMACOLOGY Muchova, L., Wong, R. J., Hsu, M., Morioka, O., Vitek, L., Zelenka, J., Schroeder, H., Stevenson, D. K. 2007; 85 (8): 800-810

    Abstract

    Heme oxygenase (HO) has a central role in cellular antioxidant defences and vascular protection, and it may mediate pleiotropic actions of drugs used in cardiovascular therapy. We investigated whether long-term use of statins upregulates HO activity and increases carbon monoxide (CO) and bilirubin levels in vivo. Adult FvB mice were given atorvastatin or rosuvastatin (5 mg/kg) daily by i.p. injections for 1, 2, or 3 weeks. HO activity, tissue CO, bilirubin, and antioxidant levels, total plasma bilirubin, and carboxyhemoglobin (COHb) were measured. Fold changes in heart HO activity significantly increased after 1, 2, and 3 weeks of atorvastatin (1.24 +/- 0.06 (p < or = 0.05); 1.29 +/- 0.26 (p < or = 0.03); 1.33 +/- 0.08 (p < 0.01), respectively) and 2 and 3 weeks of rosuvastatin (1.23 +/- 0.20 (p < or = 0.03); 1.63 +/- 0.42 (p < 0.01), respectively). Heart tissue CO and COHb levels also increased after 3 weeks with atorvastatin (1.30 +/- 0.24 (p < or = 0.05); 1.92 +/- 0.17 (p < or = 0.001), respectively) and rosuvastatin (1.47 +/- 0.13 (p < or = 0.004); 1.63 +/- 0.12 (p < or = 0.001), respectively). Significant increases in heart antioxidant levels were observed after statin treatment and corroborated by heart bilirubin content elevations. Antioxidant level increases were abolished by treatment with an HO inhibitor. These findings suggest that the induction of HO and the production of its products, CO and bilirubin, may be a mechanism by which statins exert antioxidant actions and confer cardioprotection in vivo.

    View details for DOI 10.1139/Y07-077

    View details for Web of Science ID 000250261400006

    View details for PubMedID 17901890

  • (TA)(n) UGT 1A1 promoter polymorphism: A crucial factor in the pathophysiology of jaundice in G-6-PD deficient neonates PEDIATRIC RESEARCH Kaplan, M., Renbaum, P., Vreman, H. J., Wong, R. J., Levy-Lahad, E., Hammerman, C., Stevenson, D. K. 2007; 61 (6): 727-731

    Abstract

    Increased heme catabolism has been reported in glucose-6-phosphate dehydrogenase (G-6-PD)-normal neonates who were also homozygous for (TA)7/(TA)7 (UGT1A1*28) uridine diphosphoglucuronate-glucuronosyltransferase 1A1 (UGT) promoter polymorphism (Gilbert syndrome). As G-6-PD deficiency is associated with increased hemolysis, we hypothesized that in G-6-PD-deficient neonates who also have the (TA)7/(TA)7 UGT promoter genotype, steady-state hemolysis would be even further increased. Male G-6-PD-deficient neonates were sampled for plasma total bilirubin (PTB), blood carboxyhemoglobin corrected for inhaled carbon monoxide in ambient air (COHbc) (an index of heme catabolism), and UGT (TA)n promoter genotype determination and compared with previously published G-6-PD-normal neonates. Although COHbc values were higher in the G-6-PD-deficient than in the G-6-PD-normal cohorts (0.97 +/- 0.32% of total Hb (tHb) versus 0.76 +/- 0.19% of tHb, p < 0.001), PTB values were similar (9.2 +/- 3.4 mg/dL versus 8.9 +/- 3.0 mg/dL, respectively, p = 0.3). Within the G-6-PD-deficient group, although COHbc values were alike between the three UGT promoter genotypes, PTB was higher in the (TA)7/(TA)7 homozygotes (11.1 +/- 4.0 mg/dL) compared with (TA)6/(TA)7 heterozygotes (9.1 +/- 3.2 mg/dL, p = 0.03) and wild-type (TA)6/(TA)6 homozygotes (8.8 +/- 3.4 mg/dL, p = 0.02). In the steady state, similar rates of hemolysis, but increased PTB in the G-6-PD- deficient, (TA)7/(TA)7 homozygotes, imply that (TA)7/(TA)7, homozygosity is central to increased PTB.

    View details for DOI 10.1203/pdr.0b013e31805365c5

    View details for Web of Science ID 000246787300019

    View details for PubMedID 17426648

  • The role of Bach1 in the induction of heme oxygenase by tin mesoporphyrin BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS Abate, A., Zhao, H., Wong, R. J., Stevenson, D. K. 2007; 354 (3): 757-763

    Abstract

    Tin mesoporphyrin (SnMP), a competitive heme oxygenase (HO) inhibitor, also induces HO-1 mRNA and protein expression by a mechanism that is not fully understood. We examined whether the induction by SnMP is mediated by a de-repression of Bach1, a transcription factor that suppresses the HO-1 gene. Incubation of NIH3T3-HO-1-luc cells with SnMP attenuated HO activity with a concomitant increase in HO-1 mRNA and protein and a decrease in Bach1 and HO-2 proteins, which was not due to transcriptional down-regulation, but accelerated protein decay. Similarly, HO-1 protein degradation was increased by SnMP, despite of an elevation in HO-1 transcription. Transfection of Bach1 shRNA in Hepa cells raised basal HO-1 expression significantly, and SnMP treatment further increased HO-1 mRNA. In conclusion, SnMP induces HO-1 expression not only by de-repressing the HO-1 promoter by binding Bach1, but also by accelerating Bach1 degradation.

    View details for DOI 10.1016/j.bbrc.2007.01.050

    View details for Web of Science ID 000244284300021

    View details for PubMedID 17257585

  • American Pediatric Society presidential address 2006: Science on the edge with life in the balance PEDIATRIC RESEARCH Stevenson, D. K. 2006; 60 (5): 630-635
  • Expression and regulation of heme oxygenase isozymes in the developing mouse cortex PEDIATRIC RESEARCH Zhao, H., Wong, R. J., Nguyen, X., Kalish, F., Mizobuchi, M., Vreman, H. J., Stevenson, D. K., Contag, C. H. 2006; 60 (5): 518-523

    Abstract

    Heme oxygenase (HO), the rate-limiting enzyme in heme degradation, plays a role in neonatal jaundice. Understanding the regulation of the developmental expression patterns of the two HO isozymes, HO-1 and HO-2, is essential for targeting HO to control pathologic jaundice, and uncovering the fundamental role that they play in mammalian development. Here we characterized the ontogeny of HO-1 and HO-2 expression in the developing mouse cortex by in vivo bioluminescence imaging, quantitative RT-PCR, and Western blot. HO-2, the predominant isoform in the adult cortex, was relatively stable throughout all ages. HO-1 was observed to be progressively down-regulated in an age-related manner. HO-1 expression in the adult cortex was also the lowest among the eight adult tissues analyzed. Because there is a 283-bp CpG island region in the HO-1 promoter, we hypothesized that methylation of the island is responsible for the age-related HO-1 down-regulation in the cortex. Methylation status was assessed using regular and quantitative methylation-specific PCR and the CpG island was found to be hypomethylated at all ages. Therefore, we conclude that HO-1 gene expression in the cortex is developmentally-regulated and that methylation of the HO-1 CpG island is not associated with the down-regulation of the gene.

    View details for DOI 10.1203/01.PDR.0000242374.21415.f5

    View details for Web of Science ID 000241570300003

    View details for PubMedID 16966352

  • Tissue-specific effects of statins on the expression of heme oxygenase-1 in vivo BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS HSU, M., Muchova, L., Morioka, I., Wong, R. J., Schroder, H., Stevenson, D. K. 2006; 343 (3): 738-744

    Abstract

    Heme oxygenase-1 (HO-1) plays a central role in antioxidant and anti-inflammatory actions, which may be mediated through its formation of biliverdin/bilirubin and carbon monoxide. HMG-CoA reductase inhibitors (statins) induce in vitro HO-1 expression and are reported to have pleiotropic benefits that reduce oxidative stress in the vasculature. We characterized the effects of statins on in vivo HO-1 expression in various extravascular tissues: liver, lung, brain, and heart. Adult mice were orally administered simvastatin, lovastatin, atorvastatin, or rosuvastatin. HO activity significantly increased in a statin- and tissue-specific manner, with all statins increasing heart and lung activity within 24 h. Significant elevations of HO-1 protein and mRNA were also observed in heart and lung after atorvastatin treatment. We conclude that in vivo HO-1 induction is statin- and tissue-specific. Through this pathway, statins may confer antioxidant and anti-inflammatory actions in the vasculature and extravascular systems.

    View details for DOI 10.1016/j.bbrc.2006.03.036

    View details for Web of Science ID 000236976800010

    View details for PubMedID 16563347

  • Systemic effects of orally-administered zinc and tin (IV) metalloporphyrins on heme oxygenase expression in mice PEDIATRIC RESEARCH Morioka, I., Wong, R. J., Abate, A., Vreman, H. J., Contag, C. H., Stevenson, D. K. 2006; 59 (5): 667-672

    Abstract

    Some metalloporphyrins (Mps) inhibit heme oxygenase (HO), the rate-limiting enzyme in the production of bilirubin, and are potential compounds for the treatment of neonatal jaundice. We studied the safety and efficacy of Mps following oral administration. Adult HO-1-luc reporter mice were administered 30 micromol/kg body weight of tin mesoporphyrin (SnMP), zinc bis glycol deuteroporphyrin (ZnBG), or zinc protoporphyrin (ZnPP), or vehicle by oral gavage. Bilirubin production was measured as total body carbon monoxide (CO) excretion (VeCO). HO activity was quantitated via CO measurements by gas chromatography. HO-1 protein was determined by Western blot. HO-1 transcription levels were assessed by in vivo bioluminescence imaging. A significant 28% decrease in bilirubin production occurred within 3 h of SnMP treatment and persisted beyond 48 h. Bilirubin production decreased 15% and 9% by 3 h after administration of ZnBG and ZnPP, respectively, but returned to baseline within 48 h. Maximal inhibition of liver, spleen, and intestine HO activity was seen at 3 h with inhibitory effects decreasing in the order: SnMP > or = ZnBG > or = ZnPP. After SnMP treatment, HO-1 transcription increased 5.7-fold after 24 h. Furthermore, liver and spleen HO-1 protein significantly increased 3.7- and 2.0-fold, respectively, after 24 h. HO-1 transcription and protein were not affected in ZnBG- or ZnPP-treated mice. We conclude that the three Mps are absorbed at different rates in the mouse and affect bilirubin production and HO-1 expression in a tissue- and time-dependent manner.

    View details for DOI 10.1203/01.pdr.0000215088.71481.a6

    View details for Web of Science ID 000237003800009

    View details for PubMedID 16627879

  • Transcutaneous bilirubinometry: A noninvasive tool for studying newborn jaundiced rats before and after exposure to light PEDIATRIC RESEARCH Vreman, H. J., Wong, R. J., Chan, M. L., Young, B. W., Stevenson, D. K. 2006; 59 (2): 203-209

    Abstract

    The homozygous Gunn rat is the most frequently used animal model for the study of neonatal jaundice. We evaluated the applicability of noninvasive transcutaneous bilirubin (TcB) measurements as an index of serum total bilirubin (STB) levels in neonatal rats by comparison to invasive STB measurements. TcB measurements were made during the first 96 h of life with the Model 101 Minolta/Air-Shields Jaundice Meter (JM) and SpectRx BiliCheck System (BC). Measurements with both devices displayed parallel TcB profiles, rapidly rising within 24 h, increasing during the next 6 h, then leveling off after 30 h. Linear regressions for the JM (n = 60) were as follows: STB (mg/dL) = 0.79 (JM) - 0.01 (units, r = 0.95, head); STB (mg/dL) = 0.82 (JM) + 1.51 (units, r = 0.95, upper back); and STB (mg/dL) = 0.74 (JM) + 1.60 (units, r = 0.91, lower back). Mean bias +/- imprecision were as follows: -0.02 +/- 3.99 mg/dL, -0.01 +/- 3.90, and 0.01 +/- 4.28 at the head, upper back, and lower back, respectively. For the BC, only lower back measurements were taken, and the regression was as follows: STB (mg/dL) = 0.77 (BC) + 1.65 mg/dL, (r = 0.93, n = 29) with a mean bias +/- imprecision of -1.08 +/- 3.08 mg/dL. When pups were exposed to light, correlations remained strong but intercepts increased. These results demonstrate that noninvasive TcB measurements correlate highly with STB in the Gunn rat during the first 96 h of life and after exposure to light. We conclude that JM measurements at the head and BC at the lower back reflect STB most reliably and consistently. Thus, in addition to being a useful tool for evaluating jaundice in human neonates, TcB methodology can be used successfully for the noninvasive monitoring of jaundice in neonatal Gunn rats pre- and postlight exposure.

    View details for DOI 10.1203/01.pdr.000196737.73851.8a

    View details for Web of Science ID 000234764100008

    View details for PubMedID 16439579

  • The effectiveness of oral tin mesoporphyrin prophylaxis in reducing bilirubin production after an oral heme load in a transgenic mouse model BIOLOGY OF THE NEONATE DeSandre, G. H., Wong, R. J., Morioka, I., Contag, C. H., Stevenson, D. K. 2006; 89 (3): 139-146

    Abstract

    Neonatal jaundice is commonly encountered and rarely associated with morbidity and mortality. Nonetheless, infants with glucose-6-phosphate dehydrogenase deficiency often have hemolysis (a heme load) caused by an environmental oxidant trigger, thus increasing their risk for serious morbidity. The use of tin mesoporphyrin (SnMP) has been proposed for interdicting the development of severe hyperbilirubinemia in a variety of conditions.We studied the in vivo effects of prophylactic oral SnMP on heme oxygenase (HO) activity and bilirubin production, as indexed by the excretion rate of carbon monoxide (VeCO), following a subsequent oral heme load.Adult mice were exposed serially to heme and assessed for in vivo bilirubin production rates, HO-1 transcription and protein, and HO activity. The effect of prophylaxis with a single oral dose of SnMP prior to an oral heme load was assessed by measuring VeCOand tissue HO activities.After serial heme exposures, VeCO, HO-1 transcription and protein, and liver and spleen HO activities increased incrementally. After pretreatment with oral SnMP, bilirubin production decreased in response to an oral heme load. Also, heme-mediated increases in liver, spleen, and intestine HO activities were significantly dampened.A single oral dose of SnMP results in durable inhibition of bilirubin production and HO activity for at least 24 h in a mouse model of oral heme loading. Further studies are needed to fully elucidate the duration of this protection against hyperbilirubinemia due to a delayed heme load and any long-term consequences of prophylaxis with SnMP on HO-1 transcription and HO-1 protein.

    View details for DOI 10.1159/000088717

    View details for Web of Science ID 000235915600001

    View details for PubMedID 16205054

  • Inhaled nitric oxide for premature infants with severe respiratory failure NEW ENGLAND JOURNAL OF MEDICINE Van Meurs, K. P., Wright, L. L., Ehrenkranz, R. A., Lemons, J. A., Ball, M. B., Poole, W. K., Perritt, R., Higgins, R. D., Oh, W., Hudak, M. L., Laptook, A. R., Shankaran, S., Finer, N. N., Carlo, W. A., Kennedy, K. A., Fridriksson, J. H., Steinhorn, R. H., Sokol, G. M., Konduri, G. G., Aschner, J. L., Stoll, B. J., D'Angio, C. T., Stevenson, D. K., Oh, W., Hensman, A., Gingras, D., Stoll, B. J., Jain, L., Hale, E., Seabrook, I., Sokol, G., Lorant, D., Appel, D. D., Miller, L., Chriscinske, D., Attwood, J., Steinhorn, R., Sautel, M., Van Meurs, K., Ball, B., Proud, D., Carlo, W. A., Cosby, S. S., Johnson, R. B., Fridriksson, J., Warner, B., Mersmann, M., Alexander, B., Shively, J., Mincey, H., Hoover, M., Sapienz, S., Stephenson, E., Finer, N. N., Rasmussen, M. R., Henderson, C., Demetrio, C., Rich, W., Joseph, C., Hudak, M., Osbeck, S., Case, E., Kellum, A., Hogans, L., D'Angio, C. T., Reubens, L., Hutton, G., Laptook, A., Madison, S., Hensley, G., Miller, N., Metoyer, G., Kennedy, K., McDavid, G., Emerson, D., Konduri, G., Paquette, M., Wong, S., Aschner, J., O'Shea, T. M., Peters, N., Hansell, B. J., Griffin, J., Adams, C., Shankaran, S., Bara, R. A., Muran, G., Weekfall, W., Ehrenkranz, R. A., Gettner, P., Caldwell, A., Oh, W., Fanaroff, A. A., Goldberg, R. N., Stoll, B. J., Lemons, J. A., Stevenson, D. K., Carlo, W. A., Donovan, E. F., Finer, N. N., Duara, S., Phelps, D. L., Laptook, A. R., TYSON, J. E., O'Shea, T. M., Shankaran, S., Ehrenkranz, R. A., Jobe, A., Poole, W. K., Hastings, B., Petrie, C., Higgins, R. D., Wright, L. L., McClure, E., BULAS, D., Mertens, D., Slovis, T., Avery, G., D'Alton, M., Poole, W. K., Fletcher, J. C., Gleason, C. A., Redmond, C. 2005; 353 (1): 13-22

    Abstract

    Inhaled nitric oxide is a controversial treatment for premature infants with severe respiratory failure. We conducted a multicenter, randomized, blinded, controlled trial to determine whether inhaled nitric oxide reduced the rate of death or bronchopulmonary dysplasia in such infants.We randomly assigned 420 neonates, born at less than 34 weeks of gestation, with a birth weight of 401 to 1500 g, and with respiratory failure more than four hours after treatment with surfactant to receive placebo (simulated flow) or inhaled nitric oxide (5 to 10 ppm). Infants with a response (an increase in the partial pressure of arterial oxygen of more than 10 mm Hg) were weaned according to protocol. Treatment with study gas was discontinued in infants who did not have a response.The rate of death or bronchopulmonary dysplasia was 80 percent in the nitric oxide group, as compared with 82 percent in the placebo group (relative risk, 0.97; 95 percent confidence interval, 0.86 to 1.06; P=0.52), and the rate of bronchopulmonary dysplasia was 60 percent versus 68 percent (relative risk, 0.90; 95 percent confidence interval, 0.75 to 1.08; P=0.26). There were no significant differences in the rates of severe intracranial hemorrhage or periventricular leukomalacia. Post hoc analyses suggest that rates of death and bronchopulmonary dysplasia are reduced for infants with a birth weight greater than 1000 g, whereas infants weighing 1000 g or less who are treated with inhaled nitric oxide have higher mortality and increased rates of severe intracranial hemorrhage.The use of inhaled nitric oxide in critically ill premature infants weighing less than 1500 g does not decrease the rates of death or bronchopulmonary dysplasia. Further trials are required to determine whether inhaled nitric oxide benefits infants with a birth weight of 1000 g or more.

    View details for Web of Science ID 000230267300004

    View details for PubMedID 16000352

  • Monitoring age-related susceptibility of young mice to oral Salmonella enterica serovar typhimurium infection using an in vivo murine model PEDIATRIC RESEARCH Burns-Guydish, S. M., Olomu, I. N., Zhao, H., Wong, R. J., Stevenson, D. K., Contag, C. H. 2005; 58 (1): 153-158

    Abstract

    Neonates and young children are acutely susceptible to infections by gastrointestinal bacterial pathogens, such as Salmonella enterica serovar Typhimurium (S. typhimurium). To reveal age-related differences in susceptibility to this pathogen, we used in vivo bioluminescence imaging (BLI) to monitor the progression of infection in neonatal (1-wk-old), suckling (2-wk-old), juvenile (4-wk-old), and adult (6-wk-old) BALB/c mice. Mice were orally infected with various doses of a bioluminescent-labeled wild-type or mutant S. typhimurium strain, and progression of infection was monitored by BLI for 2 wks. We found that neonatal and suckling mice were more susceptible to the wild-type strain at inoculum sizes 4 and 2 log(10)'s lower for neonatal and suckling mice, respectively, than those for adult mice. At the lower inocula, newborn mice showed disseminated systemic infection as indicated by the pattern of photon emission assessed by BLI, whereas no bioluminescent signals were detectable in adult mice. In addition, an orgA(-) mutant strain of S. typhimurium with reduced virulence in adult mice produced systemic infection in newborn, suckling, and juvenile mice. Furthermore, as low as 3 log(10) CFU could be detected by BLI in tissue. The present study demonstrates that susceptibility to S. typhimurium infection decreases with age. Also, we established that BLI can be used to monitor the progression of infection in mice. Thus, this model of age-related susceptibility to S. typhimurium using BLI can be used to advance our understanding of the mechanisms involved in newborn susceptibility to infection.

    View details for DOI 10.1203/01.PDR.0000157725.44213.C4

    View details for Web of Science ID 000230252200028

    View details for PubMedID 15774831

  • Phototherapy: Current methods and future directions SEMINARS IN PERINATOLOGY Vreman, H. J., Wong, R. J., Stevenson, D. K. 2004; 28 (5): 326-333

    Abstract

    Phototherapy is the most common therapeutic intervention used for the treatment of hyperbilirubinemia. Although it has become a mainstay since its introduction in 1958, a better understanding of the photobiology of bilirubin, characteristics of the phototherapy devices, the efficacy and safety considerations of phototherapy applications, and improvements in spectroradiometers and phototherapy devices are necessary for more predictable and improved clinical practices and outcomes. A step forward in instituting consistent, uniform, and effective use of phototherapy is the recent American Academy of Pediatrics clinical guideline on the management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation, which outlines a clinical strategy for the diagnosis of hyperbilirubinemia and contains direct recommendations for the application of phototherapy. This article reviews the parameters that determine the efficacy of phototherapy, briefly discusses current devices and methods used to deliver phototherapy, and speculates on future directions and studies that are still needed to complement our presently incomplete knowledge of the facets of this common mode of therapy.

    View details for DOI 10.1053/j.semperi.2004.09.003

    View details for Web of Science ID 000226212000003

    View details for PubMedID 15686263

  • A primer on neonatal jaundice. Advances in pediatrics Stevenson, D. K., Wong, R. J., DeSandre, G. H., Vreman, H. J. 2004; 51: 263-288

    View details for PubMedID 15366777

  • Effects of metalloporphyrins on heme oxygenase-1 transcription: correlative cell culture assays guide in vivo imaging. Molecular imaging Hajdena-Dawson, M., Zhang, W., Contag, P. R., Wong, R. J., Vreman, H. J., Stevenson, D. K., Contag, C. H. 2003; 2 (3): 138-149

    Abstract

    Heme oxygenase (HO) is the rate-limiting step in the heme degradation pathway and is a potential target for the control, or prevention, of pathologic jaundice in neonates. Metalloporphyrins (Mps), a diverse set of synthetic derivatives of heme, can competitively inhibit the HO enzymes. However, certain Mps are phototoxic and some increase transcription of HO-1, the inducible HO isozyme. Therefore, effective development of this class of compounds as therapeutics for treating pathologic jaundice will require rapid and integrated biological screens to identify the most efficacious and safe Mps. To study the safety of these compounds, we assessed their cytotoxic effects and measured luciferase activity by bioluminescent imaging (BLI) as an index of HO-1 transcription, first in live cell cultures and then in living transgenic reporter mice. A total of 12 Mps were first evaluated in the correlative cell culture assay. Based on results from this study, 2 Mps, zinc protoporphyrin (ZnPP) and zinc bis glycol porphyrin (ZnBG), were selected for further studies in the live animal model. In vitro BLI showed ZnPP to be a strong inducer of HO-1 transcription in comparison to ZnBG, which showed minimal induction. Cytotoxicity studies revealed that ZnPP was phototoxic, whereas ZnBG had no effect on cell viability. In vivo BLI showed that both ZnPP and ZnBG had minimal effects on the levels of HO-1 transcription in the animals. Furthermore, serum enzyme assays indicated that neither caused detectable liver toxicity. These findings, and especially those with ZnBG, support the use of selected Mps as therapies for pathologic jaundice. Coupling the high throughput advantage of cell culture with the capability of imaging for whole-body temporal analyses could accelerate and refine the preclinical phases of drug development. Thus, this study serves as a model for understanding the effects of specific compounds in relation to defined targets using an integrated approach.

    View details for PubMedID 14649057

  • Heme oxygenase-2 protects against lipid peroxidation-mediated cell loss and impaired motor recovery after traumatic brain injury JOURNAL OF NEUROSCIENCE Chang, E. F., Wong, R. J., Vreman, H. J., Igarashi, T., Galo, E., Sharp, F. R., Stevenson, D. K., Noble-Haeusslein, L. J. 2003; 23 (9): 3689-3696

    Abstract

    After traumatic brain injury (TBI), substantial extracellular heme is released from hemoproteins during hemorrhage and cell injury. Heme oxygenase (HO) isozymes are thought to detoxify the pro-oxidant heme to the potent antioxidant, bilirubin. HO-1, the inducible isozyme, is expressed in glial populations after injury and may play a protective role. However, the role of HO-2, the predominant and constitutively expressed isozyme in the brain, remains unclear after TBI. We used a controlled cortical impact injury model to determine the extent and mechanism of damage between HO-2 knock-out (KO) (-/-) and wild-type (WT) (+/+) mice. The specific cellular and temporal expressions of HO-2 and HO-1 were characterized by immunocytochemistry and Western blots. HO-2 was immunolocalized in neurons both before and after TBI, whereas HO-1 was highly upregulated in glia only after TBI. HO activity determined by gas chromatography using brain sonicates from injured HO-2 KO mice was significantly less than that of HO-2 wild types, despite the induction of HO-1 expression after TBI. Cell loss was significantly greater in KO mice in areas including the cortex, the CA3 region of hippocampus, and the lateral dorsal thalamus. Furthermore, motor recovery after injury, as measured by the rotarod assay and an inclined beam-walking task, was compromised in the KO mice. Finally, brain tissue from injured HO-2 KO mice exhibited decreased ability to reduce oxidative stress, as measured with an Fe(2+)/ascorbic acid-mediated carbon monoxide generation assay for lipid peroxidation susceptibility. These findings demonstrate that HO-2 expression protects neurons against TBI by reducing lipid peroxidation via the catabolism of free heme.

    View details for Web of Science ID 000182700100016

    View details for PubMedID 12736340

  • Selection of potential therapeutics based on in vivo spatiotemporal transcription patterns of heme oxygenase-1 JOURNAL OF MOLECULAR MEDICINE-JMM Zhang, W. S., Contag, P. R., Hardy, J., Zhao, H., Vreman, H. J., Hajdena-Dawson, M., Wong, R. J., Stevenson, D. K., Contag, C. H. 2002; 80 (10): 655-664

    Abstract

    Heme oxygenase (HO), a key catabolic enzyme in the conversion of heme to bilirubin, is an ideal target for reducing bilirubin production and preventing pathological jaundice in newborn infants. Metalloporphyrins (Mps) have been well characterized as competitive inhibitors of HO and have been evaluated as potential chemopreventive agents for neonatal jaundice. However, in addition to reducing HO activity, many Mps have been shown to increase HO-1 transcription, which would likely reduce their potential therapeutic utility. The differential effects of Mps on the transcription of HO-1 were therefore evaluated in living transgenic (Tg) reporter mice. Of the compounds evaluated, we observed that zinc bis-glycol porphyrin (ZnBG), a potent inhibitor of HO enzyme activity, did not alter HO-1 transcription patterns in Tg mice. Whole body images of HO-1 transcription patterns did, however; reveal increases in HO-1 transcription in Tg mice after treatment with other Mps, heme and cadmium chloride (CdCl(2)). Intravenous injections of CdCl(2) resulted in expression patterns that differed in tempo and location from those observed in Tg mice treated with intraperitoneal injections. Spatiotemporal analyses of transcriptional regulation in living animals accelerated the assessment of an adverse effect of Mps by revealing different patterns of HO-1 transcription. Among the known inhibitors of HO enzyme activity that were evaluated in this study, ZnBG did not significantly affect HO-1 transcription and therefore may be well suited for the prevention of neonatal jaundice.

    View details for DOI 10.1007/s00109-002-0375-x

    View details for Web of Science ID 000179446600007

    View details for PubMedID 12395150

  • Carbon monoxide and bilirubin production in neonates SEMINARS IN PERINATOLOGY Stevenson, D. K., Vreman, H. J., Wong, R. J., Contag, C. H. 2001; 25 (2): 85-93

    Abstract

    Neonatal hyperbilirubinemia is a normal postnatal phenomenon resulting from a transitional imbalance between the production and elimination of bilirubin in the neonate. Bilirubin has been shown to be not only a potent antioxidant, but also toxic at excessive concentrations. As a result, the biology of bilirubin, its production, regulation, and measurements have been the focus of extensive studies. Bilirubin, carbon monoxide, and iron are derived from the degradation of heme, a ubiquitous two-step pathway catalyzed by the enzyme, heme oxygenase. It has been shown that these metabolically active products from the heme catabolic pathway may, in turn, influence many other biologic processes. This report provides a brief overview of these interrelationships in the hope that it may provide insight into the central role this pathway plays in the existence of most organisms.

    View details for Web of Science ID 000168272000008

    View details for PubMedID 11339670

  • FETAL HEMOGLOBIN OF TRANSFUSED NEONATES AND SPECTROPHOTOMETRIC MEASUREMENTS OF OXYHEMOGLOBIN AND CARBOXYHEMOGLOBIN JOURNAL OF CLINICAL MONITORING Mahoney, J. J., Wong, R. J., Vreman, H. J., Stevenson, D. K. 1991; 7 (2): 154-160

    Abstract

    The records of 32 neonates in an intensive care unit were examined retrospectively to determine if fetal hemoglobin concentrations could be predicted on the basis of gestational or postnatal age, or on the volume of red blood cell transfusions. In nontransfused neonates, the correlation between measured concentrations of fetal hemoglobin and post-natal age was r = 0.53 with a 17.2 standard error of prediction. In these same neonates, the correlation between measured fetal hemoglobin divided by birth weight and gestational age was r = 0.70, with a 9.6 standard error of prediction. A three-variable regression equation (the latter two variables plus calculated fetal hemoglobin) was found to have a high correlation with data for measured fetal hemoglobin (r = 0.97) and a relatively low 8.4 standard error of prediction. In transfused neonates, however, measured hemoglobin concentrations divided by birth weight correlated poorly with gestational age (r = 0.30 and a 12.4 standard error of prediction). In addition, the transfused neonates had low correlations when fetal hemoglobin concentrations alone were compared with the total volume of red blood cell transfusions (r = 0.35) and with postnatal age (r = 0.18) and the standard errors of prediction were all approximately 17. The correlations found between concentrations of fetal hemoglobin and age in transfused neonates were poorer than those reported in earlier nontransfused infant studies. Previous studies have also shown that neonatal blood containing fetal hemoglobin interferes with the spectrophotometric measurements of carboxyhemoglobin and oxyhemoglobin. Because of the imprecision in the predictions of fetal hemoglobin using age, weight, or the volume of transfusion, we conclude that fetal hemoglobin should be measured if accurate spectrophotometric determinations of carboxyhemoglobin and oxyhemoglobin are desired.

    View details for Web of Science ID A1991FH21600004

    View details for PubMedID 1712833

  • PULMONARY EXCRETION OF CARBON-MONOXIDE IN THE HUMAN INFANT AS AN INDEX OF BILIRUBIN PRODUCTION .4. EFFECTS OF BREAST-FEEDING AND CALORIC-INTAKE IN THE 1ST POSTNATAL WEEK PEDIATRICS Stevenson, D. K., BARTOLETTI, A. L., OSTRANDER, C. R., Johnson, J. D. 1980; 65 (6): 1170-1172

    Abstract

    Measurements of the pulmonary excretion rate of carbon monoxide (VEco) as an index of bilirubin production in the first several days of life were taken from 64 breast-fed or bottle-fed infants. Twenty-one infants (greater than or equal to 37 weeks of gestation) were breast-fed; 43 infants (28 to 42 weeks of gestation) were bottle-fed a commercially prepared formula. Information pertaining to their caloric intake during the 24-hour period preceding VEco determination was taken from 38 of the 43 infants who were bottle-fed and they were placed into three groups based on their caloric intake: (1) less than or equal to 60 kcal/kg/day (19 infants); (2) 61 to 100 kcal/kg/day (7 infants); and (3) greater than 100 kcal/kg/day (12 infants). There was no significant difference in bilirubin production between bottle-fed and breast-fed infants. No effect of caloric deprivation on bilirubin production was demonstrated. The mean VEco values were 18.5 +/- 0.9 (SE) for group 1, 17.7 +/- 1.8 (SE) for group 2, and 16.2 +/- 1.1 (SE) microliter/kg/hr for group 3.

    View details for Web of Science ID A1980JU73500024

    View details for PubMedID 7375244

  • PULMONARY EXCRETION OF CARBON-MONOXIDE IN THE HUMAN INFANT AS AN INDEX OF BILIRUBIN PRODUCTION .1. EFFECTS OF GESTATIONAL AND POSTNATAL AGE AND SOME COMMON NEONATAL ABNORMALITIES JOURNAL OF PEDIATRICS BARTOLETTI, A. L., Stevenson, D. K., OSTRANDER, C. R., Johnson, J. D. 1979; 94 (6): 952-955

    Abstract

    Using a single pass, flow-through system, the pulmonary excretion rate of endogenously produced carbon monoxide was measured as an index of bilirubin production in human infants with varying gestational and postnatal ages and with a variety of clinical abnormalities. No significant difference in VECO was found related to sex or gestational age. The mean VECO for a small group of Oriental infants was significantly increased. VECO decreased with increasing postnatal age. As expected, infants with hemolytic disease of the newborn had a markedly increased mean VECO. Infants with jaundice of unknown etiology also had an elevated mean VECO, implying that increased bilirubin production may be a factor contributing to the "nonphysiologic" bilirubinemias of these infants.

    View details for Web of Science ID A1979GX74400030

    View details for PubMedID 448544

  • PULMONARY EXCRETION OF CARBON-MONOXIDE IN THE HUMAN NEWBORN-INFANT AS AN INDEX OF BILIRUBIN PRODUCTION .3. MEASUREMENT OF PULMONARY EXCRETION OF CARBON-MONOXIDE AFTER THE 1ST POSTNATAL WEEK IN PREMATURE-INFANTS PEDIATRICS Stevenson, D. K., BARTOLETTI, A. L., OSTRANDER, C. R., Johnson, J. D. 1979; 64 (5): 598-600

    Abstract

    Using a single pass, flow-through system, the excretion rate of endogenously produced carbon monoxide (VeCO) was measured as an index of bilirubin production in 41 Caucasian infants of various gestational ages after the first postnatal week. twenty-one were less than or equal to 32 weeks gestation. The mean slope for the 25 premature infants with multiple VeCO determinations was -0.21 +/- 0.11 (SE) microliters/kg/hour per day (P less than .025, one-tailed). Fifteen premature infants with at least three VeCO determinations during the first 30 days of life had an average decrease in total CO excreted of 1.33% per day compared to the extrapolated initial value of total CO excretion of 27.0 +/- 2.0 (SE) microliters/hour, giving a calculated maximum red cell life span of 75 days.

    View details for Web of Science ID A1979HT50800008

    View details for PubMedID 492832

  • In Vitro Study on the Effect of Maraviroc or Dolutegravir on Bilirubin to Albumin Binding PEDIATRIC INFECTIOUS DISEASE JOURNAL Schreiner, C. N., Ahlfors, C. E., Wong, R. J., Stevenson, D. K., Clarke, D. F., Mirochnick, M. 2018; 37 (9): 908–9

    Abstract

    We performed an in vitro evaluation of the effect of maraviroc or dolutegravir on bilirubin to albumin binding. At typical treatment and low albumin concentrations, maraviroc had no impact, while dolutegravir affected bilirubin to albumin binding to an equivalent extent as sulfisoxazole. However in vivo, neither is likely to significantly impact bilirubin to albumin binding because of their low concentrations relative to albumin.

    View details for DOI 10.1097/INF.0000000000002011

    View details for Web of Science ID 000442508900016

    View details for PubMedID 29561509

  • Extreme Preterm Infant Rates of Overweight and Obesity at School Age in the SUPPORT Neuroimaging and Neurodevelopmental Outcomes Cohort. The Journal of pediatrics Vohr, B. R., Heyne, R., Bann, C. M., Das, A., Higgins, R. D., Hintz, S. R., Eunice Kennedy Shriver National Institute of Child Health, a. D., Jobe, A. H., Caplan, M. S., Polin, R. A., Laptook, A. R., Hensman, A. M., McGowan, E. C., Vieira, E., Little, E., Johnson, K., Alksninis, B., Keszler, M. L., Knoll, A. M., Leach, T. M., Watson, V. E., Walsh, M. C., Fanaroff, A. A., Wilson-Costello, D. E., Payne, A., Newman, N. S., Taylor, H. G., Siner, B. S., Zadell, A., DiFiore, J., Bhola, M., Friedman, H. G., Yalcinkaya, G., Bulas, D., Goldberg, R. N., Cotten, C. M., Goldstein, R. F., Gustafson, K. E., Ashley, P., Auten, K. J., Fisher, K. A., Foy, K. A., Freedman, S. F., Lohmeyer, M. B., Malcolm, W. F., Wallace, D. K., Carlton, D. P., Stoll, B. J., Adams-Chapman, I., Buchter, S., Piazza, A. J., Carter, Fritz, S., Hale, E. C., Hutchinson, A. K., LaRossa, M. M., Loggins, Y., Bottcher, D., Archer, S. W., Poindexter, B. B., Sokol, G. M., Harmon, H. M., Papile, L., Hines, A. C., Wilson, L. D., Herron, D. E., Smiley, L., Kennedy, K. A., Tyson, J. E., Duncan, A. F., Dempsey, A. G., John, J., Jones, P. M., Lillie, M. L., Siddiki, S., Sperry, D. K., Berberich, M. A., Blaisdell, C. J., Gail, D. B., Kiley, J. P., Wallace, D., Gantz, M. G., Newman, J. E., Auman, J. O., Hammond, J. A., Poole, W. K., Van Meurs, K. P., Stevenson, D. K., DeAnda, M. E., Ball, M. B., Goodlin, G. T., Frantz, I. D., Fiascone, J. M., McGowan, E. C., Furey, A., MacKinnon, B. L., Nylen, E., Brussa, A., Sibley, C., Carlo, W. A., Ambalavanan, N., Peralta-Carcelen, M., Collins, M. V., Cosby, S. S., Phillips, V. A., Bailey, K. J., Biasini, F. J., Hopkins, M., Johnston, K. C., Nelson, K. G., Patterson, C. S., Rector, R. V., Rodriguez, L., Soong, A., Whitley, S., York, S., Guest, K., Smith, L. A., Finer, N. N., Garey, D., Rasmussen, M. R., Wozniak, P. R., Vaucher, Y. E., Fuller, M. G., Akshoomoff, N., Rich, W., Arnell, K., Bridge, R., Bell, E. F., Colaizy, T. T., Widness, J. A., Klein, J. M., Johnson, K. J., Acarregui, M. J., Eastman, D. L., Wilgenbusch, T. L., Watterberg, K. L., Ohls, R. K., Fuller, J., Lowe, J., Rohr, J., Lacy, C. B., Montman, R., Brown, S., Sanchez, P. J., Rosenfeld, C. R., Salhab, W. A., Brion, L., Adams, S. S., Allen, J., Grau, L., Guzman, A., Hensley, G., Heyne, E. T., Hickman, J. F., Leps, M. H., Madden, L. A., Martin, M., Miller, N. A., Morgan, J. S., Solis, A., Lee, L. E., Boatman, C. T., Vasil, D. M., Yoder, B. A., Faix, R. G., Winter, S., Baker, S., Osborne, K. A., Rau, C. A., Cunningham, S., Ford, A., Shankaran, S., Pappas, A., Sood, B. G., Bara, R., Slovis, T. L., Billian, E., Goldston, L. A., Johnson, M. 2018; 200: 132

    Abstract

    OBJECTIVE: To identify rates of overweight (body mass index [BMI] ≥85th percentile) and obesity (BMI ≥95th percentile) at 6-7 years of age and associated risk factors among extremely preterm infants born at<28 weeks of gestation.STUDY DESIGN: Anthropometrics, blood pressure, and active and sedentary activity levels were prospectively assessed. Three groups were compared, those with a BMI ≥85th percentile (overweight or obese for age, height, and sex) and ≥95th percentile (obese) vs <85th percentile. Multiple regression analyses estimated the relative risks of BMI ≥85th percentile and ≥95th percentile associated with perinatal and early childhood factors.RESULTS: Of 388 children, 22% had a BMI of ≥85th percentile and 10% were obese. Children with obesity and overweight compared with normal weight children had higher body fat (subscapular skinfold and triceps skinfold >85th percentile), central fat (waist circumference >90th percentile), spent more time in sedentary activity (20.5 vs 18.2 vs 16.7 hours/week), and had either systolic and/or diastolic hypertension (24% vs 26% vs 14%), respectively. Postdischarge weight gain velocities from 36 weeks postmenstrual age to 18 months, and 18 months to 6-7 years were independently associated with a BMI of ≥85th percentile, whereas weight gain velocity from 18 months to 6-7 years was associated with obesity.CONCLUSIONS: One in 5 former extremely preterm infants is overweight or obese and has central obesity at early school age. Postdischarge weight gain velocities were associated with overweight and obesity. These findings suggest the obesity epidemic is spreading to the most extremely preterm infants.TRIAL REGISTRATION: ClinicalTrials.gov: NCT00063063 and NCT0000.

    View details for DOI 10.1016/j.jpeds.2018.04.073

    View details for PubMedID 29793869

  • Prediction of preterm birth with and without preeclampsia using mid-pregnancy immune and growth-related molecular factors and maternal characteristics JOURNAL OF PERINATOLOGY Jelliffe-Pawlowski, L. L., Rand, L., Bedell, B., Baer, R. J., Oltmann, S. P., Norton, M. E., Shaw, G. M., Stevenson, D. K., Murray, J. C., Ryckman, K. K. 2018; 38 (8): 963–72

    Abstract

    To evaluate if mid-pregnancy immune and growth-related molecular factors predict preterm birth (PTB) with and without (±) preeclampsia.Included were 400 women with singleton deliveries in California in 2009-2010 (200 PTB and 200 term) divided into training and testing samples at a 2:1 ratio. Sixty-three markers were tested in 15-20 serum samples using multiplex technology. Linear discriminate analysis was used to create a discriminate function. Model performance was assessed using area under the receiver operating characteristic curve (AUC).Twenty-five serum biomarkers along with maternal age <34 years and poverty status identified >80% of women with PTB ± preeclampsia with best performance in women with preterm preeclampsia (AUC = 0.889, 95% confidence interval (0.822-0.959) training; 0.883 (0.804-0.963) testing).Together with maternal age and poverty status, mid-pregnancy immune and growth factors reliably identified most women who went on to have a PTB ± preeclampsia.

    View details for DOI 10.1038/s41372-018-0112-0

    View details for Web of Science ID 000441447700004

    View details for PubMedID 29795450

    View details for PubMedCentralID PMC6089890

  • The uncertain fate of the National Institutes of Health (NIH) pediatric research portfolio: In support of an investment strategy to improve the public health of the nation through perinatal research. Pediatric research Stevenson, D. K., Shaw, G. M., Katz, M. 2018

    View details for DOI 10.1038/s41390-018-0036-6

    View details for PubMedID 29976966

  • Prediction of preterm birth with and without preeclampsia using mid-pregnancy immune and growth-related molecular factors and maternal characteristics (vol 38, pg 946, 2018) JOURNAL OF PERINATOLOGY Jelliffe-Pawlowski, L. L., Rand, L., Bedell, B., Baer, R. J., Oltman, S. P., Norton, M. E., Shaw, G. M., Stevenson, D. K., Murray, J. C., Ryckman, K. K. 2018; 38 (7): 946

    Abstract

    This Article was originally published under Nature Research's License to Publish, but has nowbeen made available under a [CC BY 4.0] license. The PDF and HTML versions of the Articlehave been modified accordingly.

    View details for DOI 10.1038/s41372-018-0158-z

    View details for Web of Science ID 000440337800027

    View details for PubMedID 29941898

  • Failed umbilical artery catheterization and adverse outcomes in extremely low birth weight infants. The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians Wallenstein, M. B., Shaw, G. M., Yang, W., Stevenson, D. K. 2018: 1–5

    Abstract

    PURPOSE: To determine whether successful catheterization of the umbilical artery is associated with a reduced risk of death or neurodevelopment impairment among critically ill extremely low birth weight (ELBW) infants.STUDY DESIGN: A retrospective chart review was conducted between 2007 and 2014 at Stanford University for all ELBW infants that required intubation immediately after birth. The primary outcome was death or neurodevelopmental impairment at 18-22 months. We measured the association of successful umbilical artery catheterization with the primary outcome using multivariable logistic regression with adjustment for gestational age. Bayesian analysis was also performed due to small sample size.RESULTS: Eighty-four ELBW infants met inclusion criteria. Successful umbilical artery catheterization occurred in 88% of infants and failed catheterization in 12%. Death or neurodevelopmental impairment occurred in 41% of infants with successful catheterization, compared to 60% of infants with failed catheterization of the umbilical artery, adjusted odds ratio 0.3, 95% confidence interval 0.1-1.3, p=.11. The Bayesian analysis indicated a 92% posterior probability of reduced death or neurodevelopmental impairment with successful catheterization and a 68% posterior probability of reduced death or neurodevelopmental by absolute risk difference of 20% or more, adjusted relative risk 0.74, 95% confidence interval 0.45-1.14.CONCLUSIONS: Among critically ill ELBW infants, successful catheterization of the umbilical artery compared to failed catheterization was not statistically significantly associated with the primary outcome. However, the Bayesian analysis indicated a high likelihood of benefit associated with successful umbilical artery catheterization.

    View details for DOI 10.1080/14767058.2018.1468430

    View details for PubMedID 29681181

  • Occurrence of Selected Structural Birth Defects Among Women With Preeclampsia and Other Hypertensive Disorders AMERICAN JOURNAL OF EPIDEMIOLOGY Weber, K. A., Mayo, J. A., Carmichael, S. L., Stevenson, D. K., Winn, V. D., Shaw, G. M. 2018; 187 (4): 668–76

    Abstract

    To explore a potential association between preeclampsia and selected birth defects, we examined the prevalence of certain birth defects among women with hypertensive disorders including preeclampsia. We analyzed data from 2,499,536 singleton live births in California from 2007 to 2011, including maternal and infant demographics from birth certificates as well as clinical details from delivery hospitalization records. We examined defect groups that were recognizable at birth (e.g., spina bifida and cleft lip). Hypertensive disorders included preexisting hypertension, gestational hypertension, mild preeclampsia, severe preeclampsia/eclampsia, and preeclampsia superimposed on preexisting hypertension. Relative risk values with 95% confidence intervals for each birth defect were calculated by hypertensive group, as well as independent and joint associations of hypertensive and diabetic disorders. Risks of each type of birth defect were higher among offspring of women with hypertensive disorders compared with those without. The risks of birth defects among offspring of women with only a hypertensive disorder were significantly higher than that among women with neither hypertensive nor diabetic disorders (relative risks ranged from 1.37 to 2.77). Risks of birth defects were highest among those born to women with both hypertensive and diabetic disorders compared with those with neither (relative risks ranged from 1.80 to 6.22). These findings support the existence of an association between preeclampsia and certain birth defects and suggest that diabetes may be a contributing factor.

    View details for DOI 10.1093/aje/kwx269

    View details for Web of Science ID 000428867400005

    View details for PubMedID 29020134

  • Antecedents and Outcomes of Abnormal Cranial Imaging in Moderately Preterm Infants JOURNAL OF PEDIATRICS Natarajan, G., Shankaran, S., Saha, S., Laptook, A., Das, A., Higgins, R., Stoll, B. J., Bell, E. F., Carlo, W. A., D'Angio, C., DeMauro, S. B., Sanchez, P., Van Meurs, K., Vohr, B., Newman, N., Hale, E., Walsh, M., Eunice Kennedy Shriver Natl Inst C 2018; 195: 66-+

    Abstract

    To describe the frequency and findings of cranial imaging in moderately preterm infants (born at 290/7-336/7 weeks of gestation) across centers, and to examine the association between abnormal imaging and clinical characteristics.We used data from the Neonatal Research Network Moderately Preterm Registry, including the most severe early (≤28 days) and late (>28 days) cranial imaging. Stepwise logistic regression and CART analysis were performed after adjustment for gestational age, antenatal steroid use, and center.Among 7021 infants, 4184 (60%) underwent cranial imaging. These infants had lower gestational ages and birth weights and higher rates of small for gestational age, outborn birth, cesarean delivery, neonatal resuscitation, and treatment with surfactant, compared with those without imaging (P < .0001). Imaging abnormalities noted in 15% of the infants included any intracranial hemorrhage (13.2%), grades 3-4 intracranial hemorrhage (1.7%), cystic periventricular leukomalacia (2.6%), and ventriculomegaly (6.6%). Histologic chorioamnionitis (OR, 1.47; 95% CI, 1.19-1.83), gestational age (0.95; 95% CI, 0.94-0.97), antenatal steroids (OR, 0.55; 95% CI, 0.41-0.74), and cesarean delivery (OR, 0.66; 95% CI, 0.53-0.81) were associated with abnormal imaging. The center with the highest rate of cranial imaging, compared with the lowest, had a higher risk of abnormal imaging (OR, 2.08; 95% CI, 1.10-3.92). On the classification and regression-tree model, cesarean delivery, center, antenatal steroids, and chorioamnionitis, in that order, predicted abnormal imaging.Among the 60% of moderately preterm infants with cranial imaging, 15% had intracranial hemorrhage, cystic periventricular leukomalacia or late ventriculomegaly. Further correlation of imaging and long-term neurodevelopmental outcomes in moderately preterm infants is needed.

    View details for DOI 10.1016/j.jpeds.2017.11.036

    View details for Web of Science ID 000428232400014

    View details for PubMedID 29395186

    View details for PubMedCentralID PMC5869095

  • Delivery Room Resuscitation and Short-Term Outcomes in Moderately Preterm Infants JOURNAL OF PEDIATRICS Bajaj, M., Natarajan, G., Shankaran, S., Wyckoff, M., Laptook, A. R., Bell, E. F., Stoll, B. J., Carlo, W. A., Vohr, B. R., Saha, S., Van Meurs, K. P., Sanchez, P. J., D'Angio, C. T., Higgins, R. D., Das, A., Newman, N., Walsh, M. C., Eunice Kennedy Shriver 2018; 195: 33-+

    Abstract

    To describe the frequency and extent of delivery room resuscitation and evaluate the association of delivery room resuscitation with neonatal outcomes in moderately preterm (MPT) infants.This was an observational cohort study of MPT infants delivered at 290/7 to 336/7 weeks' gestational age (GA) enrolled in the Neonatal Research Network MPT registry. Infants were categorized into 5 groups based on the highest level of delivery room intervention: routine care, oxygen and/or continuous positive airway pressure, bag and mask ventilation, endotracheal intubation, and cardiopulmonary resuscitation including chest compressions and/or epinephrine use. The association of antepartum and intrapartum risk factors and discharge outcomes with the intensity of resuscitation was evaluated.Of 7014 included infants, 1684 (24.0%) received routine care and no additional resuscitation, 2279 (32.5%) received oxygen or continuous positive airway pressure, 1831 (26.1%) received bag and mask ventilation, 1034 (14.7%) underwent endotracheal intubation, and 186 (2.7%) received cardiopulmonary resuscitation. Among the antepartum and intrapartum factors, increasing GA, any exposure to antenatal steroids and prolonged rupture of membranes decreased the likelihood of receipt of all levels of resuscitation. Infants who were small for GA (SGA) had increased risk of delivery room resuscitation. Among the neonatal outcomes, respiratory support at 28 days, days to full oral feeds and length of stay were significantly associated with the intensity of delivery room resuscitation. Higher intensity of resuscitation was associated with increased risk of mortality.The majority of MPT infants receive some level of delivery room resuscitation. Increased intensity of delivery room interventions was associated with prolonged respiratory and nutritional support, increased mortality, and a longer length of stay.

    View details for DOI 10.1016/j.jpeds.2017.11.039

    View details for Web of Science ID 000428232400008

    View details for PubMedID 29306493

    View details for PubMedCentralID PMC5869086

  • Outcome of Preterm Infants with Transient Cystic Periventricular Leukomalacia on Serial Cranial Imaging Up to Term Equivalent Age JOURNAL OF PEDIATRICS Sarkar, S., Shankaran, S., Barks, J., Do, B. T., Laptook, A. R., Das, A., Ambalavanan, N., Van Meurs, K. P., Bell, E. F., Sanchez, P. J., Hintz, S. R., Wyckoff, M. H., Stoll, B. J., Carlo, W. A., Eunice Kennedy Shriver Natl Inst C 2018; 195: 59-+

    Abstract

    To determine the outcome of preterm infants whose cystic periventricular leukomalacia "disappeared" on serial screening cranial imaging studies.Infants ≤26 weeks of gestation born between 2002 and 2012 who had cranial imaging studies at least twice, the most abnormal study at <28 days of age and another closest to 36 weeks, were reviewed. The outcome of late death (after 36 weeks postmenstrual age) or neurodevelopmental impairment (NDI) in surviving infants at 18-26 months corrected age was compared between the infants with no cystic periventricular leukomalacia on both studies and cystic periventricular leukomalacia that disappeared (cystic periventricular leukomalacia at <28 days but not at 36 weeks), persisted (cystic periventricular leukomalacia on both studies), or appeared late (cystic periventricular leukomalacia only at 36 weeks). Predictors of NDI were evaluated by logistic regression.Of 7063 eligible infants, 433 (6.1%) had cystic periventricular leukomalacia. Among the 433 infants with cystic periventricular leukomalacia, cystic periventricular leukomalacia disappeared in 76 (18%), persisted in 87 (20%), and 270 (62%) had late cystic periventricular leukomalacia. Loss to follow-up ranged between 3% and 13%. Death or NDI was more common in infants with disappeared cystic periventricular leukomalacia compared with those with no cystic periventricular leukomalacia (38 of 72 [53%] vs 1776 of 6376 [28%]; OR [95% CI] 2.8 [1.8-4.6]). Disappeared, persistent, and late cystic periventricular leukomalacia were all also independently associated with NDI (OR 1.17, 1.21, and 1.16, respectively).Infants with "disappeared" cystic periventricular leukomalacia are at increased risk of adverse outcome similar to infants with persistent or late cystic periventricular leukomalacia.

    View details for DOI 10.1016/j.jpeds.2017.12.010

    View details for Web of Science ID 000428232400012

    View details for PubMedID 29398046

  • A directory for neonatal intensive care: potential for facilitating network-based research in neonatology. Journal of perinatology : official journal of the California Perinatal Association Ariagno, R. L., Lee, H. C., Stevenson, D. K., Benjamin, D. K., Smith, P. B., Escobedo, M. B., Bhatt, D. R. 2018

    Abstract

    Directories of contact information have evolved over time from thick paperback times such as the "Yellow Pages" to electronic forms that are searchable and have other functionalities. In our clinical specialty, the development of a professional directory helped to promote collaboration in clinical care, education, and quality improvement. However, there are opportunities for increasing the utility of the directory by taking advantage of modern web-based tools, and expanding the use of the directory to fill a gap in the area of collaborative research.

    View details for DOI 10.1038/s41372-018-0097-8

    View details for PubMedID 29545621

  • Maternal Height and Risk of Preeclampsia. Maric, I., Mayo, J. A., Druzin, M. L., Wong, R. J., Winn, V. D., Stevenson, D. K., Shaw, G. M. SAGE PUBLICATIONS INC. 2018: 207A–208A
  • Heme Oxygenase-1 Deficiency Results in T-Cell Dysregulation in Offspring of Mothers Exposed to Late Gestational Inflammation Ozen, M., Zhao, H., Kalish, F., Yang, Y., Wong, R. J., Stevenson, D. K. SAGE PUBLICATIONS INC. 2018: 248A–249A
  • Pravastatin Induces Heme Oxygenase Activity and Enhances Placental Development in a Murine Model. Tsur, A., Kalish, F., Burgess, J., Zhao, H., Casey, K. M., Druzin, M. L., Wong, R. J., Stevenson, D. K. SAGE PUBLICATIONS INC. 2018: 155A–156A
  • The Effects of Hypoxia and Progesterone/Estrogen on Polarized Macrophages In Vitro. Zhao, H., Kalish, F., Wong, R. J., Stevenson, D. K. SAGE PUBLICATIONS INC. 2018: 301A–302A
  • Mass Cytometry and Proteomic Based Prediction of the Onset of Labor. Ando, K., Han, X., Ghaemi, S., Tsai, A., Ganio, E., Gaudilliere, D., Culos, T., Shaw, G., Wong, R., Stevenson, D., Carvalho, B., Tingle, M., Angst, M., Aghaeepor, N., Gaudilliere, B., Stanford March Dimes Prematurity SAGE PUBLICATIONS INC. 2018: 153A
  • Pravastatin improves pregnancy outcome and placental development in heme oxygenase-1 deficient mice Tsur, A., Kalish, F., Burgess, J., Zhao, H., Casey, K., Druzin, M. L., Wong, R. J., Stevenson, D. K. MOSBY-ELSEVIER. 2018: S202
  • EXPOSURE TO ISOFLURANE INCREASES BILIRUBIN PRODUCTION IN NEWBORN MICE Burgess, J., Iwatani, S., Kalish, F., Onderdonk, Z., Zehnder, V. K., Vreman, H. J., Wong, R. J., Stevenson, D. K. BMJ PUBLISHING GROUP. 2018: 204–5
  • TREATMENT WITH PRAVASTATIN IMPROVES PREGNANCY OUTCOME AND PLACENTAL DEVELOPMENT IN HEME OXYGENASE-1-DEFICIENT MICE Tsur, A., Kalish, F., Burgess, J., Zhao, H., Casey, K. M., Druzin, M. L., Wong, R. J., Stevenson, D. K. BMJ PUBLISHING GROUP. 2018: 241–42
  • Out-of-hospital births in California 1991-2011 JOURNAL OF PERINATOLOGY Girsen, A. I., Mayo, J. A., Lyell, D. J., Blumenfeld, Y. J., Stevenson, D. K., El-Sayed, Y. Y., Shaw, G. M., Druzin, M. L., Stanford Univ Sch Med 2018; 38 (1): 41–45

    Abstract

    We investigated the frequencies and characteristics of out-of-hospital births in a 20-year period in California, where 1 of every 7 births in the United States occurs.Birth certificate records of deliveries in California between 1991 and 2011 were analyzed. Out-of-hospital births were assessed by year, parity, gestational age and maternal race/ethnicity.In the 20-year period there were 10 593,904 deliveries, of which 46 243 occurred out of hospital (0.44%). Out-of-hospital births decreased from 0.54 to 0.38% per year between 1991 and 2004, and increased from 0.41% in 2005 to 0.61% in 2011. In contrast, preterm out-of-hospital births declined from 7.2% in 2006 to 5.0% in 2011. The frequency of vaginal birth after cesarean in the out-of-hospital birth cohort increased from 1.2% (n=19) in 1996 to 4.2% (n=82) in 2011.California birth records from a 20-year period show an increase in out-of-hospital births from years 2005 to 2011, following a period of decline from 1991 to 2004.

    View details for DOI 10.1038/jp.2017.156

    View details for Web of Science ID 000422835200008

    View details for PubMedID 29120453

  • Residential Agricultural Pesticide Exposures and Risks of Spontaneous Preterm Birth EPIDEMIOLOGY Shaw, G. M., Yang, W., Roberts, E. M., Kegley, S. E., Stevenson, D. K., Carmichael, S. L., English, P. B. 2018; 29 (1): 8–21

    Abstract

    Pesticides exposures are aspects of the human exposome that have not been sufficiently studied for their contribution to risk for preterm birth. We investigated risks of spontaneous preterm birth from potential residential exposures to 543 individual chemicals and 69 physicochemical groupings that were applied in the San Joaquin Valley of California during the study period, 1998-2011.The study population was derived from birth certificate data linked with Office of Statewide Health Planning and Development maternal and infant hospital discharge data. After exclusions, the analytic study base included 197,461 term control births and 27,913 preterm case births. Preterm cases were more narrowly defined as 20-23 weeks (n = 515), 24-27 weeks (n = 1,792), 28-31 weeks (n = 3,098), or 32-36 weeks (n = 22,508).The frequency of any (versus none) pesticide exposure was uniformly lower in each preterm case group relative to the frequency in term controls, irrespective of gestational month of exposure. All odds ratios were below 1.0 for these any versus no exposure comparisons. The majority of odds ratios were below 1.0, many of them statistically precise, for preterm birth and exposures to specific chemical groups or chemicals.This study showed a general lack of increased risk of preterm birth associated with a range of agriculture pesticide exposures near women's residences.

    View details for DOI 10.1097/EDE.0000000000000758

    View details for Web of Science ID 000417683700009

    View details for PubMedID 28926371

    View details for PubMedCentralID PMC5718919

  • A candidate gene analysis of very low birth weight infants with clinical chorioamnionitis Spiegel, A. M., Li, J., Oehlert, J. W., Mayo, J. A., Quaintance, C. C., Druzin, M. L., El-Sayed, Y. Y., Stevenson, D. K., Shaw, G. M., Gibbs, R. S. MOSBY-ELSEVIER. 2017: 721
  • Nulliparous teenagers and preterm birth in California JOURNAL OF PERINATAL MEDICINE Mayo, J. A., Shachar, B., Stevenson, D. K., Shaw, G. M. 2017; 45 (8): 959–67

    Abstract

    Young maternal age is one of the numerous risk factors for delivery before 37 weeks of gestation, yet the mechanisms are unclear. The purpose of the current study was to investigate the association between teenagers and the risk of preterm birth (PTB) in a large and recent cohort study.We conducted a population-based retrospective cohort study using 2007-2011 California birth certificate records linked with hospital discharge indices and United States census data for nulliparous 13-20 year olds who gave birth to singletons. Maternal age was examined categorically at 1 year intervals. PTB was defined as delivery at <37 weeks of gestation with further distinction between <32 and 32-36 weeks, and between spontaneous and medically indicated deliveries. Adjusted multivariable logistic regression was used to estimate odds ratios (OR) for PTB.The prevalence of PTB was highest among the youngest (13 year olds, 14.5%) and lowest among the oldest (20 year olds, 6.7%). After adjusting for maternal and paternal race/ethnicity, paternal age, initiation of prenatal care, source of payment, pre-pregnancy body-mass-index (BMI), height, smoking, and poverty; young mothers of ages 13, 14, 15, and 16 years had increased odds for spontaneous PTB at <32 weeks [OR (CI): 3.76 (1.83-7.75), 1.65 (1.10-2.48), 1.55 (1.24-1.93), 1.19 (1.00-1.42), respectively] compared to 20 year olds. All teenagers, excluding 19 year olds, had elevated odds of spontaneous PTB at 32-36 weeks.Nulliparous teenagers were at increased risk for spontaneous PTB, especially those 16 years or younger. Medically indicated PTB was not associated with young age.

    View details for DOI 10.1515/jpm-2016-0313

    View details for Web of Science ID 000415085900008

    View details for PubMedID 28343179

  • Preterm Birth Phenotypes in Women with Autoimmune Diseases Kolstad, K. D., Mayo, J. A., Chung, L., Chaichian, Y., Kelly, V. M., Druzin, M., Stevenson, D. K., Shaw, G. M., Simard, J. F. WILEY. 2017
  • Social disadvantage and the black-white disparity in spontaneous preterm delivery among California births PLOS ONE Carmichael, S. L., Kan, P., Padula, A. M., Rehkopf, D. H., Oehlert, J. W., Mayo, J. A., Weber, A. M., Wise, P. H., Shaw, G. M., Stevenson, D. K. 2017; 12 (8): e0182862

    Abstract

    We examined the contribution of social disadvantage to the black-white disparity in preterm birth. Analyses included linked vital and hospital discharge records from 127,358 black and 615,721 white singleton California births from 2007-11. Odds ratios (OR) were estimated by 4 logistic regression models for 2 outcomes: early (<32 wks) and moderate (32-36 wks) spontaneous preterm birth (ePTB, mPTB), stratified by 2 race-ethnicity groups (blacks and whites). We then conducted a potential impact analysis. The OR for less than high school education (vs. college degree) was 1.8 (95% confidence interval 1.6, 2.1) for ePTB among whites but smaller for the other 3 outcome groups (ORs 1.3-1.4). For all 4 groups, higher census tract poverty was associated with increased odds (ORs 1.03-1.05 per 9% change in poverty). Associations were less noteworthy for the other variables (payer, and tract percent black and Gini index of income inequality). Setting 3 factors (education, poverty, payer) to 'favorable' values was associated with lower predicted probability of ePTB (25% lower among blacks, 31% among whites) but a 9% higher disparity, compared to probabilities based on observed values; for mPTB, respective percentages were 28% and 13% lower probability, and 17% lower disparity. Results suggest that social determinants contribute to preterm delivery and its disparities, and that future studies should focus on ePTB and more specific factors related to social circumstances.

    View details for DOI 10.1371/journal.pone.0182862

    View details for Web of Science ID 000407431800032

    View details for PubMedID 28800643

    View details for PubMedCentralID PMC5553771

  • STUDIES ON BILIRUBIN (BR) METABOLISM IN THE BRAIN Hansen, T. R., Whitin, J. C., Pierce, N. W., Hwang, S., Wong, R. J., Vreman, H. J., Stevenson, D. K. WILEY. 2017: 14–15
  • A DEFICIENCY IN HEME OXYGENASE-1 EXPRESSION IS ASSOCIATED WITH AN INCREASE IN THE PROGRESSION OF NEONATAL SEPSIS Fujioka, K., Wong, R. J., Stevenson, D. K. WILEY. 2017: 28
  • INDUCTION OF HEME OXYGENASE-1 IS PROTECTIVE AGAINST SEPSIS IN A PRETERM MOUSE MODEL Fujioka, K., Kalish, F., Zhao, H., Wong, R. J., Stevenson, D. K. LIPPINCOTT WILLIAMS & WILKINS. 2017: 32
  • Maternal prepregnancy body mass index and risk of bronchopulmonary dysplasia. Pediatric research Carmichael, S. L., Kan, P., Gould, J. B., Stevenson, D. K., Shaw, G. M., Lee, H. C. 2017

    Abstract

    BackgroundWe examined the relationship between women's prepregnancy BMI and development of bronchopulmonary dysplasia (BPD) in their preterm offspring, hypothesizing that obesity-associated inflammation may increase risk.MethodsWe studied infants born in California between 2007 and 2011, using linked data from California Perinatal Quality Care Collaborative neonatal intensive care units, hospital discharge, and vital statistics. We included infants with birthweight <1,500 g or gestational age at birth of 22-29 weeks. BPD was defined as continuous supplemental oxygen use at 36 weeks' postmenstrual age.ResultsAmong 12,621 infants, 4,078 (32%) had BPD. After adjustment for maternal race/ethnicity, age, education, payer source, and infant sex, BMI status underweight I (BMI <16.9, odds ratio (OR) 1.7, 95% confidence interval (CI) 1.3-2.1) and obesity III (BMI ⩾40.0, OR 1.3, 95% CI 1.0-1.6) were associated with an increased risk of BPD. When considering maternal BMI as a continuous variable, a nonlinear association with BPD was observed for male infants and infants delivered at 25-29 weeks of gestational age, but not for other subgroups.ConclusionBoth high and low maternal BMI were associated with increased BPD risk. These findings support the notion that BPD is a multi-factorial disease that may sometimes have its origins in utero and be influenced by maternal inflammation.Pediatric Research advance online publication, 31 May 2017; doi:10.1038/pr.2017.90.

    View details for DOI 10.1038/pr.2017.90

    View details for PubMedID 28399116

  • Genome-wide association study of sepsis in extremely premature infants. Archives of disease in childhood. Fetal and neonatal edition Srinivasan, L., Page, G., Kirpalani, H., Murray, J. C., Das, A., Higgins, R. D., Carlo, W. A., Bell, E. F., Goldberg, R. N., Schibler, K., Sood, B. G., Stevenson, D. K., Stoll, B. J., Van Meurs, K. P., Johnson, K. J., Levy, J., McDonald, S. A., Zaterka-Baxter, K. M., Kennedy, K. A., Sánchez, P. J., Duara, S., Walsh, M. C., Shankaran, S., Wynn, J. L., Cotten, C. M. 2017

    Abstract

    To identify genetic variants associated with sepsis (early-onset and late-onset) using a genome-wide association (GWA) analysis in a cohort of extremely premature infants.Previously generated GWA data from the Neonatal Research Network's anonymised genomic database biorepository of extremely premature infants were used for this study. Sepsis was defined as culture-positive early-onset or late-onset sepsis or culture-proven meningitis. Genomic and whole-genome-amplified DNA was genotyped for 1.2 million single-nucleotide polymorphisms (SNPs); 91% of SNPs were successfully genotyped. We imputed 7.2 million additional SNPs. p Values and false discovery rates (FDRs) were calculated from multivariate logistic regression analysis adjusting for gender, gestational age and ancestry. Target statistical value was p<10(-5). Secondary analyses assessed associations of SNPs with pathogen type. Pathway analyses were also run on primary and secondary end points.Data from 757 extremely premature infants were included: 351 infants with sepsis and 406 infants without sepsis. No SNPs reached genome-wide significance levels (5×10(-8)); two SNPs in proximity to FOXC2 and FOXL1 genes achieved target levels of significance. In secondary analyses, SNPs for ELMO1, IRAK2 (Gram-positive sepsis), RALA, IMMP2L (Gram-negative sepsis) and PIEZO2 (fungal sepsis) met target significance levels. Pathways associated with sepsis and Gram-negative sepsis included gap junctions, fibroblast growth factor receptors, regulators of cell division and interleukin-1-associated receptor kinase 2 (p values<0.001 and FDR<20%).No SNPs met genome-wide significance in this cohort of extremely low birthweight infants; however, areas of potential association and pathways meriting further study were identified.

    View details for DOI 10.1136/archdischild-2016-311545

    View details for PubMedID 28283553

  • The Complex Relationship of Obesity and Spontaneous Preterm Birth. Tsur, A., Mayo, J., Shaw, G. M., Stevenson, D. K., Gould, J. B. SAGE PUBLICATIONS INC. 2017: 189A
  • Elevation of Reactive Oxidative Species in Uterine Myeloid Cells During Early Pregnancy. Zhao, H., Kalish, F., Wong, R. J., Stevenson, D. K. SAGE PUBLICATIONS INC. 2017: 230A
  • What factors are related to recurrent preterm birth among underweight women? journal of maternal-fetal & neonatal medicine Girsen, A. I., Mayo, J. A., Wallenstein, M. B., Gould, J. B., Carmichael, S. L., Stevenson, D. K., Lyell, D. J., Shaw, G. M. 2017: 1-19

    Abstract

    Our objective was to identify factors associated with recurrent preterm birth among underweight women.Maternally linked hospital and birth certificate records of deliveries in California between 2007 and 2010 were used. Consecutive singleton pregnancies of women with underweight body mass index (BMI <18.5 kg/m(2)) in the first pregnancy were analyzed. Pregnancies were categorized based on outcome of the first and second birth as: term-term; term-preterm; preterm-term and preterm-preterm.We analyzed 4971 women with underweight BMI in the first pregnancy. Of these, 670 had at least one preterm birth. Among these 670, 86 (21.8%) women experienced a recurrent preterm birth. Odds for first term - second preterm birth were decreased for increases in maternal age (aOR: 0.90, 95%CI: 0.95-0.99) whereas inter-pregnancy interval <6 months was related to both first term - second preterm birth (aOR:1.66, 95%CI: 1.21-2.28) and first preterm birth - second term birth (aOR: 1.43, 95%CI: 1.04-1.96). Factors associated with recurrent preterm birth were: negative or no change in pre-pregnancy weight between pregnancies (aOR: 1.67, 95%CI: 1.07-2.60), inter-pregnancy interval <6 months (aOR: 2.14, 95%CI: 1.29-3.56), and maternal age in the first pregnancy (aOR: 0.93, 95%CI: 0.90-0.97).Recurrent preterm birth among underweight women was associated with younger age, short inter-pregnancy interval, and negative or no weight change between pregnancies.

    View details for DOI 10.1080/14767058.2017.1292243

    View details for PubMedID 28166677

  • Skin-to-skin contact after birth and the natural course of neurosteroid levels in healthy term newborns. Journal of perinatology McCallie, K. R., Gaikwad, N. W., Castillo Cuadrado, M. E., Aleman, M., Madigan, J. E., Stevenson, D. K., Bhutani, V. K. 2017

    Abstract

    To determine the postnatal course of neurosteroid levels in relation to gender, mode of delivery and the extent of skin-to-skin (STS) contact during the first days of life in healthy term newborns.Prospective observational study of 39 neonates in which parents recorded total duration of STS in the first 2 days and nine neurosteroids (dehydroepiandrosterone-sulfate, progesterone, pregnenolone, pregnenolone-sulfate, allopregnanolone, isopregnanolone, epipregnanolone, pregnanolone and pregnanolone-sulfate) were assayed from blood samples at birth and at 1-2 days of age.All nine neurosteroid levels declined significantly during the first 2 days of life. Gender did not significantly affect the change in neurosteroid levels. The decline in neurosteroid levels was generally more pronounced in vaginal deliveries, and there was a trend toward a larger decline with more exposure to STS.Ongoing studies may better characterize the role of neurosteroids and the influence of STS in more critically ill and premature neonates.

    View details for DOI 10.1038/jp.2016.268

    View details for PubMedID 28102853

  • The Relationship of Nosocomial Infection Reduction to Changes in Neonatal Intensive Care Unit Rates of Bronchopulmonary Dysplasia JOURNAL OF PEDIATRICS Lapcharoensap, W., Kan, P., Powers, R. J., Shaw, G. M., Stevenson, D. K., Gould, J. B., Wirtschafter, D. D., Lee, H. C. 2017; 180: 105-?

    Abstract

    To examine whether recent reductions in rates of nosocomial infection have contributed to changes in rates of bronchopulmonary dysplasia (BPD) in a population-based cohort.This was a retrospective, population-based cohort study that used the California Perinatal Quality Care Collaborative database from 2006 to 2013. Eligible infants included those less than 30 weeks' gestational age and less than 1500 g who survived to 3 days of life. Primary variables of interest were rates of nosocomial infections and BPD. Adjusted rates of nosocomial infections and BPD from a baseline period (2006-2010) were compared with a later period (2011-2013). The correlation of changes in rates across periods for both variables was assessed by hospital of care.A total of 22 967 infants from 129 hospitals were included in the study. From the first to second time period, the incidence of nosocomial infections declined from 24.7% to 15% and BPD declined from 35% to 30%. Adjusted hospital rates of BPD and nosocomial infections were correlated positively with a calculated 8% reduction of BPD rates attributable to reductions in nosocomial infections.Successful interventions to reduce rates of nosocomial infections may have a positive impact on other comorbidities such as BPD. The prevention of nosocomial infections should be viewed as a significant component in avoiding long-term neonatal morbidities.

    View details for DOI 10.1016/j.jpeds.2016.09.030

    View details for Web of Science ID 000390028100022

  • HEME OXYGENASE-1 DEFICIENCY INCREASES THE SEVERITY OF SEPSIS IN A PRETERM MOUSE MODEL Fujioka, K., Kalish, F., Zhao, H., Wong, R. J., Stevenson, D. K. BMJ PUBLISHING GROUP. 2017: 114–15
  • The twin preterm birth problem: do preterm birth subtypes matter? Ness, A., Mayo, J., Stevenson, D. K., Shaw, G. M. MOSBY-ELSEVIER. 2017: S199
  • 'The obesity paradox': a reconsideration of obesity and the risk of preterm birth. Journal of perinatology : official journal of the California Perinatal Association Tsur, A., Mayo, J. A., Wong, R. J., Shaw, G. M., Stevenson, D. K., Gould, J. B. 2017

    Abstract

    The association between obesity and spontaneous preterm births (sPTBs) has been shown to be influenced by obesity-attendant comorbidities. Our objective was to better understand the complex relationship of obesity and its attendant comorbidities with sPTBs.A retrospective analysis utilizing maternally linked hospital and birth certificate records of 2 049 196 singleton California deliveries from 2007 to 2011. Adjusted relative risks (aRRs) for sPTBs were estimated using multivariate Poisson regression modeling.Obese women had higher aRRs for sPTBs than their normal body mass index (BMI) controls. aRRs (95% confidence interval) increased with increasing BMI category: Obese I=1.10 (1.08 to 1.12); Obese II=1.15 (1.12 to 1.18); and Obese III=1.26 (1.22 to 1.30). When comparing only obese women without comorbidities to their normal BMI controls, aRRs reversed, that is, obese women had lower aRRs of sPTBs: Obese I=0.96 (0.94 to 0.98), Obese II=0.95 (0.91 to 0.98); and Obese III=0.98 (0.94 to 1.03). This same reversal of aRR direction was also observed among women with comorbidities: 0.92 (0.89 to 0.96); 0.89 (0.85 to 0.93); and 0.89 (0.85 to 0.93), respectively. Increasing BMI increased the aRRs for sPTBs among patients with gestational diabetes (P<0.05), while decreasing the risk among patients with chronic hypertension and pregnancy-related hypertensive disease (P<0.05).The obesity and preterm birth paradox is an example of what has been described as 'Simpson's Paradox'. Unmeasured confounding factors mediated by comorbidities may explain the observed protective effect of obesity upon conditioning on the presence or absence of comorbidities and thus resolve the paradox.Journal of Perinatology advance online publication, 27 July 2017; doi:10.1038/jp.2017.104.

    View details for DOI 10.1038/jp.2017.104

    View details for PubMedID 28749482

  • Survival and Neurodevelopmental Outcomes among Periviable Infants. New England journal of medicine Younge, N., Goldstein, R. F., Bann, C. M., Hintz, S. R., Patel, R. M., Smith, P. B., Bell, E. F., Rysavy, M. A., Duncan, A. F., Vohr, B. R., Das, A., Goldberg, R. N., Higgins, R. D., Cotten, C. M. 2017; 376 (7): 617-628

    Abstract

    Data reported during the past 5 years indicate that rates of survival have increased among infants born at the borderline of viability, but less is known about how increased rates of survival among these infants relate to early childhood neurodevelopmental outcomes.We compared survival and neurodevelopmental outcomes among infants born at 22 to 24 weeks of gestation, as assessed at 18 to 22 months of corrected age, across three consecutive birth-year epochs (2000-2003 [epoch 1], 2004-2007 [epoch 2], and 2008-2011 [epoch 3]). The infants were born at 11 centers that participated in the National Institute of Child Health and Human Development Neonatal Research Network. The primary outcome measure was a three-level outcome - survival without neurodevelopmental impairment, survival with neurodevelopmental impairment, or death. After accounting for differences in infant characteristics, including birth center, we used multinomial generalized logit models to compare the relative risk of survival without neurodevelopmental impairment, survival with neurodevelopmental impairment, and death.Data on the primary outcome were available for 4274 of 4458 infants (96%) born at the 11 centers. The percentage of infants who survived increased from 30% (424 of 1391 infants) in epoch 1 to 36% (487 of 1348 infants) in epoch 3 (P<0.001). The percentage of infants who survived without neurodevelopmental impairment increased from 16% (217 of 1391) in epoch 1 to 20% (276 of 1348) in epoch 3 (P=0.001), whereas the percentage of infants who survived with neurodevelopmental impairment did not change significantly (15% [207 of 1391] in epoch 1 and 16% [211 of 1348] in epoch 3, P=0.29). After adjustment for changes in the baseline characteristics of the infants over time, both the rate of survival with neurodevelopmental impairment (as compared with death) and the rate of survival without neurodevelopmental impairment (as compared with death) increased over time (adjusted relative risks, 1.27 [95% confidence interval {CI}, 1.01 to 1.59] and 1.59 [95% CI, 1.28 to 1.99], respectively).The rate of survival without neurodevelopmental impairment increased between 2000 and 2011 in this large cohort of periviable infants. (Funded by the National Institutes of Health and others; ClinicalTrials.gov numbers, NCT00063063 and NCT00009633 .).

    View details for DOI 10.1056/NEJMoa1605566

    View details for PubMedID 28199816

  • IDENTIFICATION OF RISK FOR NEONATAL HEMOLYSIS: A MULTI-CENTER STUDY Bhutani, V. K., Cuadrado, C. E., Schutzman, D. L., Aby, J. L., Bogen, D. L., Christensen, R. D., Watchko, J. F., Maisels, M., Wong, R. J., Stevenson, D. K. BMJ PUBLISHING GROUP. 2017: 123
  • CYCLED PHOTOTHERAPY IS A SAFE AND EFFECTIVE TREATMENT FOR SMALL PREMATURE INFANTS WITH HYPERBILIRUBINEMIA Arnold, C. C., Tyson, J. E., Cuadrado, C. E., Dempsey, A. G., Khan, A. M., Pedroza, C., Bhutani, V. K., Wong, R. J., Stevenson, D. K. BMJ PUBLISHING GROUP. 2017: 150–51
  • Risk of recurrent preterm birth among women according to change in partner JOURNAL OF PERINATAL MEDICINE Baer, R. J., Yang, J., Chambers, C. D., Ryckman, K. K., Saftlas, A. F., Berghella, V., Schetter, C. D., Shaw, G. M., Stevenson, D. K., Jelliffe-Pawlowski, L. L. 2017; 45 (1): 63-70

    Abstract

    There is well-established literature indicating change in partner as a risk for preeclampsia, yet the research on the risk of preterm birth after a change in partners has been sparse and inconsistent. Using a population of California live born singletons, we aimed to determine the risk of preterm birth after a change in partner between the first and second pregnancies. The risk of preterm and early term delivery in the second pregnancy was calculated for mothers who did or did not change partners between births with the referent group as women who delivered both pregnancies at term and did not change partners. Adjusted odds ratios (ORs) and their 95% confidence intervals (CIs) were calculated. Relative to women who delivered at 39 weeks or later in the second pregnancy and did not change partners, preterm birth risks were somewhat lower for women who changed partners between the first and second pregnancies compared to those women who did not change partners. For example, 10.6% of women who did not change partners and delivered their second pregnancy before 34 weeks also delivered their first pregnancy before 34 weeks, while 8.5% of women who changed partners delivered before 34 weeks. Findings suggest partner change may alter the risk of preterm birth.

    View details for DOI 10.1515/jpm-2016-0207

    View details for Web of Science ID 000393201100009

    View details for PubMedCentralID PMC5380385

  • Extreme hyperbilirubinemia and rescue exchange transfusion in California from 2007 to 2012. Journal of perinatology Bhutani, V. K., Meng, N. F., Knauer, Y., Danielsen, B. H., Wong, R. J., Stevenson, D. K., Gould, J. B. 2016; 36 (10): 853-857

    Abstract

    To evaluate the impact of statewide learning collaboratives that used national guidelines to manage jaundice on the serial prevalence of extreme hyperbilirubinemia (EHB, total bilirubin ⩾25 mg dl(-1)) and exchange transfusions introduced in California Perinatal Quality Care Collaborative (CPQCC) hospitals in 2007.Adverse outcomes were retrieved from statewide databases on re-admissions for live births ⩾35 weeks' gestation (2007 to 2012) in diverse CPQCC hospitals. Individual and cumulative select perinatal risk factors and frequencies were the outcomes measures.For 3 172 762 babies (2007 to 2012), 92.5% were ⩾35 weeks' gestation. Statewide EHB and exchange rates decreased from 28.2 to 15.3 and 3.6 to 1.9 per 100 000 live births, respectively. From 2007 to 2012, the trends for TB>25 mg dl(-1) rates were -0.92 per 100 000 live births per year (95% CI: -3.71 to 1.87, P=0.41 and R(2)=0.17).National guidelines complemented by statewide learning collaboratives can decrease or modify outcomes among all birth facilities and impact clinical practice behavior.

    View details for DOI 10.1038/jp.2016.106

    View details for PubMedID 27442156

  • Improving publication rates in a collaborative clinical trials research network. Seminars in perinatology Archer, S. W., Carlo, W. A., Truog, W. E., Stevenson, D. K., Van Meurs, K. P., Sánchez, P. J., Das, A., Devaskar, U., Nelin, L. D., Petrie Huitema, C. M., Crawford, M. M., Higgins, R. D. 2016; 40 (6): 410-417

    Abstract

    Unpublished results can bias biomedical literature, favoring positive over negative findings, primary over secondary analyses, and can lead to duplicate studies that unnecessarily endanger subjects and waste resources. The Neonatal Research Network's (NRN) publication policies for approving, reviewing, and tracking abstracts and papers work to combat these problems. In 2003, the NRN restricted investigators with unfinished manuscripts from proposing new ones and in 2010, urged authors to complete long-outstanding manuscripts. Data from 1991 to 2015 were analyzed to determine effectiveness of these policy changes. The NRN has achieved an overall publication rate of 78% for abstracts. For 1990-2002, of 137 abstracts presented, 43 (31%) were published within 2 years; for 2003-2009, after the manuscript completion policy was instituted, of 140 abstracts presented, 68 (49%) were published within 2 years. Following the effort in 2010, the rate increased to 64%. The NRN surpassed reported rates by developing a comprehensive process, holding investigators accountable and tracking abstracts from presentation to publication.

    View details for DOI 10.1053/j.semperi.2016.05.003

    View details for PubMedID 27423510

    View details for PubMedCentralID PMC5192287

  • Inflammatory biomarkers and spontaneous preterm birth among obese women. journal of maternal-fetal & neonatal medicine Wallenstein, M. B., Jelliffe-Pawlowski, L. L., Yang, W., Carmichael, S. L., Stevenson, D. K., Ryckman, K. K., Shaw, G. M. 2016; 29 (20): 3317-3322

    Abstract

    To identify associations between second-trimester serum inflammatory biomarkers and preterm birth among obese women.In this nested case-control study, we compared 65 serum inflammatory biomarkers in obese women whose pregnancies resulted in early spontaneous preterm birth (<32 weeks gestation, n = 34) to obese women whose pregnancies resulted in term birth (n = 34). These women were selected from a larger population-based California cohort. Random forest and classification and regression tree techniques were employed to identify biomarkers of importance, and adjusted odds ratios (aORs) and 95% confidence intervals (CI) were estimated using logistic regression.Random forest and classification and regression tree techniques found that soluble vascular endothelial growth factor receptor-3 (sVEGFR3), soluble interleukin-2 receptor alpha-chain (sIL-2RA) and soluble tumor necrosis factor receptor-1 (sTNFR1) were related to preterm birth. Using multivariable logistic regression to compare preterm cases and term controls, decreased serum levels of sVEGFR3 and increased serum levels of sIL-2RA and sTNFR1 were associated with increased risk of preterm birth among obese women, aOR = 3.2 (95% CI: 1.0-9.9), aOR = 2.8 (95% CI: 0.9-9.0), and aOR = 4.1 (95% CI: 1.2-14.1), respectively.In this pilot study, we identified three serum biomarkers indicative of inflammation to be associated with spontaneous preterm birth among obese women: sVEGFR3, sIL-2RA and sTNFR1.

    View details for DOI 10.3109/14767058.2015.1124083

    View details for PubMedID 26700828

  • 50 Years Ago in TheJournal ofPediatrics: Identification of the Pigment in Amniotic Fluid of Erythroblastosis as Bilirubin. journal of pediatrics Stevenson, D. K. 2016; 176: 22-?

    View details for DOI 10.1016/j.jpeds.2016.03.013

    View details for PubMedID 27568248

  • Growth Outcomes of Preterm Infants Exposed to Different Oxygen Saturation Target Ranges from Birth. journal of pediatrics Navarrete, C. T., Wrage, L. A., Carlo, W. A., Walsh, M. C., Rich, W., Gantz, M. G., Das, A., Schibler, K., Newman, N. S., Piazza, A. J., Poindexter, B. B., Shankaran, S., Sánchez, P. J., Morris, B. H., Frantz, I. D., Van Meurs, K. P., Cotten, C. M., Ehrenkranz, R. A., Bell, E. F., Watterberg, K. L., Higgins, R. D., Duara, S. 2016; 176: 62-68 e4

    Abstract

    To test whether infants randomized to a lower oxygen saturation (peripheral capillary oxygen saturation [SpO2]) target range while on supplemental oxygen from birth will have better growth velocity from birth to 36 weeks postmenstrual age (PMA) and less growth failure at 36 weeks PMA and 18-22 months corrected age.We evaluated a subgroup of 810 preterm infants from the Surfactant, Positive Pressure, and Oxygenation Randomized Trial, randomized at birth to lower (85%-89%, n = 402, PMA 26 ± 1 weeks, birth weight 839 ± 186 g) or higher (91%-95%, n = 408, PMA 26 ± 1 weeks, birth weight 840 ± 191 g) SpO2 target ranges. Anthropometric measures were obtained at birth, postnatal days 7, 14, 21, and 28; then at 32 and 36 weeks PMA; and 18-22 months corrected age. Growth velocities were estimated with the exponential method and analyzed with linear mixed models. Poor growth outcome, defined as weight <10th percentile at 36 weeks PMA and 18-22 months corrected age, was compared across the 2 treatment groups by the use of robust Poisson regression.Growth outcomes including growth at 36 weeks PMA and 18-22 months corrected age, as well as growth velocity were similar in the lower and higher SpO2 target groups.Targeting different oxygen saturation ranges between 85% and 95% from birth did not impact growth velocity or reduce growth failure in preterm infants.

    View details for DOI 10.1016/j.jpeds.2016.05.070

    View details for PubMedID 27344218

  • Body Mass Index Change between Pregnancies and Risk of Spontaneous Preterm Birth. American journal of perinatology Riley, K. L., Carmichael, S. L., Mayo, J. A., Shachar, B. Z., Girsen, A. I., Wallenstein, M. B., Gould, J. B., Stevenson, D. K., Shaw, G. M. 2016; 33 (10): 1017-1022

    Abstract

    Objective Studies have reported an increased risk of spontaneous preterm birth associated with elevated prepregnancy body mass index (BMI) among nulliparous but not multiparous women. We examined whether changes in BMI and weight between pregnancies contributed to risk of preterm birth among obese (BMI > 29 kg/m(2)) women. Study Design This study utilized maternally linked California birth records of sequential singleton births between 2007 and 2010. Preterm birth was defined as 20 to 31 or 32 to 36 weeks of gestation. BMI was examined as category change and by tertile of weight change. Primary analyses included women without diabetes or hypertensive disorders; these women were compared with those without prior preterm birth, women with preterm deliveries preceded by spontaneous preterm labor, and women without any exclusions (i.e., diabetes or hypertensive disorders). Results Analyses showed that obesity was not associated with increased risk of spontaneous preterm birth among multiparous women. Women whose BMI increased had a decreased risk of spontaneous preterm birth at 32 to 36 weeks. Change in BMI or weight between pregnancies did not substantively alter results. Conclusion Among multiparous women, obesity was associated with reduced risk of spontaneous preterm delivery. This observed association is complex and may be influenced by maternal age, gestational age, placental insufficiency, and altered immune response.

    View details for DOI 10.1055/s-0036-1572533

    View details for PubMedID 27128743

  • Recurrence of Preterm Birth and Early Term Birth. Obstetrics and gynecology Yang, J., Baer, R. J., Berghella, V., Chambers, C., Chung, P., Coker, T., Currier, R. J., Druzin, M. L., Kuppermann, M., Muglia, L. J., Norton, M. E., Rand, L., Ryckman, K., Shaw, G. M., Stevenson, D., Jelliffe-Pawlowski, L. L. 2016; 128 (2): 364-372

    Abstract

    To examine recurrent preterm birth and early term birth in women's initial and immediately subsequent pregnancies.This retrospective cohort study included 163,889 women who delivered their first and second liveborn singleton neonates between 20 and 44 weeks of gestation in California from 2005 through 2011. Data from hospital discharge records and birth certificates were used for analyses. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using logistic regression models adjusted for risk factors.Shorter gestational duration in the first pregnancy increased the risk of subsequent preterm birth (both early, before 32 weeks of gestation, and later, from 32 to 36 weeks of gestation) as well as early term birth (37-38 weeks of gestation). Compared with women with a prior term birth, women with a prior early preterm birth (before 32 weeks of gestation) were at the highest risk for a subsequent early preterm birth (58/935 [6.2%] compared with 367/118,505 [0.3%], adjusted OR 23.3, 95% CI 17.2-31.7). Women with a prior early term birth had more than a twofold increased risk for subsequent preterm birth (before 32 weeks of gestation: 171/36,017 [0.5%], adjusted OR 2.0, 95% CI 1.6-2.3; from 32 to 36 weeks of gestation: 2,086/36,017 [6.8%], adjusted OR 3.0, 95% CI 2.9-3.2) or early term birth (13,582/36,017 [37.7%], adjusted OR 2.2, 95% CI 2.2-2.3).Both preterm birth and early term birth are associated with these outcomes in a subsequent pregnancy. Increased clinical attention and research efforts may benefit from a focus on women with a prior early term birth as well as those with prior preterm birth.

    View details for DOI 10.1097/AOG.0000000000001506

    View details for PubMedID 27400000

  • Hyperbilirubinemia in Preterm Neonates CLINICS IN PERINATOLOGY Bhutani, V. K., Wong, R. J., Stevenson, D. K. 2016; 43 (2): 215-?

    Abstract

    Preterm neonates with increased bilirubin production loads are more likely to sustain adverse outcomes due to either neurotoxicity or overtreatment with phototherapy and/or exchange transfusion. Clinicians should rely on expert consensus opinions to guide timely and effective interventions until there is better evidence to refine bilirubin-induced neurologic dysfunction or benefits of bilirubin. In this article, we review the evolving evidence for bilirubin-induced brain injury in preterm infants and highlight the clinical approaches that minimize the risk of bilirubin neurotoxicity.

    View details for DOI 10.1016/j.clp.2016.01.001

    View details for Web of Science ID 000378367300003

    View details for PubMedID 27235203

  • Preterm Birth as a Calendar Event or Immunologic Anomaly JAMA PEDIATRICS Wallenstein, M. B., Shaw, G. M., Stevenson, D. K. 2016; 170 (6): 525–26
  • Preterm Neonates: Beyond the Guidelines for Neonatal Hyperbilirubinemia CLINICS IN PERINATOLOGY Stevenson, D. K., Bhutani, V. K. 2016; 43 (2): XVII-XVIII

    View details for DOI 10.1016/j.clp.2016.01.013

    View details for Web of Science ID 000378367300002

    View details for PubMedID 27235216

  • Phototherapy and the Risk of Photo-Oxidative Injury in Extremely Low Birth Weight Infants CLINICS IN PERINATOLOGY Stevenson, D. K., Wong, R. J., Arnold, C. C., Pedroza, C., Tyson, J. E. 2016; 43 (2): 291-?

    Abstract

    Phototherapy has been used to treat newborns with jaundice for more than 50 years with the presumption that it is safe and effective for all infants. In fact, this presumption may not be true for all infants, especially the smallest and most immature. The safety and efficacy of phototherapy have never really been questioned or adequately tested in the latter, yet clinical applications of phototherapy have been further refined as its mechanisms of action have been better understood and alternative light sources have become available. This article addresses what is known about the possible risks of photo-oxidative injury in extremely low birth weight infants.

    View details for DOI 10.1016/j.clp.2016.01.005

    View details for Web of Science ID 000378367300008

    View details for PubMedID 27235208

  • Identification of neonatal haemolysis: an approach to predischarge management of neonatal hyperbilirubinemia ACTA PAEDIATRICA Bhutani, V. K., Srinivas, S., Cuadrado, M. E., Aby, J. L., Wong, R. J., Stevenson, D. K. 2016; 105 (5): E189-E194

    Abstract

    Relative contributions of increased production [by end-tidal carbon monoxide concentrations (ETCOc)] and decreased elimination of bilirubin to predischarge hour-specific total bilirubin (TB) levels were assessed in healthy late-preterm and term newborns. Secondly, we report predischarge ETCOc ranges to guide clinical management of hyperbilirubinemia.TB and ETCOc (≤3 timepoints) determinations of newborns aged between six hours and <6 days (n = 79) were stratified by postnatal age epochs. Hyperbilirubinemia risk was assessed by plotting TB values as a function of ETCOc.Stratifications of ETCOc (in ppm, mean, median and interquartile ranges) by postnatal age epochs (0-24, 24-48 and 48-72) were as follows: 2.0, 1.9, 1.8-2.2 (n = 11); 1.6, 1.5, 1.1-2.0 (n = 58); and 2.0, 1.8, 1.6-2.3 (n = 9), respectively. Infants with ETCOc ≥ 2.5 were at high risk, between 1.5 and 2.5 at moderate risk and ≤1.5 were at low risk. Risk due to haemolysis alone was not independent (p < 0.01). For infants with TB >75th percentile (n = 31), 23% had ETCO ≤1.5, and 77% had ETCOc > 1.5 (p < 0.00003).Near-simultaneous ETCOc and TB measurements in infants with TB >75th percentile accurately identify haemolytic hyperbilirubinemia.

    View details for DOI 10.1111/apa.13341

    View details for Web of Science ID 000373921200001

  • The effect of hematocrit on in vitro bilirubin photoalteration PEDIATRIC RESEARCH Linfield, D. T., Lamola, A. A., Mei, E., Hwang, A. Y., Vreman, H. J., Wong, R. J., Stevenson, D. K. 2016; 79 (3): 387-390

    Abstract

    Phototherapy using light in the spectral range of 410-500 nm, which overlaps the absorption of bilirubin, is the common treatment for neonatal hyperbilirubinemia. Hemoglobin (Hb) absorbs light strongly throughout this same range and thus can compete with bilirubin for this light and consequently reduce the efficacy of phototherapy. Here, we determined the effect of hematocrit (Hct) on in vitro bilirubin photoalteration using narrow-band blue (450 nm) light-emitting diodes (LEDs).Suspensions with Hcts from 0 to 80% and 16 ± 1 mg/dl bilirubin were prepared by mixing red blood cells (RBCs), bilirubin (30 mg/dl) in 4% human serum albumin, and normal saline. Aliquots of each suspension were exposed to blue light at equal irradiances. Before and after 60 min of exposure, bilirubin levels in supernatants (n = 46) were measured using a diazo-dye method.Bilirubin photoalteration steeply decreased by ~60% as Hct increased from 0 to 10%. Over the clinically relevant range of 30-70% Hct, the decrease was significant, but less drastic, exhibiting a quasi-linear dependence on Hct.Bilirubin photoalteration under blue light in vitro is significantly reduced as Hct increases. Clinical studies are warranted to confirm these in vitro observations that Hct can affect the efficacy of phototherapy.

    View details for DOI 10.1038/pr.2015.240

    View details for Web of Science ID 000373371800004

    View details for PubMedID 26571225

  • Expression of Heme Oxygenase-1 in Immune Cells During Late Gestational Inflammation. Ozen, M., Zhao, H., Kalish, F., Yang, Y., Lewis, D. B., Wong, R. J., Stevenson, D. K. SAGE PUBLICATIONS INC. 2016: 338A
  • Heme Oxygenase-1 Expression in Myeloid Cells Affects Oxidative Stress, Uterine Infiltration and Placental Angiogenesis in Early Pregnancy. Zhao, H., Kalish, F., Wong, R. J., Stevenson, D. K. SAGE PUBLICATIONS INC. 2016: 68A–69A
  • A Multi-Omics Analysis of Human Nucleus-Coded Mitochondrial Genes with Mouse Extraembryonic Tissue/Placenta Phenotypes: Implications in Mitochondria-Mediated Maternal and Fetal Complications. Hu, G., Chen, R., Deng, X., Li, Z., Mo, L., Hao, S., Shaw, G. M., Stevenson, D. K., Cohen, H. J., Jiang, X., Sylvester, K. G., Ling, X. B. SAGE PUBLICATIONS INC. 2016: 320A
  • Failed endotracheal intubation and adverse outcomes among extremely low birth weight infants. Journal of perinatology Wallenstein, M. B., Birnie, K. L., Arain, Y. H., Yang, W., Yamada, N. K., Huffman, L. C., Palma, J. P., Chock, V. Y., Shaw, G. M., Stevenson, D. K. 2016; 36 (2): 112-115

    Abstract

    To quantify the importance of successful endotracheal intubation on the first attempt among extremely low birth weight (ELBW) infants who require resuscitation after delivery.A retrospective chart review was conducted for all ELBW infants ⩽1000 g born between January 2007 and May 2014 at a level IV neonatal intensive care unit. Infants were included if intubation was attempted during the first 5 min of life or if intubation was attempted during the first 10 min of life with heart rate <100. The primary outcome was death or neurodevelopmental impairment. The association between successful intubation on the first attempt and the primary outcome was assessed using multivariable logistic regression with adjustment for birth weight, gestational age, gender and antenatal steroids.The study sample included 88 ELBW infants. Forty percent were intubated on the first attempt and 60% required multiple intubation attempts. Death or neurodevelopmental impairment occurred in 29% of infants intubated on the first attempt, compared with 53% of infants that required multiple attempts, adjusted odds ratio 0.4 (95% confidence interval 0.1 to 1.0), P<0.05.Successful intubation on the first attempt is associated with improved neurodevelopmental outcomes among ELBW infants. This study confirms the importance of rapid establishment of a stable airway in ELBW infants requiring resuscitation after birth and has implications for personnel selection and role assignment in the delivery room.Journal of Perinatology advance online publication, 5 November 2015; doi:10.1038/jp.2015.158.

    View details for DOI 10.1038/jp.2015.158

    View details for PubMedID 26540244

  • Chorioamnionitis and Culture-Confirmed, Early-Onset Neonatal Infections. Pediatrics Wortham, J. M., Hansen, N. I., Schrag, S. J., Hale, E., Van Meurs, K., Sánchez, P. J., Cantey, J. B., Faix, R., Poindexter, B., Goldberg, R., Bizzarro, M., Frantz, I., Das, A., Benitz, W. E., Shane, A. L., Higgins, R., Stoll, B. J. 2016; 137 (1): 1-11

    Abstract

    Current guidelines for prevention of neonatal group B streptococcal disease recommend diagnostic evaluations and empirical antibiotic therapy for well-appearing, chorioamnionitis-exposed newborns. Some clinicians question these recommendations, citing the decline in early-onset group B streptococcal disease rates since widespread intrapartum antibiotic prophylaxis implementation and potential antibiotic risks. We aimed to determine whether chorioamnionitis-exposed newborns with culture-confirmed, early-onset infections can be asymptomatic at birth.Multicenter, prospective surveillance for early-onset neonatal infections was conducted during 2006-2009. Early-onset infection was defined as isolation of a pathogen from blood or cerebrospinal fluid collected ≤ 72 hours after birth. Maternal chorioamnionitis was defined by clinical diagnosis in the medical record or by histologic diagnosis by placental pathology. Hospital records of newborns with early-onset infections born to mothers with chorioamnionitis were reviewed retrospectively to determine symptom onset.Early-onset infections were diagnosed in 389 of 396,586 live births, including 232 (60%) chorioamnionitis-exposed newborns. Records for 229 were reviewed; 29 (13%) had no documented symptoms within 6 hours of birth, including 21 (9%) who remained asymptomatic at 72 hours. Intrapartum antibiotic prophylaxis exposure did not differ significantly between asymptomatic and symptomatic infants (76% vs 69%; P = .52). Assuming complete guideline implementation, we estimated that 60 to 1400 newborns would receive diagnostic evaluations and antibiotics for each infected asymptomatic newborn, depending on chorioamnionitis prevalence.Some infants born to mothers with chorioamnionitis may have no signs of sepsis at birth despite having culture-confirmed infections. Implementation of current clinical guidelines may result in early diagnosis, but large numbers of uninfected asymptomatic infants would be treated.

    View details for DOI 10.1542/peds.2015-2323

    View details for PubMedID 26719293

    View details for PubMedCentralID PMC4702021

  • Preterm birth rates by gestational age and demographic factors in twins compared to singletons in California 2007-2010 Ness, A., Mayo, J., Stevenson, D. K., Shaw, G. MOSBY-ELSEVIER. 2016: S374–S375
  • A LIPID FORMULATION OF ZINC PROTOPORPHYRIN FOR THE PREVENTION OF NEONATAL HYPERBILIRUBINEMIA DUE TO CHRONIC HEMOLYSIS Konecny, C. M., Fujioka, K., Wong, S., Lu, S., Kalish, F., Zhao, H., Wong, R. J., Stevenson, D. K. LIPPINCOTT WILLIAMS & WILKINS. 2016: 253–54
  • IN VIVO INDUCTION OF HEME OXYGENASE-1 BY ASPIRIN Konecny, C. M., Wong, S., Lu, S., Fujioka, K., Kalish, F., Zhao, H., Wong, R. J., Stevenson, D. K. LIPPINCOTT WILLIAMS & WILKINS. 2016: 181
  • IDENTIFICATION OF NEONATAL HEMOLYSIS IN THE WELL BABY NURSERY Srinivas, S., Cuadrado, M., Wong, R. J., Stevenson, D. K., Bhutani, V. K. LIPPINCOTT WILLIAMS & WILKINS. 2016: 287
  • Teenage pregnancy, body mass index, and preterm birth Mayo, J., Shachar, B., Stevenson, D. K., Shaw, G. M. MOSBY-ELSEVIER. 2016: S394–S395
  • Association between gestational duration in first pregnancies and birth timing in second pregnancies Yang, J., Baer, R. J., Berghella, V., Chambers, C., Chung, P., Coker, T., Currier, R. J., Druzin, M. L., Kuppermann, M., Muglia, L. J., Norton, M. E., Rand, L., Ryckman, K., Shaw, G. M., Stevenson, D., Wise, P., Jelliffe-Pawlowski, L. L. MOSBY-ELSEVIER. 2016: S442
  • Risk of recurrent preterm birth among women according to change in paternity Baer, R. J., Yang, J., Chambers, C. D., Ryckman, K., Shaw, G. M., Stevenson, D. K., Schetter, C., Saftlas, A. F., Berghella, V., Jelliffe-Pawlowski, L. L. MOSBY-ELSEVIER. 2016: S324
  • INDUCTION OF HEME OXYGENASE-1 ATTENUATES THE SEVERITY OF SEPSIS IN A NON-SURGICAL NEONATAL MOUSE MODEL Fujioka, K., Lu, S., Wong, S., Kalish, F., Zhao, H., Wong, R. J., Stevenson, D. K. LIPPINCOTT WILLIAMS & WILKINS. 2016: 253
  • Leading by Example and Design: The Joseph St Geme Jr Leadership Award, 2016. Pediatrics Stevenson, D. K. 2016; 138 (5)

    View details for PubMedID 27940790

  • Neonatal brain microstructure correlates of neurodevelopment and gait in preterm children 18-22 mo of age: an MRI and DTI study PEDIATRIC RESEARCH Rose, J., Cahill-Rowley, K., Vassar, R., Yeom, K. W., Stecher, X., Stevenson, D. K., Hintz, S. R., Barnea-Goraly, N. 2015; 78 (6): 700-708

    Abstract

    Near-term brain structure was examined in preterm infants in relation to neurodevelopment. We hypothesized that near-term macrostructural brain abnormalities identified using conventional magnetic resonance imaging (MRI), and white matter (WM) microstructure detected using diffusion tensor imaging (DTI), would correlate with lower cognitive and motor development and slower, less-stable gait at 18-22 mo of age.One hundred and two very-low-birth-weight preterm infants (≤1,500 g birth weight; ≤32 wk gestational age) were recruited prior to routine near-term brain MRI at 36.6 ± 1.8 wk postmenstrual age. Cerebellar and WM macrostructure was assessed on conventional structural MRI. DTI was obtained in 66 out of 102 and WM microstructure was assessed using fractional anisotropy and mean diffusivity (MD) in six subcortical brain regions defined by DiffeoMap neonatal atlas. Neurodevelopment was assessed with Bayley-Scales-of-Infant-Toddler-Development, 3rd-Edition (BSID-III); gait was assessed using an instrumented mat.Neonates with cerebellar abnormalities identified using MRI demonstrated lower mean BSID-III cognitive composite scores (89.0 ± 10.1 vs. 97.8 ± 12.4; P = 0.002) at 18-22 mo. Neonates with higher DTI-derived left posterior limb of internal capsule (PLIC) MD demonstrated lower cognitive and motor composite scores (r = -0.368; P = 0.004; r = -0.354; P = 0.006) at 18-22 mo; neonates with higher genu MD demonstrated slower gait velocity (r = -0.374; P = 0.007). Multivariate linear regression significantly predicted cognitive (adjusted r(2) = 0.247; P = 0.002) and motor score (adjusted r(2) = 0.131; P = 0.017).Near-term cerebellar macrostructure and PLIC and genu microstructure were predictive of early neurodevelopment and gait.

    View details for DOI 10.1038/pr.2015.157

    View details for Web of Science ID 000367114900015

    View details for PubMedID 26322412

  • Reply to Keelan and Payne: Microbiota-related pathways for preterm birth PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA DiGiulio, D. B., Stevenson, D. K., Shaw, G., Lyell, D. J., Relman, D. A. 2015; 112 (47): E6415

    View details for DOI 10.1073/pnas.1517939112

    View details for Web of Science ID 000365173100005

    View details for PubMedID 26515091

    View details for PubMedCentralID PMC4664308

  • Effects of race/ethnicity and BMI on the association between height and risk for spontaneous preterm birth. American journal of obstetrics and gynecology Shachar, B. Z., Mayo, J. A., Lee, H. C., Carmichael, S. L., Stevenson, D. K., Shaw, G. M., Gould, J. B. 2015; 213 (5): 700 e1-9

    Abstract

    Short height and obesity have each been associated with increased risk for preterm birth (PTB). However, the effect of short height on PTB risk, across different race/ethnicities and body mass index (BMI) categories, has not been studied. Our objective was to determine the influence of maternal height on the risk for PTB within race/ethnic groups, BMI groups, or adjusted for weight.All California singleton live births from 2007 through 2010 were included from birth certificate data (vital statistics) linked to hospital discharge data. Prepregnancy BMI (kg/m(2)) was categorized as underweight (<18.5), normal (18.5-24.9), overweight (25.0-29.9), or obese (≥30.0). Maternal race/ethnicity was categorized as: non-Hispanic white, non-Hispanic black, Hispanic, and Asian. Maternal height was classified into 5 categories (shortest, short, middle, tall, tallest) based on racial/ethnic-specific height distributions, with the middle category serving as reference. Poisson regression models were used to estimate relative risks for the association between maternal height and risk of spontaneous PTB (<37 weeks and <32 weeks). Models were stratified on race/ethnicity and BMI. Generalized additive regression models were used to detect nonlinearity of the association. Covariates considered were: maternal age, weight, parity, prenatal care, education, medical payment, previous PTB, gestational and pregestational diabetes, pregestational hypertension, preeclampsia/eclampsia, and smoking.Among 1,655,385 California singleton live births, 5.2% were spontaneous PTB <37 weeks. Short stature (first height category) was associated with increased risk for PTB for non-Hispanic whites and Hispanics across all BMI categories. Among obese women, tall stature (fifth category) was associated with reduced risk for spontaneous PTB for non-Hispanic whites, Asians, and Hispanics. The same pattern of association was seen for height and risk for spontaneous PTB <32 weeks. In the generalized additive regression model plots, short stature was associated with increased risk for spontaneous PTB of <32 and <37 weeks of gestation among whites and Asians. However, this association was not observed for blacks and Hispanics.Maternal shorter height is associated with a modest increased risk for spontaneous PTB regardless of BMI. Our results suggest that PTB risk assessment should consider race/ethnicity-specific height with respect to the norm in addition to BMI assessment.

    View details for DOI 10.1016/j.ajog.2015.07.005

    View details for PubMedID 26187451

    View details for PubMedCentralID PMC4631690

  • Role of infant sex in the association between air pollution and preterm birth ANNALS OF EPIDEMIOLOGY Cossi, M., Zuta, S., Padula, A. M., Gould, J. B., Stevenson, D. K., Shaw, G. M. 2015; 25 (11): 874-876
  • Effects of race/ethnicity and BMI on the association between height and risk for spontaneous preterm birth AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY Shachar, B. Z., Mayo, J. A., Lee, H. C., Carmichael, S. L., Stevenson, D. K., Shaw, G. M., Gould, J. B. 2015; 213 (5)

    View details for DOI 10.1016/j.ajog.2015.07.005

    View details for Web of Science ID 000365763400027

    View details for PubMedID 26187451

  • Prepregnancy Obesity and Risks of Stillbirth PLOS ONE Carmichael, S. L., Blumenfeld, Y. J., Mayo, J., Wei, E., Gould, J. B., Stevenson, D. K., Shaw, G. M. 2015; 10 (10)

    Abstract

    We examined the association of maternal obesity with risk of stillbirth, focusing on whether the pattern of results varied by gestational age or maternal race-ethnicity or parity.Analyses included 4,012 stillbirths and 1,121,234 liveborn infants delivered in California from 2007-2010. We excluded stillbirths due to congenital anomalies, women with hypertensive disorders or diabetes, and plural births, to focus on fetuses and women without these known contributing conditions. We used Poisson regression to estimate relative risks (RR) and 95% confidence intervals (CI). Separate models were run for stillbirths delivered at 20-23, 24-27, 28-31, 32-36, 37-41 weeks, relative to liveborn deliveries at 37-41 weeks.For stillbirth at 20-23 weeks, RRs were elevated for all race-ethnicity and parity groups. The RR for a 20-unit change in BMI (which reflects the approximate BMI difference between a normal weight and an Obese III woman) was 3.5 (95% CI 2.2, 5.6) for nulliparous white women and ranged from 1.8 to 5.0 for other sub-groups. At 24-27 weeks, the association was significant (p<0.05) only for multiparous non-Hispanic whites; at 28-31 weeks, for multiparous whites and nulliparous whites and blacks; at 32-36 weeks, for multiparous whites and nulliparous blacks; and at 37-41 weeks, for all groups except nulliparous blacks. The pattern of results was similar when restricted to stillbirths due to unknown causes and somewhat stronger when restricted to stillbirths attributable to obstetric causes.Increased risks were observed across all gestational ages, and some evidence of heterogeneity of the associations was observed by race-ethnicity and parity.

    View details for DOI 10.1371/journal.pone.0138549

    View details for Web of Science ID 000363183100017

    View details for PubMedID 26466315

    View details for PubMedCentralID PMC4605840

  • Maternal Asthma, Preterm Birth, and Risk of Bronchopulmonary Dysplasia. journal of pediatrics Gage, S., Kan, P., Lee, H. C., Gould, J. B., Stevenson, D. K., Shaw, G. M., O'Brodovich, H. M. 2015; 167 (4): 875-880 e1

    Abstract

    To study the relationship between maternal asthma and the development of bronchopulmonary dysplasia (BPD).Using a large population-based California cohort, we investigated associations between maternal asthma and preterm birth subtype, as well as maternal asthma and BPD. We used data from 2007-2010 maternal delivery discharge records of 2 009 511 pregnancies and International Classification of Diseases, Ninth Revision codes. Preterm birth was defined as <37 weeks gestational age (GA), with subgroups of <28 weeks, 28-32 weeks, and 33-37 weeks GA, as well as preterm subtype, defined as spontaneous, medically indicated, or unknown. Linkage between the 2 California-wide datasets yielded 21 944 singleton preterm infants linked to their mother's records, allowing estimation of the risk of BPD in mothers with asthma and those without asthma.Maternal asthma was associated with increased odds (OR, 1.42; 95% CI, 1.38-1.46) of preterm birth at <37 weeks GA, with the greatest risk for 28-32 GA (aOR, 1.60; 95% CI, 1.47-1.74). Among 21 944 preterm infants, we did not observe an elevated risk for BPD in infants born to mothers with asthma (aOR, 1.03; 95% CI, 0.9-1.2). Stratification by maternal treatment with antenatal steroids revealed increased odds of BPD in infants whose mothers had asthma but did not receive antenatal steroids (aOR, 1.54; 95% CI, 1.15-2.06), but not in infants whose mothers had asthma and were treated with antenatal steroids (aOR, 0.85; 95% CI, 0.67-1.07).Asthma in mothers who did not receive antenatal steroid treatment is associated with an increased risk of BPD in their preterm infants.

    View details for DOI 10.1016/j.jpeds.2015.06.048

    View details for PubMedID 26254835

  • Maternal Asthma, Preterm Birth, and Risk of Bronchopulmonary Dysplasia. journal of pediatrics Gage, S., Kan, P., Lee, H. C., Gould, J. B., Stevenson, D. K., Shaw, G. M., O'Brodovich, H. M. 2015; 167 (4): 875-880 e1

    Abstract

    To study the relationship between maternal asthma and the development of bronchopulmonary dysplasia (BPD).Using a large population-based California cohort, we investigated associations between maternal asthma and preterm birth subtype, as well as maternal asthma and BPD. We used data from 2007-2010 maternal delivery discharge records of 2 009 511 pregnancies and International Classification of Diseases, Ninth Revision codes. Preterm birth was defined as <37 weeks gestational age (GA), with subgroups of <28 weeks, 28-32 weeks, and 33-37 weeks GA, as well as preterm subtype, defined as spontaneous, medically indicated, or unknown. Linkage between the 2 California-wide datasets yielded 21 944 singleton preterm infants linked to their mother's records, allowing estimation of the risk of BPD in mothers with asthma and those without asthma.Maternal asthma was associated with increased odds (OR, 1.42; 95% CI, 1.38-1.46) of preterm birth at <37 weeks GA, with the greatest risk for 28-32 GA (aOR, 1.60; 95% CI, 1.47-1.74). Among 21 944 preterm infants, we did not observe an elevated risk for BPD in infants born to mothers with asthma (aOR, 1.03; 95% CI, 0.9-1.2). Stratification by maternal treatment with antenatal steroids revealed increased odds of BPD in infants whose mothers had asthma but did not receive antenatal steroids (aOR, 1.54; 95% CI, 1.15-2.06), but not in infants whose mothers had asthma and were treated with antenatal steroids (aOR, 0.85; 95% CI, 0.67-1.07).Asthma in mothers who did not receive antenatal steroid treatment is associated with an increased risk of BPD in their preterm infants.

    View details for DOI 10.1016/j.jpeds.2015.06.048

    View details for PubMedID 26254835

  • Heightened risk of preterm birth and growth restriction after a first-born son ANNALS OF EPIDEMIOLOGY Bruckner, T. A., Mayo, J. A., Gould, J. B., Stevenson, D. K., Lewis, D. B., Shaw, G. M., Carmichael, S. L. 2015; 25 (10): 743-747

    Abstract

    In Scandinavia, delivery of a first-born son elevates the risk of preterm delivery and intrauterine growth restriction of the next-born infant. External validity of these results remains unclear. We test this hypothesis for preterm delivery and growth restriction using the linked California birth cohort file. We examined the hypothesis separately by race and/or ethnicity.We retrieved data on 2,852,976 births to 1,426,488 mothers with at least two live births. Our within-mother tests applied Cox proportional hazards (preterm delivery, defined as less than 37 weeks gestation) and linear regression models (birth weight for gestational age percentiles).For non-Hispanic whites, Hispanics, Asians, and American Indian and/or Alaska Natives, analyses indicate heightened risk of preterm delivery and growth restriction after a first-born male. The race-specific hazard ratios for preterm delivery range from 1.07 to 1.18. Regression coefficients for birth weight for gestational age percentile range from -0.73 to -1.49. The 95% confidence intervals for all these estimates do not contain the null. By contrast, we could not reject the null for non-Hispanic black mothers.Whereas California findings generally support those from Scandinavia, the null results among non-Hispanic black mothers suggest that we do not detect adverse outcomes after a first-born male in all racial and/or ethnic groups.

    View details for DOI 10.1016/j.annepidem.2015.07.002

    View details for Web of Science ID 000361419000004

    View details for PubMedID 26265442

  • Maternal characteristics and mid-pregnancy serum biomarkers as risk factors for subtypes of preterm birth. BJOG : an international journal of obstetrics and gynaecology Jelliffe-Pawlowski, L. L., Baer, R. J., Blumenfeld, Y. J., Ryckman, K. K., O'Brodovich, H. M., Gould, J. B., Druzin, M. L., El-Sayed, Y. Y., Lyell, D. J., Stevenson, D. K., Shaw, G. M., Currier, R. J. 2015; 122 (11): 1484-1493

    Abstract

    To examine the relationship between maternal characteristics, serum biomarkers and preterm birth (PTB) by spontaneous and medically indicated subtypes.Population-based cohort.California, United States of America.From a total population of 1 004 039 live singleton births in 2009 and 2010, 841 665 pregnancies with linked birth certificate and hospital discharge records were included.Characteristics were compared for term and preterm deliveries by PTB subtype using logistic regression and odds ratios adjusted for maternal characteristics and obstetric factors present in final stepwise models and 95% confidence intervals. First-trimester and second-trimester serum marker levels were analysed in a subset of 125 202 pregnancies with available first-trimester and second-trimester serum biomarker results.PTB by subtype.In fully adjusted models, ten characteristics and three serum biomarkers were associated with increased risk in each PTB subtype (Black race/ethnicity, pre-existing hypertension with and without pre-eclampsia, gestational hypertension with pre-eclampsia, pre-existing diabetes, anaemia, previous PTB, one or two or more previous caesarean section(s), interpregnancy interval ≥ 60 months, low first-trimester pregnancy-associated plasma protein A, high second-trimester α-fetoprotein, and high second-trimester dimeric inhibin A). These risks occurred in 51.6-86.2% of all pregnancies ending in PTB depending on subtype. The highest risk observed was for medically indicated PTB <32 weeks in women with pre-existing hypertension and pre-eclampsia (adjusted odds ratio 89.7, 95% CI 27.3-111.2).Our findings suggest a shared aetiology across PTB subtypes. These commonalities point to targets for further study and exploration of risk reduction strategies.Findings suggest a shared aetiology across preterm birth subtypes. Patterns may inform risk reduction efforts.

    View details for DOI 10.1111/1471-0528.13495

    View details for PubMedID 26111589

  • Serological Targeted Analysis of an ITIH4 Peptide Isoform: A Preterm Birth Biomarker and Its Associated SNP Implications JOURNAL OF GENETICS AND GENOMICS Tan, Z., Hu, Z., Cai, E. Y., Alev, C., Yang, T., Li, Z., Sung, J., El-Sayed, Y. Y., Shaw, G. M., Stevenson, D. K., Butte, A. J., Sheng, G., Sylvester, K. G., Cohen, H. J., Ling, X. B. 2015; 42 (9): 507-510

    View details for DOI 10.1016/j.jgg.2015.06.001

    View details for Web of Science ID 000361919400006

    View details for PubMedID 26408095

  • Trends in Care Practices, Morbidity, and Mortality of Extremely Preterm Neonates, 1993-2012. JAMA Stoll, B. J., Hansen, N. I., Bell, E. F., Walsh, M. C., Carlo, W. A., Shankaran, S., Laptook, A. R., Sánchez, P. J., Van Meurs, K. P., Wyckoff, M., Das, A., Hale, E. C., Ball, M. B., Newman, N. S., Schibler, K., Poindexter, B. B., Kennedy, K. A., Cotten, C. M., Watterberg, K. L., D'Angio, C. T., DeMauro, S. B., Truog, W. E., Devaskar, U., Higgins, R. D. 2015; 314 (10): 1039-1051

    Abstract

    Extremely preterm infants contribute disproportionately to neonatal morbidity and mortality.To review 20-year trends in maternal/neonatal care, complications, and mortality among extremely preterm infants born at Neonatal Research Network centers.Prospective registry of 34,636 infants, 22 to 28 weeks' gestation, birth weight of 401 to 1500 g, and born at 26 network centers between 1993 and 2012.Extremely preterm birth.Maternal/neonatal care, morbidities, and survival. Major morbidities, reported for infants who survived more than 12 hours, were severe necrotizing enterocolitis, infection, bronchopulmonary dysplasia, severe intracranial hemorrhage, cystic periventricular leukomalacia, and/or severe retinopathy of prematurity. Regression models assessed yearly changes and were adjusted for study center, race/ethnicity, gestational age, birth weight for gestational age, and sex.Use of antenatal corticosteroids increased from 1993 to 2012 (24% [348 of 1431 infants]) to 87% (1674 of 1919 infants]; P < .001), as did cesarean delivery (44% [625 of 1431 births] to 64% [1227 of 1921]; P < .001). Delivery room intubation decreased from 80% (1144 of 1433 infants) in 1993 to 65% (1253 of 1922) in 2012 (P < .001). After increasing in the 1990s, postnatal steroid use declined to 8% (141 of 1757 infants) in 2004 (P < .001), with no significant change thereafter. Although most infants were ventilated, continuous positive airway pressure without ventilation increased from 7% (120 of 1666 infants) in 2002 to 11% (190 of 1756 infants) in 2012 (P < .001). Despite no improvement from 1993 to 2004, rates of late-onset sepsis declined between 2005 and 2012 for infants of each gestational age (median, 26 weeks [37% {109 of 296} to 27% {85 of 320}]; adjusted relative risk [RR], 0.93 [95% CI, 0.92-0.94]). Rates of other morbidities declined, but bronchopulmonary dysplasia increased between 2009 and 2012 for infants at 26 to 27 weeks' gestation (26 weeks, 50% [130 of 258] to 55% [164 of 297]; P < .001). Survival increased between 2009 and 2012 for infants at 23 weeks' gestation (27% [41 of 152] to 33% [50 of 150]; adjusted RR, 1.09 [95% CI, 1.05-1.14]) and 24 weeks (63% [156 of 248] to 65% [174 of 269]; adjusted RR, 1.05 [95% CI, 1.03-1.07]), with smaller relative increases for infants at 25 and 27 weeks' gestation, and no change for infants at 22, 26, and 28 weeks' gestation. Survival without major morbidity increased approximately 2% per year for infants at 25 to 28 weeks' gestation, with no change for infants at 22 to 24 weeks' gestation.Among extremely preterm infants born at US academic centers over the last 20 years, changes in maternal and infant care practices and modest reductions in several morbidities were observed, although bronchopulmonary dysplasia increased. Survival increased most markedly for infants born at 23 and 24 weeks' gestation and survival without major morbidity increased for infants aged 25 to 28 weeks. These findings may be valuable in counseling families and developing novel interventions.clinicaltrials.gov Identifier: NCT00063063.

    View details for DOI 10.1001/jama.2015.10244

    View details for PubMedID 26348753

  • Exome Sequencing of Neonatal Blood Spots and the Identification of Genes Implicated in Bronchopulmonary Dysplasia. American journal of respiratory and critical care medicine Li, J., Yu, K., Oehlert, J., Jeliffe-Pawlowski, L. L., Gould, J. B., Stevenson, D. K., Snyder, M., Shaw, G. M., O'Brodovich, H. M. 2015; 192 (5): 589-596

    Abstract

    Bronchopulmonary dysplasia (BPD), a prevalent severe lung disease of premature infants, has a strong genetic component. Large-scale genome-wide association studies for common variants have not revealed its genetic basis.Given the historical high mortality rate of extremely preterm infants who now survive and develop BPD, we hypothesized that risk loci underlying this disease are under severe purifying selection during evolution; thus, rare variants likely explain greater risk of the disease.We performed exome sequencing on 50 BPD-affected and unaffected twin pairs using DNA isolated from neonatal blood spots and identified genes affected by extremely rare nonsynonymous mutations. Functional genomic approaches were then used to systematically compare these affected genes.We identified 258 genes with rare nonsynonymous mutations in patients with BPD. These genes were highly enriched for processes involved in pulmonary structure and function including collagen fibril organization, morphogenesis of embryonic epithelium, and regulation of Wnt signaling pathway; displayed significantly elevated expression in fetal and adult lungs; and were substantially up-regulated in a murine model of BPD. Analyses of mouse mutants revealed their phenotypic enrichment for embryonic development and the cyanosis phenotype, a clinical manifestation of BPD.Our study supports the role of rare variants in BPD, in contrast with the role of common variants targeted by genome-wide association studies. Overall, our study is the first to sequence BPD exomes from newborn blood spot samples and identify with high confidence genes implicated in BPD, thereby providing important insights into its biology and molecular etiology.

    View details for DOI 10.1164/rccm.201501-0168OC

    View details for PubMedID 26030808

  • Bilirubin production and hour-specific bilirubin levels JOURNAL OF PERINATOLOGY Bhutani, V. K., Wong, R. J., Vreman, H. J., Stevenson, D. K. 2015; 35 (9): 735-738

    Abstract

    We assessed the relative contributions of increased bilirubin production (indexed by end-tidal carbon monoxide (CO) concentrations, corrected for ambient CO (ETCOc)) to hour-specific total bilirubin (TB) levels in healthy late preterm and term newborns.Post hoc analyses of concurrent ETCOc and TB (at 30±6 h of age) and follow-up TB levels at age 96±12 h and up to 168 h after birth were performed in a cohort of 641 term and late preterm infants.Increased bilirubin production (hour-specific ETCOc ⩾1.7 p.p.m. at age 30±6 h) was noted in ~80%, 42% and 32% of infants in the high-, intermediate- and low-risk TB zones, respectively. One infant with TB <40th percentile and ETCOc <1.7 p.p.m. developed TB ⩾95th percentile at age 168 h, probably due to decreased bilirubin elimination.Infants in the high-risk quartile of the hour-specific bilirubin nomogram have a higher mean bilirubin production. Infants with TB levels ⩾95th percentile without increased bilirubin production have impaired bilirubin elimination.

    View details for DOI 10.1038/jp.2015.32

    View details for Web of Science ID 000360408600015

  • Determinants of chronic lung disease severity in the first year of life; A population based study PEDIATRIC PULMONOLOGY Gage, S., Kan, P., Oehlert, J., Gould, J. B., Stevenson, D. K., Shaw, G. M., O'Brodovich, H. M. 2015; 50 (9): 878-888

    Abstract

    First, create a clinical severity score for patients with chronic lung disease of infancy (CLDi) following neonatal intensive care unit (NICU) stay. Second, using California wide population-based data, identify factors associated with clinical severity of CLDi at 4-9 months corrected gestational age (CGA).Pediatric pulmonologists ranked and weighted eight factors reflecting clinical severity of CLDi. Utilizing these data we scored and assigned these to 4-9 month old CGA moderate/severe bronchopulmonary dysplasia (BPD) infants, born<30 weeks gestational age (GA), within the California High Risk Infant Follow up (HRIF) program. Infants were studied relative to factors from the California Perinatal Quality Care Collaborative (CPQCC).We received survey responses from 43/88 pediatric pulmonologists from 28/53 North American training centers who are experts in CLDi. Strong agreement between ranking (72-100%) of respiratory system parameters and weighting (out of 100 points weighting was within 20 points) was observed with severity of CLDi. Data from 940 CLDi premature infants <30 weeks GA were obtained. Infants with severe CLDi scores at 4-9 months CGA (relative to a zero score) showed positive associations with being male, odds ratio[OR] = 2.45[confidence interval (CI) 1.26-4.77]), >30 ventilator days, OR = 3.82 (1.30-11.2), postnatal steroids OR = 3.94 (1.94-7.84), and a surprising inverse association with retinopathy of prematurity stage 3-4, OR = 0.24 (0.09-0.67) CONCLUSIONS: The CLDi clinical severity score allowed for standardized assessment of pulmonary morbidity, and evaluation of risk factors in the NICU for CLDi following NICU discharge. These observations point to risk factors associated with CLDi outcomes at 4-9 months CGA. Pediatr Pulmonol. 2015; 50:878-888. © 2015 Wiley Periodicals, Inc.

    View details for DOI 10.1002/ppul.23148

    View details for Web of Science ID 000360091000007

  • Association of HMOX1 gene promoter polymorphisms with hyperbilirubinemia in the early neonatal period PEDIATRICS INTERNATIONAL Katayama, Y., Yokota, T., Zhao, H., Wong, R. J., Stevenson, D. K., Taniguchi-Ikeda, M., Nakamura, H., Iijima, K., Morioka, I. 2015; 57 (4): 645-649

    Abstract

    Heme oxygenase (HO) is the rate-limiting enzyme in the heme degradation pathway that produces bilirubin. The promoter region of human heme oxygenase-1 (HMOX1) contains a polymorphic (GT)n repeat that can regulate gene expression. Here, we investigated the association of (GT)n repeat length in the HMOX1 promoter region with neonatal hyperbilirubinemia in a population of Japanese term neonates.Using polymerase chain reaction and fragment analysis, we determined the number of (GT)n repeats in 149 Japanese neonates. To omit the effects of the G71R mutation in uridine diphosphoglucuronosyltransferase on hyperbilirubinemia, we excluded 41 neonates with the G71R mutation. As a result, 25 neonates with hyperbilirubinemia and 83 non-hyperbilirubinemic controls were included in this prospective case-control study. Allele and genotype frequencies of (GT)n repeats in the HMOX1 gene were compared between hyperbilirubinemic and non-hyperbilirubinemic control neonates.The prevalence of short alleles (< 22 (GT)n repeats) was significantly higher in hyperbilirubinemic than in control neonates (18% vs 7%, P = 0.015). Hyperbilirubinemia was more frequent in homozygous or heterozygous short allele carriers than control neonates (28% vs 11%, respectively, P = 0.03). Possession of short alleles was significantly associated with the development of neonatal hyperbilirubinemia (OR, 3.1; 95%CI: 1.03-9.53).Infants carrying short alleles (< 22 (GT)n repeats) in the HMOX1 gene promoter region appear to be at a higher risk for developing neonatal hyperbilirubinemia.

    View details for DOI 10.1111/ped.12591

    View details for Web of Science ID 000360501500024

  • Case 1: Lactic Acidosis and Respiratory Distress in a 10-Day-Old Infant. NeoReviews Wallenstein, M. B., Olson, K., Peng, D. M., Stevenson, D. K., Shaw, G. M., Palma, J. P., Bain, L. C. 2015; 16 (7): e431-e433

    View details for PubMedID 26236172

    View details for PubMedCentralID PMC4520797

  • Evaluation of a new end-tidal carbon monoxide monitor from the bench tothe bedside ACTA PAEDIATRICA Cuadrado, M. E., Bhutani, V. K., Aby, J. L., Vreman, H. J., Wong, R. J., Stevenson, D. K. 2015; 104 (6): E279-E282

    View details for DOI 10.1111/apa.12938

    View details for Web of Science ID 000354528100008

  • Spatial and temporal patterns in preterm birth in the United States PEDIATRIC RESEARCH Byrnes, J., Mahoney, R., Quaintance, C., Gould, J. B., Carmichael, S., Shaw, G. M., Showen, A., Phibbs, C., Stevenson, D. K., Wise, P. H. 2015; 77 (6): 836-844

    Abstract

    Despite years of research, the etiologies of preterm birth remain unclear. In order to help generate new research hypotheses, this study explored spatial and temporal patterns of preterm birth in a large, total-population dataset.Data on 145 million US births in 3,000 counties from the Natality Files of the National Center for Health Statistics for 1971-2011 were examined. State trends in early (<34 wk) and late (34-36 wk) preterm birth rates were compared. K-means cluster analyses were conducted to identify gestational age distribution patterns for all US counties over time.A weak association was observed between state trends in <34 wk birth rates and the initial absolute <34 wk birth rate. Significant associations were observed between trends in <34 wk and 34-36 wk birth rates and between white and African American <34 wk births. Periodicity was observed in county-level trends in <34 wk birth rates. Cluster analyses identified periods of significant heterogeneity and homogeneity in gestational age distributional trends for US counties.The observed geographic and temporal patterns suggest periodicity and complex, shared influences among preterm birth rates in the United States. These patterns could provide insight into promising hypotheses for further research.

    View details for DOI 10.1038/pr.2015.55

    View details for Web of Science ID 000354755000017

    View details for PubMedID 25760546

  • Serial aEEG recordings in a cohort of extremely preterm infants: feasibility and safety JOURNAL OF PERINATOLOGY Davis, A. S., Gantz, M. G., Do, B., Shankaran, S., Hamrick, S. E., Kennedy, K. A., TYSON, J. E., Chalak, L. F., Laptook, A. R., Goldstein, R. F., Hintz, S. R., Das, A., Higgins, R. D., Ball, M. B., HALE, E. C., Van Meurs, K. P. 2015; 35 (5): 373-378

    Abstract

    Objective:Amplitude-integrated electroencephalography (aEEG) monitoring is increasing in the neonatal population, but the safety and feasibility of performing aEEG in extremely preterm infants have not been systematically evaluated.Study Design:Inborn infants 23(0/7) to 28(6/7) weeks gestation or birth weight 401 to 1000 g were eligible. Serial, 6-h aEEG recordings were obtained from first week of life until 36 weeks postmenstrual age. Adverse events were documented, and surveys evaluated the impact of the aEEGs on routine care. Success of performing aEEGs according to protocol and aEEG quality were assessed.Result:A total of 102 infants were enrolled, with 755 recordings performed. 83% of recordings were performed according to schedule, and 96% were without adverse event. Bedside nurses reported no interference with routine care for 89% of recordings. 92% of recordings had acceptable signal quality.Conclusion:Serial aEEG monitoring is safe in preterm infants, with few adverse events and general acceptance by nursing staff.Journal of Perinatology advance online publication, 4 December 2014; doi:10.1038/jp.2014.217.

    View details for DOI 10.1038/jp.2014.217

    View details for Web of Science ID 000353565200013

    View details for PubMedID 25474559

  • Unique Roles of Infiltrating Myeloid Cells in the Murine Uterus during Early to Midpregnancy. Journal of immunology Zhao, H., Kalish, F., Schulz, S., Yang, Y., Wong, R. J., Stevenson, D. K. 2015; 194 (8): 3713-3722

    Abstract

    Leukocyte infiltration into the uterus is a characteristic feature in early to midpregnancy, but the composition and function of these leukocytes are not well understood. Using a pregnant murine model, we showed that myeloid cells and uterine NK (uNK) cells were the predominant populations in uteri during early to midgestation, whereas T and B cells were constrained. Uterine myeloid populations included cells that infiltrated from the circulation (myeloid-derived suppressor cells [MDSCs], monocyte-derived macrophages [Mφs], and dendritic cells [DCs]) or proliferated from resident precursors (resident Mφs [Re-Mφs] and DCs). CD11b(hi)Ly6-G(hi) cells, representing neutrophils in both blood and uterine MDSCs, significantly increased from embryonic days 8.5 to 9.5. To understand their putative functions, we used anti-Gr-1 Ab to deplete circulating neutrophils and uterine MDSCs. In the absence of MDSC suppression, uterine DCs, T cells, and regulatory T cells expanded. Conversely, uterine MDSCs responded to LPS-induced inflammation and transformed into CD14(+)-activated neutrophils, resulting in an upregulation of tolerogenic DCs. A high dose of LPS (2.5 μg/mouse) significantly increased the influx of neutrophils and production of proinflammatory cytokines, such as IL-1β and TNF-α, resulting in the reduction of Re-Mφs and uNK cells, and led to placental hemorrhages and fetal deaths. In summary, uterine MDSCs are important in early to midpregnancy by responding to the maternal immunologic milieu and protecting uNK cells and Re-Mφs via MDSC's suppressive and anti-inflammatory functions. Upsetting this delicate immune balance by factors leading to either insufficient MDSCs or excessive neutrophil infiltration in the fetomaternal interface may contribute to pregnancy failure.

    View details for DOI 10.4049/jimmunol.1401930

    View details for PubMedID 25780045

  • Effect of Heme Oxygenase-1 on the immunosuppressive Function of DecIdual Myeloid Cells. Zhao, H., Kalish, F., Wong, R. J., Stevenson, D. K. SAGE PUBLICATIONS INC. 2015: 325A
  • Acute Subclinical Maternal Inflammation in Late Pregnancy Ozen, M., Zhao, H., Winn, V. D., Lewis, D. B., Kalish, F., Palmer, T. D., Wong, R. J., Stevenson, D. K. SAGE PUBLICATIONS INC. 2015: 89A–90A
  • Cognitive Outcomes After Neonatal Encephalopathy PEDIATRICS Pappas, A., Shankaran, S., McDonald, S. A., Vohr, B. R., Hintz, S. R., Ehrenkranz, R. A., Tyson, J. E., Yolton, K., Das, A., Bara, R., Hammond, J., Higgins, R. D. 2015; 135 (3): E624-E634

    Abstract

    To describe the spectrum of cognitive outcomes of children with and without cerebral palsy (CP) after neonatal encephalopathy, evaluate the prognostic value of early developmental testing and report on school services and additional therapies.The participants of this study are the school-aged survivors of the National Institute of Child Health and Human Development Neonatal Research Network randomized controlled trial of whole-body hypothermia. Children underwent neurologic examinations and neurodevelopmental and cognitive testing with the Bayley Scales of Infant Development-II at 18 to 22 months and the Wechsler intelligence scales and the Neuropsychological Assessment-Developmental Neuropsychological Assessment at 6 to 7 years. Parents were interviewed about functional status and receipt of school and support services. We explored predictors of cognitive outcome by using multiple regression models.Subnormal IQ scores were identified in more than a quarter of the children: 96% of survivors with CP had an IQ <70, 9% of children without CP had an IQ <70, and 31% had an IQ of 70 to 84. Children with a mental developmental index <70 at 18 months had, on average, an adjusted IQ at 6 to 7 years that was 42 points lower than that of those with a mental developmental index >84 (95% confidence interval, -49.3 to -35.0; P < .001). Twenty percent of children with normal IQ and 28% of those with IQ scores of 70 to 84 received special educational support services or were held back ≥1 grade level.Cognitive impairment remains an important concern for all children with neonatal encephalopathy.

    View details for DOI 10.1542/peds.2014-1566

    View details for Web of Science ID 000352206600010

    View details for PubMedID 25713280

    View details for PubMedCentralID PMC4338321

  • Hospital variation and risk factors for bronchopulmonary dysplasia in a population-based cohort. JAMA pediatrics Lapcharoensap, W., Gage, S. C., Kan, P., Profit, J., Shaw, G. M., Gould, J. B., Stevenson, D. K., O'Brodovich, H., Lee, H. C. 2015; 169 (2)

    View details for DOI 10.1001/jamapediatrics.2014.3676

    View details for PubMedID 25642906

  • Hospital variation and risk factors for bronchopulmonary dysplasia in a population-based cohort. JAMA pediatrics Lapcharoensap, W., Gage, S. C., Kan, P., Profit, J., Shaw, G. M., Gould, J. B., Stevenson, D. K., O'Brodovich, H., Lee, H. C. 2015; 169 (2)

    Abstract

    Bronchopulmonary dysplasia (BPD) remains a serious morbidity in very low-birth-weight (VLBW) infants (<1500 g). Deregionalization of neonatal care has resulted in an increasing number of VLBW infants treated in community hospitals with unknown impact on the development of BPD.To identify individual risk factors for BPD development and hospital variation of BPD rates across all levels of neonatal intensive care units (NICUs) within the California Perinatal Quality Care Collaborative.Retrospective cohort study (January 2007 to December 2011) from the California Perinatal Quality Care Collaborative including more than 90% of California's NICUs. Eligible VLBW infants born between 22 to 29 weeks' gestational age.Varying levels of intensive care.Bronchopulmonary dysplasia was defined as continuous supplemental oxygen use at 36 weeks' postmenstrual age. A combined outcome of BPD or mortality prior to 36 weeks was used. Multivariable logistic regression accounting for hospital as a random effect and gestational age as a risk factor was used to assess individual risk factors for BPD. This model was applied to determine risk-adjusted rates of BPD across hospitals and assess associations between levels of care and BPD rates.The study cohort included 15 779 infants, of which 1534 infants died prior to 36 weeks' postmenstrual age. A total of 7081 infants, or 44.8%, met the primary outcome of BPD or death prior to 36 weeks. Combined BPD or death rates across 116 NICUs varied from 17.7% to 73.4% (interquartile range, 38.7%-54.1%). Compared with level IV NICUs, the risk for developing BPD was higher for level II NICUs (odds ratio, 1.23; 95% CI, 1.02-1.49) and similar for level III NICUs (odds ratio, 1.04; 95% CI, 0.95-1.14).Bronchopulmonary dysplasia or death prior to 36 weeks' postmenstrual age affects approximately 45% of VLBW infants across California. The wide variability in BPD occurrence across hospitals could offer insights into potential risk or preventive factors. Additionally, our findings suggest that increased regionalization of NICU care may reduce BPD among VLBW infants.

    View details for DOI 10.1001/jamapediatrics.2014.3676

    View details for PubMedID 25642906

  • New technique for umbilical artery catheter placement in the neonate. journal of pediatrics Wallenstein, M. B., Stevenson, D. K. 2015; 166 (2): 501-?

    View details for DOI 10.1016/j.jpeds.2014.10.027

    View details for PubMedID 25453247

  • Neonatal hemolysis and risk of bilirubin-induced neurologic dysfunction. Seminars in fetal & neonatal medicine Wong, R. J., Stevenson, D. K. 2015; 20 (1): 26-30

    Abstract

    The pathologic phenotype of severe hyperbilirubinemia in the newborn infant is primarily due to excessive bilirubin production and/or impaired conjugation, resulting in an increased bilirubin load. This may, in turn, increase an infant's risk for the development of bilirubin-induced neurologic dysfunction (BIND). The highest-risk infants are those with increased bilirubin production rates due to hemolysis. Several immune and non-immune conditions have been found to cause severe hemolysis, and these are often exacerbated in those infants with perinatal sepsis and genetic predispositions. Therefore, identification of these infants, with novel technologies, is paramount in reducing the incidence of BIND and the long-term neurologic sequelae for these at-risk infants.

    View details for DOI 10.1016/j.siny.2014.12.005

    View details for PubMedID 25560401

  • Neonatal bilirubin binding capacity discerns risk of neurological dysfunction. Pediatric research Lamola, A. A., Bhutani, V. K., Du, L., Castillo Cuadrado, M., Chen, L., Shen, Z., Wong, R. J., Stevenson, D. K. 2015; 77 (2): 334-339

    Abstract

    Bilirubin binding capacity (BBC) defines the dynamic relationship between an infant's level of unbound or "free" bilirubin and his/her ability to "tolerate" increasing bilirubin loads. BBC is not synonymous with albumin (Alb) levels because Alb binding of bilirubin is confounded by a variety of molecular, biologic, and metabolic factors.We utilized a novel modification of a previously developed hematofluorometric method to directly assay BBC in whole blood from preterm and term neonates and then combined these data with an archived database. Total bilirubin (TB) was also measured, and multiple regression modeling was used to determine whether BBC in combination with TB measurements can assess an infant's risk for developing bilirubin-induced neurotoxicity.TB and BBC levels ranged from 0.7-22.8 to 6.3-47.5 mg/dl, respectively. Gestational age (GA) correlated with BBC (r = 0.54; P < 0.0002) with a slope of 0.93 mg/dl/wk by logistic regression. Our calculations demonstrate that recently recommended GA-modulated TB thresholds for phototherapy and exchange transfusion correspond to 45 and 67% saturation of our observed regression line, respectively.We speculate that the spread of BBC levels around the regression line (±5.8 mg/dl) suggests that individualized BBC assays would provide a robust approach to gauge risk of bilirubin neurotoxicity compared with TB and GA.

    View details for DOI 10.1038/pr.2014.191

    View details for PubMedID 25420178

  • Causes and timing of death in extremely premature infants from 2000 through 2011. New England journal of medicine Patel, R. M., Kandefer, S., Walsh, M. C., Bell, E. F., Carlo, W. A., Laptook, A. R., Sánchez, P. J., Shankaran, S., Van Meurs, K. P., Ball, M. B., Hale, E. C., Newman, N. S., Das, A., Higgins, R. D., Stoll, B. J. 2015; 372 (4): 331-340

    Abstract

    Understanding the causes and timing of death in extremely premature infants may guide research efforts and inform the counseling of families.We analyzed prospectively collected data on 6075 deaths among 22,248 live births, with gestational ages of 22 0/7 to 28 6/7 weeks, among infants born in study hospitals within the National Institute of Child Health and Human Development Neonatal Research Network. We compared overall and cause-specific in-hospital mortality across three periods from 2000 through 2011, with adjustment for baseline differences.The number of deaths per 1000 live births was 275 (95% confidence interval [CI], 264 to 285) from 2000 through 2003 and 285 (95% CI, 275 to 295) from 2004 through 2007; the number decreased to 258 (95% CI, 248 to 268) in the 2008-2011 period (P=0.003 for the comparison across three periods). There were fewer pulmonary-related deaths attributed to the respiratory distress syndrome and bronchopulmonary dysplasia in 2008-2011 than in 2000-2003 and 2004-2007 (68 [95% CI, 63 to 74] vs. 83 [95% CI, 77 to 90] and 84 [95% CI, 78 to 90] per 1000 live births, respectively; P=0.002). Similarly, in 2008-2011, as compared with 2000-2003, there were decreases in deaths attributed to immaturity (P=0.05) and deaths complicated by infection (P=0.04) or central nervous system injury (P<0.001); however, there were increases in deaths attributed to necrotizing enterocolitis (30 [95% CI, 27 to 34] vs. 23 [95% CI, 20 to 27], P=0.03). Overall, 40.4% of deaths occurred within 12 hours after birth, and 17.3% occurred after 28 days.We found that from 2000 through 2011, overall mortality declined among extremely premature infants. Deaths related to pulmonary causes, immaturity, infection, and central nervous system injury decreased, while necrotizing enterocolitis-related deaths increased. (Funded by the National Institutes of Health.).

    View details for DOI 10.1056/NEJMoa1403489

    View details for PubMedID 25607427

  • Heme oxygenase-1 in pregnancy and cancer: similarities in cellular invasion, cytoprotection, angiogenesis, and immunomodulation FRONTIERS IN PHARMACOLOGY Zhao, H., Ozen, M., Wong, R. J., Stevenson, D. K. 2015; 5
  • Heme oxygenase and the immune system in normal and pathological pregnancies. Frontiers in pharmacology Ozen, M., Zhao, H., Lewis, D. B., Wong, R. J., Stevenson, D. K. 2015; 6: 84-?

    Abstract

    Normal pregnancy is an immunotolerant state. Many factors, including environmental, socioeconomic, genetic, and immunologic changes by infection and/or other causes of inflammation, may contribute to inter-individual differences resulting in a normal or pathologic pregnancy. In particular, imbalances in the immune system can cause many pregnancy-related diseases, such as infertility, abortions, pre-eclampsia, and preterm labor, which result in maternal/fetal death, prematurity, or small-for-gestational age newborns. New findings imply that myeloid regulatory cells and regulatory T cells (Tregs) may mediate immunotolerance during normal pregnancy. Effector T cells (Teffs) have, in contrast, been implicated to cause adverse pregnancy outcomes. Furthermore, feto-maternal tolerance affects the developing fetus. It has been shown that the Treg/Teff balance affects litter size and adoptive transfer of pregnancy-induced Tregs can prevent fetal rejection in the mouse. Heme oxygenase-1 (HO-1) has a protective role in many conditions through its anti-inflammatory, anti-apoptotic, antioxidative, and anti-proliferative actions. HO-1 is highly expressed in the placenta and plays a role in angiogenesis and placental vascular development and in regulating vascular tone in pregnancy. In addition, HO-1 is a major regulator of immune homeostasis by mediating crosstalk between innate and adaptive immune systems. Moreover, HO-1 can inhibit inflammation-induced phenotypic maturation of immune effector cells and pro-inflammatory cytokine secretion and promote anti-inflammatory cytokine production. HO-1 may also be associated with T-cell activation and can limit immune-based tissue injury by promoting Treg suppression of effector responses. Thus, HO-1 and its byproducts may protect against pregnancy complications by its immunomodulatory effects, and the regulation of HO-1 or its downstream effects has the potential to prevent or treat pregnancy complications and prematurity.

    View details for DOI 10.3389/fphar.2015.00084

    View details for PubMedID 25964759

    View details for PubMedCentralID PMC4408852

  • THE EFFECT OF HEMATOCRIT ON IN VITRO BILIRUBIN PHOTOALTERATION UNDER BLUE AND BLUE-GREEN LIGHT Linfield, D. T., Mei, E., Hwang, A. Y., Vreman, H. J., Lamola, A. A., Wong, R. J., Stevenson, D. K. LIPPINCOTT WILLIAMS & WILKINS. 2015: 133
  • EFFICACY AND SAFETY OF A NEW HEME FORMULATION FOR USE IN THE STUDY OF SEVERE NEONATAL HYPERBILIRUBINEMIA Lin, D. N., Wagner, M., Wong, R. J., Stevenson, D. K. LIPPINCOTT WILLIAMS & WILKINS. 2015: 149–50
  • HEME OXYGENASE-1 PROMOTER POLYMORPHISMS AND RISK OF SPINA BIFIDA Fujioka, K., Yang, W., Wallenstein, M. B., Zhao, H., Wong, R. J., Stevenson, D. K., Shaw, G. M. LIPPINCOTT WILLIAMS & WILKINS. 2015: 174–75
  • THE EFFECT OF HEMATOCRIT ON IN VITRO BILIRUBIN PHOTOALTERATION UNDER BLUE AND BLUE-GREEN LIGHT Linfield, D. T., Mei, E., Hwang, A. Y., Vreman, H. J., Lamola, A. A., Wong, R. J., Stevenson, D. K. LIPPINCOTT WILLIAMS & WILKINS. 2015: 147–48
  • A MURINE MODEL OF ACUTE SUBCLINICAL MATERNAL INFLAMMATION IN LATE PREGNANCY Ozen, M., Zhao, H., Winn, V. D., Kalish, F., Palmer, T. D., Wong, R. J., Stevenson, D. K. LIPPINCOTT WILLIAMS & WILKINS. 2015: 190
  • Evaluation of a cumulative first trimester characteristic and serum marker risk score for predicting early spontaneous preterm birth Jelliffe-Pawlowski, L. L., Baer, R., Blumenfeld, Y., Chambers, C., Druzin, M., El-Sayed, Y., Kuppermann, M., Lyell, D., Norton, M., O'Brodovich, H., Ryckman, K., Shaw, G., Stevenson, D., Currier, R. MOSBY-ELSEVIER. 2015: S142
  • Spontaneous preterm birth risk among inter-racial/ethnic couples Shachar, B., Mayo, J., Lyell, D., Stevenson, D., Shaw, G., Blumenfeld, Y. MOSBY-ELSEVIER. 2015: S82
  • IN VIVO INHIBITION OF HEME OXYGENASE ACTIVITY IN THE HEME-LOADED NEWBORN MOUSE USING A MICROPARTICLE FORMULATION OF ZINC PROTOPORPHYRIN Fujioka, K., Wong, R. J., Stevenson, D. K. LIPPINCOTT WILLIAMS & WILKINS. 2015: 213
  • Prediction of early spontaneous preterm birth using placental, lipid, and immune related markers Jelliffe-Pawlowski, L., Ryckman, K., Bedell, B., Baer, R., O'Brodovich, H., Gould, J., Currier, R., Shaw, G., Murray, J., Stevenson, D. MOSBY-ELSEVIER. 2015: S292
  • Antenatal magnesium sulfate exposure and acute cardiorespiratory events in preterm infants AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY De Jesus, L. C., Sood, B. G., Shankaran, S., Kendrick, D., Das, A., Bell, E. F., Stoll, B. J., Laptook, A. R., Walsh, M. C., Carlo, W. A., Sanchez, P. J., Van Meurs, K. P., Bara, R., Hale, E. C., Newman, N. S., Ball, M. B., Higgins, R. D. 2015; 212 (1)

    Abstract

    Antenatal magnesium (anteMg) is used for various obstetric indications including fetal neuroprotection. Infants exposed to anteMg may be at risk for respiratory depression and delivery room (DR) resuscitation. The study objective was to compare the risk of acute cardiorespiratory events among preterm infants who were and were not exposed to anteMg.This was a retrospective analysis of prospective data collected in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network's Generic Database from April 1, 2011, through March 31, 2012. The primary outcome was DR intubation or respiratory support at birth or on day 1 of life. Secondary outcomes were invasive mechanical ventilation, hypotension treatment, neonatal morbidities, and mortality. Logistic regression analysis evaluated the risk of primary outcome after adjustment for covariates.We evaluated 1544 infants <29 weeks' gestational age (1091 in anteMg group and 453 in nonexposed group). Mothers in the anteMg group were more likely to have higher education, pregnancy-induced hypertension, and antenatal corticosteroids, while their infants were younger in gestation and weighed less (P < .05). The primary outcome (odds ratio [OR], 1.2; 95% confidence interval [CI], 0.88-1.65) was similar between groups. Hypotension treatment (OR, 0.70; 95% CI, 0.51-0.97) and invasive mechanical ventilation (OR, 0.54; 95% CI, 0.41-0.72) were significantly less in the anteMg group.Among preterm infants age <29 weeks' gestation, anteMg exposure was not associated with an increase in cardiorespiratory events in the early newborn period. The safety of anteMg as measured by the need for DR intubation or respiratory support on day 1 of life was comparable between groups.

    View details for DOI 10.1016/j.ajog.2014.07.023

    View details for Web of Science ID 000346585700032

    View details for PubMedID 25046806

    View details for PubMedCentralID PMC4275326

  • Heme oxygenase and the immune system in normal and pathological pregnancies. Frontiers in pharmacology Ozen, M., Zhao, H., Lewis, D. B., Wong, R. J., Stevenson, D. K. 2015; 6: 84-?

    View details for DOI 10.3389/fphar.2015.00084

    View details for PubMedID 25964759

  • Neuroimaging and neurodevelopmental outcome in extremely preterm infants. Pediatrics Hintz, S. R., Barnes, P. D., Bulas, D., Slovis, T. L., Finer, N. N., Wrage, L. A., Das, A., Tyson, J. E., Stevenson, D. K., Carlo, W. A., Walsh, M. C., Laptook, A. R., Yoder, B. A., Van Meurs, K. P., Faix, R. G., Rich, W., Newman, N. S., Cheng, H., Heyne, R. J., Vohr, B. R., Acarregui, M. J., Vaucher, Y. E., Pappas, A., Peralta-Carcelen, M., Wilson-Costello, D. E., Evans, P. W., Goldstein, R. F., Myers, G. J., Poindexter, B. B., McGowan, E. C., Adams-Chapman, I., Fuller, J., Higgins, R. D. 2015; 135 (1): e32-42

    View details for DOI 10.1542/peds.2014-0898

    View details for PubMedID 25554820

  • Neuroimaging and neurodevelopmental outcome in extremely preterm infants. Pediatrics Hintz, S. R., Barnes, P. D., Bulas, D., Slovis, T. L., Finer, N. N., Wrage, L. A., Das, A., Tyson, J. E., Stevenson, D. K., Carlo, W. A., Walsh, M. C., Laptook, A. R., Yoder, B. A., Van Meurs, K. P., Faix, R. G., Rich, W., Newman, N. S., Cheng, H., Heyne, R. J., Vohr, B. R., Acarregui, M. J., Vaucher, Y. E., Pappas, A., Peralta-Carcelen, M., Wilson-Costello, D. E., Evans, P. W., Goldstein, R. F., Myers, G. J., Poindexter, B. B., McGowan, E. C., Adams-Chapman, I., Fuller, J., Higgins, R. D. 2015; 135 (1): e32-42

    Abstract

    Extremely preterm infants are at risk for neurodevelopmental impairment (NDI). Early cranial ultrasound (CUS) is usual practice, but near-term brain MRI has been reported to better predict outcomes. We prospectively evaluated MRI white matter abnormality (WMA) and cerebellar lesions, and serial CUS adverse findings as predictors of outcomes at 18 to 22 months' corrected age.Early and late CUS, and brain MRI were read by masked central readers, in a large cohort (n = 480) of infants <28 weeks' gestation surviving to near term in the Neonatal Research Network. Outcomes included NDI or death after neuroimaging, and significant gross motor impairment or death, with NDI defined as cognitive composite score <70, significant gross motor impairment, and severe hearing or visual impairment. Multivariable models evaluated the relative predictive value of neuroimaging while controlling for other factors.Of 480 infants, 15 died and 20 were lost. Increasing severity of WMA and significant cerebellar lesions on MRI were associated with adverse outcomes. Cerebellar lesions were rarely identified by CUS. In full multivariable models, both late CUS and MRI, but not early CUS, remained independently associated with NDI or death (MRI cerebellar lesions: odds ratio, 3.0 [95% confidence interval: 1.3-6.8]; late CUS: odds ratio, 9.8 [95% confidence interval: 2.8-35]), and significant gross motor impairment or death. In models that did not include late CUS, MRI moderate-severe WMA was independently associated with adverse outcomes.Both late CUS and near-term MRI abnormalities were associated with outcomes, independent of early CUS and other factors, underscoring the relative prognostic value of near-term neuroimaging.

    View details for DOI 10.1542/peds.2014-0898

    View details for PubMedID 25554820

  • Effect of Depth and Duration of Cooling on Deaths in the NICU Among Neonates With Hypoxic Ischemic Encephalopathy A Randomized Clinical Trial JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Shankaran, S., Laptook, A. R., Pappas, A., McDonald, S. A., Das, A., Tyson, J. E., Poindexter, B. B., Schibler, K., Bell, E. F., Heyne, R. J., Pedroza, C., Bara, R., Van Meurs, K. P., Grisby, C., Huitema, C. M., Garg, M., Ehrenkranz, R. A., Shepherd, E. G., Chalak, L. F., Hamrick, S. E., Khan, A. M., Reynolds, A. M., Laughon, M. M., Truog, W. E., Dysart, K. C., Carlo, W. A., Walsh, M. C., Watterberg, K. L., Higgins, R. D. 2014; 312 (24): 2629-2639

    Abstract

    Hypothermia at 33.5°C for 72 hours for neonatal hypoxic ischemic encephalopathy reduces death or disability to 44% to 55%; longer cooling and deeper cooling are neuroprotective in animal models.To determine if longer duration cooling (120 hours), deeper cooling (32.0°C), or both are superior to cooling at 33.5°C for 72 hours in neonates who are full-term with moderate or severe hypoxic ischemic encephalopathy.A randomized, 2 × 2 factorial design clinical trial performed in 18 US centers in the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Neonatal Research Network between October 2010 and November 2013.Neonates were assigned to 4 hypothermia groups; 33.5°C for 72 hours, 32.0°C for 72 hours, 33.5°C for 120 hours, and 32.0°C for 120 hours.The primary outcome of death or disability at 18 to 22 months is ongoing. The independent data and safety monitoring committee paused the trial to evaluate safety (cardiac arrhythmia, persistent acidosis, major vessel thrombosis and bleeding, and death in the neonatal intensive care unit [NICU]) after the first 50 neonates were enrolled, then after every subsequent 25 neonates. The trial was closed for emerging safety profile and futility analysis after the eighth review with 364 neonates enrolled (of 726 planned). This report focuses on safety and NICU deaths by marginal comparisons of 72 hours' vs 120 hours' duration and 33.5°C depth vs 32.0°C depth (predefined secondary outcomes).The NICU death rates were 7 of 95 neonates (7%) for the 33.5°C for 72 hours group, 13 of 90 neonates (14%) for the 32.0°C for 72 hours group, 15 of 96 neonates (16%) for the 33.5°C for 120 hours group, and 14 of 83 neonates (17%) for the 32.0°C for 120 hours group. The adjusted risk ratio (RR) for NICU deaths for the 120 hours group vs 72 hours group was 1.37 (95% CI, 0.92-2.04) and for the 32.0°C group vs 33.5°C group was 1.24 (95% CI, 0.69-2.25). Safety outcomes were similar between the 120 hours group vs 72 hours group and the 32.0°C group vs 33.5°C group, except major bleeding occurred among 1% in the 120 hours group vs 3% in the 72 hours group (RR, 0.25 [95% CI, 0.07-0.91]). Futility analysis determined that the probability of detecting a statistically significant benefit for longer cooling, deeper cooling, or both for NICU death was less than 2%.Among neonates who were full-term with moderate or severe hypoxic ischemic encephalopathy, longer cooling, deeper cooling, or both compared with hypothermia at 33.5°C for 72 hours did not reduce NICU death. These results have implications for patient care and design of future trials.clinicaltrials.gov Identifier: NCT01192776.

    View details for DOI 10.1001/jama.2014.16058

    View details for Web of Science ID 000346966100015

    View details for PubMedID 25536254

  • Traffic-related air pollution and risk of preterm birth in the San Joaquin Valley of California ANNALS OF EPIDEMIOLOGY Padula, A. M., Mortimer, K. M., Tager, I. B., Hammond, S. K., Lurmann, F. W., Yang, W., Stevenson, D. K., Shaw, G. M. 2014; 24 (12): 888-895

    Abstract

    To evaluate associations between traffic-related air pollution during pregnancy and preterm birth in births in four counties in California during years 2000 to 2006.We used logistic regression to examine the association between the highest quartile of ambient air pollutants (carbon monoxide, nitrogen dioxide, particulate matter <10 and 2.5 μm) and traffic density during pregnancy and each of five levels of prematurity based on gestational age at birth (20-23, 24-27, 28-31, 32-33, and 34-36 weeks) versus term (37-42 weeks). We examined trimester averages and the last month and the last 6 weeks of pregnancy. Models were adjusted for birthweight, maternal age, race/ethnicity, education, prenatal care, and birth costs payment. Neighborhood socioeconomic status (SES) was evaluated as a potential effect modifier.There were increased odds ratios (ORs) for early preterm birth for those exposed to the highest quartile of each pollutant during the second trimester and the end of pregnancy (adjusted OR, 1.4-2.8). Associations were stronger among mothers living in low SES neighborhoods (adjusted OR, 2.1-4.3). We observed exposure-response associations for multiple pollutant exposures and early preterm birth. Inverse associations during the first trimester were observed.The results confirm associations between traffic-related air pollution and prematurity, particularly among very early preterm births and low SES neighborhoods.

    View details for DOI 10.1016/j.annepidem.2014.10.004

    View details for Web of Science ID 000345497100004

    View details for PubMedCentralID PMC4355392

  • Direct Antiglobulin Titer Strength and Hyperbilirubinemia PEDIATRICS Kaplan, M., Hammerman, C., Vreman, H. J., Wong, R. J., Stevenson, D. K. 2014; 134 (5): E1340-E1344

    Abstract

    We recently demonstrated that direct antiglobulin titer (DAT) positive, blood group A or B newborns born to group O mothers had a high incidence of hyperbilirubinemia, attributable to increased hemolysis. We reanalyzed our data asking whether increasing DAT strength plays a modulating role in the pathophysiology of the hemolysis and hyperbilirubinemia.Data from previously published DAT-positive, ABO-heterospecific neonates were analyzed for hyperbilirubinemia and hemolysis according to strength of DAT. DAT was measured by using a gel agglutination technique and reported as values ranging from DAT ± to DAT ++++. Hemolysis was evaluated by blood carboxyhemoglobin corrected for inspired, ambient CO (COHbc), and expressed as percent total hemoglobin (tHb). Hyperbilirubinemia was defined as any plasma total bilirubin value >95th percentile on the hour-specific nomogram.Hyperbilirubinemia was more prevalent in those with DAT ++ readings (16 of 20, 80%) than those both DAT ± (37 of 87 [42.5%], relative risk: 1.88, 95% confidence interval: 1.35-2.61) and DAT + (32 of 56 [57.1%], relative risk: 1.40, 95% confidence interval: 1.02-1.92). COHbc values were higher for those with DAT ++ (1.45 ± 0.49% tHb [mean ± SD]) than those DAT ± (1.20 ± 0.37% tHb, P = .01) or DAT + (1.22 ± 0.37% tHb, P = .02).DAT ++ readings were associated with a higher incidence of hyperbilirubinemia and higher COHbc values than DAT ± or DAT + counterparts. Increasing DAT strength may be a modulator of hemolysis and hyperbilirubinemia in ABO-heterospecific neonates. DAT strength, and not merely DAT presence or absence, should be taken into consideration in the management of ABO-heterospecific newborns.

    View details for DOI 10.1542/peds.2014-1290

    View details for Web of Science ID 000344385900009

  • Functional status at 18 months of age as a predictor of childhood disability after neonatal hypoxic-ischemic encephalopathy DEVELOPMENTAL MEDICINE AND CHILD NEUROLOGY Natarajan, G., Shankaran, S., Pappas, A., Bann, C., Tyson, J. E., McDonald, S., Das, A., Hintz, S., Vohr, B., Higgins, R. 2014; 56 (11): 1052-1058

    Abstract

    In children with neonatal hypoxic-ischemic encephalopathy (HIE), we examined the association between 18-month functional status by parental report and disability at 6-7 years.Prospective observational study involving participants in the NICHD randomized controlled trial of hypothermia for HIE. Parent questionnaires-Functional Status-II (FS-II), Impact on Family (IOF) and Family Resource Scale (FRS) at 18 months were correlated with 6- to 7-year developmental assessments. Disability at 6-7 years was defined as IQ < 70, gross motor functional classification scale level III-V, bilateral blindness, deafness, or epilepsy.Rates of severe HIE (32 vs. 15%), public insurance (73% vs. 47%) and IOF scales were higher and mean (SD) FS-II independence (I) {54 (SD 35) vs. 98 (SD 8)} and general health (GH) {87 (SD 14) vs. 98 (SD 6)} scores were significantly lower in children with disability (n=37) at 6-7 years, compared to those (n=74) without disability. FS-II I scores were significantly associated with disability (OR 0.92; 95% CI 0.87-0.97; p=0.003). On path analysis, severe HIE, greater IOF and public insurance were associated with poorer 18-month FS-II I scores, which, in turn, were associated with disability at 6 to 7 years.Poor independent functioning by parental report at 18 months in children with HIE was associated with childhood disability.

    View details for DOI 10.1111/dmcn.12512

    View details for Web of Science ID 000343803100012

    View details for PubMedCentralID PMC4324462

  • Prophylactic Indomethacin and Intestinal Perforation in Extremely Low Birth Weight Infants PEDIATRICS Kelleher, J., Salas, A. A., Bhat, R., Ambalavanan, N., Saha, S., Stoll, B. J., Bell, E. F., Walsh, M. C., Laptook, A. R., Sanchez, P. J., Shankaran, S., VanMeurs, K. P., Hale, E. C., Newman, N. S., Ball, M. B., Das, A., Higgins, R. D., Peralta-Carcelen, M., Carlo, W. A. 2014; 134 (5): E1369-E1377
  • Prevention of traumatic stress in mothers of preterms: 6-month outcomes. Pediatrics Shaw, R. J., St John, N., Lilo, E., Jo, B., Benitz, W., Stevenson, D. K., Horwitz, S. M. 2014; 134 (2): e481-8

    Abstract

    Symptoms of posttraumatic stress disorder are a well-recognized phenomenon in mothers of preterm infants, with implications for maternal health and infant outcomes. This randomized controlled trial evaluated 6-month outcomes from a skills-based intervention developed to reduce symptoms of posttraumatic stress disorder, anxiety, and depression.One hundred five mothers of preterm infants were randomly assigned to (1) a 6- or 9-session intervention based on principles of trauma-focused cognitive behavior therapy with infant redefinition or (2) a 1-session active comparison intervention based on education about the NICU and parenting of the premature infant. Outcome measures included the Davidson Trauma Scale, the Beck Depression Inventory II, and the Beck Anxiety Inventory. Participants were assessed at baseline, 4 to 5 weeks after birth, and 6 months after the birth of the infant.At the 6-month assessment, the differences between the intervention and comparison condition were all significant and sizable and became more pronounced when compared with the 4- to 5-week outcomes: Davidson Trauma Scale (Cohen's d = -0.74, P < .001), Beck Anxiety Inventory (Cohen's d = -0.627, P = .001), Beck Depression Inventory II (Cohen's d = -0.638, P = .002). However, there were no differences in the effect sizes between the 6- and 9-session interventions.A brief 6-session intervention based on principles of trauma-focused cognitive behavior therapy was effective at reducing symptoms of trauma, anxiety, and depression in mothers of preterm infants. Mothers showed increased benefits at the 6-month follow-up, suggesting that they continue to make use of techniques acquired during the intervention phase.

    View details for DOI 10.1542/peds.2014-0529

    View details for PubMedID 25049338

  • Respiratory Outcomes of the Surfactant Positive Pressure and Oximetry Randomized Trial (SUPPORT). journal of pediatrics Stevens, T. P., Finer, N. N., Carlo, W. A., Szilagyi, P. G., Phelps, D. L., Walsh, M. C., Gantz, M. G., Laptook, A. R., Yoder, B. A., Faix, R. G., Newman, J. E., Das, A., Do, B. T., Schibler, K., Rich, W., Newman, N. S., Ehrenkranz, R. A., Peralta-Carcelen, M., Vohr, B. R., Wilson-Costello, D. E., Yolton, K., Heyne, R. J., Evans, P. W., Vaucher, Y. E., Adams-Chapman, I., McGowan, E. C., Bodnar, A., Pappas, A., Hintz, S. R., Acarregui, M. J., Fuller, J., Goldstein, R. F., Bauer, C. R., O'Shea, T. M., Myers, G. J., Higgins, R. D. 2014; 165 (2): 240-249 e4

    Abstract

    To explore the early childhood pulmonary outcomes of infants who participated in the National Institute of Child Health and Human Development's Surfactant Positive Airway Pressure and Pulse Oximetry Randomized Trial (SUPPORT), using a factorial design that randomized extremely preterm infants to lower vs higher oxygen saturation targets and delivery room continuous positive airway pressure (CPAP) vs intubation/surfactant.The Breathing Outcomes Study, a prospective secondary study to the Surfactant Positive Airway Pressure and Pulse Oximetry Randomized Trial, assessed respiratory morbidity at 6-month intervals from hospital discharge to 18-22 months corrected age (CA). Two prespecified primary outcomes-wheezing more than twice per week during the worst 2-week period and cough longer than 3 days without a cold-were compared for each randomized intervention.One or more interviews were completed for 918 of the 922 eligible infants. The incidences of wheezing and cough were 47.9% and 31.0%, respectively, and did not differ between the study arms of either randomized intervention. Infants randomized to lower vs higher oxygen saturation targets had a similar risk of death or respiratory morbidity (except for croup and treatment with oxygen or diuretics at home). Infants randomized to CPAP vs intubation/surfactant had fewer episodes of wheezing without a cold (28.9% vs 36.5%; P < .05), respiratory illnesses diagnosed by a doctor (47.7% vs 55.2%; P < .05), and physician or emergency room visits for breathing problems (68.0% vs 72.9%; P < .05) by 18-22 months CA.Treatment with early CPAP rather than intubation/surfactant is associated with less respiratory morbidity by 18-22 months CA. Longitudinal assessment of pulmonary morbidity is necessary to fully evaluate the potential benefits of respiratory interventions for neonates.

    View details for DOI 10.1016/j.jpeds.2014.02.054

    View details for PubMedID 24725582

    View details for PubMedCentralID PMC4111960

  • Surgery and neurodevelopmental outcome of very low-birth-weight infants. JAMA pediatrics Morriss, F. H., Saha, S., Bell, E. F., Colaizy, T. T., Stoll, B. J., Hintz, S. R., Shankaran, S., Vohr, B. R., Hamrick, S. E., Pappas, A., Jones, P. M., Carlo, W. A., Laptook, A. R., Van Meurs, K. P., Sánchez, P. J., Hale, E. C., Newman, N. S., Das, A., Higgins, R. D. 2014; 168 (8): 746-754

    Abstract

    Reduced death and neurodevelopmental impairment among infants is a goal of perinatal medicine.To assess the association between surgery during the initial hospitalization and death or neurodevelopmental impairment of very low-birth-weight infants.A retrospective cohort analysis was conducted of patients enrolled in the National Institute of Child Health and Human Development Neonatal Research Network Generic Database from 1998 through 2009 and evaluated at 18 to 22 months' corrected age. Twenty-two academic neonatal intensive care units participated. Inclusion criteria were birth weight 401 to 1500 g, survival to 12 hours, and availability for follow-up. A total of 12 111 infants were included in analyses.Surgical procedures; surgery also was classified by expected anesthesia type as major (general anesthesia) or minor (nongeneral anesthesia).Multivariable logistic regression analyses planned a priori were performed for the primary outcome of death or neurodevelopmental impairment and for the secondary outcome of neurodevelopmental impairment among survivors. Multivariable linear regression analyses were performed as planned for the adjusted mean scores of the Mental Developmental Index and Psychomotor Developmental Index of the Bayley Scales of Infant Development, Second Edition, for patients born before 2006.A total of 2186 infants underwent major surgery, 784 had minor surgery, and 9141 infants did not undergo surgery. The risk-adjusted odds ratio of death or neurodevelopmental impairment for all surgery patients compared with those who had no surgery was 1.29 (95% CI, 1.08-1.55). For patients who had major surgery compared with those who had no surgery, the risk-adjusted odds ratio of death or neurodevelopmental impairment was 1.52 (95% CI, 1.24-1.87). Patients classified as having minor surgery had no increased adjusted risk. Among survivors who had major surgery compared with those who had no surgery, the adjusted risk of neurodevelopmental impairment was greater and the adjusted mean Bayley scores were lower.Major surgery in very low-birth-weight infants is independently associated with a greater than 50% increased risk of death or neurodevelopmental impairment and of neurodevelopmental impairment at 18 to 22 months' corrected age. The role of general anesthesia is implicated but remains unproven.

    View details for DOI 10.1001/jamapediatrics.2014.307

    View details for PubMedID 24934607

    View details for PubMedCentralID PMC4142429

  • Combined elevated midpregnancy tumor necrosis factor alpha and hyperlipidemia in pregnancies resulting in early preterm birth. American journal of obstetrics and gynecology Jelliffe-Pawlowski, L. L., Ryckman, K. K., Bedell, B., O'Brodovich, H. M., Gould, J. B., Lyell, D. J., Borowski, K. S., Shaw, G. M., Murray, J. C., Stevenson, D. K. 2014; 211 (2): 141 e1-9

    View details for DOI 10.1016/j.ajog.2014.02.019

    View details for PubMedID 24831886

  • Prevention of traumatic stress in mothers of preterms: 6-month outcomes. Pediatrics Shaw, R. J., St John, N., Lilo, E., Jo, B., Benitz, W., Stevenson, D. K., Horwitz, S. M. 2014; 134 (2): e481-8

    View details for DOI 10.1542/peds.2014-0529

    View details for PubMedID 25049338

  • Combined elevated midpregnancy tumor necrosis factor alpha and hyperlipidemia in pregnancies resulting in early preterm birth. American journal of obstetrics and gynecology Jelliffe-Pawlowski, L. L., Ryckman, K. K., Bedell, B., O'Brodovich, H. M., Gould, J. B., Lyell, D. J., Borowski, K. S., Shaw, G. M., Murray, J. C., Stevenson, D. K. 2014; 211 (2): 141 e1-9

    Abstract

    The objective of the study was to determine whether pregnancies resulting in early preterm birth (PTB) (<30 weeks) were more likely than term pregnancies to have elevated midtrimester serum tumor necrosis factor alpha (TNF-α) levels combined with lipid patterns suggestive of hyperlipidemia.In 2 nested case-control samples drawn from California and Iowa cohorts, we examined the frequency of elevated midpregnancy serum TNF-α levels (in the fourth quartile [4Q]) and lipid patterns suggestive of hyperlipidemia (eg, total cholesterol, low-density-lipoproteins, or triglycerides in the 4Q, high-density lipoproteins in the first quartile) (considered independently and by co-occurrence) in pregnancies resulting in early PTB compared with those resulting in term birth (n = 108 in California and n = 734 in Iowa). Odds ratios (ORs) and 95% confidence intervals (CIs) estimated in logistic regression models were used for comparisons.Early preterm pregnancies were 2-4 times more likely than term pregnancies to have a TNF-α level in the 4Q co-occurring with indicators of hyperlipidemia (37.5% vs 13.9% in the California sample (adjusted OR, 4.0; 95% CI, 1.1-16.3) and 26.3% vs 14.9% in the Iowa sample (adjusted OR, 2.7; 95% CI, 1.1-6.3). No differences between early preterm and term pregnancies were observed when TNF-α or target lipid abnormalities occurred in isolation. Observed differences were not explicable to any maternal or infant characteristics.Pregnancies resulting in early PTB were more likely than term pregnancies to have elevated midpregnancy TNF-α levels in combination with lipid patterns suggestive of hyperlipidemia.

    View details for DOI 10.1016/j.ajog.2014.02.019

    View details for PubMedID 24831886

  • End-tidal carbon monoxide and hemolysis JOURNAL OF PERINATOLOGY Tidmarsh, G. F., Wong, R. J., Stevenson, D. K. 2014; 34 (8): 577-581

    Abstract

    Hemolytic disease in newborns can result from a number of conditions, which can place such infants at an increased risk for the development of severe hyperbilirubinemia. Because the catabolism of heme produces equimolar amounts of carbon monoxide (CO) and bilirubin, measurements of end-tidal breath CO (corrected for ambient CO) or ETCOc can serve as an index of hemolysis as well as of bilirubin production from any cause. Elevated levels of ETCOc have been correlated with blood carboxyhemoglobin levels and thus hemolysis. However, the detection of hemolysis can be a clinically challenging problem in newborns. Here, we describe the importance of determining ETCOc levels and their application in identifying infants at risk for developing hyperbilirubinemia associated with hemolysis and other causes of increased bilirubin production.

    View details for DOI 10.1038/jp.2014.66

    View details for Web of Science ID 000339706400001

    View details for PubMedID 24743136

  • Maternal prepregnancy body mass index and risk of spontaneous preterm birth. Paediatric and perinatal epidemiology Shaw, G. M., Wise, P. H., Mayo, J., Carmichael, S. L., Ley, C., Lyell, D. J., Shachar, B. Z., Melsop, K., Phibbs, C. S., Stevenson, D. K., Parsonnet, J., Gould, J. B. 2014; 28 (4): 302-311

    Abstract

    Findings from studies examining risk of preterm birth associated with elevated prepregnancy body mass index (BMI) have been inconsistent.Within a large population-based cohort, we explored associations between prepregnancy BMI and spontaneous preterm birth across a spectrum of BMI, gestational age, and racial/ethnic categories. We analysed data for 989 687 singleton births in California, 2007-09. Preterm birth was grouped as 20-23, 24-27, 28-31, or 32-36 weeks gestation (compared with 37-41 weeks). BMI was categorised as <18.5 (underweight); 18.5-24.9 (normal); 25.0-29.9 (overweight); 30.0-34.9 (obese I); 35.0-39.9 (obese II); and ≥40.0 (obese III). We assessed associations between BMI and spontaneous preterm birth of varying severity among non-Hispanic White, Hispanic, and non-Hispanic Black women.Analyses of mothers without hypertension and diabetes, adjusted for age, education, height, and prenatal care initiation, showed obesity categories I-III to be associated with increased risk of spontaneous preterm birth at 20-23 and 24-27 weeks among those of parity 1 in each race/ethnic group. Relative risks for obese III and preterm birth at 20-23 weeks were 6.29 [95% confidence interval (CI) 3.06, 12.9], 4.34 [95% CI 2.30, 8.16], and 4.45 [95% CI 2.53, 7.82] for non-Hispanic Whites, non-Hispanic Blacks, and Hispanics, respectively. A similar, but lower risk, pattern was observed for women of parity ≥2 and preterm birth at 20-23 weeks. Underweight was associated with modest risks for preterm birth at ≥24 weeks among women in each racial/ethnic group regardless of parity.The association between women's prepregnancy BMI and risk of spontaneous preterm birth is complex and is influenced by race/ethnicity, gestational age, and parity.

    View details for DOI 10.1111/ppe.12125

    View details for PubMedID 24810721

  • The ethics and practice of neonatal resuscitation at the limits of viability: an international perspective ACTA PAEDIATRICA Fanaroff, J. M., Hascoet, J., Hansen, T., Levene, M., Norman, M., Papageorgiou, A., Shinwell, E., van de Bor, M., Stevenson, D. K., IPC 2014; 103 (7): 701–8

    Abstract

    Premature infants at the limits of viability raise difficult ethical, legal, social and economic questions. Neonatologists attending an international Collegium were surveyed about delivery room behaviour, and the approach taken by selected countries practicing 'modern' medicine was explored.There were strong preferences for comfort care at 22 weeks and full resuscitation at 24 weeks. Resuscitation was a grey area at 23 weeks. Cultural, social and legal factors also had a considerable impact on decision-making.

    View details for DOI 10.1111/apa.12633

    View details for Web of Science ID 000337572700016

    View details for PubMedID 24635758

  • Investigation of maternal environmental exposures in association with self-reported preterm birth. Reproductive toxicology Patel, C. J., Yang, T., Hu, Z., Wen, Q., Sung, J., El-Sayed, Y. Y., Cohen, H., Gould, J., Stevenson, D. K., Shaw, G. M., Ling, X. B., Butte, A. J. 2014; 45: 1-7

    Abstract

    Identification of maternal environmental factors influencing preterm birth risks is important to understand the reasons for the increase in prematurity since 1990. Here, we utilized a health survey, the US National Health and Nutrition Examination Survey (NHANES) to search for personal environmental factors associated with preterm birth. 201 urine and blood markers of environmental factors, such as allergens, pollutants, and nutrients were assayed in mothers (range of N: 49-724) who answered questions about any children born preterm (delivery <37 weeks). We screened each of the 201 factors for association with any child born preterm adjusting by age, race/ethnicity, education, and household income. We attempted to verify the top finding, urinary bisphenol A, in an independent study of pregnant women attending Lucile Packard Children's Hospital. We conclude that the association between maternal urinary levels of bisphenol A and preterm birth should be evaluated in a larger epidemiological investigation.

    View details for DOI 10.1016/j.reprotox.2013.12.005

    View details for PubMedID 24373932

  • Developmental outcomes of very preterm infants with tracheostomies. journal of pediatrics DeMauro, S. B., D'Agostino, J. A., Bann, C., Bernbaum, J., Gerdes, M., Bell, E. F., Carlo, W. A., D'Angio, C. T., Das, A., Higgins, R., Hintz, S. R., Laptook, A. R., Natarajan, G., Nelin, L., Poindexter, B. B., Sanchez, P. J., Shankaran, S., Stoll, B. J., Truog, W., Van Meurs, K. P., Vohr, B., Walsh, M. C., Kirpalani, H. 2014; 164 (6): 1303-10 e2

    Abstract

    To evaluate the neurodevelopmental outcomes of very preterm (<30 weeks) infants who underwent tracheostomy.Retrospective cohort study from 16 centers of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network over 10 years (2001-2011). Infants who survived to at least 36 weeks (N = 8683), including 304 infants with tracheostomies, were studied. Primary outcome was death or neurodevelopmental impairment (NDI; a composite of ≥1 of developmental delay, neurologic impairment, profound hearing loss, severe visual impairment) at a corrected age of 18-22 months. Outcomes were compared using multiple logistic regression. We assessed the impact of timing by comparing outcomes of infants who underwent tracheostomy before and after 120 days of life.Tracheostomies were associated with all neonatal morbidities examined and with most adverse neurodevelopmental outcomes. Death or NDI occurred in 83% of infants with tracheostomies and 40% of those without (OR adjusted for center 7.0, 95% CI 5.2-9.5). After adjustment for potential confounders, odds of death or NDI remained higher (OR 3.3, 95% CI 2.4-4.6), but odds of death alone were lower (OR 0.4, 95% CI 0.3-0.7) among infants with tracheostomies. Death or NDI was lower in infants who received their tracheostomies before, rather than after, 120 days of life (aOR 0.5, 95% CI 0.3-0.9).Tracheostomy in preterm infants is associated with adverse developmental outcomes and cannot mitigate the significant risk associated with many complications of prematurity. These data may inform counseling about tracheostomy in this vulnerable population.

    View details for DOI 10.1016/j.jpeds.2013.12.014

    View details for PubMedID 24472229

    View details for PubMedCentralID PMC4035374

  • The gender gap in academic medicine: comparing results from a multifaceted intervention for stanford faculty to peer and national cohorts. Academic medicine Valantine, H. A., Grewal, D., Ku, M. C., Moseley, J., Shih, M., Stevenson, D., Pizzo, P. A. 2014; 89 (6): 904-911

    Abstract

    To assess whether the proportion of women faculty, especially at the full professor rank, increased from 2004 to 2010 at Stanford University School of Medicine after a multifaceted intervention.The authors surveyed gender composition and faculty satisfaction five to seven years after initiating a multifaceted intervention to expand recruitment and development of women faculty. The authors assessed pre/post relative change and rates of increase in women faculty at each rank, and faculty satisfaction; and differences in pre/post change and estimated rate of increase between Stanford and comparator cohorts (nationally and at peer institutions).Post intervention, women faculty increased by 74% (234 to 408), with assistant, associate, and full professors increasing by 66% (108 to 179), 87% (74 to 138), and 75% (52 to 91), respectively. Nationally and at peer institutions, women faculty increased by about 30% (30,230 to 39,200 and 4,370 to 5,754, respectively), with lower percentages at each rank compared with Stanford. Estimated difference (95% CI) in annual rate of increase was larger for Stanford versus the national cohort: combined ranks 0.36 (0.17 to 0.56), P = .001; full professor 0.40 (0.18 to 0.62), P = .001; and versus the peer cohort: combined ranks 0.29 (0.07 to 0.51), P = .02; full professor 0.37 (0.14 to 0.60), P = .003. Stanford women faculty satisfaction increased from 48% (2003) to 71% (2008).Increased satisfaction and proportion of women faculty, especially full professors, suggest that the intervention may ameliorate the gender gap in academic medicine.

    View details for DOI 10.1097/ACM.0000000000000245

    View details for PubMedID 24871242

  • Safety and Efficacy of Filtered Sunlight in Treatment of Jaundice in African Neonates PEDIATRICS Slusher, T. M., Vreman, H. J., Olusanya, B. O., Wong, R. J., Brearley, A. M., Vaucher, Y. E., Stevenson, D. K. 2014; 133 (6): E1568-E1574

    Abstract

    Evaluate safety and efficacy of filtered-sunlight phototherapy (FS-PT).Term/late preterm infants #14 days old with clinically significant jaundice, assessed by total bilirubin (TB) levels, were recruited from a maternity hospital in Lagos, Nigeria. Sunlight was filtered with commercial window-tinting films that remove most UV and significant levels of infrared light and transmit effective levels of therapeutic blue light. After placing infants under an FS-PT canopy, hourly measurements of axillary temperatures, monitoring for sunburn, dehydration, and irradiances of filtered sunlight were performed. Treatment was deemed safe and efficacious if infants were able to stay in FS-PT for $5 hours and rate of rise of TB was ,0.2 mg/dL/h for infants #72 hours of age or TB decreased for infants .72 hours of age.A total of 227 infants received 258 days of FS-PT. No infant developed sunburn or dehydration. On 85 (33%) of 258 treatment days, infants were removed briefly from FS-PT due to minor temperature-related adverse events. No infant met study exit criteria. FS-PT was efficacious in 92% (181/197) of evaluable treatment days. Mean 6 SD TB change was –0.06 6 0.19 mg/dL/h. The mean 6 SD (range) irradiance of FS-PT was 38 6 22 (2–115) mW/cm2/nm, measured by the BiliBlanket Meter II.With appropriate monitoring, filtered sunlight is a novel, practical, and inexpensive method of PT that potentially offers safe and efficacious treatment strategy for management of neonatal jaundice in tropical countries where conventional PT treatment is not available.

    View details for DOI 10.1542/peds.2013-3500

    View details for Web of Science ID 000337172600012

    View details for PubMedID 24864170

  • The Initiative on Subspecialty Clinical Training and Certification (SCTC) : Background and Recommendations PEDIATRICS Stevenson, D. K., McGuinness, G. A., Bancroft, J. D., Boyer, D. M., Cohen, A. R., Gilhooly, J. T., Hazinski, M. F., Holmboe, E. S., Jones, D., Land, M. L., Long, S. S., Norwood, V. F., Schumacher, D. J., Sectish, T. C., St Geme, J. W., West, D. C. 2014; 133: S53-S57
  • Pediatric Subspecialty Fellowship Clinical Training Project: Recent Graduates and Midcareer Survey Comparison PEDIATRICS Freed, G. L., Dunham, K. M., Moran, L. M., Spera, L., McGuinness, G. A., Stevenson, D. K. 2014; 133: S70-S75
  • Pediatric Subspecialty Fellowship Clinical Training Project: Current Fellows PEDIATRICS Freed, G. L., Dunham, K. M., Moran, L. M., Spera, L., McGuinness, G. A., Stevenson, D. K. 2014; 133: S58-S63
  • Fellowship Program Directors Perspectives on Fellowship Training PEDIATRICS Freed, G. L., Dunham, K. M., Moran, L. M., Spera, L., McGuinness, G. A., Stevenson, D. K. 2014; 133: S64-S69
  • Specialty Specific Comparisons Regarding Perspectives on Fellowship Training PEDIATRICS Freed, G. L., Dunham, K. M., Moran, L. M., Spera, L., McGuinness, G. A., Stevenson, D. K. 2014; 133: S76-S77
  • Maternal Characteristics and Mid-Pregnancy Serum Markers in Spontaneous and Medically Indicated Preterm Birth Jelliffe-Pawlowski, L. L., Baer, R. J., O'Brodovich, H. M., Stevenson, D. K., Gould, J. B., Shaw, G. M., Currier, R. J. SAGE PUBLICATIONS INC. 2014: 239A
  • Apolipoprotein E genotype and outcome in infants with hypoxic-ischemic encephalopathy. Pediatric research Cotten, C. M., Goldstein, R. F., McDonald, S. A., Goldberg, R. N., Salhab, W. A., Carlo, W. A., Tyson, J. E., Finer, N. N., Walsh, M. C., Ehrenkranz, R. A., Laptook, A. R., Guillet, R., Schibler, K., Van Meurs, K. P., Poindexter, B. B., Stoll, B. J., O'Shea, T. M., Duara, S., Das, A., Higgins, R. D., Shankaran, S. 2014; 75 (3): 424-430

    Abstract

    Background:Adults with the apolipoprotein E (APOE) gene alleles e4 and e2 are at high risk of poor neurological outcome after brain injury. The e4 allele has been associated with cerebral palsy (CP), and the e2 allele has been associated with worse neurological outcome with congenital heart disease. This study was done to test the hypothesis that the APOE genotype is associated with outcome among neonates who survive after hypoxic-ischemic encephalopathy (HIE).Methods:We conducted a cohort study of infants who survived HIE and had 18-22 mo standardized neurodevelopmental evaluations to assess associations between disability and the APOE genotypes e3/e3, e4/-, and e2/-.Results:A total of 139 survivors were genotyped. Of these, 86 (62%) were of the e3/e3, 41 (29%) were of the e4/-, and 14 (10%) were of the e2/- genotypes. One hundred and twenty-nine infants had genotype and follow-up data; 26% had moderate or severe disabilities. Disability prevalence was 30 and 19% among those with and without the e3/e3 genotype, 25 and 26% among those with and without the e2 allele, and 18 and 29% among those with and without the e4 allele, respectively. None of the differences were statistically significant. CP prevalence was also similar among genotype groups.Conclusion:Disability was not associated with the APOE genotype in this cohort of HIE survivors.

    View details for DOI 10.1038/pr.2013.235

    View details for PubMedID 24322171

  • Dynamic Alterations in the Murine Myeloid Cell Population during Pregnancy Zhao, H., Kalish, F., Schulz, S., Yang, Y., Wong, R. J., Stevenson, D. K. SAGE PUBLICATIONS INC. 2014: 417A–418A
  • Maternal Body Mass and Risk for Premature Birth among 1.2 Million California Births Shaw, G. M., Wise, P. H., Mayo, J., Carmichael, S. L., Ley, C., Lyell, D. J., Shachar, B., Melsop, K., Phibbs, C. S., Stevenson, D. K., Parsonnet, J., Gould, J. B. SAGE PUBLICATIONS INC. 2014: 340A
  • Brain microstructural development at near-term age in very-low-birth-weight preterm infants: An atlas-based diffusion imaging study. NeuroImage Rose, J., Vassar, R., Cahill-Rowley, K., Guzman, X. S., Stevenson, D. K., Barnea-Goraly, N. 2014; 86: 244-256

    Abstract

    At near-term age the brain undergoes rapid growth and development. Abnormalities identified during this period have been recognized as potential predictors of neurodevelopment in children born preterm. This study used diffusion tensor imaging (DTI) to examine white matter (WM) microstructure in very-low-birth-weight (VLBW) preterm infants to better understand regional WM developmental trajectories at near-term age. DTI scans were analyzed in a cross-sectional sample of 45 VLBW preterm infants (BW≤1500g, GA≤32weeks) within a cohort of 102 neonates admitted to the NICU and recruited to participate prior to standard-of-care MRI, from 2010 to 2011, 66/102 also had DTI. For inclusion in this analysis, 45 infants had DTI, no evidence of brain abnormality on MRI, and were scanned at PMA ≤40weeks (34.7-38.6). White matter microstructure was analyzed in 19 subcortical regions defined by DiffeoMap neonatal brain atlas, using threshold values of trace <0.006mm(2)s(-1) and FA >0.15. Regional fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) were calculated and temporal-spatial trajectories of development were examined in relation to PMA and brain region location. Posterior regions within the corona radiata (CR), corpus callosum (CC), and internal capsule (IC) demonstrated significantly higher mean FA values compared to anterior regions. Posterior regions of the CR and IC demonstrated significantly lower RD values compared to anterior regions. Centrally located projection fibers demonstrated higher mean FA and lower RD values than peripheral regions including the posterior limb of the internal capsule (PLIC), cerebral peduncle, retrolenticular part of the IC, posterior thalamic radiation, and sagittal stratum. Centrally located association fibers of the external capsule had higher FA and lower RD than the more peripherally-located superior longitudinal fasciculus (SLF). A significant relationship between PMA-at-scan and FA, MD, and RD was demonstrated by a majority of regions, the strongest correlations were observed in the anterior limb of the internal capsule, a region undergoing early stages of myelination at near-term age, in which FA increased (r=.433, p=.003) and MD (r=-.545, p=.000) and RD (r=-.540, p=.000) decreased with PMA-at-scan. No correlation with PMA-at-scan was observed in the CC or SLF, regions that myelinate later in infancy. Regional patterns of higher FA and lower RD were observed at this near-term age, suggestive of more advanced microstructural development in posterior compared to anterior regions within the CR, CC, and IC and in central compared to peripheral WM structures. Evidence of region-specific rates of microstructural development was observed. Temporal-spatial patterns of WM microstructure development at near-term age have important implications for interpretation of near-term DTI and for identification of aberrations in typical developmental trajectories that may signal future impairment.

    View details for DOI 10.1016/j.neuroimage.2013.09.053

    View details for PubMedID 24091089

  • Mortality and Morbidity of VLBW Infants With Trisomy 13 or Trisomy 18 PEDIATRICS Boghossian, N. S., Hansen, N. I., Bell, E. F., Stoll, B. J., Murray, J. C., Carey, J. C., Adams-Chapman, I., Shankaran, S., Walsh, M. C., Laptook, A. R., Faix, R. G., Newman, N. S., Hale, E. C., Das, A., Wilson, L. D., Hensman, A. M., Grisby, C., Collins, M. V., Vasil, D. M., Finkle, J., Maffett, D., Ball, M., Lacy, C. B., Bara, R., Higgins, R. D., Eunice Kennedy Shriver Natl Inst C 2014; 133 (2): 226–35

    Abstract

    Little is known about how very low birth weight (VLBW) affects survival and morbidities among infants with trisomy 13 (T13) or trisomy 18 (T18). We examined the care plans for VLBW infants with T13 or T18 and compared their risks of mortality and neonatal morbidities with VLBW infants with trisomy 21 and VLBW infants without birth defects.Infants with birth weight 401 to 1500 g born or cared for at a participating center of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network during the period 1994-2009 were studied. Poisson regression models were used to examine risk of death and neonatal morbidities among infants with T13 or T18.Of 52,262 VLBW infants, 38 (0.07%) had T13 and 128 (0.24%) had T18. Intensity of care in the delivery room varied depending on whether the trisomy was diagnosed before or after birth. The plan for subsequent care for the majority of the infants was to withdraw care or to provide comfort care. Eleven percent of infants with T13 and 9% of infants with T18 survived to hospital discharge. Survivors with T13 or T18 had significantly increased risk of patent ductus arteriosus and respiratory distress syndrome compared with infants without birth defects. No infant with T13 or T18 developed necrotizing enterocolitis.In this cohort of liveborn VLBW infants with T13 or T18, the timing of trisomy diagnosis affected the plan for care, survival was poor, and death usually occurred early.

    View details for DOI 10.1542/peds.2013-1702

    View details for Web of Science ID 000333413600008

    View details for PubMedID 24446439

    View details for PubMedCentralID PMC3904274

  • Neonatal physiological correlates of near-term brain development on MRI and DTI in very-low-birth-weight preterm infants. NeuroImage. Clinical Rose, J., Vassar, R., Cahill-Rowley, K., Stecher Guzman, X., Hintz, S. R., Stevenson, D. K., Barnea-Goraly, N. 2014; 5: 169-177

    Abstract

    Structural brain abnormalities identified at near-term age have been recognized as potential predictors of neurodevelopment in children born preterm. The aim of this study was to examine the relationship between neonatal physiological risk factors and early brain structure in very-low-birth-weight (VLBW) preterm infants using structural MRI and diffusion tensor imaging (DTI) at near-term age. Structural brain MRI, diffusion-weighted scans, and neonatal physiological risk factors were analyzed in a cross-sectional sample of 102 VLBW preterm infants (BW ≤ 1500 g, gestational age (GA) ≤ 32 weeks), who were admitted to the Lucile Packard Children's Hospital, Stanford NICU and recruited to participate prior to routine near-term brain MRI conducted at 36.6 ± 1.8 weeks postmenstrual age (PMA) from 2010 to 2011; 66/102 also underwent a diffusion-weighted scan. Brain abnormalities were assessed qualitatively on structural MRI, and white matter (WM) microstructure was analyzed quantitatively on DTI in six subcortical regions defined by DiffeoMap neonatal brain atlas. Specific regions of interest included the genu and splenium of the corpus callosum, anterior and posterior limbs of the internal capsule, the thalamus, and the globus pallidus. Regional fractional anisotropy (FA) and mean diffusivity (MD) were calculated using DTI data and examined in relation to neonatal physiological risk factors including gestational age (GA), bronchopulmonary dysplasia (BPD), necrotizing enterocolitis (NEC), retinopathy of prematurity (ROP), and sepsis, as well as serum levels of C-reactive protein (CRP), glucose, albumin, and total bilirubin. Brain abnormalities were observed on structural MRI in 38/102 infants including 35% of females and 40% of males. Infants with brain abnormalities observed on MRI had higher incidence of BPD (42% vs. 25%) and sepsis (21% vs. 6%) and higher mean and peak serum CRP levels, respectively, (0.64 vs. 0.34 mg/dL, p = .008; 1.57 vs. 0.67 mg/dL, p= .006) compared to those without. The number of signal abnormalities observed on structural MRI correlated to mean and peak CRP (rho = .316, p = .002; rho = .318, p= .002). The number of signal abnormalities observed on MRI correlated with thalamus MD (left: r= .382, p= .002; right: r= .400, p= .001), controlling for PMA-at-scan. Thalamus WM microstructure demonstrated the strongest associations with neonatal risk factors. Higher thalamus MD on the left and right, respectively, was associated with lower GA (r = -.322, p = .009; r= -.381, p= .002), lower mean albumin (r = -.276, p= .029; r= -.385, p= .002), and lower mean bilirubin (r = -.293, p= .020; r= -.337 p= .007). Results suggest that at near-term age, thalamus WM microstructure may be particularly vulnerable to certain neonatal risk factors. Interactions between albumin, bilirubin, phototherapy, and brain development warrant further investigation. Identification of physiological risk factors associated with selective vulnerability of certain brain regions at near-term age may clarify the etiology of neurodevelopmental impairment and inform neuroprotective treatment for VLBW preterm infants.

    View details for DOI 10.1016/j.nicl.2014.05.013

    View details for PubMedID 25068107

    View details for PubMedCentralID PMC4110350

  • SPECIAL FEATURE William A Silverman lecture JOURNAL OF PERINATOLOGY Stevenson, D. K. 2014; 34 (1): 1–5

    Abstract

    This is the text of the William A Silverman lecture given by Dr David K Stevenson at the Pediatric Academic Societies Annual Meeting in Washington, DC, May 4-7, 2013.

    View details for DOI 10.1038/jp.2013.104

    View details for Web of Science ID 000329123000001

    View details for PubMedID 23970208

  • CHEMOPREVENTION OF NEONATAL JAUNDICE USING POLYMERIC PARTICULATE DELIVERY OF ZINC PROTOPORPHYRIN Wong, R. J., Espadas, C., Inayathullah, M., Lechuga-Ballesteros, D., Kalish, F., Rajadas, J., Stevenson, D. K. LIPPINCOTT WILLIAMS & WILKINS. 2014: 156
  • EFFICACY AND SAFETY OF BLUE-GREEN LIGHT FOR PHOTOTHERAPY Linfield, D. T., Lin, D., Schulz, S., Vreman, H. J., Wong, R. J., Stevenson, D. K. LIPPINCOTT WILLIAMS & WILKINS. 2014: 155–56
  • Neurodevelopmental outcomes of extremely low birth weight infants with spontaneous intestinal perforation or surgical necrotizing enterocolitis JOURNAL OF PERINATOLOGY Wadhawan, R., Oh, W., Hintz, S. R., Blakely, M. L., Das, A., Bell, E. F., Saha, S., Laptook, A. R., Shankaran, S., Stoll, B. J., Walsh, M. C., Higgins, R. D. 2014; 34 (1): 64-70

    Abstract

    To determine if extremely low birth weight infants with surgical necrotizing enterocolitis have a higher risk of death or neurodevelopmental impairment and neurodevelopmental impairment among survivors (secondary outcome) at 18-22 months corrected age compared with infants with spontaneous intestinal perforation and infants without necrotizing enterocolitis or spontaneous intestinal perforation.Retrospective analysis of the Neonatal Research Network very low birth weight registry, evaluating extremely low birth weight infants born between 2000 and 2005. The study infants were designated into three groups: (1) spontaneous intestinal perforation without necrotizing enterocolitis; (2) surgical necrotizing enterocolitis (Bell's stage III); and (3) neither spontaneous intestinal perforation nor necrotizing enterocolitis. Multivariate logistic regression analysis was performed to evaluate the association between the clinical group and death or neurodevelopmental impairment, controlling for multiple confounding factors including center.Infants with surgical necrotizing enterocolitis had the highest rate of death before hospital discharge (53.5%) and death or neurodevelopmental impairment (82.3%) compared with infants in the spontaneous intestinal perforation group (39.1 and 79.3%) and no necrotizing enterocolitis/no spontaneous intestinal perforation group (22.1 and 53.3%; P<0.001). Similar results were observed for neurodevelopmental impairment among survivors. On logistic regression analysis, both spontaneous intestinal perforation and surgical necrotizing enterocolitis were associated with increased risk of death or neurodevelopmental impairment (adjusted odds ratio 2.21, 95% confidence interval (CI): 1.5, 3.2 and adjusted OR 2.11, 95% CI: 1.5, 2.9, respectively) and neurodevelopmental impairment among survivors (adjusted OR 2.17, 95% CI: 1.4, 3.2 and adjusted OR 1.70, 95% CI: 1.2, 2.4, respectively).Spontaneous intestinal perforation and surgical necrotizing enterocolitis are associated with a similar increase in the risk of death or neurodevelopmental impairment and neurodevelopmental impairment among extremely low birth weight survivors at 18-22 months corrected age.

    View details for DOI 10.1038/jp.2013.128

    View details for Web of Science ID 000329123000013

    View details for PubMedID 24135709

    View details for PubMedCentralID PMC3877158

  • Outcomes of extremely low birthweight infants with acidosis at birth. Archives of disease in childhood. Fetal and neonatal edition Randolph, D. A., Nolen, T. L., Ambalavanan, N., Carlo, W. A., Peralta-Carcelen, M., Das, A., Bell, E. F., Davis, A. S., Laptook, A. R., Stoll, B. J., Shankaran, S., Higgins, R. D. 2014

    Abstract

    To test the hypothesis that acidosis at birth is associated with the combined primary outcome of death or neurodevelopmental impairment (NDI) in extremely low birthweight (ELBW) infants, and to develop a predictive model of death/NDI exploring perinatal acidosis as a predictor variable.The study population consisted of ELBW infants born between 2002 and 2007 at National Institute of Child Health and Development (NICHD) Neonatal Research Network hospitals. Infants with cord blood gas data and documentation of either mortality prior to discharge or 18-22 month neurodevelopmental outcomes were included. Multiple logistic regression analysis was used to determine the contribution of perinatal acidosis, defined as a cord blood gas with a pH<7 or base excess (BE) <-12, to death/NDI in ELBW infants. In addition, a multivariable model predicting death/NDI was developed.3979 patients were identified of whom 249 had a cord gas pH<7 or BE<-12 mEq/L. 2124 patients (53%) had the primary outcome of death/NDI. After adjustment for confounding variables, pH<7 and BE<-12 mEq/L were each significantly associated with death/NDI (OR=2.5 (1.6, 4.2) and OR=1.5 (1.1, 2.0), respectively). However, inclusion of pH or BE did not improve the ability of the multivariable model to predict death/NDI.Perinatal acidosis is significantly associated with death/NDI in ELBW infants. Perinatal acidosis is infrequent in ELBW infants, however, and other factors are more important in predicting death/NDI.

    View details for DOI 10.1136/archdischild-2013-304179

    View details for PubMedID 24554564

  • Death or Neurodevelopmental Impairment at 18 to 22 Months Corrected Age in a Randomized Trial of Early Dexamethasone to Prevent Death or Chronic Lung Disease in Extremely Low Birth Weight Infants JOURNAL OF PEDIATRICS Stark, A. R., Carlo, W. A., Vohr, B. R., Papile, L. A., Saha, S., Bauer, C. R., Oh, W., Shankaran, S., Tyson, J. E., Wright, L. L., Poole, W. K., Das, A., Stoll, B. J., Fanaroff, A. A., Korones, S. B., Ehrenkranz, R. A., Stevenson, D. K., Peralta-Carcelen, M., Wilson-Costello, D. E., Bada, H. S., Heyne, R. J., Johnson, Y. R., Lee, K. G., Steichen, J. J. 2014; 164 (1): 34-?

    Abstract

    To evaluate the incidence of death or neurodevelopmental impairment (NDI) at 18-22 months corrected age in subjects enrolled in a trial of early dexamethasone treatment to prevent death or chronic lung disease in extremely low birth weight infants.Evaluation of infants at 18-22 months corrected age included anthropomorphic measurements, a standard neurological examination, and the Bayley Scales of Infant Development-II, including the Mental Developmental Index and the Psychomotor Developmental Index. NDI was defined as moderate or severe cerebral palsy, Mental Developmental Index or Psychomotor Developmental Index <70, blindness, or hearing impairment.Death or NDI at 18-22 months corrected age was similar in the dexamethasone and placebo groups (65% vs 66%, P = .99 among those with known outcome). The proportion of survivors with NDI was also similar, as were mean values for weight, length, and head circumference and the proportion of infants with poor growth (50% vs 41%, P = .42 for weight less than 10th percentile); 49% of infants in the placebo group received treatment with corticosteroid compared with 32% in the dexamethasone group (P = .02).The risk of death or NDI and rate of poor growth were high but similar in the dexamethasone and placebo groups. The lack of a discernible effect of early dexamethasone on neurodevelopmental outcome may be due to frequent clinical corticosteroid use in the placebo group.

    View details for DOI 10.1016/j.jpeds.2013.07.027

    View details for Web of Science ID 000328734700009

    View details for PubMedID 23992673

    View details for PubMedCentralID PMC4120744

  • Treatment of neonatal jaundice with filtered sunlight in Nigerian neonates: study protocol of a non-inferiority, randomized controlled trial TRIALS Slusher, T. M., Olusanya, B. O., Vreman, H. J., Wong, R. J., Brearley, A. M., Vaucher, Y. E., Stevenson, D. K. 2013; 14

    Abstract

    Severe neonatal jaundice and its progression to kernicterus is a leading cause of death and disability among newborns in poorly-resourced countries, particularly in sub-Saharan Africa. The standard treatment for jaundice using conventional phototherapy (CPT) with electric artificial blue light sources is often hampered by the lack of (functional) CPT devices due either to financial constraints or erratic electrical power. In an attempt to make phototherapy (PT) more readily available for the treatment of pathologic jaundice in underserved tropical regions, we set out to test the hypothesis that filtered sunlight phototherapy (FS-PT), in which potentially harmful ultraviolet and infrared rays are appropriately screened, will be as efficacious as CPT.This prospective, non-blinded randomized controlled non-inferiority trial seeks to enroll infants with elevated total serum/plasma bilirubin (TSB, defined as 3 mg/dl below the level recommended by the American Academy of Pediatrics for high-risk infants requiring PT) who will be randomly and equally assigned to receive FS-PT or CPT for a total of 616 days at an inner-city maternity hospital in Lagos, Nigeria. Two FS-PT canopies with pre-tested films will be used. One canopy with a film that transmits roughly 33% blue light (wavelength range: 400 to 520 nm) will be used during sunny periods of a day. Another canopy with a film that transmits about 79% blue light will be used during overcast periods of the day. The infants will be moved from one canopy to the other as needed during the day with the goal of keeping the blue light irradiance level above 8 μW/cm²/nm.Primary outcome: FS-PT will be as efficacious as CPT in reducing the rate of rise in bilirubin levels. Secondary outcome: The number of infants requiring exchange transfusion under FS-PT will not be more than those under CPT.This novel study offers the prospect of an effective treatment for infants at risk of severe neonatal jaundice and avoidable exchange transfusion in poorly-resourced settings without access to (reliable) CPT in the tropics.ClinicalTrials.gov Identifier: NCT01434810.

    View details for DOI 10.1186/1745-6215-14-446

    View details for Web of Science ID 000329516800001

    View details for PubMedID 24373547

    View details for PubMedCentralID PMC3879162

  • Could genetic polymorphisms related to oxidative stress modulate effects of heavy metals for risk of human preterm birth? Reproductive toxicology Shachar, B. Z., Carmichael, S. L., Stevenson, D. K., Shaw, G. M. 2013; 42: 24-26

    Abstract

    Human preterm birth (PTB) is a complex medical outcome influenced by a combination of genetic and environmental factors. Research on the causative factors of PTB has mostly focused on demographic, socio-behavioral and environmental risk factors. Recent studies turn the spotlight on the effects of heavy metals exposure on adverse pregnancy outcomes. Here we present and evaluate the hypothesis that heavy metals may cause PTB through oxidative stress, and that this effect may be modified by polymorphisms in genes related to oxidative stress. Indeed, accumulating data suggest that the risk of PTB is correlated with polymorphisms in genes involved in detoxification, oxidative stress and lipid metabolism. These and other polymorphisms have independently been associated with susceptibility to the adverse effects of heavy metals.

    View details for DOI 10.1016/j.reprotox.2013.06.072

    View details for PubMedID 23811355

  • Immunogenicity of Haemophilus influenzae type b protein conjugate vaccines in very low birth weight infants. Pediatric infectious disease journal D'Angio, C. T., Murray, T. E., Li, L., Heyne, R. J., O'Shea, T. M., Schelonka, R. L., Shankaran, S., Duara, S., Goldberg, R. N., Stoll, B. J., Stevenson, D. K., Vohr, B. R., Phelps, D. L., Carlo, W. A., Pichichero, M. E., Das, A., Higgins, R. D. 2013; 32 (12): 1400-1402

    View details for DOI 10.1097/01.inf.0000437263.04493.7c

    View details for PubMedID 24569312

    View details for PubMedCentralID PMC3960569

  • Early working memory as a racially and ethnically neutral measure of outcome in extremely preterm children at 18-22months. Early human development Lowe, J. R., Duncan, A. F., Bann, C. M., Fuller, J., Hintz, S. R., Das, A., Higgins, R. D., Watterberg, K. L. 2013; 89 (12): 1055-1061

    Abstract

    Difficulties with executive function have been found in preterm children, resulting in difficulties with learning and school performance.This study evaluated the relationship of early working memory as measured by object permanence items to the cognitive and language scores on the Bayley Scales-III in a cohort of children born extremely preterm.Logistic regression models were conducted to compare object permanence scores derived from the Bayley Scales-III by race/ethnicity and maternal education, controlling for medical covariates.Extremely preterm toddlers (526), who were part of a Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network's multi-center study, were evaluated at 18-22 months corrected age.Object permanence scores derived from the Bayley Developmental Scales were compared by race/ethnicity and maternal education, controlling for medical covariates.There were no significant differences in object permanence mastery and scores among the treatment groups after controlling for medical and social variables, including maternal education and race/ethnicity. Males and children with intraventricular hemorrhage, retinopathy of prematurity, and bronchopulmonary dysplasia were less likely to demonstrate object permanence mastery and had lower object permanence scores. Children who attained object permanence mastery had significantly higher Bayley Scales-III cognitive and language scores after controlling for medical and socio-economic factors.Our measure of object permanence is free of influence from race, ethnic and socio-economic factors. Adding this simple task to current clinical practice could help detect early executive function difficulties in young children.

    View details for DOI 10.1016/j.earlhumdev.2013.08.009

    View details for PubMedID 23993309

    View details for PubMedCentralID PMC3830714

  • Evaluation of window-tinting films for sunlight phototherapy. Journal of tropical pediatrics Vreman, H. J., Slusher, T. M., Wong, R. J., Schulz, S., Olusanya, B. O., Stevenson, D. K. 2013; 59 (6): 496-501

    Abstract

    We evaluated nine semi-transparent plastic window-tinting films for their ability to block ultraviolet A (UVA) and infrared (IR) radiation and transmit therapeutic blue light (400-520 nm) for treating jaundiced newborns. For indoor testing, three light sources (TL/52 special blue fluorescent, Black Light UVA and IR heat lamps) were positioned above each film and measured successively using a thermocouple thermometer, UVA radiometer and blue light irradiance meter, placed below each film. For outdoor testing, the same setup was used with the sun at zenith and a cloudless sky. Compared with unfiltered radiation, blue light transmission through films ranged from 24 to 83%, UVA transmission was 0.1-7.1% and reductions in IR heat were 6-12°C and 5-10°C for heat lamp and sun, respectively. The data suggest that most of the relatively low-cost window-tinting films tested can effectively reduce sunlight UV and IR and offer a range of significant attenuations of therapeutic blue light.

    View details for DOI 10.1093/tropej/fmt062

    View details for PubMedID 23880667

  • Integrating multiple 'omics' analyses identifies serological protein biomarkers for preeclampsia BMC MEDICINE Liu, L. Y., Yang, T., Ji, J., Wen, Q., Morgan, A. A., Jin, B., Chen, G., Lyell, D. J., Stevenson, D. K., Ling, X. B., Butte, A. J. 2013; 11

    Abstract

    Preeclampsia (PE) is a pregnancy-related vascular disorder which is the leading cause of maternal morbidity and mortality. We sought to identify novel serological protein markers to diagnose PE with a multi-'omics' based discovery approach.Seven previous placental expression studies were combined for a multiplex analysis, and in parallel, two-dimensional gel electrophoresis was performed to compare serum proteomes in PE and control subjects. The combined biomarker candidates were validated with available ELISA assays using gestational age-matched PE (n=32) and control (n=32) samples. With the validated biomarkers, a genetic algorithm was then used to construct and optimize biomarker panels in PE assessment.In addition to the previously identified biomarkers, the angiogenic and antiangiogenic factors (soluble fms-like tyrosine kinase (sFlt-1) and placental growth factor (PIGF)), we found 3 up-regulated and 6 down-regulated biomakers in PE sera. Two optimal biomarker panels were developed for early and late onset PE assessment, respectively.Both early and late onset PE diagnostic panels, constructed with our PE biomarkers, were superior over sFlt-1/PIGF ratio in PE discrimination. The functional significance of these PE biomarkers and their associated pathways were analyzed which may provide new insights into the pathogenesis of PE.

    View details for DOI 10.1186/1741-7015-11-236

    View details for Web of Science ID 000329052900001

    View details for PubMedID 24195779

    View details for PubMedCentralID PMC4226208

  • Apgar scores at 10 min and outcomes at 6-7 years following hypoxic-ischaemic encephalopathy ARCHIVES OF DISEASE IN CHILDHOOD-FETAL AND NEONATAL EDITION Natarajan, G., Shankaran, S., Laptook, A. R., Pappas, A., Bann, C. M., McDonald, S. A., Das, A., Higgins, R. D., Hintz, S. R., Vohr, B. R. 2013; 98 (6): F473-F479

    Abstract

    To determine the association between 10 min Apgar scores and 6-7-year outcomes in children with perinatal hypoxic-ischaemic encephalopathy (HIE) enrolled in the National Institute of Child Health and Human Development Neonatal Research Network (NICHD NRN) whole body cooling randomised controlled trial (RCT).Evaluations at 6-7 years included the Wechsler Preschool and Primary Scale of Intelligence III or Wechsler Intelligence Scale for Children IV and Gross Motor Functional Classification Scale. Primary outcome was death/moderate or severe disability. Logistic regression was used to examine the association between 10 min Apgar scores and outcomes after adjusting for birth weight, gestational age, gender, outborn status, hypothermia treatment and centre.In the study cohort (n=174), 64/85 (75%) of those with 10 min Apgar score of 0-3 had death/disability compared with 40/89 (45%) of those with scores >3. Each point increase in 10 min Apgar scores was associated with a significantly lower adjusted risk of death/disability, death, death/IQ <70, death/cerebral palsy (CP) and disability, IQ<70 and CP among survivors (all p<0.05). Among the 24 children with a 10 min Apgar score of 0, five (20.8%) survived without disability. The risk-adjusted probabilities of death/disability were significantly lower in cooled infants with Apgar scores of 0-3; there was no significant interaction between cooling and Apgar scores (p=0.26).Among children with perinatal HIE enrolled in the NICHD cooling RCT, 10 min Apgar scores were significantly associated with school-age outcomes. A fifth of infants with 10 min Apgar score of 0 survived without disability to school age, suggesting the need for caution in limiting resuscitation to a specified duration.

    View details for DOI 10.1136/archdischild-2013-303692

    View details for Web of Science ID 000325556000003

    View details for PubMedID 23896791

  • Prevention of Traumatic Stress in Mothers With Preterm Infants: A Randomized Controlled Trial PEDIATRICS Shaw, R. J., St John, N., Lilo, E. A., Jo, B., Benitz, W., Stevenson, D. K., Horwitz, S. M. 2013; 132 (4): E886-E894

    Abstract

    The current study evaluates a treatment intervention developed with the goal of reducing symptoms of posttraumatic stress, depression, and anxiety in parents of premature infants.A total of 105 mothers of preterm infants (25-34 weeks' gestational age; >600 g) were randomized to receive a 6-session intervention developed to target parental trauma as well as facilitate infant redefinition (n = 62) or to an active comparison group (n = 43). Mothers in the intervention group received a combination of trauma-focused treatments, including psychoeducation, cognitive restructuring, progressive muscle relaxation, and development of their trauma narrative. The intervention also incorporated material targeting infant redefinition, defined as the process of changing the mother's negative perceptions of her infant and the parenting experience.Mothers in the intervention group reported a greater reduction in both trauma symptoms (Cohen's d = 0.41, P = .023) and depression (Cohen's d = 0.59, P < .001) compared with the comparison group. Patients under both conditions improved significantly in terms of anxiety, with no differences between groups. Results of the moderator analysis showed that mothers with higher ratings of baseline NICU stress benefited more from the intervention compared with mothers who had lower ratings (P = .036).This short, highly manualized intervention for mothers of preterm infants statistically significantly reduced symptoms of trauma and depression. The intervention is feasible, can be delivered with fidelity, and has high ratings of maternal satisfaction. Given that improvements in mothers' distress may lead to improved infant outcomes, this intervention has the potential for a high public health impact.

    View details for DOI 10.1542/peds.2013-1331

    View details for Web of Science ID 000325095400010

    View details for PubMedID 23999956

    View details for PubMedCentralID PMC3784295

  • Neurodevelopmental outcome of extremely low birth weight infants with Candida infection. journal of pediatrics Adams-Chapman, I., Bann, C. M., Das, A., Goldberg, R. N., Stoll, B. J., Walsh, M. C., Sánchez, P. J., Higgins, R. D., Shankaran, S., Watterberg, K. L., Duara, S., Miller, N. A., Heyne, R. J., Peralta-Carcelen, M., Goldstein, R. F., Steichen, J. J., Bauer, C. R., Hintz, S. R., Evans, P. W., Acarregui, M. J., Myers, G. J., Vohr, B. R., Wilson-Costello, D. E., Pappas, A., Vaucher, Y. E., Ehrenkranz, R. A., McGowan, E. C., Dillard, R. G., Fuller, J., Benjamin, D. K. 2013; 163 (4): 961-7 e3

    Abstract

    OBJECTIVE: Candida remains an important cause of late-onset infection in preterm infants. Mortality and neurodevelopmental outcome of extremely low birth weight (ELBW) infants enrolled in the Candida study were evaluated based on infection status. STUDY DESIGN: ELBW infants born at Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network (NRN) centers between March 2004 and July 2007 who were screened for suspected sepsis were eligible for inclusion in the Candida study. Primary outcome data for neurodevelopmental impairment (NDI) or death were available for 1317 of the 1515 infants (87%) enrolled in the Candida study. The Bayley Scales of Infant Development-II or -III was administered at 18 months' adjusted age. A secondary comparison was performed with 864 infants enrolled in the NRN Generic Database during the same cohort who were never screened for sepsis and therefore not eligible for the Candida study. RESULTS: Among ELBW infants enrolled in the Candida study, 31% with Candida and 31% with late-onset non-Candida sepsis had NDI at 18 months. Infants with Candida sepsis and/or meningitis had an increased risk of death and were more likely to have the composite outcome of death and/or NDI compared with uninfected infants in adjusted analysis. Compared with infants in the NRN registry never screened for sepsis, overall risk for death were similar but those with Candida infection were more likely to have NDI (OR 1.83, 95% CI 1.01-3.33, P = .047). CONCLUSIONS: In this cohort of ELBW infants, those with infection and/or meningitis were at increased risk for death and/or NDI. This risk was highest among those with Candida sepsis and/or meningitis.

    View details for DOI 10.1016/j.jpeds.2013.04.034

    View details for PubMedID 23726546

  • Cerebral Palsy and Growth Failure at 6 to 7 Years PEDIATRICS Vohr, B. R., Stephens, B. E., McDonald, S. A., Ehrenkranz, R. A., Laptook, A. R., Pappas, A., Hintz, S. R., Shankaran, S., Higgins, R. D., Das, A. 2013; 132 (4): E905-E914

    View details for DOI 10.1542/peds.2012-3915

    View details for Web of Science ID 000325095400012

    View details for PubMedID 24019415

  • Raltegravir in vitro effect on bilirubin binding. Pediatric infectious disease journal Clarke, D. F., Wong, R. J., Wenning, L., Stevenson, D. K., Mirochnick, M. 2013; 32 (9): 978-980

    Abstract

    Drugs that displace bilirubin from albumin may increase the risk of kernicterus in neonates. We evaluated the effect of raltegravir on bilirubin-albumin binding in pooled neonatal serum using the peroxidase method. Raltegravir had minimal effect on bilirubin-albumin binding at concentrations of 5 and 10 µM, caused a small but statistically significant increase in unbound bilirubin at 100 µM and caused potentially harmful increases at 500 and 1000 µM. Our data suggest that the effect of raltegravir on neonatal bilirubin binding is unlikely to be clinically significant at typical peak concentrations reached with usual dosing.

    View details for DOI 10.1097/INF.0b013e31829044a8

    View details for PubMedID 23470680

    View details for PubMedCentralID PMC3856729

  • A Genome-Wide Association Study (GWAS) for Bronchopulmonary Dysplasia. Pediatrics Wang, H., St Julien, K. R., Stevenson, D. K., Hoffmann, T. J., Witte, J. S., Lazzeroni, L. C., Krasnow, M. A., Quaintance, C. C., Oehlert, J. W., Jelliffe-Pawlowski, L. L., Gould, J. B., Shaw, G. M., O'Brodovich, H. M. 2013; 132 (2): 290-297

    Abstract

    Twin studies suggest that heritability of moderate-severe bronchopulmonary dysplasia (BPD) is 53% to 79%, we conducted a genome-wide association study (GWAS) to identify genetic variants associated with the risk for BPD.The discovery GWAS was completed on 1726 very low birth weight infants (gestational age = 25(0)-29(6/7) weeks) who had a minimum of 3 days of intermittent positive pressure ventilation and were in the hospital at 36 weeks' postmenstrual age. At 36 weeks' postmenstrual age, moderate-severe BPD cases (n = 899) were defined as requiring continuous supplemental oxygen, whereas controls (n = 827) inhaled room air. An additional 795 comparable infants (371 cases, 424 controls) were a replication population. Genomic DNA from case and control newborn screening bloodspots was used for the GWAS. The replication study interrogated single-nucleotide polymorphisms (SNPs) identified in the discovery GWAS and those within the HumanExome beadchip.Genotyping using genomic DNA was successful. We did not identify SNPs associated with BPD at the genome-wide significance level (5 × 10(-8)) and no SNP identified in previous studies reached statistical significance (Bonferroni-corrected P value threshold .0018). Pathway analyses were not informative.We did not identify genomic loci or pathways that account for the previously described heritability for BPD. Potential explanations include causal mutations that are genetic variants and were not assayed or are mapped to many distributed loci, inadequate sample size, race ethnicity of our study population, or case-control differences investigated are not attributable to underlying common genetic variation.

    View details for DOI 10.1542/peds.2013-0533

    View details for PubMedID 23897914

    View details for PubMedCentralID PMC3727675

  • The effect of hematocrit on the efficacy of phototherapy for neonatal jaundice PEDIATRIC RESEARCH Lamola, A. A., Bhutani, V. K., Wong, R. J., Stevenson, D. K., McDonagh, A. F. 2013; 74 (1): 54-60

    Abstract

    Background:The therapeutic phototherapy action spectrum ranges from 420 to 500nm. However, a recent report of improved efficacy offluorescent "turquoise"light (~490 nm) compared toblue light(~450 nm) underscores the need to define an optimal action spectrum for precision-targeted phototherapy using very narrow wavelength ranges.Methods:We used a current semi-empirical model of theoptical properties of skinfor robust calculations of the fraction of light absorbed by bilirubin at various wavelengths that could be confounded by hemoglobin, melanin and skin thickness. Applying assumptions regarding the wavelength dependence of bilirubin photochemistry, "action spectra"wereassembled from the calculated values.Results:All the calculated action spectra displayed a peak between 472 and 480 nm (most at 476 nm), which is a significant shift from the well-reported 460 nm absorption peak of bilirubin. Interestingly, the relative amplitudes of the action spectra showed an inverse relationship with hematocrit.Conclusion:We speculate that narrow range of light at 476 nmshould be 60% more effective than blue (broad-band) fluorescent lamps. Because hemoglobin serves as a major competitor of bilirubin for light absorption, the calculations also predict that the efficacy of phototherapy is dependent on the hematocrit.A high hematocrit could reduce therapeutic efficiency.Pediatric Research (2013); doi:10.1038/pr.2013.67.

    View details for DOI 10.1038/pr.2013.67

    View details for Web of Science ID 000321795300009

    View details for PubMedID 23604171

  • Ten-year review of major birth defects in VLBW infants. Pediatrics Adams-Chapman, I., Hansen, N. I., Shankaran, S., Bell, E. F., Boghossian, N. S., Murray, J. C., Laptook, A. R., Walsh, M. C., Carlo, W. A., Sánchez, P. J., Van Meurs, K. P., Das, A., Hale, E. C., Newman, N. S., Ball, M. B., Higgins, R. D., Stoll, B. J. 2013; 132 (1): 49-61

    Abstract

    OBJECTIVE:Birth defects (BDs) are an important cause of infant mortality and disproportionately occur among low birth weight infants. We determined the prevalence of BDs in a cohort of very low birth weight (VLBW) infants cared for at the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network (NRN) centers over a 10-year period and examined the relationship between anomalies, neonatal outcomes, and surgical care.METHODS:Infant and maternal data were collected prospectively for infants weighing 401 to 1500 g at NRN sites between January 1, 1998, and December 31, 2007. Poisson regression models were used to compare risk of outcomes for infants with versus without BDs while adjusting for gestational age and other characteristics.RESULTS:A BD was present in 1776 (4.8%) of the 37 262 infants in our VLBW cohort. Yearly prevalence of BDs increased from 4.0% of infants born in 1998 to 5.6% in 2007, P < .001. Mean gestational age overall was 28 weeks, and mean birth weight was 1007 g. Infants with BDs were more mature but more likely to be small for gestational age compared with infants without BDs. Chromosomal and cardiovascular anomalies were most frequent with each occurring in 20% of affected infants. Mortality was higher among infants with BDs (49% vs 18%; adjusted relative risk: 3.66 [95% confidence interval: 3.41-3.92]; P < .001) and varied by diagnosis. Among those surviving >3 days, more infants with BDs underwent major surgery (48% vs 13%, P < .001).CONCLUSIONS:Prevalence of BDs increased during the 10 years studied. BDs remain an important cause of neonatal morbidity and mortality among VLBW infants.

    View details for DOI 10.1542/peds.2012-3111

    View details for PubMedID 23733791

  • Should we screen newborns for glucose-6-phosphate dehydrogenase deficiency in the United States? JOURNAL OF PERINATOLOGY Watchko, J. F., Kaplan, M., Stark, A. R., Stevenson, D. K., Bhutani, V. K. 2013; 33 (7): 499-504

    Abstract

    Glucose-6-phosphate dehydrogenase (G6PD) deficiency, a common X-linked enzymopathy can lead to severe hyperbilirubinemia, acute bilirubin encephalopathy and kernicterus in the United States. Neonatal testing for G6PD deficiency is not yet routine and the American Academy of Pediatrics recommends testing only in jaundiced newborns who are receiving phototherapy whose family history, ethnicity, or geographic origin suggest risk for the condition, or for infants whose response to phototherapy is poor. Screening tests for G6PD deficiency are available, are suitable for use in newborns and have been used in birth hospitals. However, US birth hospitals experience is limited and no national consensus has emerged regarding the need for newborn G6PD testing, its effectiveness or the best approach. Our review of current state of G6PD deficiency screening highlights research gaps and informs specific operational challenges to implement universal newborn G6PD testing concurrent to bilirubin screening in the United States.

    View details for DOI 10.1038/jp.2013.14

    View details for Web of Science ID 000321000800001

    View details for PubMedID 23429543

  • Peptidomic Identification of Serum Peptides Diagnosing Preeclampsia PLOS ONE Wen, Q., Liu, L. Y., Yang, T., Alev, C., Wu, S., Stevenson, D. K., Sheng, G., Butte, A. J., Ling, X. B. 2013; 8 (6)

    Abstract

    We sought to identify serological markers capable of diagnosing preeclampsia (PE). We performed serum peptide analysis (liquid chromatography mass spectrometry) of 62 unique samples from 31 PE patients and 31 healthy pregnant controls, with two-thirds used as a training set and the other third as a testing set. Differential serum peptide profiling identified 52 significant serum peptides, and a 19-peptide panel collectively discriminating PE in training sets (n = 21 PE, n = 21 control; specificity = 85.7% and sensitivity = 100%) and testing sets (n = 10 PE, n = 10 control; specificity = 80% and sensitivity = 100%). The panel peptides were derived from 6 different protein precursors: 13 from fibrinogen alpha (FGA), 1 from alpha-1-antitrypsin (A1AT), 1 from apolipoprotein L1 (APO-L1), 1 from inter-alpha-trypsin inhibitor heavy chain H4 (ITIH4), 2 from kininogen-1 (KNG1), and 1 from thymosin beta-4 (TMSB4). We concluded that serum peptides can accurately discriminate active PE. Measurement of a 19-peptide panel could be performed quickly and in a quantitative mass spectrometric platform available in clinical laboratories. This serum peptide panel quantification could provide clinical utility in predicting PE or differential diagnosis of PE from confounding chronic hypertension.

    View details for DOI 10.1371/journal.pone.0065571

    View details for Web of Science ID 000322361200025

    View details for PubMedCentralID PMC3686758

  • Association of early-preterm birth with abnormal levels of routinely collected first- and second-trimester biomarkers AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY Jelliffe-Pawlowski, L. L., Shaw, G. M., Currier, R. J., Stevenson, D. K., Baer, R. J., O'Brodovich, H. M., Gould, J. B. 2013; 208 (6)

    Abstract

    The purpose of this study was to examine the relationship between typically measured prenatal screening biomarkers and early-preterm birth in euploid pregnancies.The study included 345 early-preterm cases (<30 weeks of gestation) and 1725 control subjects who were drawn from a population-based sample of California pregnancies who had both first- and second-trimester screening results. Logistic regression analyses were used to compare patterns of biomarkers in cases and control subjects and to develop predictive models. Replicability of the biomarker early-preterm relationships that was revealed by the models was evaluated by examination of the frequency and associated adjusted relative risks (RRs) for early-preterm birth and for preterm birth in general (<37 weeks of gestation) in pregnancies with identified abnormal markers compared with pregnancies without these markers in a subsequent independent California cohort of screened pregnancies (n = 76,588).The final model for early-preterm birth included first-trimester pregnancy-associated plasma protein A in the ≤5th percentile, second-trimester alpha-fetoprotein in the ≥95th percentile, and second-trimester inhibin in the ≥95th percentile (odds ratios, 2.3-3.6). In general, pregnancies in the subsequent cohort with a biomarker pattern that were found to be associated with early-preterm delivery in the first sample were at an increased risk for early-preterm birth and preterm birth in general (<37 weeks of gestation; adjusted RR, 1.6-27.4). Pregnancies with ≥2 biomarker abnormalities were at particularly increased risk (adjusted RR, 3.6-27.4).When considered across cohorts and in combination, abnormalities in routinely collected biomarkers reveal predictable risks for early-preterm birth.

    View details for DOI 10.1016/j.ajog.2013.02.012

    View details for Web of Science ID 000320596600029

    View details for PubMedID 23395922

    View details for PubMedCentralID PMC3672244

  • HEME OXYGENASE-1 DEFICIENCY IMPAIRS ADAPTIVE IMMUNITY IN THE INTESTINES OF YOUNG MICE VIA CHANGES IN T-REGULATORY CELLS Schulz, S., Chisholm, K. M., Kalish, F., Zhao, H., Yang, Y., Wong, R. J., Stevenson, D. K. SPRINGER. 2013: S93–S94
  • Neurodevelopmental outcomes of extremely low-gestational-age neonates with low-grade periventricular-intraventricular hemorrhage. JAMA pediatrics Payne, A. H., Hintz, S. R., Hibbs, A. M., Walsh, M. C., Vohr, B. R., Bann, C. M., Wilson-Costello, D. E. 2013; 167 (5): 451-459

    Abstract

    Low-grade periventricular-intraventricular hemorrhage is a common neurologic morbidity among extremely low-gestational-age neonates, yet the outcomes associated with this morbidity are not fully understood. In a contemporary multicenter cohort, we evaluated the impact of such hemorrhages on early (18-22 month) neurodevelopmental outcomes of extremely premature infants.To compare neurodevelopmental outcomes at 18 to 22 months' corrected age for extremely low-gestational-age infants with low-grade (grade 1 or 2) periventricular-intraventricular hemorrhage with those of infants with either no hemorrhage or severe (grade 3 or 4) hemorrhage demonstrated on cranial ultrasonography.Longitudinal observational study.Sixteen centers of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network.A total of 1472 infants born at less than 27 weeks' gestational age between January 1, 2006, and December 31, 2008, with ultrasonography results within the first 28 days of life and surviving to 18 to 22 months with complete follow-up assessments were eligible.Low-grade periventricular-intraventricular hemorrhage.Outcomes included cerebral palsy; gross motor functional limitation; cognitive and language scores according to the Bayley Scales of Infant Development, 3rd Edition; and composite measures of neurodevelopmental impairment. Regression modeling evaluated the association of hemorrhage severity with adverse outcomes while controlling for potentially confounding variables and center differences.Low-grade hemorrhage was not associated with significant differences in unadjusted or adjusted risk of any adverse neurodevelopmental outcome compared with infants without hemorrhage. Compared with low-grade hemorrhage, severe hemorrhage was associated with decreased adjusted continuous cognitive (β, -3.91 [95% CI, -6.41 to -1.42]) and language (β, -3.19 [-6.19 to -0.19]) scores as well as increased odds of each adjusted categorical outcome except severe cognitive impairment (odds ratio [OR], 1.46 [0.74 to 2.88]) and mild language impairment (OR, 1.35 [0.88 to 2.06]).At 18 to 22 months, the neurodevelopmental outcomes of extremely low-gestational-age infants with low-grade periventricular-intraventricular hemorrhage are not significantly different from those without hemorrhage. Additional study at school age and beyond would be informative.

    View details for DOI 10.1001/jamapediatrics.2013.866

    View details for PubMedID 23460139

  • Early Sepsis Does Not Increase the Risk of Late Sepsis in Very Low Birth Weight Neonates JOURNAL OF PEDIATRICS Wynn, J. L., Hansen, N. I., Das, A., Cotten, C. M., Goldberg, R. N., Sanchez, P. J., Bell, E. F., Van Meurs, K. P., Carlo, W. A., Laptook, A. R., Higgins, R. D., Benjamin, D. K., Stoll, B. J. 2013; 162 (5): 942-U92

    Abstract

    To examine whether preterm very low birth weight (VLBW) infants have an increased risk of late-onset sepsis (LOS) following early-onset sepsis (EOS).Retrospective analysis of VLBW infants (401-1500 g) born September 1998 through December 2009 who survived >72 hours and were cared for within the National Institute of Child Health and Human Development Neonatal Research Network. Sepsis was defined by growth of bacteria or fungi in a blood culture obtained ≤72 hours of birth (EOS) or >72 hours (LOS) and antimicrobial therapy for ≥5 days or death <5 days while receiving therapy. Regression models were used to assess risk of death or LOS by 120 days and LOS by 120 days among survivors to discharge or 120 days, adjusting for gestational age and other covariates.Of 34 396 infants studied, 504 (1.5%) had EOS. After adjustment, risk of death or LOS by 120 days did not differ overall for infants with EOS compared with those without EOS [risk ratio (RR): 0.99 (0.89-1.09)] but was reduced in infants born at <25 weeks gestation [RR: 0.87 (0.76-0.99), P = .048]. Among survivors, no difference in LOS risk was found overall for infants with versus without EOS [RR: 0.88 (0.75-1.02)], but LOS risk was reduced in infants with birth weight 401-750 g who had EOS [RR: 0.80 (0.64-0.99), P = .047].Risk of LOS after EOS was not increased in VLBW infants. Surprisingly, risk of LOS following EOS appeared to be reduced in the smallest, most premature infants, underscoring the need for age-specific analyses of immune function.

    View details for DOI 10.1016/j.jpeds.2012.11.027

    View details for Web of Science ID 000317836300016

    View details for PubMedID 23295144

    View details for PubMedCentralID PMC3622770

  • The Transformation of Child Health Research Innovation, Market Failure, and the Public Good JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Stoll, B. J., Stevenson, D. K., Wise, P. H. 2013; 309 (17): 1779-1780

    View details for Web of Science ID 000318235600023

    View details for PubMedID 23632719

  • Considering the vascular hypothesis for the pathogenesis of small intestinal atresia: A case control study of genetic factors AMERICAN JOURNAL OF MEDICAL GENETICS PART A Gupta, T., Yang, W., Iovannisci, D. M., Carmichael, S. L., Stevenson, D. K., Shaw, G. M., Lammer, E. J. 2013; 161A (4): 702-710

    Abstract

    Small intestinal atresia (SIA) is a rare congenital occlusion of the small intestine. SIA development, particularly in the jejunum and ileum, has been associated with in utero disruption of vascular supply. However, the number of studies of the vascular hypothesis is limited. This study considers the vascular hypothesis by exploring risks associated with 32 SNPs of genes involved in vascular processes of homocysteine metabolism, coagulation, cell-cell interactions, inflammatory response, and blood pressure regulation. A total of 206 SIA cases were ascertained by the California Birth Defects Monitoring Program, and 573 infants with no major congenital anomalies by their first birthday were selected as controls. Genomic DNA was genotyped for 32 SNPs involving the following genes: MTHFR, F2, F5, F7, SERPINE1, FGB, ITGA2, ITGB3, SELE, ICAM1, MMP3, TNF, LTA, NOS3, AGTR1, AGT, NPPA, ADD1, SCNN1A, GNB3, and ADRB2. Risks were estimated as odds ratios, adjusted for maternal age and race, with 95% confidence intervals. Cases were considered collectively and by subgroups based on atresia location (duodenal/jejunum/ileum). Three SNPs had reduced risk: SERPINE1 11053 T/G, MMP3 (-1171) A6/A5, and ADRB2 gln27glu. Two had increased risk: ITGA2 873 G/A and NPPA 2238 T/C. No intestinal subphenotypes showed a unique pattern of SNP associations. The association of two SNPs with increased risk lends some, albeit limited, support to vascular impairment as a possible mechanism leading to SIA. These results also identify genes meriting further exploration in SIA studies. Hence, this study makes an important contribution by exploring the long-held but not well-investigated vascular hypothesis.

    View details for DOI 10.1002/ajmg.a.35775

    View details for Web of Science ID 000316631300012

  • Predischarge screening for severe neonatal hyperbilirubinemia identifies infants who need phototherapy. journal of pediatrics Bhutani, V. K., Stark, A. R., Lazzeroni, L. C., Poland, R., Gourley, G. R., Kazmierczak, S., Meloy, L., Burgos, A. E., Hall, J. Y., Stevenson, D. K. 2013; 162 (3): 477-482 e1

    Abstract

    To test whether the combined use of total plasma/serum bilirubin (TSB) levels and clinical risk factors more accurately identifies infants who receive phototherapy than does the use of either method alone.We recruited healthy infants of ≥35 weeks' gestation at 6 centers that practiced universal predischarge TSB screening. Transcutaneous bilirubin (TcB) was measured at 24 hours, with TSB at 24-60 hours and at 3- to 5- and 7- to 14-day follow-up visits. Clinical risk factors were identified systematically.Of 1157 infants, 1060 (92%) completed follow-up, and 982 (85%) had complete datasets for analysis. Infant characteristics included 25% were nonwhite and 55% were Hispanic/Latino; >90% were breastfed. During the first week, jaundice was documented in 84% of subjects. Predischarge TSB identified the 41 (4.2%) and 34 (3.5%) infants who received phototherapy before and after discharge, respectively. Prediction of postdischarge phototherapy was similar for combined clinical risk factors (earlier gestational age [GA], bruising, positive direct antiglobulin test, Asian race, exclusive breastfeeding, blood type incompatibility, jaundice extent) and age-adjusted TSB (area under the curve [AUC] = .86 vs .87), but combined screening was better (AUC = .95). TcB/TSB combined with GA alone was equally predictive (AUC = .95; 95% CI .93-.97).Jaundice is present in 4 of 5 (84%) healthy newborns. Predischarge TcB/TSB (adjusted for postnatal age) combined with specific clinical factors (especially GA) best predicts subsequent phototherapy use. Universal implementation of this strategy in the US should improve outcomes of healthy newborns discharged early.

    View details for DOI 10.1016/j.jpeds.2012.08.022

    View details for PubMedID 23043681

  • Efficacy of phototherapy devices and outcomes among extremely low birth weight infants: multi-center observational study JOURNAL OF PERINATOLOGY Morris, B. H., TYSON, J. E., Stevenson, D. K., Oh, W., Phelps, D. L., O'Shea, T. M., MCDAVID, G. E., Van Meurs, K. P., Vohr, B. R., Grisby, C., Yao, Q., Kandefer, S., Wallace, D., Higgins, R. D. 2013; 33 (2): 126-133

    Abstract

    Evaluate the efficacy of phototherapy (PT) devices and the outcomes of extremely premature infants treated with those devices.This substudy of the National Institute of Child Health and Human Development Neonatal Research Network PT trial included 1404 infants treated with a single type of PT device during the first 24±12 h of treatment. The absolute (primary outcome) and relative decrease in total serum bilirubin (TSB) and other measures were evaluated. For infants treated with one PT type during the 2-week intervention period (n=1223), adjusted outcomes at discharge and 18 to 22 months corrected age were determined.In the first 24 h, the adjusted absolute (mean (±s.d.)) and relative (%) decrease in TSB (mg dl(-1)) were: light-emitting diodes (LEDs) -2.2 (±3), -22%; Spotlights -1.7 (±2), -19%; Banks -1.3 (±3), -8%; Blankets -0.8 (±3), -1%; (P<0.0002). Some findings at 18 to 22 months differed between groups.LEDs achieved the greatest initial absolute reduction in TSB but were similar to Spots in the other performance measures. Long-term effects of PT devices in extremely premature infants deserve rigorous evaluation.

    View details for DOI 10.1038/jp.2012.39

    View details for Web of Science ID 000314434200008

    View details for PubMedID 22499082

    View details for PubMedCentralID PMC3570170

  • High quality genome-wide genotyping from archived dried blood spots without DNA amplification. PloS one St Julien, K. R., Jelliffe-Pawlowski, L. L., Shaw, G. M., Stevenson, D. K., O'Brodovich, H. M., Krasnow, M. A. 2013; 8 (5)

    Abstract

    Spots of blood are routinely collected from newborn babies onto filter paper called Guthrie cards and used to screen for metabolic and genetic disorders. The archived dried blood spots are an important and precious resource for genomic research. Whole genome amplification of dried blood spot DNA has been used to provide DNA for genome-wide SNP genotyping. Here we describe a 96 well format procedure to extract DNA from a portion of a dried blood spot that provides sufficient unamplified genomic DNA for genome-wide single nucleotide polymorphism (SNP) genotyping. We show that SNP genotyping of the unamplified DNA is more robust than genotyping amplified dried blood spot DNA, is comparable in cost, and can be done with thousands of samples. This procedure can be used for genome-wide association studies and other large-scale genomic analyses that require robust, high-accuracy genotyping of dried blood spot DNA.

    View details for DOI 10.1371/journal.pone.0064710

    View details for PubMedID 23737996

  • Transcriptomics and proteomics ensemble analyses reveal serological protein panel for preeclampsia diagnosis 33rd Annual Pregnancy Meeting of the Society-for-Maternal-Fetal-Medicine (SMFM) Liu, L., Cooper, M., Yang, T., Ji, J., Wen, Q., Chen, G., Morgan, A., Stevenson, D., Ling, X., Butte, A. MOSBY-ELSEVIER. 2013: S272–S272
  • High Quality Genome-Wide Genotyping from Archived Dried Blood Spots without DNA Amplification. PloS one St Julien, K. R., Jelliffe-Pawlowski, L. L., Shaw, G. M., Stevenson, D. K., O'Brodovich, H. M., Krasnow, M. A. 2013; 8 (5): e64710

    Abstract

    Spots of blood are routinely collected from newborn babies onto filter paper called Guthrie cards and used to screen for metabolic and genetic disorders. The archived dried blood spots are an important and precious resource for genomic research. Whole genome amplification of dried blood spot DNA has been used to provide DNA for genome-wide SNP genotyping. Here we describe a 96 well format procedure to extract DNA from a portion of a dried blood spot that provides sufficient unamplified genomic DNA for genome-wide single nucleotide polymorphism (SNP) genotyping. We show that SNP genotyping of the unamplified DNA is more robust than genotyping amplified dried blood spot DNA, is comparable in cost, and can be done with thousands of samples. This procedure can be used for genome-wide association studies and other large-scale genomic analyses that require robust, high-accuracy genotyping of dried blood spot DNA.

    View details for DOI 10.1371/journal.pone.0064710

    View details for PubMedID 23737996

    View details for PubMedCentralID PMC3667813

  • Peptidomic Identification of Serum Peptides Diagnosing Preeclampsia. PloS one Wen, Q., Liu, L. Y., Yang, T., Alev, C., Wu, S., Stevenson, D. K., Sheng, G., Butte, A. J., Ling, X. B. 2013; 8 (6): e65571

    Abstract

    We sought to identify serological markers capable of diagnosing preeclampsia (PE). We performed serum peptide analysis (liquid chromatography mass spectrometry) of 62 unique samples from 31 PE patients and 31 healthy pregnant controls, with two-thirds used as a training set and the other third as a testing set. Differential serum peptide profiling identified 52 significant serum peptides, and a 19-peptide panel collectively discriminating PE in training sets (n = 21 PE, n = 21 control; specificity = 85.7% and sensitivity = 100%) and testing sets (n = 10 PE, n = 10 control; specificity = 80% and sensitivity = 100%). The panel peptides were derived from 6 different protein precursors: 13 from fibrinogen alpha (FGA), 1 from alpha-1-antitrypsin (A1AT), 1 from apolipoprotein L1 (APO-L1), 1 from inter-alpha-trypsin inhibitor heavy chain H4 (ITIH4), 2 from kininogen-1 (KNG1), and 1 from thymosin beta-4 (TMSB4). We concluded that serum peptides can accurately discriminate active PE. Measurement of a 19-peptide panel could be performed quickly and in a quantitative mass spectrometric platform available in clinical laboratories. This serum peptide panel quantification could provide clinical utility in predicting PE or differential diagnosis of PE from confounding chronic hypertension.

    View details for DOI 10.1371/journal.pone.0065571

    View details for PubMedID 23840341

    View details for PubMedCentralID PMC3686758

  • Brain injury following trial of hypothermia for neonatal hypoxic-ischaemic encephalopathy ARCHIVES OF DISEASE IN CHILDHOOD-FETAL AND NEONATAL EDITION Shankaran, S., Barnes, P. D., Hintz, S. R., Laptook, A. R., Zaterka-Baxter, K. M., McDonald, S. A., Ehrenkranz, R. A., Walsh, M. C., Tyson, J. E., Donovan, E. F., Goldberg, R. N., Bara, R., Das, A., Finer, N. N., Sanchez, P. J., Poindexter, B. B., Van Meurs, K. P., Carlo, W. A., Stoll, B. J., Duara, S., Guillet, R., Higgins, R. D. 2012; 97 (6): F398-F404

    Abstract

    The objective of our study was to examine the relationship between brain injury and outcome following neonatal hypoxic-ischaemic encephalopathy treated with hypothermia.Neonatal MRI scans were evaluated in the National Institute of Child Health and Human Development (NICHD) randomised controlled trial of whole-body hypothermia and each infant was categorised based upon the pattern of brain injury on the MRI findings. Brain injury patterns were assessed as a marker of death or disability at 18-22 months of age.Scans were obtained on 136 of 208 trial participants (65%); 73 in the hypothermia and 63 in the control group. Normal scans were noted in 38 of 73 infants (52%) in the hypothermia group and 22 of 63 infants (35%) in the control group. Infants in the hypothermia group had fewer areas of infarction (12%) compared to infants in the control group (22%). Fifty-one of the 136 infants died or had moderate or severe disability at 18 months. The brain injury pattern correlated with outcome of death or disability and with disability among survivors. Each point increase in the severity of the pattern of brain injury was independently associated with a twofold increase in the odds of death or disability.Fewer areas of infarction and a trend towards more normal scans were noted in brain MRI following whole-body hypothermia. Presence of the NICHD pattern of brain injury is a marker of death or moderate or severe disability at 18-22 months following hypothermia for neonatal encephalopathy.

    View details for DOI 10.1136/archdischild-2011-301524

    View details for Web of Science ID 000311022800003

    View details for PubMedID 23080477

  • Introductory address for the John Howland Award recipient, Philip A. Pizzo, MD PEDIATRIC RESEARCH Stevenson, D. K. 2012; 72 (3): 321-323

    View details for DOI 10.1038/pr.2012.82

    View details for Web of Science ID 000308280500014

    View details for PubMedID 22717691

  • Does aggressive phototherapy increase mortality while decreasing profound impairment among the smallest and sickest newborns? JOURNAL OF PERINATOLOGY Tyson, J. E., Pedroza, C., Langer, J., Green, C., Morris, B., Stevenson, D., Van Meurs, K. P., Oh, W., Phelps, D., O'Shea, M., MCDAVID, G. E., Grisby, C., Higgins, R. 2012; 32 (9): 677-684

    Abstract

    Aggressive phototherapy (AgPT) is widely used and assumed to be safe and effective for even the most immature infants. We assessed whether the benefits and hazards for the smallest and sickest infants differed from those for other extremely low-birth-weight (ELBW; ≤ 1000 g) infants in our Neonatal Research Network trial, the only large trial of AgPT.ELBW infants (n=1974) were randomized to AgPT or conservative phototherapy at age 12 to 36 h. The effect of AgPT on outcomes (death, impairment, profound impairment, death or impairment (primary outcome), and death or profound impairment) at 18 to 22 months of corrected age was related to BW stratum (501 to 750 g; 751 to 1000 g) and baseline severity of illness using multilevel regression equations. The probability of benefit and of harm was directly assessed with Bayesian analyses.Baseline illness severity was well characterized using mechanical ventilation and FiO(2) at 24 h age. Among mechanically ventilated infants ≤ 750 g BW (n=684), a reduction in impairment and in profound impairment was offset by higher mortality (P for interaction <0.05) with no significant effect on composite outcomes. Conservative Bayesian analyses of this subgroup identified a 99% (posterior) probability that AgPT increased mortality, a 97% probability that AgPT reduced impairment, and a 99% probability that AgPT reduced profound impairment.Findings from the only large trial of AgPT suggest that AgPT may increase mortality while reducing impairment and profound impairment among the smallest and sickest infants. New approaches to reduce their serum bilirubin need development and rigorous testing.

    View details for DOI 10.1038/jp.2012.64

    View details for Web of Science ID 000308278000006

    View details for PubMedID 22652561

    View details for PubMedCentralID PMC3558278

  • Are Outcomes of Extremely Preterm Infants Improving? Impact of Bayley Assessment on Outcomes JOURNAL OF PEDIATRICS Vohr, B. R., Stephens, B. E., Higgins, R. D., Bann, C. M., Hintz, S. R., Das, A., Newman, J. E., Peralta-Carcelen, M., Yolton, K., Dusick, A. M., Evans, P. W., Goldstein, R. F., Ehrenkranz, R. A., Pappas, A., Adams-Chapman, I., Wilson-Costello, D. E., Bauer, C. R., Bodnar, A., Heyne, R. J., Vaucher, Y. E., Dillard, R. G., Acarregui, M. J., McGowan, E. C., Myers, G. J., Fuller, J. 2012; 161 (2): 222-?

    Abstract

    To compare 18- to 22-month cognitive scores and neurodevelopmental impairment (NDI) in 2 time periods using the National Institute of Child Health and Human Development's Neonatal Research Network assessment of extremely low birth weight infants with the Bayley Scales of Infant Development, Second Edition (Bayley II) in 2006-2007 (period 1) and using the Bayley Scales of Infant and Toddler Development, Third Edition (Bayley III), with separate cognitive and language scores, in 2008-2011 (period 2).Scores were compared with bivariate analysis, and regression analyses were run to identify differences in NDI rates.Mean Bayley III cognitive scores were 11 points higher than mean Bayley II cognitive scores. The NDI rate was reduced by 70% (from 43% in period 1 to 13% in period 2; P < .0001). Multivariate analyses revealed that Bayley III contributed to a decreased risk of NDI by 5 definitions: cognitive score <70 and <85, cognitive or language score <70; cognitive or motor score <70, and cognitive, language, or motor score <70 (P < .001).Whether the Bayley III is overestimating cognitive performance or whether it is a more valid assessment of emerging cognitive skills than the Bayley II is uncertain. Because the Bayley III identifies significantly fewer children with disability, it is recommended that all extremely low birth weight infants be offered early intervention services at the time of discharge from the neonatal intensive care unit, and that Bayley scores be interpreted with caution.

    View details for DOI 10.1016/j.jpeds.2012.01.057

    View details for Web of Science ID 000306693800013

    View details for PubMedID 22421261

  • Empiric Antifungal Therapy and Outcomes in Extremely Low Birth Weight Infants with Invasive Candidiasis JOURNAL OF PEDIATRICS Greenberg, R. G., Benjamin, D. K., Gantz, M. G., Cotten, C. M., Stoll, B. J., Walsh, M. C., Sanchez, P. J., Shankaran, S., Das, A., Higgins, R. D., Miller, N. A., Auten, K. J., Walsh, T. J., Laptook, A. R., Carlo, W. A., Kennedy, K. A., Finer, N. N., Duara, S., Schibler, K., Ehrenkranz, R. A., Van Meurs, K. P., Frantz, I. D., Phelps, D. L., Poindexter, B. B., Bell, E. F., O'Shea, T. M., Watterberg, K. L., Goldberg, R. N., Smith, P. B. 2012; 161 (2): 264-?

    Abstract

    To assess the impact of empiric antifungal therapy for invasive candidiasis on subsequent outcomes in premature infants.This was a cohort study of infants with a birth weight ≤ 1000 g receiving care at Neonatal Research Network sites. All infants had at least one positive culture for Candida. Empiric antifungal therapy was defined as receipt of a systemic antifungal on the day of or the day before the first positive culture for Candida was drawn. We created Cox proportional hazards and logistic regression models stratified on propensity score quartiles to determine the effect of empiric antifungal therapy on survival, time to clearance of infection, retinopathy of prematurity, bronchopulmonary dysplasia, end-organ damage, and neurodevelopmental impairment (NDI).A total of 136 infants developed invasive candidiasis. The incidence of death or NDI was lower in infants who received empiric antifungal therapy (19 of 38; 50%) compared with those who had not (55 of 86; 64%; OR, 0.27; 95% CI, 0.08-0.86). There was no significant difference between the groups for any single outcome or other combined outcomes.Empiric antifungal therapy was associated with increased survival without NDI. A prospective randomized trial of this strategy is warranted.

    View details for DOI 10.1016/j.jpeds.2012.01.053

    View details for Web of Science ID 000306693800020

    View details for PubMedID 22424952

    View details for PubMedCentralID PMC3380169

  • Feasibility Study of Early Blood Pressure Management in Extremely Preterm Infants JOURNAL OF PEDIATRICS Batton, B. J., Li, L., Newman, N. S., Das, A., Watterberg, K. L., Yoder, B. A., Faix, R. G., Laughon, M. M., Van Meurs, K. P., Carlo, W. A., Higgins, R. D., Walsh, M. C. 2012; 161 (1): 65-?

    Abstract

    To assess the feasibility of a randomized placebo controlled trial (RCT) of blood pressure (BP) management for extremely preterm infants.This was a prospective pilot RCT of infants 23-0/7 to 26-6/7 weeks gestation who had protocol-defined low BP in the first 24 postnatal hours. Enrolled infants were administered a study infusion (dopamine or placebo) and a study syringe medication (hydrocortisone or placebo).Of the 366 infants screened, 119 (33%) had low BP, 58 (16%) met all entry criteria, and 10 (3%) were enrolled. A total of 161 infants (44%) were ineligible because they received early indomethacin. Only 17% of eligible infants were enrolled. Problems with consent included insufficient time, parent unavailability, and physician unwillingness to enroll critically ill infants. Two infants were withdrawn from the study because of the potential risk of intestinal perforation with simultaneous administration of hydrocortisone and indomethacin.This pilot RCT was not feasible because of low eligibility and consent rates. An RCT of BP management for extremely preterm infants may require a waiver of consent for research in emergency care. The frequent use of early indomethacin and the associated risk of intestinal perforation when used with hydrocortisone may limit future investigations to only inotropic medications.

    View details for DOI 10.1016/j.jpeds.2012.01.014

    View details for Web of Science ID 000305753700016

    View details for PubMedID 22336574

    View details for PubMedCentralID PMC3357442

  • Childhood Outcomes after Hypothermia for Neonatal Encephalopathy NEW ENGLAND JOURNAL OF MEDICINE Shankaran, S., Pappas, A., McDonald, S. A., Vohr, B. R., Hintz, S. R., Epi, M. S., Yolton, K., Gustafson, K. E., Leach, T. M., Green, C., Bara, R., Huitema, C. M., Ehrenkranz, R. A., Tyson, J. E., Das, A., Hammond, J., Peralta-Carcelen, M., Evans, P. W., Heyne, R. J., Wilson-Costello, D. E., Vaucher, Y. E., Bauer, C. R., Dusick, A. M., Adams-Chapman, I., Goldstein, R. F., Guillet, R., Papile, L., Higgins, R. D. 2012; 366 (22): 2085-2092

    Abstract

    We previously reported early results of a randomized trial of whole-body hypothermia for neonatal hypoxic-ischemic encephalopathy showing a significant reduction in the rate of death or moderate or severe disability at 18 to 22 months of age. Long-term outcomes are now available.In the original trial, we assigned infants with moderate or severe encephalopathy to usual care (the control group) or whole-body cooling to an esophageal temperature of 33.5°C for 72 hours, followed by slow rewarming (the hypothermia group). We evaluated cognitive, attention and executive, and visuospatial function; neurologic outcomes; and physical and psychosocial health among participants at 6 to 7 years of age. The primary outcome of the present analyses was death or an IQ score below 70.Of the 208 trial participants, primary outcome data were available for 190. Of the 97 children in the hypothermia group and the 93 children in the control group, death or an IQ score below 70 occurred in 46 (47%) and 58 (62%), respectively (P=0.06); death occurred in 27 (28%) and 41 (44%) (P=0.04); and death or severe disability occurred in 38 (41%) and 53 (60%) (P=0.03). Other outcome data were available for the 122 surviving children, 70 in the hypothermia group and 52 in the control group. Moderate or severe disability occurred in 24 of 69 children (35%) and 19 of 50 children (38%), respectively (P=0.87). Attention-executive dysfunction occurred in 4% and 13%, respectively, of children receiving hypothermia and those receiving usual care (P=0.19), and visuospatial dysfunction occurred in 4% and 3% (P=0.80).The rate of the combined end point of death or an IQ score of less than 70 at 6 to 7 years of age was lower among children undergoing whole-body hypothermia than among those undergoing usual care, but the differences were not significant. However, hypothermia resulted in lower death rates and did not increase rates of severe disability among survivors. (Funded by the National Institutes of Health and the Eunice Kennedy Shriver NICHD Neonatal Research Network; ClinicalTrials.gov number, NCT00005772.).

    View details for DOI 10.1056/NEJMoa1112066

    View details for Web of Science ID 000304613400008

    View details for PubMedID 22646631

    View details for PubMedCentralID PMC3459579

  • Risk of bronchopulmonary dysplasia by second-trimester maternal serum levels of alpha-fetoprotein, human chorionic gonadotropin, and unconjugated estriol PEDIATRIC RESEARCH Jelliffe-Pawlowski, L. L., Shaw, G. M., Stevenson, D. K., Oehlert, J. W., Quaintance, C., Santos, A. J., Baer, R. J., Currier, R. J., O'Brodovich, H. M., Gould, J. B. 2012; 71 (4): 399-406

    Abstract

    Although maternal serum α-fetoprotein (AFP), human chorionic gonandotropin (hCG), and estriol play important roles in immunomodulation and immunoregulation during pregnancy, their relationship with the development of bronchopulmonary dysplasia (BPD) in young infants is unknown despite BPD being associated with pre- and postnatal inflammatory factors.We found that these serum biomarkers were associated with an increased risk of BPD. Risks were especially high when AFP and/or hCG levels were above the 95th percentile and/or when unconjugated estriol (uE3) levels were below the 5th percentile (relative risks (RRs) 3.1-6.7). Risks increased substantially when two or more biomarker risks were present (RRs 9.9-75.9).Data suggested that pregnancies that had a biomarker risk and yielded an offspring with BPD were more likely to have other factors present that suggested early intrauterine fetal adaptation to stress, including maternal hypertension and asymmetric growth restriction.The objective of this population-based study was to examine whether second-trimester levels of AFP, hCG, and uE3 were associated with an increased risk of BPD.

    View details for DOI 10.1038/pr.2011.73

    View details for Web of Science ID 000301884500013

    View details for PubMedID 22391642

    View details for PubMedCentralID PMC3616500

  • Metalloporphyrins - an update FRONTIERS IN PHARMACOLOGY Schulz, S., Wong, R. J., Vreman, H. J., Stevenson, D. K. 2012; 3

    Abstract

    Metalloporphyrins are structural analogs of heme and their potential use in the management of neonatal hyperbilirubinemia has been the subject of considerable research for more than three decades. The pharmacological basis for using this class of compounds to control bilirubin levels is the targeted blockade of bilirubin production through the competitive inhibition of heme oxygenase (HO), the rate-limiting enzyme in the bilirubin production pathway. Ongoing research continues in the pursuit of identifying ideal metalloporphyrins, which are safe and effective, by defining therapeutic windows and targeted interventions for the treatment of excessive neonatal hyperbilirubinemia.

    View details for DOI 10.3389/fphar.2012.00068

    View details for Web of Science ID 000209177700066

    View details for PubMedCentralID PMC3337460

  • EFFECT OF A LOW DOSE OF ZINC DEUTEROPORPHYRIN BIS GLYCOL IN INHIBITING HEME OXYGENASE ACTIVITY AFTER HEME-LOADING Katayama, Y., Kalish, F. S., Zhao, H., Wong, R. J., Stevenson, D. K. LIPPINCOTT WILLIAMS & WILKINS. 2012: 210
  • CONSIDERING A VASCULAR PATHOGENESIS OF SMALL INTESTINAL ATRESIA: RISKS ASSOCIATED WITH 32 SINGLE NUCLEOTIDE POLYMORPHISMS INVOLVED IN HOMOCYSTEINE METABOLISM, COAGULATION, CELL-CELL INTERACTIONS, INFLAMMATORY RESPONSE, AND BLOOD PRESSURE REGULATION Gupta, T., Yang, W., Iovannisci, D. M., Carmichael, S. L., Stevenson, D. K., Shaw, G. M., Lammer, E. J. LIPPINCOTT WILLIAMS & WILKINS. 2012: 202
  • HEME OXYGENASE-1 DEFICIENCY PROMOTES NECROTIZING ENTEROCOLITIS DEVELOPMENT IN A MURINE MOUSE MODEL Western Regional Meeting of the American-Federation-for-Medical-Research Schulz, S., Jang, K., Kalish, F. S., Zhao, H., Vreman, H. J., Sylvester, K. S., Wong, R. J., Stevenson, D. K. LIPPINCOTT WILLIAMS & WILKINS. 2012: 158–58
  • IN VITRO BILIRUBIN PHOTODESTRUCTION ACTION SPECTRUM REVISITED Western Regional Meeting of the American-Federation-for-Medical-Research Schulz, S., Vreman, H. J., Wong, R. J., Cline, B., Stevenson, D. K. LIPPINCOTT WILLIAMS & WILKINS. 2012: 210–10
  • The effects of aggressive vs. conservative phototherapy on the brainstem auditory evoked responses of extremely-low-birth-weight infants PEDIATRIC RESEARCH Lasky, R. E., Church, M. W., Orlando, M. S., Morris, B. H., Parikh, N. A., Tyson, J. E., McDavid, G. E., Oh, W., Stevenson, D. K., Van Meurs, K. P., Guillet, R., Phelps, D. L. 2012; 71 (1): 77-84

    Abstract

    This study was a two-center, stratified, parallel-group randomized trial comparing the effects of aggressive vs. conservative phototherapy on brainstem auditory evoked response (BAER) latencies in infants with extremely low birth weight (ELBW, ≤ 1,000 g).BAER latencies of 751-1,000 g birth-weight infants were shorter by 0.37 ms (95% confidence interval (CI) = 0.02, 0.73) for wave V, 0.39 ms (0.08, 0.70) for wave III, and 0.33 ms (0.01, 0.65) for wave I after aggressive phototherapy at one center. Interwave intervals did not differ significantly. Similar nonsignificant trends were recorded for 501-750 g birth-weight infants. At the other participating center, no significant differences were recorded, cautioning against overgeneralizing these results.The effects of bilirubin on the auditory pathway in ELBW infants depend on a complex interaction of bilirubin exposure, newborn characteristics, and clinical management.Aggressive phototherapy was initiated sooner and continued at lower bilirubin levels than conservative phototherapy. A total of 174 ELBW infants were enrolled in the study; 111 infants were successfully tested at 35 weeks postmenstrual age (PMA); 57 died; and 6 were not successfully tested.

    View details for DOI 10.1038/pr.2011.17

    View details for Web of Science ID 000303453600012

    View details for PubMedID 22289854

    View details for PubMedCentralID PMC3326602

  • Association of Antenatal Corticosteroids With Mortality and Neurodevelopmental Outcomes Among Infants Born at 22 to 25 Weeks' Gestation JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Carlo, W. A., McDonald, S. A., Fanaroff, A. A., Vohr, B. R., Stoll, B. J., Ehrenkranz, R. A., Andrews, W. W., Wallace, D., Das, A., Bell, E. F., Walsh, M. C., Laptook, A. R., Shankaran, S., Poindexter, B. B., Hale, E. C., Newman, N. S., Davis, A. S., Schibler, K., Kennedy, K. A., Sanchez, P. J., Van Meurs, K. P., Goldberg, R. N., Watterberg, K. L., Faix, R. G., Frantz, I. D., Higgins, R. D. 2011; 306 (21): 2348-2358

    Abstract

    Current guidelines, initially published in 1995, recommend antenatal corticosteroids for mothers with preterm labor from 24 to 34 weeks' gestational age, but not before 24 weeks due to lack of data. However, many infants born before 24 weeks' gestation are provided intensive care.To determine if use of antenatal corticosteroids is associated with improvement in major outcomes for infants born at 22 and 23 weeks' gestation.Cohort study of data collected prospectively on inborn infants with a birth weight between 401 g and 1000 g (N = 10,541) born at 22 to 25 weeks' gestation between January 1, 1993, and December 31, 2009, at 23 academic perinatal centers in the United States. Certified examiners unaware of exposure to antenatal corticosteroids performed follow-up examinations on 4924 (86.5%) of the infants born between 1993 and 2008 who survived to 18 to 22 months. Logistic regression models generated adjusted odds ratios (AORs), controlling for maternal and neonatal variables.Mortality and neurodevelopmental impairment at 18 to 22 months' corrected age.Death or neurodevelopmental impairment at 18 to 22 months was significantly lower for infants who had been exposed to antenatal corticosteroids and were born at 23 weeks' gestation (83.4% with exposure to antenatal corticosteroids vs 90.5% without exposure; AOR, 0.58 [95% CI, 0.42-0.80]), at 24 weeks' gestation (68.4% with exposure to antenatal corticosteroids vs 80.3% without exposure; AOR, 0.62 [95% CI, 0.49-0.78]), and at 25 weeks' gestation (52.7% with exposure to antenatal corticosteroids vs 67.9% without exposure; AOR, 0.61 [95% CI, 0.50-0.74]) but not in those infants born at 22 weeks' gestation (90.2% with exposure to antenatal corticosteroids vs 93.1% without exposure; AOR, 0.80 [95% CI, 0.29-2.21]). If the mothers had received antenatal corticosteroids, the following events occurred significantly less in infants born at 23, 24, and 25 weeks' gestation: death by 18 to 22 months; hospital death; death, intraventricular hemorrhage, or periventricular leukomalacia; and death or necrotizing enterocolitis. For infants born at 22 weeks' gestation, the only outcome that occurred significantly less was death or necrotizing enterocolitis (73.5% with exposure to antenatal corticosteroids vs 84.5% without exposure; AOR, 0.54 [95% CI, 0.30-0.97]).Among infants born at 23 to 25 weeks' gestation, antenatal exposure to corticosteroids compared with nonexposure was associated with a lower rate of death or neurodevelopmental impairment at 18 to 22 months.

    View details for Web of Science ID 000297680300020

    View details for PubMedID 22147379

  • Cytokines and Neurodevelopmental Outcomes in Extremely Low Birth Weight Infants JOURNAL OF PEDIATRICS Carlo, W. A., McDonald, S. A., Tyson, J. E., Stoll, B. J., Ehrenkranz, R. A., Shankaran, S., Goldberg, R. N., Das, A., Schendel, D., Thorsen, P., Skogstrand, K., Hougaard, D. M., Oh, W., Laptook, A. R., Duara, S., Fanaroff, A. A., Donovan, E. F., Korones, S. B., Stevenson, D. K., Papile, L., Finer, N. N., O'Shea, T. M., Poindexter, B. B., Wright, L. L., Ambalavanan, N., Higgins, R. D. 2011; 159 (6): 919-U77

    Abstract

    To determine if selected pro-inflammatory and anti-inflammatory cytokines and/or mediators of inflammation reported to be related to the development of cerebral palsy (CP) predict neurodevelopmental outcome in extremely low birth weight infants.Infants with birth weights ≤1000 g (n = 1067) had blood samples collected at birth and on days 3 ± 1, 7 ± 1, 14 ± 3, and 21 ± 3 to examine the association between cytokines and neurodevelopmental outcomes. The analyses were focused on 5 cytokines (interleukin [IL] 1β; IL-8; tumor necrosis factor-α; regulated upon activation, normal T-cell expressed, and secreted (RANTES); and IL-2) reported to be most predictive of CP in term and late preterm infants.IL-8 was higher on days 0-4 and subsequently in infants who developed CP compared with infants who did not develop CP in both unadjusted and adjusted analyses. Other cytokines (IL-12, IL-17, tumor necrosis factor-β, soluble IL rα, macrophage inflammatory protein 1β) were found to be altered on days 0-4 in infants who developed CP.CP in former preterm infants may, in part, have a late perinatal and/or early neonatal inflammatory origin.

    View details for DOI 10.1016/j.jpeds.2011.05.042

    View details for Web of Science ID 000296849400010

    View details for PubMedID 21798559

    View details for PubMedCentralID PMC3215787

  • Predictive Value of an Early Amplitude Integrated Electroencephalogram and Neurologic Examination PEDIATRICS Shankaran, S., Pappas, A., McDonald, S. A., Laptook, A. R., Bara, R., Ehrenkranz, R. A., Tyson, J. E., Goldberg, R., Donovan, E. F., Fanaroff, A. A., Das, A., Poole, W. K., Walsh, M., Higgins, R. D., Welsh, C., Salhab, W., Carlo, W. A., Poindexter, B., Stoll, B. J., Guillet, R., Finer, N. N., Stevenson, D. K., Bauer, C. R. 2011; 128 (1): E112-E120

    Abstract

    To examine the predictive validity of the amplitude integrated electroencephalogram (aEEG) and stage of encephalopathy among infants with hypoxic-ischemic encephalopathy (HIE) eligible for therapeutic whole-body hypothermia.Neonates were eligible for this prospective study if moderate or severe HIE occurred at <6 hours and an aEEG was obtained at <9 hours of age. The primary outcome was death or moderate/severe disability at 18 months.There were 108 infants (71 with moderate HIE and 37 with severe HIE) enrolled in the study. aEEG findings were categorized as normal, with continuous normal voltage (n=12) or discontinuous normal voltage (n=12), or abnormal, with burst suppression (n=22), continuous low voltage (n=26), or flat tracing (n=36). At 18 months, 53 infants (49%) experienced death or disability. Severe HIE and an abnormal aEEG were related to the primary outcome with univariate analysis, whereas severe HIE alone was predictive of outcome with multivariate analysis. Addition of aEEG pattern to HIE stage did not add to the predictive value of the model; the area under the curve changed from 0.72 to 0.75 (P=.19).The aEEG background pattern did not significantly enhance the value of the stage of encephalopathy at study entry in predicting death and disability among infants with HIE.

    View details for DOI 10.1542/peds.2010-2036

    View details for Web of Science ID 000292299500015

    View details for PubMedID 21669899

    View details for PubMedCentralID PMC3124102

  • Prediction of Bronchopulmonary Dysplasia by Postnatal Age in Extremely Premature Infants AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE Laughon, M. M., Langer, J. C., Bose, C. L., Smith, P. B., Ambalavanan, N., Kennedy, K. A., Stoll, B. J., Buchter, S., Laptook, A. R., Ehrenkranz, R. A., Cotten, C. M., Wilson-Costello, D. E., Shankaran, S., Van Meurs, K. P., Davis, A. S., Gantz, M. G., Finer, N. N., Yoder, B. A., Faix, R. G., Carlo, W. A., Schibler, K. R., Newman, N. S., Rich, W., Das, A., Higgins, R. D., Walsh, M. C. 2011; 183 (12): 1715-1722

    Abstract

    Benefits of identifying risk factors for bronchopulmonary dysplasia in extremely premature infants include providing prognostic information, identifying infants likely to benefit from preventive strategies, and stratifying infants for clinical trial enrollment.To identify risk factors for bronchopulmonary dysplasia, and the competing outcome of death, by postnatal day; to identify which risk factors improve prediction; and to develop a Web-based estimator using readily available clinical information to predict risk of bronchopulmonary dysplasia or death.We assessed infants of 23-30 weeks' gestation born in 17 centers of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network and enrolled in the Neonatal Research Network Benchmarking Trial from 2000-2004.Bronchopulmonary dysplasia was defined as a categorical variable (none, mild, moderate, or severe). We developed and validated models for bronchopulmonary dysplasia risk at six postnatal ages using gestational age, birth weight, race and ethnicity, sex, respiratory support, and Fi(O(2)), and examined the models using a C statistic (area under the curve). A total of 3,636 infants were eligible for this study. Prediction improved with advancing postnatal age, increasing from a C statistic of 0.793 on Day 1 to a maximum of 0.854 on Day 28. On Postnatal Days 1 and 3, gestational age best improved outcome prediction; on Postnatal Days 7, 14, 21, and 28, type of respiratory support did so. A Web-based model providing predicted estimates for bronchopulmonary dysplasia by postnatal day is available at https://neonatal.rti.org.The probability of bronchopulmonary dysplasia in extremely premature infants can be determined accurately using a limited amount of readily available clinical information.

    View details for DOI 10.1164/rccm.201101-0055OC

    View details for Web of Science ID 000292305600024

    View details for PubMedID 21471086

    View details for PubMedCentralID PMC3136997

  • The Need for Technologies to Prevent Bilirubin-Induced Neurologic Dysfunction Syndrome SEMINARS IN PERINATOLOGY Bhutani, V. K., Stevenson, D. K. 2011; 35 (3): 97-100

    Abstract

    Dramatic improvements in the overall socioeconomic conditions have yet to impact the unacceptably high maternal (approximately 1500 maternal deaths daily, worldwide) and neonatal morbidity and mortality (more than 10,000 deaths per daily 200,000 live-births, worldwide) in the developing nations. Thus, nations with emerging markets have unique health-societal needs. All infants require a safer transition from a birthing facility to home during the first week after birth and providing for a nurturing environment to prevent neonatal illnesses is integral to "good clinical practice." The unmonitored occurrence of severe hyperbilirubinemia and kernicterus are emblematic of a fractured maternal child healthcare system. The "know-do" gaps that span private versus public health care systems in the emerging markets have led us to conclude that building an interdisciplinary leadership approach to provide innovative strategies and affordable technologies will help bridge and access existing social barriers in the micro- and macro-health environments. Thus, unfettered access, global benchmarks, and culturally relevant strategies are dependent on evidence-based affordable technologies to successfully transform societal health care practices. Implementation of jaundice-related technologies should serve as a template for other affordable newborn health products.

    View details for DOI 10.1053/j.semperi.2011.02.002

    View details for Web of Science ID 000292057900001

    View details for PubMedID 21641481

  • Heme Oxygenase-1 Deletion Affects Stress Erythropoiesis PLOS ONE Cao, Y., Kusy, S., Luong, R., Wong, R. J., Stevenson, D. K., Contag, C. H. 2011; 6 (5)

    Abstract

    Homeostatic erythropoiesis leads to the formation of mature red blood cells under non-stress conditions, and the production of new erythrocytes occurs as the need arises. In response to environmental stimuli, such as bone marrow transplantation, myelosuppression, or anemia, erythroid progenitors proliferate rapidly in a process referred to as stress erythropoiesis. We have previously demonstrated that heme oxygenase-1 (HO-1) deficiency leads to disrupted stress hematopoiesis. Here, we describe the specific effects of HO-1 deficiency on stress erythropoiesis.We used a transplant model to induce stress conditions. In irradiated recipients that received hmox(+/-) or hmox(+/+) bone marrow cells, we evaluated (i) the erythrocyte parameters in the peripheral blood; (ii) the staining intensity of CD71-, Ter119-, and CD49d-specific surface markers during erythroblast differentiation; (iii) the patterns of histological iron staining; and (iv) the number of Mac-1(+)-cells expressing TNF-α. In the spleens of mice that received hmox(+/-) cells, we show (i) decreases in the proerythroblast, basophilic, and polychromatophilic erythroblast populations; (ii) increases in the insoluble iron levels and decreases in the soluble iron levels; (iii) increased numbers of Mac-1(+)-cells expressing TNF-α; and (iv) decreased levels of CD49d expression in the basophilic and polychromatophilic erythroblast populations.As reflected by effects on secreted and cell surface proteins, HO-1 deletion likely affects stress erythropoiesis through the retention of erythroblasts in the erythroblastic islands of the spleen. Thus, HO-1 may serve as a therapeutic target for controlling erythropoiesis, and the dysregulation of HO-1 may be a predisposing condition for hematologic diseases.

    View details for DOI 10.1371/journal.pone.0020634

    View details for Web of Science ID 000291097600112

    View details for PubMedID 21655188

    View details for PubMedCentralID PMC3105104

  • Quantitating carbon monoxide production from heme by vascular plant preparations in vitro PLANT PHYSIOLOGY AND BIOCHEMISTRY Vreman, H. J., Wong, R. J., Stevenson, D. K. 2011; 49 (1): 61-68

    Abstract

    Heme in animals is mainly degraded enzymatically, producing a predictable amount of carbon monoxide (CO). Under some conditions, alternative sources of CO production are important, such as lipid peroxidation and photo-oxidation. Less is known about CO production in plants as a reflection of enzymatic activity or coupled oxidation, but a sensitive assay for CO production in plants would be a valuable tool to explore the various sources in plants as the conditions of the reactions and mechanisms are defined. Using gas chromatography, we determined the requirements for heme-supported in vitro CO generation by exogenous reactants (NADPH, tissue supernatant, oxygen), optimum reaction conditions (time, temperature, pH, light), and effects of various cofactors and substrates using supernatants from Spinacia oleracea (spinach) leaf and Solanum tuberosa (potato) tuber homogenates. We then determined the CO production rate distribution between organ (root, stem, leaf, flower, fruit) supernatants in a number of commercially available plant species. CO production ranged from 4-65 nmol CO/h/g fresh weight and occurred in all vascular plant tissues examined, with the highest rates in chloroplast-containing tissues. In spinach leaves, CO production was concentrated (>2-fold) in the particulate fraction, whereas in potato tubers, the particulate fraction accounted for <50% of the rates in homogenates. We conclude that gas chromatography is uniquely suited for the determination of CO production in pigmented, heterogeneous plant tissue preparations.

    View details for DOI 10.1016/j.plaphy.2010.09.021

    View details for Web of Science ID 000286998800009

    View details for PubMedID 21055958

  • Early-Childhood Neurodevelopmental Outcomes Are Not Improving for Infants Born at < 25 Weeks' Gestational Age PEDIATRICS Hintz, S. R., Kendrick, D. E., Wilson-Costello, D. E., Das, A., Bell, E. F., Vohr, B. R., Higgins, R. D. 2011; 127 (1): 62-70

    Abstract

    We compared neurodevelopmental outcomes at 18 to 22 months' corrected age of infants born with extremely low birth weight at an estimated gestational age of <25 weeks during 2 periods: 1999-2001 (epoch 1) and 2002-2004 (epoch 2).We conducted a multicenter, retrospective analysis of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Perinatal and neonatal variables and outcomes were compared between epochs. Neurodevelopmental outcomes at 18 to 22 months' corrected age were evaluated with neurologic exams and Bayley Scales of Infant Development II. Logistic regression analyses determined the independent risk of epoch for adverse outcomes.Infant survival was similar between epochs (epoch 1, 35.4%, vs epoch 2, 32.3%; P = .09). A total of 411 of 452 surviving infants in epoch 1 and 405 of 438 surviving infants in epoch 2 were evaluated at 18 to 22 months' corrected age. Cesarean delivery (P = .03), surgery for patent ductus arteriosus (P = .004), and late sepsis (P = .01) were more common in epoch 2, but postnatal steroid use was dramatically reduced (63.5% vs 32.8%; P < .0001). Adverse outcomes at 18 to 22 months' corrected age were common in both epochs. Moderate-to-severe cerebral palsy was diagnosed in 11.1% of surviving infants in epoch 1 and 14.9% in epoch 2 (adjusted odds ratio [OR]: 1.52 [95% confidence interval (CI): 0.86-2.71]; P = .15), the Mental Developmental Index was <70 in 44.9% in epoch 1 and 51% in epoch 2 (OR: 1.30 [95% CI: 0.91-1.87]; P = .15), and neurodevelopmental impairment was diagnosed in 50.1% of surviving infants in epoch 1 and 58.7% in epoch 2 (OR: 1.4 [95% CI: 0.98-2.04]; P = .07).Early-childhood outcomes for infants born at <25 weeks' estimated gestational age were unchanged between the 2 periods.

    View details for DOI 10.1542/peds.2010-1150

    View details for Web of Science ID 000285782200046

    View details for PubMedID 21187312

    View details for PubMedCentralID PMC3375467

  • HEME OXYGENASE-1 DEFICIENCY IMPAIRS PLACENTAL VASCULAR FORMATION AND EMBRYONIC DEVELOPMENT Zhao, H., Azuma, J., Kalish, F. S., Wong, R. J., Stevenson, D. K. LIPPINCOTT WILLIAMS & WILKINS. 2011: 167
  • HEME OXYGENASE-1 IS PROTECTIVE IN AN EXPERIMENTAL MODEL OF ABDOMINAL AORTIC ANEURYSM Azuma, J., Wong, R. J., Maegdefessel, L., Zhao, H., Kalish, F. S., Deng, A., Stevenson, D. K., Tsao, P. S. LIPPINCOTT WILLIAMS & WILKINS. 2011: 150
  • THE INHIBITORY POTENCY OF LOW DOSES OF ZINC DEUTEROPORPHYRIN BIS GLYCOL ON HEME OXYGENASE ACTIVITY IN 3-DAY-OLD MICE Western Regional Meeting of the American-Federation-for-Medical-Research Katayama, Y., Shaw, N., Yaffe, Z. A., He, C. X., Kalish, F. S., Schulz-Geske, S., Zhao, H., Wong, R. J., Stevenson, D. K. LIPPINCOTT WILLIAMS & WILKINS. 2011: 170–70
  • HEME OXYGENASE-1 EXPRESSION IS DIFFERENTIALLY REGULATED IN VITRO BY METALLOPORPHYRINS Western Regional Meeting of the American-Federation-for-Medical-Research Schulz-Geske, S., Zhao, H., Kalish, F. S., McCarthy, E., Vreman, H. J., Wong, R. J., Stevenson, D. K. LIPPINCOTT WILLIAMS & WILKINS. 2011: 196–96
  • ROLE OF IIEME OXYGENASE IN A MURINE MODEL OF EARLY NECROTIZING ENTEROCOLITIS Western Regional Meeting of the American-Federation-for-Medical-Research Schulz-Geske, S., Kalish, F. S., Jang, K. Y., Zhao, H., Huey, M., Vreman, H. J., Sylvester, K. S., Wong, R. J., Stevenson, D. K. LIPPINCOTT WILLIAMS & WILKINS. 2011: 126–27
  • EFFECT OF FLUORESCENT LIGHT EXPOSURE ON METALLOPORHYRIN-TREATED NEWBORN MICE Western Regional Meeting of the American-Federation-for-Medical-Research Schulz-Geske, S., Kalish, F. S., Zhao, H., Katayama, Y., Champion, K. A., Vreman, H. J., Wong, R. J., Stevenson, D. K. LIPPINCOTT WILLIAMS & WILKINS. 2011: 126–26
  • Beneficial Effects of Heme Oxygenase-1 Expression and Activity in Experimental Abdominal Aortic Aneurysm Azuma, J., Wong, R., Maegdefessel, L., Zhao, H., Deng, A., Stevenson, D. K., Tsao, P. S., Kalish, F. S. LIPPINCOTT WILLIAMS & WILKINS. 2010
  • Hemolysis and Hyperbilirubinemia in Antiglobulin Positive, Direct ABO Blood Group Heterospecific Neonates JOURNAL OF PEDIATRICS Kaplan, M., Hammerman, C., Vreman, H. J., Wong, R. J., Stevenson, D. K. 2010; 157 (5): 772-777

    Abstract

    We quantified hemolysis and determined the incidence of hyperbilirubinemia in neonates who were direct antiglobulin titer (DAT)-positive, ABO heterospecific, and compared variables among O-A and O-B subgroups.Plasma total bilirubin (PTB) was determined before the neonates were discharged from the hospital and more frequently when clinically warranted, in neonates who were DAT positive with blood group A or B and with mothers who had blood group O. Heme catabolism (and therefore bilirubin production) was indexed by blood carboxyhemoglobin corrected for inspired carbon monoxide (COHbc). Hyperbilirubinemia was defined as any PTB concentration >95th percentile on the hour-of-life-specific bilirubin nomogram.Of 164 neonates, 111 were O-A and 53 O-B. Overall, hyperbilirubinemia developed 85 neonates (51.8%), and it tended to be more prevalent in the O-B neonates than O-A neonates (62.3% versus 46.8%; P = .053). Hyperbilirubinemia developed in more O-B newborns than O-A newborns at <24 hours (93.9% versus 48.1%; P< .0001). COHbc values were globally higher than our previously published newborn values. Babies in whom hyperbilirubinemia developed had higher COHbc values than the already high values of babies who were non-hyperbilirubinemic, and O-B newborns tended to have higher values than their O-A counterparts.DAT-positive, ABO heterospecificity is associated with increased hemolysis and a high incidence of neonatal hyperbilirubinemia. O-B heterospecificity tends to confer even higher risk than O-A counterparts.

    View details for DOI 10.1016/j.jpeds.2010.05.024

    View details for Web of Science ID 000283045900020

    View details for PubMedID 20598320

    View details for PubMedCentralID PMC2951500

  • Seizures in Extremely Low Birth Weight Infants Are Associated with Adverse Outcome JOURNAL OF PEDIATRICS Davis, A. S., Hintz, S. R., Van Meurs, K. P., Li, L., Das, A., Stoll, B. J., Walsh, M. C., Pappas, A., Bell, E. F., Laptook, A. R., Higgins, R. D. 2010; 157 (5): 720-U47

    Abstract

    To examine risk factors for neonatal clinical seizures and to determine the independent association with death or neurodevelopmental impairment (NDI) in extremely low birth weight (ELBW) infants.A total of 6499 ELBW infants (401-1000 g) surviving to 36 weeks postmenstrual age (PMA) were included in this retrospective study. Unadjusted comparisons were performed between infants with (n = 414) and without (n = 6085) clinical seizures during the initial hospitalization. Using multivariate logistic regression modeling, we examined the independent association of seizures with late death (after 36 weeks PMA) or NDI after controlling for multiple demographic, perinatal, and neonatal variables.Infants with clinical seizures had a greater proportion of neonatal morbidities associated with poor outcome, including severe intraventricular hemorrhage, sepsis, meningitis, and cystic periventricular leukomalacia (all P < .01). Survivors were more likely to have NDI or moderate-severe cerebral palsy at 18 to 22 months corrected age (both P < .01). After adjusting for multiple confounders, clinical seizures remained significantly associated with late death or NDI (odds ratio, 3.15; 95% CI, 2.37-4.19).ELBW infants with clinical seizures are at increased risk for adverse neurodevelopmental outcome, independent of multiple confounding factors.

    View details for DOI 10.1016/j.jpeds.2010.04.065

    View details for Web of Science ID 000283045900008

    View details for PubMedID 20542294

  • Neonatal Candidiasis: Epidemiology, Risk Factors, and Clinical Judgment PEDIATRICS Benjamin, D. K., Stoll, B. J., Gantz, M. G., Walsh, M. C., Sanchez, P. J., Das, A., Shankaran, S., Higgins, R. D., Auten, K. J., Miller, N. A., Walsh, T. J., Laptook, A. R., Carlo, W. A., Kennedy, K. A., Finer, N. N., Duara, S., Schibler, K., Chapman, R. L., Van Meurs, K. P., Frantz, I. D., Phelps, D. L., Poindexter, B. B., Bell, E. F., O'Shea, T. M., Watterberg, K. L., Goldberg, R. N. 2010; 126 (4): E865-E873

    Abstract

    Invasive candidiasis is a leading cause of infection-related morbidity and mortality in extremely low birth weight (<1000-g) infants. We quantified risk factors that predict infection in premature infants at high risk and compared clinical judgment with a prediction model of invasive candidiasis.The study involved a prospective observational cohort of infants≤1000 g birth weight at 19 centers of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. At each sepsis evaluation, clinical information was recorded, cultures were obtained, and clinicians prospectively recorded their estimate of the probability of invasive candidiasis. Two models were generated with invasive candidiasis as their outcome: (1) potentially modifiable risk factors; and (2) a clinical model at time of blood culture to predict candidiasis.Invasive candidiasis occurred in 137 of 1515 (9.0%) infants and was documented by positive culture from ≥1 of these sources: blood (n=96); cerebrospinal fluid (n=9); urine obtained by catheterization (n=52); or other sterile body fluid (n=10). Mortality rate was not different for infants who had positive blood culture compared with those with isolated positive urine culture. Incidence of candida varied from 2% to 28% at the 13 centers that enrolled≥50 infants. Potentially modifiable risk factors included central catheter, broad-spectrum antibiotics (eg, third-generation cephalosporins), intravenous lipid emulsion, endotracheal tube, and antenatal antibiotics. The clinical prediction model had an area under the receiver operating characteristic curve of 0.79 and was superior to clinician judgment (0.70) in predicting subsequent invasive candidiasis.Previous antibiotics, presence of a central catheter or endotracheal tube, and center were strongly associated with invasive candidiasis. Modeling was more accurate in predicting invasive candidiasis than clinical judgment.

    View details for DOI 10.1542/peds.2009-3412

    View details for Web of Science ID 000282526100014

    View details for PubMedID 20876174

    View details for PubMedCentralID PMC3045840

  • Neonatal Outcomes of Extremely Preterm Infants From the NICHD Neonatal Research Network PEDIATRICS Stoll, B. J., Hansen, N. I., Bell, E. F., Shankaran, S., Laptook, A. R., Walsh, M. C., Hale, E. C., Newman, N. S., Schibler, K., Carlo, W. A., Kennedy, K. A., Poindexter, B. B., Finer, N. N., Ehrenkranz, R. A., Duara, S., Sanchez, P. J., O'Shea, T. M., Goldberg, R. N., Van Meurs, K. P., Faix, R. G., Phelps, D. L., Frantz, I. D., Watterberg, K. L., Saha, S., Das, A., Higgins, R. D. 2010; 126 (3): 443-456

    Abstract

    This report presents data from the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network on care of and morbidity and mortality rates for very low birth weight infants, according to gestational age (GA).Perinatal/neonatal data were collected for 9575 infants of extremely low GA (22-28 weeks) and very low birth weight (401-1500 g) who were born at network centers between January 1, 2003, and December 31, 2007.Rates of survival to discharge increased with increasing GA (6% at 22 weeks and 92% at 28 weeks); 1060 infants died at or=24 weeks survive, high rates of morbidity among survivors continue to be observed.

    View details for DOI 10.1542/peds.2009-2959

    View details for Web of Science ID 000281535700006

    View details for PubMedID 20732945

    View details for PubMedCentralID PMC2982806

  • Impact of Timing of Birth and Resident Duty-Hour Restrictions on Outcomes for Small Preterm Infants PEDIATRICS Bell, E. F., Hansen, N. I., Morriss, F. H., Stoll, B. J., Ambalavanan, N., Gould, J. B., Laptook, A. R., Walsh, M. C., Carlo, W. A., Shankaran, S., Das, A., Higgins, R. D. 2010; 126 (2): 222-231

    Abstract

    The goal was to examine the impact of birth at night, on the weekend, and during July or August (the first months of the academic year) and the impact of resident duty-hour restrictions on mortality and morbidity rates for very low birth weight infants.Outcomes were analyzed for 11,137 infants with birth weights of 501 to 1250 g who were enrolled in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network registry in 2001-2005. Approximately one-half were born before the introduction of resident duty-hour restrictions in 2003. Follow-up assessments at 18 to 22 months were completed for 4508 infants. Mortality rate, short-term morbidities, and neurodevelopmental outcome were examined with respect to the timing of birth.There was no effect of the timing of birth on mortality rate and no impact on the risks of short-term morbidities except that the risk of retinopathy of prematurity (stage > or =2) was higher after the introduction of duty-hour restrictions and the risk of retinopathy of prematurity requiring operative treatment was lower for infants born during the late night than during the day. There was no impact of the timing of birth on neurodevelopmental outcome except that the risk of hearing impairment or death was slightly lower among infants born in July or August.In this network, the timing of birth had little effect on the risks of death and morbidity for very low birth weight infants, which suggests that staffing patterns were adequate to provide consistent care.

    View details for DOI 10.1542/peds.2010-0456

    View details for Web of Science ID 000280565700005

    View details for PubMedID 20643715

  • Heptavalent Pneumococcal Conjugate Vaccine Immunogenicity in Very-Low-Birth-Weight, Premature Infants PEDIATRIC INFECTIOUS DISEASE JOURNAL D'Angio, C. T., Heyne, R. J., O'Shea, T. M., Schelonka, R. L., Shankaran, S., Duara, S., Goldberg, R. N., Stoll, B. J., Van Meurs, K. P., Vohr, B. R., Das, A., Li, L., Burton, R. L., Hastings, B., Phelps, D. L., Sanchez, P. J., Carlo, W. A., Stevenson, D. K., Higgins, R. D. 2010; 29 (7): 600-606

    Abstract

    The heptavalent pneumococcal CRM197 conjugate vaccine (PCV-7) has been incompletely studied in very-low-birth-weight (< or =1500 g) infants.To assess PCV-7 immunogenicity in very-low-birth-weight, premature infants. We hypothesized that the frequency of postvaccine antibody concentrations > or =0.15 microg/mL would vary directly with birth weight.This was a multicenter observational study. Infants 401 to 1500 g birth weight and <32 0/7 weeks gestation, stratified by birth weight, were enrolled from 9 National Institute of Child Health and Human Development Neonatal Research Network centers. Infants received PCV-7 at 2, 4, and 6 months after birth and had blood drawn 4 to 6 weeks following the third dose. Antibodies against the 7 vaccine serotypes were measured by enzyme-linked immunosorbent assay.Of 369 enrolled infants, 244 completed their primary vaccine series by 8 months and had serum obtained. Subjects were 27.8 +/- 2.2 (mean +/- standard deviation) weeks gestation and 1008 +/- 282 g birth weight. Twenty-six percent had bronchopulmonary dysplasia and 16% had received postnatal glucocorticoids. Infants 1001 to 1500 g birth weight were more likely than those 401 to 1000 g to achieve antibody concentrations > or =0.15 microg/mL against the least 2 immunogenic serotypes (6B: 96% vs. 85%, P = 0.003 and 23F: 97% vs. 88%, P = 0.009). In multiple logistic regression analysis, lower birth weight, postnatal glucocorticoid use, lower weight at blood draw, and Caucasian race were each independently associated with antibody concentrations <0.35 microg/mL against serotypes 6B and/or 23F.When compared with larger premature infants, infants weighing < or =1000 g at birth have similar antibody responses to most, but not all, PCV-7 vaccine serotypes.

    View details for DOI 10.1097/INF.0b013e3181d264a6

    View details for Web of Science ID 000279348900004

    View details for PubMedID 20234331

    View details for PubMedCentralID PMC2949965

  • Target Ranges of Oxygen Saturation in Extremely Preterm Infants. NEW ENGLAND JOURNAL OF MEDICINE Carlo, W. A., Finer, N. N., Walsh, M. C., Rich, W., Gantz, M. G., Laptook, A. R., Yoder, B. A., Faix, R. G., Das, A., Poole, W. K., Schibler, K., Newman, N. S., Ambalavanan, N., Frantz, I. D., Piazza, A. J., Sanchez, P. J., Morris, B. H., Laroia, N., Phelps, D. L., Poindexter, B. B., Cotten, C. M., Van Meurs, K. P., Duara, S., Narendran, V., Sood, B. G., O'Shea, T. M., Bell, E. F., Ehrenkranz, R. A., Watterberg, K. L., Higgins, R. D., Jobe, A. H., Caplan, M. S., Oh, W., Hensman, A. M., Gingras, D., Barnett, S., LILLIE, S., Francis, K., Andrews, D., Angela, K., Fanaroff, A. A., SINER, B. S., Zadell, A., DiFiore, J., Donovan, E. F., Bridges, K., Alexander, B., Grisby, C., Mersmann, M. W., Mincey, H. L., Hessling, J., Goldberg, R. N., Auten, K. J., Fisher, K. A., Foy, K. A., Siaw, G., Stoll, B. J., Buchter, S., Carlton, D. P., HALE, E. C., Hutchinson, A. K., Archer, S. W., Lemons, J. A., HAMER, F., Herron, D. E., Miller, L. C., Wilson, L. D., Berberich, M. A., Blaisdell, C. J., Gail, D. B., Kiley, J. P., Cunningham, M., Hastings, B. K., Irene, A. R., Auman, J. O., Huitema, C. P., Pickett, J. W., Wallace, D., Zaterka-Baxter, K. M., Stevenson, D. K., Ball, M. B., Proud, M. S., Fiascone, J. M., Furey, A., MacKinnon, B. L., Nylen, E., Collins, M. V., Cosby, S. S., Phillips, V. A., Rasmussen, M. R., Wozniak, P. R., Arnell, K., Bridge, R., Demetrio, C., Widness, J. A., Klein, J. M., Johnson, K. J., Everett-Thomas, R., Ohls, R. K., Rohr, J., Lacy, C. B., Markowitz, G. D., Reubens, L. J., BURNELL, E., Rosenfeld, C. R., Salhab, W. A., Guzman, A., Hensley, G., Lepps, M. H., Miller, N. A., Allen, J., Grau, L., Martin, M., Solis, A., Vasil, D. M., Wilder, K., Kennedy, K. A., TYSON, J. E., HARRIS, B. F., Lis, A. E., Martin, S., MCDAVID, G. E., Tate, P. L., Wright, S. L., Burnett, J., Jensen, J. J., Osborne, K. A., Spencer, C., Weaver-Lewis, K., Peters, N. J., Shankaran, S., Bara, R., Billian, E., Johnson, M., Bhandari, V., Jacobs, H. C., Cervone, P., Gettner, P., Konstantino, M., Poulsen, J., Taft, J., Avery, G., Gleason, C. A., Allen, M. C., Bangdiwala, S. I., Blaisdell, C. J., Boyle, R. J., Clemons, T., D'Alton, M. E., Das, A., Gail, D. B., Hunt, C., Keszler, M., Poole, W. K., Redmond, C. K., Ross, M. G., Thomson, M. A., WEINER, S. J., Willinger, M., Markowitz, G. D., Hutchinson, A. K., Wallace, D. K., Freedman, S. F. 2010; 362 (21): 1959-1969

    Abstract

    Previous studies have suggested that the incidence of retinopathy is lower in preterm infants with exposure to reduced levels of oxygenation than in those exposed to higher levels of oxygenation. However, it is unclear what range of oxygen saturation is appropriate to minimize retinopathy without increasing adverse outcomes.We performed a randomized trial with a 2-by-2 factorial design to compare target ranges of oxygen saturation of 85 to 89% or 91 to 95% among 1316 infants who were born between 24 weeks 0 days and 27 weeks 6 days of gestation. The primary outcome was a composite of severe retinopathy of prematurity (defined as the presence of threshold retinopathy, the need for surgical ophthalmologic intervention, or the use of bevacizumab), death before discharge from the hospital, or both. All infants were also randomly assigned to continuous positive airway pressure or intubation and surfactant.The rates of severe retinopathy or death did not differ significantly between the lower-oxygen-saturation group and the higher-oxygen-saturation group (28.3% and 32.1%, respectively; relative risk with lower oxygen saturation, 0.90; 95% confidence interval [CI], 0.76 to 1.06; P=0.21). Death before discharge occurred more frequently in the lower-oxygen-saturation group (in 19.9% of infants vs. 16.2%; relative risk, 1.27; 95% CI, 1.01 to 1.60; P=0.04), whereas severe retinopathy among survivors occurred less often in this group (8.6% vs. 17.9%; relative risk, 0.52; 95% CI, 0.37 to 0.73; P<0.001). There were no significant differences in the rates of other adverse events.A lower target range of oxygenation (85 to 89%), as compared with a higher range (91 to 95%), did not significantly decrease the composite outcome of severe retinopathy or death, but it resulted in an increase in mortality and a substantial decrease in severe retinopathy among survivors. The increase in mortality is a major concern, since a lower target range of oxygen saturation is increasingly being advocated to prevent retinopathy of prematurity. (ClinicalTrials.gov number, NCT00233324.)

    View details for DOI 10.1056/NEJMoa0911781

    View details for Web of Science ID 000278054000004

    View details for PubMedID 20472937

    View details for PubMedCentralID PMC2891970

  • Influence of clinical status on the association between plasma total and unbound bilirubin and death or adverse neurodevelopmental outcomes in extremely low birth weight infants ACTA PAEDIATRICA Oh, W., Stevenson, D. K., TYSON, J. E., Morris, B. H., Ahlfors, C. E., Bender, G. J., Wong, R. J., Perritt, R., Vohr, B. R., Van Meurs, K. P., Vreman, H. J., Das, A., Phelps, D. L., O'Shea, T. M., Higgins, R. D. 2010; 99 (5): 673-678

    Abstract

    To assess the influence of clinical status on the association between total plasma bilirubin and unbound bilirubin on death or adverse neurodevelopmental outcomes at 18-22 months corrected age in extremely low birth weight infants.Total plasma bilirubin and unbound bilirubin were measured in 1101 extremely low birth weight infants at 5 +/- 1 days of age. Clinical criteria were used to classify infants as clinically stable or unstable. Survivors were examined at 18-22 months corrected age by certified examiners. Outcome variables were death or neurodevelopmental impairment, death or cerebral palsy, death or hearing loss, and death prior to follow-up. For all outcomes, the interaction between bilirubin variables and clinical status was assessed in logistic regression analyses adjusted for multiple risk factors.Regardless of clinical status, an increasing level of unbound bilirubin was associated with higher rates of death or neurodevelopmental impairment, death or cerebral palsy, death or hearing loss and death before follow-up. Total plasma bilirubin values were directly associated with death or neurodevelopmental impairment, death or cerebral palsy, death or hearing loss, and death before follow-up in unstable infants, but not in stable infants. An inverse association between total plasma bilirubin and death or cerebral palsy was found in stable infants. CONCLUSIONs: In extremely low birth weight infants, clinical status at 5 days of age affects the association between total plasma bilirubin and death or adverse neurodevelopmental outcomes at 18-22 months of corrected age. An increasing level of UB is associated a higher risk of death or adverse neurodevelopmental outcomes regardless of clinical status. Increasing levels of total plasma bilirubin are directly associated with increasing risk of death or adverse neurodevelopmental outcomes in unstable, but not in stable infants.

    View details for DOI 10.1111/j.1651-2227.2010.01688.x

    View details for Web of Science ID 000276034800011

    View details for PubMedID 20105142

    View details for PubMedCentralID PMC2875328

  • Perinatal Systemic Inflammatory Response Syndrome and Retinopathy of Prematurity PEDIATRIC RESEARCH Sood, B. G., Madan, A., Saha, S., Schendel, D., Thorsen, P., Skogstrand, K., Hougaard, D., Shankaran, S., Carlo, W., NICHD Neonatal Res Network 2010; 67 (4): 394–400

    Abstract

    Fetal and neonatal inflammation is associated with several morbidities of prematurity. Its relationship to retinopathy of prematurity (ROP) has not been investigated. Our objective was to determine the relationship between cytokine levels and ROP in the first 3 postnatal wks. Data for this study were derived from the NICHD Cytokine Study. Dried blood spots (DBS) were obtained from infants <1000 g on days 0-1, 3 +/- 1, 7 +/- 2, 14 +/- 3, and 21 +/- 3. Infants were classified into three groups-no, mild, and severe ROP. Multiplex Luminex assay was used to quantify 20 cytokines. Temporal profiles of cytokines were evaluated using mixed-effects models after controlling for covariates. Of 1074 infants enrolled, 890 were examined for ROP and 877 included in the analysis. ROP was associated with several clinical characteristics on unadjusted analyses. Eight cytokines remained significantly different across ROP groups in adjusted analyses. IL-6 and IL-17 showed significant effects in early time periods (D0-3); TGF-beta, brain-derived neurotrophic factor (BDNF), and regulated on activation, normal T cell expressed and secreted (RANTES) in later time periods (D7-21) and IL-18, C-reactive protein (CRP), and neurotrophin-4 (NT-4) in both early and later time periods. We conclude that perinatal inflammation may be involved in the pathogenesis of ROP.

    View details for DOI 10.1203/PDR.0b013e3181d01a36

    View details for Web of Science ID 000275881600011

    View details for PubMedID 20032809

    View details for PubMedCentralID PMC2873779

  • ELEVATED EXHALED CARBON MONOXIDE CONCENTRATION IN HEMOGLOBINOPATHIES AND ITS RELATION TO RED BLOOD CELL TRANSFUSION THERAPY PEDIATRIC HEMATOLOGY AND ONCOLOGY James, E. B., Vreman, H. J., Wong, R. J., Stevenson, D. K., Vichinsky, E., Schumacher, L., Hall, J. Y., Simon, J., Golden, D. W., Harmatz, P. 2010; 27 (2): 112-121

    Abstract

    In this study, the authors examined a possible role of measurements of end-tidal carbon monoxide (CO), corrected for inhaled CO (ETCOc), as a noninvasive screening tool for hemoglobinopathies and as an indicator for when transfusions would be required in patients receiving chronic transfusions. ETCOc measurements were obtained in subjects with sickle cell disease (n = 18), thalassemia (n = 21), and healthy controls (n = 62). ETCOc values less than 3 parts per million (ppm) yielded a positive predictive value of 93% and negative predictive value of 94% in identifying hemoglobinopathies. Subsequently, 7 subjects with thalassemia had laboratory parameters and ETCOc measured over 2 transfusion cycles. ETCOc values were 4.90 +/- 0.32 ppm (mean +/- SD), with 89% of values being above normal (>or=3 ppm). Pretransfusion ETCOc levels significantly correlated with pretransfusion reticulocyte count (r = .96, P <.001), but not with pretransfusion hemoglobin (r = .44, P = .16) or pretransfusion soluble transferrin receptors (sTfR, r = .52, P = .10). In conclusion, we found that patients with hemoglobinopathies have ETCOc values above the range for healthy controls and ETCOc measurements can be used as an adjunct to hemoglobin measurements to determine the proper timing of transfusions.

    View details for DOI 10.3109/08880010903536227

    View details for Web of Science ID 000275286100004

    View details for PubMedID 20201692

  • MOLECULAR MECHANISM OF HEME OXYGENASE-1 INDUCTION BY STATINS Western Regional Meeting of the American-Federation-for-Medical-Research Schulz-Geske, S., Kalish, F. S., Zhao, H., Vreman, H. J., Wong, R. J., Stevenson, D. K. LIPPINCOTT WILLIAMS & WILKINS. 2010: 208–
  • IN VITRO POTENCY OF ZINC BIS GLYCOL PORPHYRIN ON LIVER TISSUE FOLLOWING A HEME LOAD Barlow, A., Yung, A. W., He, C. X., Rhine, I., Hempel, I., Wong, R. J., Stevenson, D. K. BMJ PUBLISHING GROUP. 2010: 141–42
  • EFFICACY OF ZINC BIS GLYCOL PORPHYRIN IN INHIBITING HEME OXYGENASE ACTIVITY IN THE HEME-LOADED NEWBORN MOUSE He, C. X., Zhao, H., Kalish, F., Wong, R. J., Stevenson, D. K. BMJ PUBLISHING GROUP. 2010: 142
  • Predicting Time to Hospital Discharge for Extremely Preterm Infants PEDIATRICS Hintz, S. R., Bann, C. M., Ambalavanan, N., Cotten, M., Das, A., Higgins, R. D. 2010; 125 (1): E146-E154

    Abstract

    As extremely preterm infant mortality rates have decreased, concerns regarding resource use have intensified. Accurate models for predicting time to hospital discharge could aid in resource planning, family counseling, and stimulate quality-improvement initiatives.To develop, validate, and compare several models for predicting the time to hospital discharge for infants <27 weeks' estimated gestational age, on the basis of time-dependent covariates as well as the presence of 5 key risk factors as predictors.We conducted a retrospective analysis of infants <27 weeks' estimated gestational age who were born between July 2002 and December 2005 and survived to discharge from a Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network site. Time to discharge was modeled as continuous (postmenstrual age at discharge) and categorical (early and late discharge) variables. Three linear and logistic regression models with time-dependent covariate inclusion were developed (perinatal factors only, perinatal + early-neonatal factors, and perinatal + early-neonatal + later factors). Models for early and late discharge that used the cumulative presence of 5 key risk factors as predictors were also evaluated. Predictive capabilities were compared by using the coefficient of determination (R(2)) for the linear models and the area under the curve (AUC) of the receiver operating characteristic curve for the logistic models.Data from 2254 infants were included. Prediction of postmenstrual age at discharge was poor. However, models that incorporated later clinical characteristics were more accurate in predicting early or late discharge (AUC: 0.76-0.83 [full models] vs 0.56-0.69 [perinatal factor models]). In simplified key-risk-factors models, the predicted probabilities for early and late discharge compared favorably with the observed rates. Furthermore, the AUC (0.75-0.77) was similar to those of the models that included the full factor set.Prediction of early or late discharge is poor if only perinatal factors are considered, but it improves substantially with knowledge of later-occurring morbidities. Predictive models that use a few key risk factors are comparable to the full models and may offer a clinically applicable strategy.

    View details for DOI 10.1542/peds.2009-0810

    View details for Web of Science ID 000273348000047

    View details for PubMedID 20008430

    View details for PubMedCentralID PMC2951502

  • AGE-DEPENDENT EXPRESSION OF HEME OXYGENASE-1 IN MICE FOLLOWING ORAL ADMINISTRATION OF ZING BIS GLYCOL PORPHYRIN Western Regional Meeting of the American-Federation-for-Medical-Research He, C. X., Zhao, H., Kalish, F., Wong, R. J., Stevenson, D. K. LIPPINCOTT WILLIAMS & WILKINS. 2010: 162–63
  • Synchronized Nasal Intermittent Positive-Pressure Ventilation and Neonatal Outcomes PEDIATRICS Bhandari, V., Finer, N. N., Ehrenkranz, R. A., Saha, S., Das, A., Walsh, M. C., Engle, W. A., Van Meurs, K. P. 2009; 124 (2): 517-526

    Abstract

    Synchronized nasal intermittent positive-pressure ventilation (SNIPPV) use reduces reintubation rates compared with nasal continuous positive airway pressure (NCPAP). Limited information is available on the outcomes of infants managed with SNIPPV.To compare the outcomes of infants managed with SNIPPV (postextubation or for apnea) to infants not treated with SNIPPV at 2 sites.Clinical retrospective data was used to evaluate the use of SNIPPV in infants

    View details for DOI 10.1542/peds.2008-1302

    View details for Web of Science ID 000268377000011

    View details for PubMedID 19651577

    View details for PubMedCentralID PMC2924622

  • Neonatal brain structure on MRI and diffusion tensor imaging, sex, and neurodevelopment in very-low-birthweight preterm children DEVELOPMENTAL MEDICINE AND CHILD NEUROLOGY Rose, J., Butler, E. E., Lamont, L. E., Barnes, P. D., Atlas, S. W., Stevenson, D. K. 2009; 51 (7): 526-535

    Abstract

    The neurological basis of an increased incidence of cerebral palsy (CP) in preterm males is unknown. This study examined neonatal brain structure on magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI) at term-equivalent age, sex, and neurodevelopment at 1 year 6 months on the basis of the Amiel-Tison neurological examination, Gross Motor Function Classification System, and Bayley Scales of Infant Development in 78 very-low-birthweight preterm children (41 males, 37 females; mean gestational age 27.6 wks, SD 2.5; mean birthweight 1021 g, SD 339). Brain abnormalities on MRI and DTI were not different between males and females except in the splenium of the corpus callosum, where males had lower DTI fractional anisotropy (p=0.025) and a higher apparent diffusion coefficient (p=0.013), indicating delayed splenium development. In the 26 infants who were at higher risk on the basis of DTI, males had more abnormalities on MRI (p=0.034) and had lower fractional anisotropy and a higher apparent diffusion coefficient in the splenium (p=0.049; p=0.025) and right posterior limb of the internal capsule (PLIC; p=0.003; p=0.033). Abnormal neurodevelopment was more common in males (n=9) than in females (n=2; p=0.036). Children with abnormal neurodevelopment had more abnormalities on MRI (p=0.014) and reduced splenium and right PLIC fractional anisotropy (p=0.001; p=0.035). In children with abnormal neurodevelopment, right PLIC fractional anisotropy was lower than left (p=0.035), whereas in those with normal neurodevelopment right PLIC fractional anisotropy was higher than left (p=0.001). Right PLIC fractional anisotropy correlated to neurodevelopment (rho=0.371, p=0.002). Logistic regression predicted neurodevelopment with 94% accuracy; only right PLIC fractional anisotropy was a significant logistic coefficient. Results indicate that the higher incidence of abnormal neurodevelopment in preterm males relates to greater incidence and severity of brain abnormalities, including reduced PLIC and splenium development.

    View details for DOI 10.1111/j.1469-8749.2008.03231.x

    View details for Web of Science ID 000266696900007

    View details for PubMedID 19459915

  • Inhaled Nitric Oxide for Preterm Premature Rupture of Membranes, Oligohydramnios, and Pulmonary Hypoplasia AMERICAN JOURNAL OF PERINATOLOGY Chock, V. Y., Van Meurs, K. P., Hintz, S. R., Ehrenkranz, R. A., Lemons, J. A., Kendrick, D. E., Stevenson, D. K. 2009; 26 (4): 317-322

    Abstract

    We sought to determine if inhaled nitric oxide (iNO) administered to preterm infants with premature rupture of membranes (PPROM), oligohydramnios, and pulmonary hypoplasia improved oxygenation, survival, or other clinical outcomes. Data were analyzed from infants with suspected pulmonary hypoplasia, oligohydramnios, and PPROM enrolled in the National Institute of Child Health and Development Neonatal Research Network Preemie Inhaled Nitric Oxide (PiNO) trial, where patients were randomized to receive placebo (oxygen) or iNO at 5 to 10 ppm. Outcome variables assessed were PaO (2) response, mortality, bronchopulmonary dysplasia (BPD), and severe intraventricular hemorrhage (IVH) or periventricular leukomalacia (PVL). Twelve of 449 infants in the PiNO trial met criteria. Six infants received iNO and six received placebo. The iNO group had a mean increase in PaO (2) of 39 +/- 50 mm Hg versus a mean decrease of 11 +/- 15 mm Hg in the control group. Mortality was 33% versus 67%, BPD (2/5) 40% versus (2/2) 100%, and severe IVH or PVL (1/5) 20% versus (1/2) 50% in the iNO and control groups, respectively. None of these changes were statistically significant. Review of a limited number of cases from a large multicenter trial suggests that iNO use in the setting of PPROM, oligohydramnios, and suspected pulmonary hypoplasia improves oxygenation and may decrease the rate of BPD and death without increasing severe IVH or PVL. However, the small sample size precludes definitive conclusions. Further studies are required to determine if iNO is of benefit in this specific patient population.

    View details for DOI 10.1055/s-0028-1104743

    View details for Web of Science ID 000264506400012

    View details for PubMedID 19067285

    View details for PubMedCentralID PMC2676224

  • Impact of Postnatal Corticosteroid Use on Neurodevelopment at 18 to 22 Months' Adjusted Age: Effects of Dose, Timing, and Risk of Bronchopulmonary Dysplasia in Extremely Low Birth Weight Infants PEDIATRICS Wilson-Costello, D., Walsh, M. C., Langer, J. C., Guillet, R., Laptook, A. R., Stoll, B. J., Shankaran, S., Finer, N. N., Van Meurs, K. P., Engle, W. A., Das, A. 2009; 123 (3): e430-e437

    Abstract

    Postnatal steroid use decreases lung inflammation but increases impairment. We hypothesized that increased dose is associated with increased neurodevelopmental impairment, lower postmenstrual age at exposure increases impairment, and risk of bronchopulmonary dysplasia modifies the effect of postnatal corticosteroid.Steroid dose and timing of exposure beyond 7 days was assessed among 2358 extremely low birth weight infants nested in a prospective trial, with 1667 (84%) survivors examined at 18 to 22 months' postmenstrual age. Logistic regression tested the relationship between impairment (Bayley Mental Developmental Index/Psychomotor Developmental Index of <70, disabling cerebral palsy, or sensory impairment), total dose (tertiles: <0.9, 0.9-1.9, and >/=1.9 mg/kg), and postmenstrual age at first dose. Separate logistic regression tested effect modification according to bronchopulmonary dysplasia severity (Romagnoli risk > 0.5 as high risk, n = 2336 (99%) for days of life 4-7).Three hundred sixty-six (16%) neonates were steroid-treated (94% dexamethasone). Treated neonates were smaller and less mature; 72% of those treated were at high risk for bronchopulmonary dysplasia. Exposure was associated with neurodevelopmental impairment/death. Impairment increased with higher dose; 71% dead or impaired at highest dose tertile. Each 1 mg/kg dose was associated with a 2.0-point reduction on the Mental Developmental Index and a 40% risk increase for disabling cerebral palsy. Older age did not mitigate the harm. Treatment after 33 weeks' postmenstrual age was associated with greatest harm despite not receiving the highest dose. The relationship between steroid exposure and impairment was modified by the bronchopulmonary dysplasia risk, with those at highest risk experiencing less harm.Higher steroid dose was associated with increased neurodevelopmental impairment. There is no "safe" window for steroid use in extremely low birth weight infants. Neonates with low bronchopulmonary dysplasia risk should not be exposed. A randomized trial of steroid use in infants at highest risk is warranted.

    View details for DOI 10.1542/peds.2008-1928

    View details for Web of Science ID 000263825500057

    View details for PubMedID 19204058

    View details for PubMedCentralID PMC2846831

  • Commentary on the bilirubin supplement JOURNAL OF PERINATOLOGY Stevenson, D. K. 2009; 29: S2-S3

    View details for DOI 10.1038/jp.2008.220

    View details for Web of Science ID 000263604400002

    View details for PubMedID 19177055

  • Safe and effective devices for use in the neonatal intensive care unit: NICHD Workshop Summary. Biomed Instrum Technol Raju TNK, Stevenson DK, Higgins, RD, Stark AR 2009; 43: 408-18
  • ROSUVASTATIN SUPPRESSES THE DEVELOPMENT OF EXPERIMENTAL ABDOMINAL AORTIC ANEURYSMS IN MICE THROUGH THE INDUCTION OF HEME OXYGENASE-1 Azuma, J., Wong, R. J., Morisawa, T., Hsu, M., Stevenson, D. K., Tsao, P. S. LIPPINCOTT WILLIAMS & WILKINS. 2009: 107
  • REAL-TIME, NONINVASIVE MEASUREMENTS OF PLASMA BILIRUBIN LEVELS USING VISIBLE LIGHT SPECTROSCOPY Knauer, Y., Fierro, M., van Thillo, E., Benaron, D. A., Wong, R. J., Stevenson, D. K. LIPPINCOTT WILLIAMS & WILKINS. 2009: 177–78
  • DOSE-DEPENDENT EFFECTS OF ZINC BIS GLYCOL PORPHYRIN ON THE EXPRESSION OF HEME OXYGENASE IN NEWBORN MICE Campbell, C. M., Morisawa, T., Wong, R. J., Stevenson, D. K. LIPPINCOTT WILLIAMS & WILKINS. 2009: 177
  • EXERCISE-INDUCED AORTIC HEME OXYGENASE ACTIVITY IS ASSOCIATED WITH ATTENUATION OF EXPERIMENTAL ABDOMINAL AORTIC ANEURYSM DISEASE Schultz, G. M., Tedesco, M. M., Morisawa, T., Azuma, J., Wong, R. J., Stevenson, D. K., Dalman, R. L. LIPPINCOTT WILLIAMS & WILKINS. 2009: 107–8
  • A NEW MOUSE MODEL OF NEONATAL BRAIN INJURY Western Regional Meeting of the American-Federation-for-Medical-Research Knauer, Y., Wong, R. J., Zhao, H., Stevenson, D. K. LIPPINCOTT WILLIAMS & WILKINS. 2009: 129–30
  • AGE-DEPENDENT EXPRESSION OF HEME OXYGENASE-1 IN MICE FOLLOWING ORAL ADMINISTRATION OF CHROMIUM MESOPORPHYRIN Western Regional Meeting of the American-Federation-for-Medical-Research He, C. X., Morisawa, T., Zhao, H., Wong, R. J., Stevenson, D. K. LIPPINCOTT WILLIAMS & WILKINS. 2009: 177–77
  • Federation of Pediatric Organizations Task Force on Women in Pediatrics: Considerations for Part-Time Training and Employment for Research-Intensive Fellows and Faculty JOURNAL OF PEDIATRICS Alexander, D., Boat, T., Britto, M., Burke, A., Homes, A., Sectish, T., Stanton, B., Stevenson, D. 2009; 154 (1): 1-3

    View details for DOI 10.1016/j.jpeds.2008.08.010

    View details for Web of Science ID 000262272500001

    View details for PubMedID 19187728

  • Failure to Predict Hemolysis and Hyperbilirubinemia by IgG Subclass in Blood Group A or B Infants Born to Group O Mothers PEDIATRICS Kaplan, M., Na'amad, M., Kenan, A., Rudensky, B., Hammerman, C., Vreman, H. J., Wong, R. J., Stevenson, D. K. 2009; 123 (1): E132-E137

    Abstract

    Direct antibody titer-positive, blood group A or B neonates who are born to group O mothers may be at risk for hemolysis and hyperbilirubinemia. Immunoglobulin G1 and immunoglobulin G3 subclasses are associated with increased hemolysis relative to immunoglobulin G2 and immunoglobulin G4. We investigated whether identification of immunoglobulin G subclass 1 or 3 may be predictive of hemolysis and hyperbilirubinemia.Direct antibody titer-positive, blood group A and B neonates born to group O mothers were tested for the presence of immunoglobulin G subclasses 1 and 3 in umbilical cord blood by using a commercially available gel testing technology. By inference, neonates in whom neither immunoglobulin G1 nor immunoglobulin G3 were detected were designated immunoglobulin G2 and/or 4. Mandatory plasma total bilirubin was measured at discharge, and additional measurements performed as clinically indicated. Hyperbilirubinemia was defined as any plasma total bilirubin value >95th percentile for hour of life. Blood carboxyhemoglobin and total hemoglobin concentrations were also measured on the predischarge sample. Measured carboxyhemoglobin, expressed as percentage of total hemoglobin, was corrected for ambient carbon monoxide to derive "corrected carboxyhemoglobin," a sensitive index of heme catabolism. The corrected carboxyhemoglobin/total hemoglobin ratio was calculated to correct for any differences in total hemoglobin mass between groups.Eighty-two infants were studied, 18 of whom were designated as immunoglobulin G1, 0 as immunoglobulin G3, and 64 as immunoglobulin G2 and/or 4. The incidence of plasma total bilirubin >95th percentile was similar between the subgroupings. Corrected carboxyhemoglobin values and corrected carboxyhemoglobin/total hemoglobin ratio were also similar between the subgroupings.Immunoglobulin G1 was found in 22% of direct antibody titer-positive, group A and B neonates who were born to group O mothers, whereas immunoglobulin G3 was rare. Hemolysis and hyperbilirubinemia could not be predicted by this gel technique that enabled identification of these immunoglobulin G subclasses.

    View details for DOI 10.1542/peds.2008-2617

    View details for Web of Science ID 000262046400077

    View details for PubMedID 19114458

  • Photoisomers: Obfuscating Factors in Clinical Peroxidase Measurements of Unbound Bilirubin? PEDIATRICS McDonagh, A. F., Vreman, H. J., Wong, R. J., Stevenson, D. K. 2009; 123 (1): 67-76

    Abstract

    The objectives of the study were to measure the effect of 4Z,15E-bilirubin on peroxidase free bilirubin measurements and to review the literature on this topic.4Z,15E-Bilirubin was generated in situ in serum or serum albumin solution through controlled irradiation of isomerically pure 4Z,15Z-bilirubin IXalpha, under conditions in which the total amount of bilirubin remained constant. Reactions were monitored by difference spectroscopy, to ensure that solutions were not irradiated beyond the initial photostationary state and that concentrations of other isomers were kept to a minimum. Prepared in this way, 10% to 25% of the total bilirubin in the final solutions was in the form of the 4Z,15E-isomer. Free bilirubin in the solutions was measured with a peroxidase method, before and after irradiation. The use of bovine serum albumin as a surrogate for human albumin in in vitro studies also was investigated.The findings of previous studies are not altogether consistent, with a common flaw in several being the failure to measure photoisomer concentrations. For bilirubin in serum albumin solution, conversion of approximately 25% of the 4Z,15Z-isomer to 4Z,15E-bilirubin led to a much smaller decrease (<20%) in the apparent free bilirubin concentration; for bilirubin in serum, conversion of approximately 15% of the 4Z,15Z-isomer to photoisomers resulted in a much larger increase ( approximately 40%). Irradiation of bilirubin in bovine serum albumin solution generated a very different array of photoisomers than that observed in human albumin solutions.The effect of photoisomers on the accuracy and specificity of free 4Z,15Z-bilirubin measurements remains uncertain. In a clinical setting, free bilirubin measurements need to be interpreted with caution when samples contain photoisomers. Irradiated bovine albumin solutions of isomerically impure bilirubin used in previous studies are poor models for investigating the effects of phototherapy in humans and the albumin binding of photoisomers.

    View details for DOI 10.1542/peds.2008-0492

    View details for Web of Science ID 000262046400010

    View details for PubMedID 19117862

  • Treatmeant with Rosuvastatin Suppresses the Development of Experimental Abdominal Aortic Aneurysms in Mice by Heme Oxygenase-1 Induction Azuma, J., Wong, R. J., Morisawa, T., Hus, M., Stevenson, D. K., Tsao, P. S. LIPPINCOTT WILLIAMS & WILKINS. 2008: S1052
  • Community supports after surviving extremely low-birth-weight, extremely preterm birth - Special outpatient services in early childhood ARCHIVES OF PEDIATRICS & ADOLESCENT MEDICINE Hintz, S. R., Kendrick, D. E., Vohr, B. R., Poole, W. K., Higgins, R. D. 2008; 162 (8): 748-755

    Abstract

    To determine special outpatient services (SOS) use, need, associated factors, and neurodevelopmental and functional outcomes among extremely preterm infants at 18 to 22 months' corrected age.Retrospective analysis.National Institute of Child Health and Human Development (NICHD) Neonatal Research Network.Infants younger than 28 weeks' gestational age who had been born weighing less than 1000 g at an NICHD Neonatal Research Network center from January 1, 1997, to December 31, 2000, and who were receiving follow-up at 18 to 22 months' corrected age.Questionnaires were administered at the 18- to 22-month follow-up visit regarding SOS use since hospital discharge and the current need for SOS (social work, visiting nurse, medical specialty, early intervention, speech and language services, occupational therapy and physical therapy, and neurodevelopmental and behavioral services).The use of and need for SOS were analyzed by gestational age. Logistic regression analysis identified factors independently associated with the use of more than 5 services and with the need for any services.Of 2315 infants, 54.7% used more than 3 SOS by 18 to 22 months, and 19.1% used 6 to 7 SOS. The need for any SOS was reported by approximately 37%. The following variables that were commonly associated with adverse neurodevelopmental outcomes were also associated with the use of more than 5 SOS: sepsis, birth weight, postnatal corticosteroid use, bronchopulmonary dysplasia, and cystic periventricular leukomalacia or grade 3 or 4 intraventricular hemorrhage. Male sex was associated with the need for any SOS. Although high SOS use was more likely among children with adverse neurodevelopmental outcomes, a reported need for SOS was common even among those with mild developmental impairment (39.7%) and mild cerebral palsy (42.2%).High SOS use is common, has identifiable neonatal risk factors, and is associated with neurodevelopmental impairment. Extremely preterm survivors have substantial need for community supports regardless of their impairment level. Efforts to improve comprehensive delivery of family-centered community-based services are urgently needed.

    View details for Web of Science ID 000258225200006

    View details for PubMedID 18678807

    View details for PubMedCentralID PMC2748992

  • Predictors of death or bronchopulmonary dysplasia in preterm infants with respiratory failure JOURNAL OF PERINATOLOGY Ambalavanan, N., Van Meurs, K. P., Perritt, R., Carlo, W. A., Ehrenkranz, R. A., Stevenson, D. K., Lemons, J. A., Poole, W. K., Higgins, R. D. 2008; 28 (6): 420-426

    Abstract

    To identify the variables that predict death/physiologic bronchopulmonary dysplasia (BPD) in preterm infants with severe respiratory failure.The study was a secondary analysis of data from the NICHD Neonatal Research Network trial of inhaled nitric oxide (iNO) in preterm infants. Stepwise logistic regression models and Classification and Regression Tree (CART) models were developed for the outcome of death or physiologic BPD (O(2) at 36 weeks post-menstrual age).Death and/or BPD was associated with lower birth weight, higher oxygen requirement, male gender, additional surfactant doses, higher oxygenation index and outborn status, but not the magnitude of response in PaO(2) to iNO. The positive predictive value of the CART model was 82% at 95% sensitivity.The major factors associated with death/BPD were an increased severity of respiratory failure, lower birth weight, male gender and outborn status, but not the magnitude of initial response to iNO.

    View details for DOI 10.1038/jp.2008.18

    View details for Web of Science ID 000256437600007

    View details for PubMedID 18337740

    View details for PubMedCentralID PMC2776028

  • Readmission for neonatal jaundice in California, 1991-2000: Trends and implications PEDIATRICS Burgos, A. E., Schmitt, S. K., Stevenson, D. K., Phibbs, C. S. 2008; 121 (4): E864-E869

    Abstract

    We sought to describe population-based trends, potential risk factors, and hospital costs of readmission for jaundice for term and late preterm infants.Birth-cohort data were obtained from the California Office of Statewide Health Planning and Development and contained infant vital statistics data linked to infant and maternal hospital discharge summaries. The study population was limited to healthy, routinely discharged infants through the use of multiple exclusion criteria. All linked readmissions occurred within 14 days of birth. International Classification of Diseases, Ninth Revision, codes were used to further limit the sample to readmission for jaundice. Hospital discharge records were the source of diagnoses, hospital charges, and length-of-stay information. Hospital costs were estimated using hospital-specific ratios of costs to charges and adjusted to 1991.Readmission rates for jaundice generally rose after 1994 and peaked in 1998 at 11.34 per 1000. The readmission rate for late preterm infants (as a share of all infants) over the study period remained at <2 per 1000. Factors associated with increased likelihood of hospital readmission for jaundice included gestational age 34 to 39 weeks, birth weight of <2500 g, male gender, Medicaid or private insurance, and Asian race. Factors associated with a decreased likelihood of readmission for jaundice were cesarean section delivery and black race. The mean cost of readmission for all infants was $2764, with a median cost of $1594.Risk-adjusted readmission rates for jaundice rose following the 1994 hyperbilirubinemia guidelines and declined after postpartum length-of-stay legislation in 1998. In 2000, the readmission rate remained 6% higher than in 1991. These findings highlight the complex relationship among newborn physiology, socioeconomics, race or ethnicity, public policy, clinical guidelines, and physician practice. These trend data provide the necessary baseline to study whether revised guidelines will change practice patterns or improve outcomes. Cost data also provide a break-even point for prevention strategies.

    View details for DOI 10.1542/peds.2007-1214

    View details for Web of Science ID 000254576800064

    View details for PubMedID 18381515

  • Severe hemolysis with normal blood count in a glucose-6-phosphate dehydrogenase deficient neonate JOURNAL OF PERINATOLOGY Kaplan, M., Hammerman, C., Vreman, H. J., Wong, R. J., Stevenson, D. K. 2008; 28 (4): 306-309

    Abstract

    A premature glucose-6-phosphate dehydrogenase (G-6-PD) deficient neonate was readmitted for exponential rise in the plasma bilirubin concentration to 33.0 mg dl(-1). Blood carboxyhemoglobin (2.8% of total hemoglobin, >threefold normal value) confirmed the presence of hemolysis; however, hematological indices were unchanged from the birth hospitalization. Serum unbound bilirubin, although present, was probably at a concentration insufficient to cause bilirubin encephalopathy. In G-6-PD deficient neonates, severe hemolysis may occur in the absence of hematological changes typical of a hemolytic process.

    View details for DOI 10.1038/sj.jp.7211919

    View details for Web of Science ID 000254782000012

    View details for PubMedID 18379570

  • Heme oxygenase-1 and simvastatin: molecular mechanisms and in vivo effects 49th Annual Meeting of the German-Society-for-Experimental-and-Clinical-Pharmacology-and-Toxicology Hinkelmann, U., Schulz, S., Grosser, N., Wong, R. J., Morisawa, T., Stevenson, D. K., Muchova, L., Schroeder, H. SPRINGER. 2008: 58–58
  • Upregulation of the HO-1 gene by proton pump inhibitors - molecular mechanisms and functinal consequences 49th Annual Meeting of the German-Society-for-Experimental-and-Clinical-Pharmacology-and-Toxicology Schulz, S., Grosser, N., Erdmann, K., Hinkelmann, U., Wong, R. J., Stevenson, D. K., Schroeder, H. SPRINGER. 2008: 60–60
  • Efficacy of chromium mesoporphyrin in inhibiting heme oxygenase activity in heme-loaded newborn mice Western Regional Meeting of the American-Federation-for-Medical-Research Morisawa, T., Xiao, H. H., Wong, R. J., Bhutani, V. K., Vreman, H. J., Stevenson, D. K. LIPPINCOTT WILLIAMS & WILKINS. 2008: 198–98
  • Time-dependent effects of chromium mesoporphyrin on the inhibition of heme oxygenase activity in newborn mice Western Regional Meeting of the American-Federation-for-Medical-Research Xiao, H. H., Morisawa, T., Wong, R. J., Stevenson, D. K. LIPPINCOTT WILLIAMS & WILKINS. 2008: 260–61
  • Neonatal microstructural development of the internal capsule on diffusion tensor imaging correlates with severity of gait and motor deficits DEVELOPMENTAL MEDICINE AND CHILD NEUROLOGY Rose, J., Mirmiran, M., Butler, E. E., Lin, C. Y., Barnes, P. D., Kermoian, R., Stevenson, D. K. 2007; 49 (10): 745-750

    Abstract

    Neonatal microstructural development in the posterior limbs of the internal capsule (PLIC) was assessed using diffusion tensor imaging (DTI) fractional anisotropy (FA) in 24 very-low-birthweight preterm infants at 37 weeks' gestational age and compared with the children's gait and motor deficits at 4 years of age. There were 14 participants with normal neonatal FA values (seven females, seven males; born at 27.6 weeks [SD 2.3] gestational age; birthweight 1027g [SD 229]) and 10 participants with low FA values in the PLIC (four females, six males; born at 28.4 weeks [SD 2.0] gestational age; birthweight 1041g [SD 322]). Seven of the 10 children with low FA and none of the children with normal FA had been diagnosed with CP by the time of gait testing. Among children with low neonatal FA, there was a strong negative correlation between FA of the combined left and right side PLIC and log NI (r=-0.89, p=0.001) and between FA and GMFCS (r=-0.65, p=0.04) at 4 years of age. There was no correlation between FA and gait NI or GMFCS at 4 years of age among children with normal neonatal FA. This preliminary study suggests neonatal DTI may be an important predictor of the severity of future gait and motor deficits.

    View details for Web of Science ID 000249660400007

    View details for PubMedID 17880643

  • Beware of the weaker sex: Don't get too close to your twin brother PEDIATRICS Stevenson, D. K., Tyson, J. E. 2007; 120 (3): 638-639

    View details for DOI 10.1542/peds.2007-0950

    View details for Web of Science ID 000249232000021

    View details for PubMedID 17766536

  • Neurodevelopmental outcomes of premature infants with severe respiratory failure enrolled in a randomized controlled trial of inhaled nitric oxide JOURNAL OF PEDIATRICS Hintz, S. R., Van Meurs, K. P., Perritt, R., Poole, W. K., Das, A., Stevenson, D. K., Ehrenkranz, R. A., Lemons, J. A., Vohr, B. R., Heyne, R., Childers, D. O., Peralta-Carcelen, M., Dusick, A., Johnson, Y. R., Morris, B., Dillard, R., Vaucher, Y., Steichen, J., Adams-Chapman, I., Konduri, G., Myers, G. J., De Ungria, M., Tyson, J. E., Higgins, R. D. 2007; 151 (1): 16-22

    Abstract

    We hypothesized that inhaled nitric oxide (iNO) would not decrease death or neurodevelopmental impairment (NDI) in infants enrolled in the National Institute of Child Health and Human Development Preemie iNO Trial (PiNO) trial, nor improve neurodevelopmental outcomes in the follow-up group.Infants <34 weeks of age, weighing <1500 g, with severe respiratory failure were enrolled in the multicenter, randomized, controlled trial. NDI at 18 to 22 months corrected age was defined as: moderate to severe cerebral palsy (CP; Mental Developmental Index or Psychomotor score Developmental Index <70), blindness, or deafness.Of 420 patients enrolled, 109 who received iNO (52%) and 98 who received placebo (47%) died. The follow-up rate in survivors was 90%. iNO did not reduce death or NDI (78% versus 73%; relative risk [RR], 1.07; 95% CI, 0.95-1.19), or NDI or Mental Developmental Index <70 in the follow-up group. Moderate-severe CP was slightly higher with iNO (RR, 2.41; 95% CI, 1.01-5.75), as was death or CP in infants weighing <1000 g (RR, 1.22; 95% CI, 1.05-1.43).In this extremely ill cohort, iNO did not reduce death or NDI or improve neurodevelopmental outcomes. Routine iNO use in premature infants should be limited to research settings until further data are available.

    View details for DOI 10.1016/j.jpeds.2007.03.017

    View details for Web of Science ID 000247851900007

    View details for PubMedID 17586184

    View details for PubMedCentralID PMC2770191

  • Inhaled nitric oxide in infants > 1500 g and < 34 weeks gestation with severe respiratory failure JOURNAL OF PERINATOLOGY Van Meurs, K. P., Hintz, S. R., Ehrenkranz, R. A., Lemons, J. A., Ball, M. B., Poole, W. K., Perritt, R., Das, A., Higgins, R. D., Stevenson, D. K. 2007; 27 (6): 347-352

    Abstract

    Inhaled nitric oxide (iNO) use in infants >1500 g, but <34 weeks gestation with severe respiratory failure will reduce the incidence of death and/or bronchopulmonary dysplasia (BPD).Infants born at <34 weeks gestation with a birth weight >1500 g with respiratory failure were randomly assigned to receive placebo or iNO.Twenty-nine infants were randomized. There were no differences in baseline characteristics, but the status at randomization showed a statistically significant difference in the use of high-frequency ventilation (P=0.03). After adjustment for oxygenation index entry strata, there was no difference in death and/or BPD (adjusted relative risk (RR) 0.80, 95% confidence interval (CI) 0.43 to 1.48; P=0.50), death (adjusted RR 1.26, 95% CI 0.47 to 3.41; P=0.65) or BPD (adjusted RR 0.40, 95% CI 0.47 to 3.41; P=0.21).Although sample size limits our ability to make definitive conclusions, this small pilot trial of iNO use in premature infants >1500 g and <34 weeks with severe respiratory failure suggests that iNO does not affect the rate of BPD and/or death.

    View details for DOI 10.1038/sj.jp.7211690

    View details for Web of Science ID 000246905800005

    View details for PubMedID 17443204

  • Interobserver reliability and accuracy of cranial ultrasound scanning interpretation in premature infants JOURNAL OF PEDIATRICS Hintz, S. R., Slovis, T., Bulas, D., Van Meurs, K. P., Perritt, R., Stevenson, D. K., Poole, W. K., Das, A., Higgins, R. D. 2007; 150 (6): 592-596

    Abstract

    To assess interobserver reliability between 2 central readers of cranial ultrasound scanning (CUS) and accuracy of local, compared with central, interpretations.The study was a retrospective analysis of CUS data from the National Institute of Child Health and Human Development (NICHD) trial of inhaled nitric oxide for premature infants. Interobserver reliability of 2 central readers was assessed with kappa or weighted kappa. Accuracy of local, compared with central, interpretations was assessed by using sensitivity and specificity.CUS from 326 infants had both central reader and local interpretations. Central reader agreement for grade 3/4 intraventricular hemorrhage (IVH), grade 3/4 IVH or periventricular leukomalacia (PVL), grade of IVH, and degree of ventriculomegaly was very good (kappa = 0.84, 0.81, 0.79, and 0.75, respectively). Agreement was poor for lower grade IVH and for PVL alone. Local interpretations were highly accurate for grade 3/4 IVH or PVL (sensitivity, 87%-90%; specificity, 92%-93%), but sensitivity was poor-to-fair for grade 1/2 IVH (48%-68%) and PVL (20%-44%).Our findings demonstrate reliability and accuracy of highly unfavorable CUS findings, but suggest caution when interpreting mild to moderate IVH or white matter injury.

    View details for DOI 10.1016/j.jpeds.2007.02.012

    View details for Web of Science ID 000246939700011

    View details for PubMedID 17517240

    View details for PubMedCentralID PMC2757063

  • Effects of sample dilution, peroxidase concentration, and chloride ion on the measurement of unbound bilirubin in premature newborns CLINICAL BIOCHEMISTRY Ahlfors, C. E., Vreman, H. J., Wong, R. J., Bender, G. J., Oh, W., Morris, B. H., Stevenson, D. K. 2007; 40 (3-4): 261-267

    Abstract

    To assess the effects of sample dilution, peroxidase concentration, and chloride ion (Cl(-)) on plasma unbound bilirubin (B(f)) measurements made using a commercial peroxidase methodology (UB Analyzer) in a study population of ill, premature newborns.B(f) was measured with a UB Analyzer in 74 samples at the standard 42-fold sample dilution and compared with B(f) measured at a 2-fold sample dilution using a FloPro Analyzer. B(f) was measured at two peroxidase concentrations to determine whether the peroxidase steady state B(f) (B(fss)) measurements were significantly less than the equilibrium B(f) (B(feq)), in which case it was necessary to calculate B(feq) from the two B(fss) measurements. B(f) was also measured before and after adding 100 mmol/L Cl(-) to the UB Analyzer assay buffer.B(feq) at the 42-fold dilution was nearly 10-fold less than but it correlated significantly with B(feq) at the 2-fold dilution (mean 8.2+/-5.2 nmol/L versus 73.5+/-70 nmol/L, respectively, p<0.0001; correlation r=0.6). The two UB Analyzer B(fss) measurements were significantly less than B(feq) in 42 of 74 (57%) samples, and Cl(-) increased B(feq) in 66 of 74 (89%) samples by a mean of 82+/-67%.B(fss) measured by the UB Analyzer at the standard 42-fold sample dilution using assay buffer without Cl(-) and a single peroxidase concentration is significantly less than the B(feq) in undiluted plasma. Accurate B(f) measurements can be made only in minimally diluted serum or plasma.

    View details for DOI 10.1016/j.clinbiochem.2006.09.006

    View details for Web of Science ID 000244193000020

    View details for PubMedID 17069786

  • The potential Salmonella aroA(-) vaccine strain is safe and effective in young BALB/c mice NEONATOLOGY Burns-Guydish, S. M., Zhao, H., Stevenson, D. K., Contag, C. H. 2007; 91 (2): 114-120

    Abstract

    Due to the increased susceptibility of neonates to pathogens including those with mutations, the use of live vaccine strategies in the human population may present a potential risk to the young.The specific aim of this study was to assess the risk that prospective Salmonella enterica serovar Typhimurium vaccine strains pose for the neonate and determine whether the strains are an effective vaccine by assessing the adaptive immune response.To evaluate the susceptibility of young mice to potential vaccine strains, S. typhimuriumaroA(-) and Delta phoP mutant strains were labeled by chromosomal insertion of the lux operon--this serves as a readily traceable marker of infection using noninvasive imaging methods. BALB/c mice ages 1, 2, 4, and 6 weeks of age were fed the bioluminescent aroA(-) or Delta phoP strains and the course of infection was monitored by in vivobioluminescence imaging. In addition, blood samples were collected post-inoculation to assess the IgG response of mice to S. typhimurium LPS.Young BALB/c mice were not susceptible to the aroA(-) strain in contrast to their susceptibility to the Delta phoP strain at a dose of 10(9) colony forming units. Delivery by oral feeding of the aroA(-) and Delta phoP strains in young mice also produced a robust IgG anti-LPS response.Here, we report that young 2-week-old mice orally fed the bioluminescent aroA(-) S. typhimurium strain were not susceptible to infection and elicited a protective immune response.

    View details for DOI 10.1159/000097128

    View details for Web of Science ID 000244967400006

    View details for PubMedID 17344661

  • Inhibition of heme oxygenase activity following repeated heme loads by tin mesoporphyrin in newborn mice. 8th Conference of the Western Student Medical Research Forum/Western Section of the American-Federation-for-Medical-Research/Western Association-of-Physicians/Western-Society-for-Pediatric-Research/Western-Society-for-Clinical-Investigation Wong, R. J., Morioka, I., Muchova, L., Vreman, H. J., Stevenson, D. K. LIPPINCOTT WILLIAMS & WILKINS. 2007: S88–S88
  • Efficacy of azalanstat in inhibiting heme oxygenase activity in newborn mice. 8th Conference of the Western Student Medical Research Forum/Western Section of the American-Federation-for-Medical-Research/Western Association-of-Physicians/Western-Society-for-Pediatric-Research/Western-Society-for-Clinical-Investigation Morisawa, T., Wong, R. J., Bhutani, V. K., Vreman, H. J., Stevenson, D. K. LIPPINCOTT WILLIAMS & WILKINS. 2007: S89–S89
  • End-tidal carbon monoxide measurements in infant respiratory distress syndrome ACTA PAEDIATRICA Krediet, T. G., Cirkel, G. A., Vreman, H. J., Wong, R. J., Stevenson, D. K., Groenendaal, F., Egberts, J., van Bel, F. 2006; 95 (9): 1075-1082

    Abstract

    RDS involving inflammatory and oxidative processes may lead to increased production of carbon monoxide (CO).The relationship between end-tidal CO, corrected for inhaled CO (ETCOc), and RDS severity was investigated in preterm infants as well as the value of early ETCOc measurements to predict chronic lung disease.78 infants (30 no RDS, 32 moderate RDS, 16 severe RDS) were included. ETCOc was measured using the CO-Stat End Tidal Breath Analyzer.ETCOc was significantly higher in RDS compared to no RDS during the first week (p<0.05). Severity of RDS was the most significant independent variable in a stepwise regression model related to ETCOc (F-test: 18.17). Negative predictive value of early (within first 12 h of life) ETCOc measurement (<2.5 ppm) for development of chronic lung disease was excellent (100%).During severe RDS, inflammation may contribute to increased lipid peroxidation leading to increased local CO production in the lung, indicated by increased ETCOc. Early ETCOc determinations may be helpful to exclude occurrence of chronic lung disease.

    View details for DOI 10.1080/08035250500537017

    View details for Web of Science ID 000240122500009

    View details for PubMedID 16938753

  • Neonatal hyperbilirubinemia in African American males: The importance of glucose-6-phosphate dehydrogenase deficiency JOURNAL OF PEDIATRICS Kaplan, M., Herschel, M., Hammerman, C., Hoyer, J. D., Heller, G. Z., Stevenson, D. K. 2006; 149 (1): 83-88

    Abstract

    To perform risk factor analysis for the prediction of hyperbilirubinemia in an African American male neonatal cohort.A database of 500 previously published term and near-term African American male neonates was further analyzed to determine the role of risk factors for hyperbilirubinemia. Factors studied included birth weight >/=4.0 kg, gestational age /=75(th) percentile. Hyperbilirubinemia was defined as any bilirubin value >/=95(th) percentile on the hour-of-life-specific bilirubin nomogram.Forty-three (8.6%) neonates developed hyperbilirubinemia. At 48 +/- 12 hours, median transcutaneous bilirubin was 8.3 mg/dL, 75(th) percentile 10.0 mg/dL, and 95(th) percentile 12.6 mg/dL. Of the risk factors, only exclusive breast-feeding, G-6-PD deficiency and predischarge bilirubin >/=75(th) percentile were significant (Adjusted Odds Ratios [95% Confidence Intervals; CI] 3.15 [1.39-7.14], P = .006; 4.96 [2.28-10.80], P = .001; and 7.47 [3.50-15.94], P < .0001, respectively). G-6-PD-deficient neonates who were also premature and breast-feeding had the highest incidence of hyperbilirubinemia (60%).African American male neonates may be at higher risk for hyperbilirubinemia than previously thought. Screening for G-6-PD deficiency and predischarge bilirubin determination may be useful adjuncts in hyperbilirubinemia prediction in these newborns.

    View details for DOI 10.1016/j.jpeds.2006.02.011

    View details for Web of Science ID 000239352000023

    View details for PubMedID 16860133

  • Promoting antenatal steroid use for fetal maturation: Results from the California Perinatal Quality Care Collaborative JOURNAL OF PEDIATRICS Wirtschafter, D. D., Danielsen, B. H., Main, E. K., Korst, L. M., Gregory, K. D., Wertz, A., Stevenson, D. K., Gould, J. B. 2006; 148 (5): 606-612

    Abstract

    The California Perinatal Quality Care Collaborative (CPQCC) was formed to seek perinatal care improvements by creating a confidential multi-institutional database to identify topics for quality improvement (QI). We aimed to evaluate this approach by assessing antenatal steroid administration before preterm (24 to 33 weeks of gestation) delivery. We hypothesized that mean performance would improve and the number of centers performing below the lowest quartile of the baseline year would decrease.In 1998, a statewide QI cycle targeting antenatal steroid use was announced, calling for the evaluation of the 1998 baseline data, dissemination of recommended interventions using member-developed educational materials, and presentations to California neonatologists in 1999-2000. Postintervention data were assessed for the year 2001 and publicly released in 2003. A total of 25 centers voluntarily participated in the intervention.Antenatal steroid administration rate increased from 76% of 1524 infants in 1998 to 86% of 1475 infants in 2001 (P < .001). In 2001, 23 of 25 hospitals exceeded the 1998 lower-quartile cutoff point of 69.3%.Regional collaborations represent an effective strategy for improving the quality of perinatal care.

    View details for DOI 10.1016/j.jpeds.2005.12.058

    View details for Web of Science ID 000237885500019

    View details for PubMedID 16737870

  • Laparotomy versus peritoneal drainage for necrotizing enterocolitis or isolated intestinal perforation in extremely low birth weight infants: Outcomes through 18 months adjusted age PEDIATRICS Blakely, M. L., TYSON, J. E., Lally, K. P., McDonald, S., Stoll, B. J., Stevenson, D. K., Poole, W. K., Jobe, A. H., Wright, L. L., Higgins, R. D. 2006; 117 (4): E680-E687

    Abstract

    Extremely low birth weight (ELBW; < or =1000 g) infants with necrotizing enterocolitis (NEC) or isolated intestinal perforation (IP) are treated surgically with either initial laparotomy or peritoneal drain placement. The only published data comparing these therapies are from small, retrospective, single-center studies that do not address outcomes beyond nursery discharge. The objective of this study was to conduct a prospective, multicenter, observational study to (1) develop a hypothesis about the relative effect of these 2 therapies on risk-adjusted outcomes through 18 to 22 months in ELBW infants and (2) to obtain data that would be useful in designing and conducting a successful trial of this hypothesis.A prospective, cohort study was conducted at 16 clinical centers within the National Institute of Child Health and Human Development Neonatal Research Network. To assist in risk adjustment, the attending pediatric surgeon recorded the preoperative diagnosis and intraoperative diagnosis and identified infants who were considered to be too ill for laparotomy. Predefined measures of short- and longer-term outcome included (1) either predischarge death or prolonged parenteral nutrition (>85 days) after enrollment and (2) either death or neurodevelopmental impairment on a standardized examination at 18 to 22 months' adjusted age.Severe NEC or IP occurred in 156 (5.2%) of 2987 ELBW infants; 80 were treated with initial drainage, and 76 were treated with initial laparotomy. By 18 to 22 months, 78 (50%) had died; 112 (72%) had died or were shown to be impaired. Outcome was worse in the subgroup with NEC. Laparotomy was never performed in 76% (28 of 36) of drain-treated survivors.Drainage was commonly used, and outcome was poor. Our findings, particularly the risk-adjusted odds ratio favoring laparotomy for death or impairment, indicate the need for a large, multicenter clinical trial to assess the effect of the initial surgical therapy on outcome at > or =18 months.

    View details for DOI 10.1542/peds.2005-1273

    View details for Web of Science ID 000236540500010

    View details for PubMedID 16549503

  • Studies in hemolysis in glucose-6-phosphate dehydrogenase-deficient African American neonates Annual Meeting of the Pediatric-Academic-Societies Kaplan, M., Herschel, M., Hammerman, C., Karrison, T., Hoyer, J. D., Stevenson, D. K. ELSEVIER SCIENCE BV. 2006: 177–82

    Abstract

    The role of hemolysis in the mechanism and prediction of hyperbilirubinemia was contrasted between glucose-6-phosphate dehydrogenase (G-6-PD)-deficient and -normal African American neonates.Corrected end tidal carbon monoxide (ETCOc) values from the subset of male neonates born to non-smoking African American mothers, drawn from a previously published study, were analyzed. The relationship between ETCOc and bilirubin values, the latter represented as percentiles on the hour of life specific bilirubin nomogram, was determined. Hyperbilirubinemia was defined as any bilirubin value > or =95th percentile for hour of life.18.6% of 59 G-6-PD-deficient neonates developed hyperbilirubinemia, compared with 7.5% of 362 controls (relative risk 2.50, 95% confidence interval 1.31 to 4.76). As reported, ETCOc values (median, interquartile range) were significantly higher among G-6-PD-deficient neonates than controls (2.4 [2.0-2.9] vs. 2.1 [1.7-2.5] ppm, p<0.001. However, higher ETCOc values were limited to those G-6-PD-deficient neonates with lower bilirubin percentiles: among those whose bilirubin value did not exceed the 95th percentile ETCOc was 2.30 [2.00-2.85] vs. 2.00 [1.70-2.40] ppm in controls, p=0.001. In contrast, among the hyperbilirubinemic neonates ETCOc values were similar between G-6-PD-deficient neonates and controls: 2.7 [2.03-3.33] vs. 2.6 [2.33-3.45] ppm, p=0.9. In the G-6-PD-deficient neonates ETCOc > or =75th percentile contributed no additional predictive value for hyperbilirubinemia (likelihood ratio 1.8).G-6-PD-deficient African American neonates have increased hemolysis and increased rate of hyperbilirubinemia, but the hemolysis is neither a predominant factor in the pathogenesis of hyperbilirubinemia nor is it predictive of hyperbilirubinemia, over and above the already increased risk conferred by G-6-PD deficiency.

    View details for DOI 10.1016/j.cca.2005.08.015

    View details for Web of Science ID 000235646400023

    View details for PubMedID 16188248

  • Selectivity of imidazole-dioxolane compounds for in vitro inhibition of microsomal haem oxygenase isoforms BRITISH JOURNAL OF PHARMACOLOGY Kinobe, R. T., Vlahakis, J. Z., Vreman, H. J., Stevenson, D. K., Brien, J. F., Szarek, W. A., Nakatsu, K. 2006; 147 (3): 307-315

    Abstract

    Haem oxygenases (HO) are involved in the catalytic breakdown of haem to generate carbon monoxide (CO), iron and biliverdin. It is widely accepted that products of haem catabolism are involved in biological signaling in many physiological processes. Conclusions to most studies in this field have gained support from the judicious use of synthetic metalloporphyrins such as chromium mesoporphyrin (CrMP) to selectively inhibit HO. However, metalloporphyrins have also been found to inhibit other haem-dependent enzymes, such as nitric oxide synthase (NOS), cytochromes P-450 (CYPs) and soluble guanylyl cyclase (sGC), induce the expression of HO-1 or exhibit varied toxic effects. To obviate some of these problems, we have been examining non-porphyrin HO inhibitors and the present study describes imidazole-dioxolane compounds with high selectivity for inhibition of HO-1 (rat spleen microsomes) compared to HO-2 (rat brain microsomes) in vitro. (2R,4R)-2-[2-(4-chlorophenyl)ethyl]-2-[(1H-imidazol-1-yl)methyl]-4-methyl-1,3-dioxolane hydrochloride) was identified as the most selective inhibitor with a concentration of 0.6 microM inhibiting HO-1(inducible) by 50% compared with 394 microM for HO-2 (constitutive). These compounds were found to have no effects on the catalytic activities of rat brain NOS and lung sGC, but were potent inhibitors of microsomal CYP2E1 and CYP3A1/3A2 activities. In conclusion, we have identified imidazole-dioxolanes that are able to inhibit microsomal HO in vitro with high selectivity for HO-1 compared to HO-2, and little or no effect on the activities of neuronal NOS and sGC. These molecules could be used to facilitate studies on the elucidation of physiological roles of HO/CO in biological systems.

    View details for DOI 10.1038/sj.bjp.0706555

    View details for Web of Science ID 000235152100010

    View details for PubMedID 16331285

  • Whole-body hypothermia for neonates with hypoxic-ischemic encephalopathy NEW ENGLAND JOURNAL OF MEDICINE Shankaran, S., Laptook, A. R., Ehrenkranz, R. A., TYSON, J. E., McDonald, S. A., Donovan, E. F., Fanaroff, A. A., Poole, W. K., Wright, L. L., Higgins, R. D., Finer, N. N., Carlo, W. A., Duara, S., Oh, W., Cotten, C. M., Stevenson, D. K., Stoll, B. J., Lemons, J. A., Guillet, R., Jobe, A. H. 2005; 353 (15): 1574-1584

    Abstract

    Hypothermia is protective against brain injury after asphyxiation in animal models. However, the safety and effectiveness of hypothermia in term infants with encephalopathy is uncertain.We conducted a randomized trial of hypothermia in infants with a gestational age of at least 36 weeks who were admitted to the hospital at or before six hours of age with either severe acidosis or perinatal complications and resuscitation at birth and who had moderate or severe encephalopathy. Infants were randomly assigned to usual care (control group) or whole-body cooling to an esophageal temperature of 33.5 degrees C for 72 hours, followed by slow rewarming (hypothermia group). Neurodevelopmental outcome was assessed at 18 to 22 months of age. The primary outcome was a combined end point of death or moderate or severe disability.Of 239 eligible infants, 102 were assigned to the hypothermia group and 106 to the control group. Adverse events were similar in the two groups during the 72 hours of cooling. Primary outcome data were available for 205 infants. Death or moderate or severe disability occurred in 45 of 102 infants (44 percent) in the hypothermia group and 64 of 103 infants (62 percent) in the control group (risk ratio, 0.72; 95 percent confidence interval, 0.54 to 0.95; P=0.01). Twenty-four infants (24 percent) in the hypothermia group and 38 (37 percent) in the control group died (risk ratio, 0.68; 95 percent confidence interval, 0.44 to 1.05; P=0.08). There was no increase in major disability among survivors; the rate of cerebral palsy was 15 of 77 (19 percent) in the hypothermia group as compared with 19 of 64 (30 percent) in the control group (risk ratio, 0.68; 95 percent confidence interval, 0.38 to 1.22; P=0.20).Whole-body hypothermia reduces the risk of death or disability in infants with moderate or severe hypoxic-ischemic encephalopathy.

    View details for Web of Science ID 000232486000011

    View details for PubMedID 16221780

  • Apigenin decreases hemin-mediated heme oxygenase-1 induction FREE RADICAL BIOLOGY AND MEDICINE Abate, A., Yang, G., Wong, R. J., Schroder, H., Stevenson, D. K., Dennery, P. A. 2005; 39 (6): 711-718

    Abstract

    Hemin is a strong inducer of heme oxygenase-1 (HO-1) expression in vitro and in vivo. Whereas moderate overexpression of HO-1 is protective against oxidative stress, uncontrolled levels of HO-1 can be detrimental. Therefore, we evaluated the effects of apigenin (APG), a flavonoid involved in a number of phosphorylation pathways and also known to inhibit inducible genes, such as iNOS and COX-2, on HO-1 expression. Incubation of mouse embryonic fibroblasts with APG (5--40 microM) decreased hemin-induced HO-1 protein and mRNA expression. APG also reduced the induction of HO-1 promoter activity, as assessed by bioluminescence imaging, in NIH3T3 cells transfected with the 15-kb HO-1 promoter fused with the reporter gene luciferase (HO-1-luc). Furthermore, through the use of specific inhibitors, APG's effect was found to be unrelated to its PKC, CK 2, PI 3 K, p38, or ERK inhibitory activities. Quercetin (10--40 microM), also a flavonoid, also inhibited hemin-induced HO-1 expression. Additionally, in vivo studies using HO-1-luc transgenic mice showed that APG (50 mg/kg) decreased hemin-induced HO activity and HO-1 protein expression in the liver. These results suggest that hemin-induced HO-1 expression can be attenuated by flavonoids, such as APG.

    View details for DOI 10.1016/j.freeradbiomed.2005.01.020

    View details for Web of Science ID 000231583500002

    View details for PubMedID 16109301

  • Determination of carbon monoxide (CO) in rodent tissue: Effect of heme administration and environmental CO exposure ANALYTICAL BIOCHEMISTRY Vreman, H. J., Wong, R. J., Kadotani, T., Stevenson, D. K. 2005; 341 (2): 280-289

    Abstract

    Carbon monoxide (CO), produced endogenously during heme degradation, is considered a messenger molecule in vascular and neurologic tissues. To study this role, it is important to determine CO concentration in target tissues pre- and post-perturbations. Here, we describe a sensitive and reproducible method, which is linear and accurate, and provide some examples of its application for quantitation of CO concentrations in tissues pre- and post-perturbations. Tissues from adult rats and mice were sonicated (20% w/w), and volumes representing 0.04-8 mg fresh weight (FW) were incubated at 0 degrees C for 30 min with sulfosalicylic acid. CO liberated into the headspace was quantitated by gas chromatography. Tissue CO concentrations (mean+/-SD, pmol CO/mg FW) were as follows: blood (47+/-10, 45+/-5), muscle (4+/-4, 10+/-1), kidney (5+/-2, 7+/-2), heart (6+/-3, 6+/-1), spleen (11+/-3, 6+/-1), liver (4+/-1, 5+/-1), intestine (2+/-1, 4+/-2), lung (2+/-1, 3+/-1), testes (1+/-1, 2+/-1), and brain (2+/-1, 2+/-0) in untreated rat (n=3) and mouse (n=5), respectively. Between the rat and the mouse, only CO concentrations in the muscle and spleen were significantly different (p0.05). Endogenous CO generation, after administration of heme arginate to mice (n=3), increased CO concentrations by 0-43 pmol/mg FW. Exposure of mice (n=3) to 500 ppm CO for 30 min yielded significantly elevated CO concentrations by 4-2603 pmol/mg FW in all tissues over the native state. While blood had the highest CO concentration for all conditions, muscle, kidney, heart, spleen, and liver, all rich in hemoglobin and/or other CO-binding hemoproteins, also contained substantial CO concentrations. Intestine, lung, testes, and brain contained the lowest CO concentrations.

    View details for DOI 10.1016/j.ab.2005.03.019

    View details for Web of Science ID 000229460800011

    View details for PubMedID 15907874

  • Glucose-6-phosphate dehydrogenase activity in term and near-term, male African American neonates CLINICA CHIMICA ACTA Kaplan, M., Hoyer, J. D., Herschel, M., Hammerman, C., Stevenson, D. K. 2005; 355 (1-2): 113-117

    Abstract

    We determined values for glucose-6-phosphate dehydrogenase (G-6-PD) activity in African American neonates.G-6-PD activity was measured on umbilical cord blood from term and near-term healthy, male neonates. Neonates were stratified according to the number of neonates for each numerical unit of G-6-PD activity. Corrected end tidal carbon monoxide (ETCOc), a non-invasive index of hemolysis, was performed on each neonate. At least one predischarge transcutaneous bilirubin determination was performed.Five hundred neonates were studied. Two subpopulations were apparent, with no overlap between the subgroups. Mean value for the 64 (12.8%) infants with the lower values (G-6-PD deficient) was 2.7+/-1.1 U/g Hb, range 0.4-6.6 U/g Hb, while that for the 436 neonates with the higher values (G-6-PD normal) was 21.8+/-2.9 U/g Hb, range 14.5-33.8 U/g Hb. No significant differences in activity were noted between those neonates <37 weeks gestational age and those >37 weeks. Enzyme activity in the lower range in both groups was not related to the development of hyperbilirubinemia. G-6-PD enzyme activity did not correlate with ETCOc values either for the entire cohort or for the individual subsets.G-6-PD-deficient neonates formed a separate subgroup from those with normal enzyme activity. The data supplied should facilitate interpretation of G-6-PD test results.

    View details for DOI 10.1016/j.cccn.2004.12.008

    View details for Web of Science ID 000228707500014

    View details for PubMedID 15820485

  • Reduction in red blood cell transfusions among preterm infants: Results of a randomized trial with an in-line blood gas and chemistry monitor PEDIATRICS Widness, J. A., Madan, A., Grindeanu, L. A., Zimmerman, B., Wong, D. K., Stevenson, D. K. 2005; 115 (5): 1299-1306

    Abstract

    Critically ill, extremely premature infants develop anemia because of intensive laboratory blood testing and undergo multiple red blood cell (RBC) transfusions in the early weeks of life. To date, researchers have had only limited success in finding ways to reduce transfusions significantly in this patient population.To reduce RBC transfusions for these infants by using a point-of-care bedside monitor that returns analyzed blood to the patient.This was a prospective, 2-center, randomized, open, controlled, clinical trial with a 1:1 assignment of extremely low birth weight infants (weighing 500-1000 g at birth) to control or monitor groups and analysis with the intention-to-treat approach. Predefined RBC transfusion criteria were applied uniformly in the 2 groups.Clinical treatment of study subjects with an in-line, ex vivo, bedside monitor that withdraws blood through an umbilical artery catheter, analyzes blood gases and sodium, potassium, and hematocrit levels, and returns the sample to the patient.The total volume and number of RBC transfusions during the first 2 weeks of life and the total volume of blood removed for laboratory testing.The trial was terminated prematurely when one center's NICU changed its standard method of laboratory testing. In the first 2 weeks of life, there was a nonsignificant 17% lower cumulative RBC transfusion volume in the monitor group (n = 46), compared with the control group (n = 47). However, data from the first week only (the period of greater catheter use) demonstrated a significant 33% lower cumulative RBC transfusion volume in the monitor group. Cumulative phlebotomy loss was approximately 25% less in the monitor group throughout the 2-week study period. There was no difference between groups in neonatal mortality, morbidity, and neurodevelopmental outcome rates at 18 to 24 months. This is the first randomized trial documenting that RBC transfusions administered to neonates can by reduced by decreasing laboratory phlebotomy loss.As long as an umbilical artery catheter is available for blood sampling with an in-line blood gas and chemistry monitor, significant reductions in neonatal RBC transfusions can be achieved. The patients most likely to benefit from monitor use are the smallest, most critically ill newborns.

    View details for DOI 10.1542/peds.2004-1680

    View details for Web of Science ID 000228833500029

    View details for PubMedID 15867038

  • Neonatal bilirubin production-conjugation imbalance: effect of glucose-6-phosphate dehydrogenase deficiency and borderline prematurity Annual Meeting of the Pediatric-Academic-Societies/Society-for-Pediatric-Research Kaplan, M., Muraca, M., Vreman, H. J., Hammerman, C., Vilei, M. T., Rubaltelli, F. F., Stevenson, D. K. BMJ PUBLISHING GROUP. 2005: 123–27
  • Is carbon monoxide-mediated cyclic guanosine monophosphate production responsible for low blood pressure in neonatal respiratory distress syndrome? JOURNAL OF APPLIED PHYSIOLOGY van Bel, F., Latour, V., Vreman, H. J., Wong, R. J., Stevenson, D. K., Steendijk, P., Egberts, J., Krediet, T. G. 2005; 98 (3): 1044-1049

    Abstract

    Infant respiratory distress syndrome (RDS) involves inflammatory processes, causing an increased expression of inducible heme oxygenase with subsequent production of carbon monoxide (CO). We hypothesized that increased production of CO during RDS might be responsible for increased plasma levels of vasodilatory cGMP and, consequently, low blood pressure observed in infants with RDS. Fifty-two infants (no-RDS, n = 21; RDS, n = 31), consecutively admitted to the neonatal intensive care unit (NICU) between January and October 2003 were included. Hemoglobin-bound carbon monoxide (COHb), plasma cGMP, plasma nitric oxide (NOx), and bilirubin were determined at 0-12, 48-72, and at 168 h postnatally, with simultaneous registration of arterial blood pressure. Infants with RDS had higher levels of cGMP and COHb compared with no-RDS infants (RDS vs. no-RDS: cGMP ranging from 76 to 101 vs. 58 to 82 nmol/l; COHb ranging from 1.2 to 1.4 vs. 0.9 to 1.0%). Highest values were reached at 48-72 h [RDS vs. no-RDS mean (SD): cGMP 100 (39) vs. 82 (25) nmol/l (P < 0.001); COHb 1.38 (0.46) vs. 0.91 (0.26)% (P < 0.0001)]. Arterial blood pressure was lower and more blood pressure support was needed in RDS infants at that point of time [RDS vs. no-RDS mean (SD): mean arterial blood pressure 33 (6) vs. 42 (5) mmHg (P < 0.05)]. NOx was not different between groups and did not vary with time. Multiple linear regression analysis showed a significant correlation between cGMP and COHb, suggesting a causal relationship. Mean arterial blood pressure appeared to be primarily correlated to cGMP levels (P < 0.001). We conclude that a CO-mediated increase in cGMP causes systemic vasodilation with a consequent lower blood pressure and increased need for blood pressure support in preterm infants with RDS.

    View details for DOI 10.1152/japplphysiol.00760.2004

    View details for Web of Science ID 000226863100036

    View details for PubMedID 15516362

  • Reduction in hospital readmission rates for hyperbilirubinemia is associated with use of transcutaneous bilirubin measurements CLINICAL CHEMISTRY Stevenson, D. K., Wong, R. J., Vreman, H. J. 2005; 51 (3): 481-482

    View details for DOI 10.1373/clinchem.2004.046789

    View details for Web of Science ID 000227230600001

    View details for PubMedID 15738511

  • Attenuation of heme induction following exposure to tin mesoporphyrin in mice. DeSandre, G. H., Wong, R. J., Morioka, I., Vreman, H. J., Stevenson, D. K. LIPPINCOTT WILLIAMS & WILKINS. 2005: S125–S125
  • Phototherapy and photo-oxidation in premature neonates BIOLOGY OF THE NEONATE Kaplan, M., Gold, V., Hammerman, C., Hochman, A., Goldschmidt, D., Vreman, H. J., Stevenson, D. K. 2005; 87 (1): 44-50

    Abstract

    The potential for photo-oxidation during phototherapy in premature neonates was assessed by measuring parameters reflective of photo-oxidation.Blood was sampled from premature neonates prior to, and after 4 and 24 h of phototherapy, respectively. Total plasma bilirubin (TPB), blood carboxyhemoglobin corrected for inspired carbon monoxide (COHbc) (a sensitive index of heme catabolism), blood thiobarbituric acid reacting substances (TBARS) (a measure of lipid peroxidation), and plasma protein carbonyls (representative of protein oxidation) were determined. Study measurements were compared with baseline values both for the entire study group, and also individually for subgroups < and > or = 1.5 kg birthweight, respectively. The percentage difference (%delta) between baseline and the 24-hour measurement was calculated for each parameter.Forty-one premature neonates (mean [+/- SD] gestational age 30.5 +/- 2.7 weeks and birthweight 1,499 +/- 448 g) were studied. Mean TPB values decreased from a baseline of 9.1 +/- 2.3 to one of 7.2 +/- 2.8 mg/dl, p < 0.01, during the first 24 h of phototherapy. For the entire patient sample, neither COHbc, TBARS or protein carbonyl values increased significantly over baseline measurements: COHbc: 0.90 +/- 0.26% vs. 0.92 +/- 0.32%; TBARS: 19.0 +/- 5.6 vs. 18.0 +/- 4.5 nmol/ml, and protein carbonyls 7.73 +/- 3.78 vs. 7.63 +/- 3.56 U/ml (baseline and 24-hour samples only are shown in the abstract). Similarly, for the entire group, %delta (mean, interquartile range) were not significantly different between COHbc [-3.77 (-15.89-17.65)%], TBARS [-7.47 (-17.37-7.38)%], and protein carbonyls [-1.47 (-28.51-43.48)%], respectively. For subgroup analysis of neonates < or > or = 1.5 kg birthweight, respectively, no significant increases in COHbc, TBARS or protein carbonyls were documented. A significant increase in %delta for COHbc in the <1.5 kg birthweight subgroup compared with those > or =1.5 kg, possibly indicative of hemolysis, was not matched by similar changes in %delta for TBARS or protein carbonyls, and may therefore not be a result of photo-oxidation.Except for changes in %delta in COHbc alone and in the smallest babies only, overall, short term phototherapy in premature infants was effective in reducing TPB concentrations without associated evidence reflective of photo-oxidation.

    View details for DOI 10.1159/000081085

    View details for Web of Science ID 000226010200010

    View details for PubMedID 15467291

  • NICHD Conference on Kernicterus: Research on Prevention of Bilirubin-Induced Brain Injury and Kernicterus: Bench-to-Bedside--Diagnostic Methods and Prevention and Treatment Strategies. Journal of perinatology Stevenson, D. K., Wong, R. J., Vreman, H. J., McDonagh, A. F., Maisels, M. J., Lightner, D. A. 2004; 24 (8): 521-525

    Abstract

    In July 2003, the National Institute of Child Health and Human Development (NICHD) organized a consensus conference, where a group of experts were invited to review and discuss the current state of knowledge regarding neonatal hyperbilirubinemia and identify areas in which where future research should be directed. This paper summarizes the presentations addressing the current methodologies for direct and noninvasive assessments of serum total bilirubin concentrations as well as prevention and treatment strategies for the management of neonatal hyperbilirubinemia.

    View details for PubMedID 15129227

  • Hyperbilirubinemia among African American, glucose-6-phosphate dehydrogenase-deficient neonates Annual Meeting of the Pediatric-Academic-Societies/Society-for-Pediatric-Research Kaplan, M., Herschel, M., Hammerman, C., Hoyer, J. D., Stevenson, D. K. AMER ACAD PEDIATRICS. 2004: 213–19
  • Cesarean delivery rates and neonatal morbidity in a low-risk population OBSTETRICS AND GYNECOLOGY Gould, J. B., Danielsen, B., Korst, L. M., Phibbs, R., Chance, K., Main, E., Wirtschafter, D. D., Stevenson, D. K. 2004; 104 (1): 11-19

    Abstract

    To estimate the relationship between case-mix adjusted cesarean delivery rates and neonatal morbidity and mortality in infants born to low-risk mothers.This retrospective cohort study used vital and administrative data for 748,604 California singletons born without congenital abnormalities in 1998-2000. A total of 282 institutions was classified as average-, low-, or high-cesarean delivery hospitals based on their cesarean delivery rate for mothers without a previous cesarean delivery, in labor at term, with no evidence of maternal, fetal, or placental complications. Neonatal mortality, diagnoses, and therapeutic interventions determined by International Classification of Diseases, 9th Revision, Clinical Modification codes, and neonatal length of stay were compared across these hospital groupings.Compared with average-cesarean delivery-rate hospitals, infants born to low-risk mothers at low-cesarean delivery hospitals had increased fetal hemorrhage, birth asphyxia, meconium aspiration syndrome, feeding problems, and electrolyte abnormalities (P <.02). Infused medication, pressors, transfusion for shock, mechanical ventilation, and length of stay were also increased (P <.001). This suggests that some infants born in low-cesarean delivery hospitals might have benefited from cesarean delivery. Infants delivered at high-cesarean delivery hospitals demonstrated increased fetal hemorrhage, asphyxia, birth trauma, electrolyte abnormalities, and use of mechanical ventilation (P <.001), suggesting that high cesarean delivery rates themselves are not protective.Neonatal morbidity is increased in infants born to low-risk women who deliver at both low- and high-cesarean delivery-rate hospitals. The quality of perinatal care should be assessed in these outlier hospitals.III

    View details for DOI 10.1097/01.AOG.0000127035.64602.97

    View details for Web of Science ID 000225414600004

    View details for PubMedID 15228995

  • Continuous, noninvasive, and localized microvascular tissue oximetry using visible light spectroscopy ANESTHESIOLOGY Benaron, D. A., Parachikov, I. H., Friedland, S., Soetikno, R., Brock-Utne, J., van der Starre, P. J., Nezhat, C., Terris, M. K., Maxim, P. G., Carson, J. J., Razavi, M. K., Gladstone, H. B., Fincher, E. F., Hsu, C. P., Clark, F. L., Cheong, W. F., Duckworth, J. L., Stevenson, D. K. 2004; 100 (6): 1469-1475

    Abstract

    The authors evaluated the ability of visible light spectroscopy (VLS) oximetry to detect hypoxemia and ischemia in human and animal subjects. Unlike near-infrared spectroscopy or pulse oximetry (SpO2), VLS tissue oximetry uses shallow-penetrating visible light to measure microvascular hemoglobin oxygen saturation (StO2) in small, thin tissue volumes.In pigs, StO2 was measured in muscle and enteric mucosa during normoxia, hypoxemia (SpO2 = 40-96%), and ischemia (occlusion, arrest). In patients, StO2 was measured in skin, muscle, and oral/enteric mucosa during normoxia, hypoxemia (SpO2 = 60-99%), and ischemia (occlusion, compression, ventricular fibrillation).In pigs, normoxic StO2 was 71 +/- 4% (mean +/- SD), without differences between sites, and decreased during hypoxemia (muscle, 11 +/- 6%; P < 0.001) and ischemia (colon, 31 +/- 11%; P < 0.001). In patients, mean normoxic StO2 ranged from 68 to 77% at different sites (733 measures, 111 subjects); for each noninvasive site except skin, variance between subjects was low (e.g., colon, 69% +/- 4%, 40 subjects; buccal, 77% +/- 3%, 21 subjects). During hypoxemia, StO2 correlated with SpO2 (animals, r2 = 0.98; humans, r2 = 0.87). During ischemia, StO2 initially decreased at -1.3 +/- 0.2%/s and decreased to zero in 3-9 min (r2 = 0.94). Ischemia was distinguished from normoxia and hypoxemia by a widened pulse/VLS saturation difference (Delta < 30% during normoxia or hypoxemia vs. Delta > 35% during ischemia).VLS oximetry provides a continuous, noninvasive, and localized measurement of the StO2, sensitive to hypoxemia, regional, and global ischemia. The reproducible and narrow StO2 normal range for oral/enteric mucosa supports use of this site as an accessible and reliable reference point for the VLS monitoring of systemic flow.

    View details for Web of Science ID 000221551300018

    View details for PubMedID 15166566

  • Transcutaneous bilirubin measurements and serum total bilirubin levels in indigenous African infants PEDIATRICS Slusher, T. M., Angyo, I. A., Bode-Thomas, F., Akor, F., Pam, S. D., Adetunji, A. A., McLaren, D. W., Wong, R. J., Vreman, H. J., Stevenson, D. K. 2004; 113 (6): 1636-1641

    Abstract

    The objective of this study was to determine whether transcutaneous bilirubin (TcB) measurements correlate with serum total bilirubin (STB) levels in indigenous, darkly pigmented African newborns with varying degrees of skin pigmentation, some of which had developed kernicterus.Jaundiced infants who were < or =2 weeks of age and admitted to Baptist Medical Center-Eku (Eku; n = 29) and Jos University Teaching Hospital (Jos; n = 98) in Nigeria were studied. TcB measurements using the BiliChek were made simultaneously with blood sampling for STB measurements by spectrophotometry before phototherapy.Using linear regression analysis, we found that measurements of TcB correlated well with those of STB with r values of.90 and.88 for Eku and Jos, respectively. Mean bias and imprecision of TcB measurements as compared with STB measurements for the total population was 0.5 +/- 7.6 mg/dL using the method of Bland and Altman. At STB > or 12 mg/dL, correlation (r =.84) and bias and imprecision (-1.2 +/- 8.6 mg/dL) of measurements were only slightly poorer. Furthermore, when infants were grouped by degree of skin pigmentation, correlations of TcB and STB measurements remained strong.From these results, we can conclude that TcB measurements are a useful and reliable index for estimating STB levels in pigmented neonates, including those with hyperbilirubinemia and kernicterus. In the absence of reliable STB measurements, the relatively simple and noninvasive TcB measurements can be an important adjunct in directing phototherapy and exchange transfusions, thereby preventing bilirubin-induced morbidity and mortality in low-technology clinical environments.

    View details for Web of Science ID 000221781500012

    View details for PubMedID 15173484

  • Parenteral glutamine supplementation does not reduce the risk of mortality or late-onset sepsis in extremely low birth weight infants Annual Meeting of the Pediatric-Academic-Societies Poindexter, B. B., Ehrenkranz, R. A., Stoll, B. J., Wright, L. L., Poole, W. K., Oh, W., Bauer, C. R., Papile, L. A., TYSON, J. E., Carlo, W. A., Laptook, A. R., Narendran, V., Stevenson, D. K., Fanaroff, A. A., Korones, S. B., Shankaran, S., Finer, N. N., Lemons, J. A. AMER ACAD PEDIATRICS. 2004: 1209–15

    Abstract

    Glutamine is one of the most abundant amino acids in both plasma and human milk, yet it is not included in standard intravenous amino acid solutions. Previous studies have suggested that parenteral nutrition (PN) supplemented with glutamine may reduce sepsis and mortality in critically ill adults. Whether glutamine supplementation would provide a similar benefit to extremely low birth weight (ELBW) infants is not known.We performed a multicenter, randomized, double-masked, clinical trial to assess the safety and efficacy of early PN supplemented with glutamine in decreasing the risk of death or late-onset sepsis in ELBW infants. Infants 401 to 1000 g were randomized within 72 hours of birth to receive either TrophAmine (control) or an isonitrogenous study amino acid solution with 20% glutamine whenever they received PN up to 120 days of age, death, or discharge from the hospital. The primary outcome was death or late-onset sepsis.Of the 721 infants who were assigned to glutamine supplementation, 370 (51%) died or developed late-onset sepsis, as compared with 343 of the 712 infants (48%) assigned to control (relative risk: 1.07; 95% confidence interval: 0.97-1.17). Glutamine had no effect on tolerance of enteral feeds, necrotizing enterocolitis, or growth. No significant adverse events were observed with glutamine supplementation.Parenteral glutamine supplementation as studied did not decrease mortality or the incidence of late-onset sepsis in ELBW infants. Consequently, although no harm was demonstrated, routine use of parenteral glutamine supplementation cannot be recommended in this population.

    View details for Web of Science ID 000221169200006

    View details for PubMedID 15121931

  • To tap or not to tap: High likelihood of meningitis without sepsis among very low birth weight infants PEDIATRICS Stoll, B. J., Hansen, N., Fanaroff, A. A., Wright, L. L., Carlo, W. A., Ehrenkranz, R. A., Lemons, J. A., Donovan, E. F., Stark, A. R., TYSON, J. E., Oh, W., Bauer, C. R., Korones, S. B., Shankaran, S., Laptook, A. R., Stevenson, D. K., Papile, L. A., Poole, W. K. 2004; 113 (5): 1181-1186

    Abstract

    Neonatal meningitis is associated with significant morbidity and mortality. We speculated that meningitis may be underdiagnosed among very low birth weight (VLBW) infants because of the failure to perform lumbar punctures (LPs) in infants with suspected sepsis.This study was undertaken to review the epidemiology of late-onset meningitis in VLBW (401-1500 g) infants and to evaluate the concordance of cerebrospinal fluid (CSF) and blood culture (BC) results.VLBW infants (excluding those with intraventricular shunts) born at centers of the National Institute of Child Health and Human Development Neonatal Research Network from September 1, 1998, through December 31, 2001, were studied. Late-onset meningitis was defined by culture-based criteria and classified as meningitis with or without associated sepsis. Unadjusted comparisons were made using chi2 tests and adjusted comparisons using regression models.Of 9641 VLBW infants who survived >3 days, 2877 (30%) had > or = 1 LPs, and 6056 (63%) had > or = 1 BC performed after day 3. One hundred thirty-four infants had late-onset meningitis (1.4% of all patients; 5% of those with an LP). Pathogens associated with meningitis were similar to those associated with sepsis. One third (45 of 134) of the infants with meningitis had negative BCs. Lower gestational age and prior sepsis increased risk for meningitis. Compared with uninfected infants, those with meningitis had a longer time on mechanical ventilation (28 vs 18 days), had longer hospitalizations (91 vs 79 days), were more likely to have seizures (25% vs 2%), and were more likely to die (23% vs 2%).Meningitis is a serious complication among VLBW infants, associated with increased severity of illness and risk of death. Of note, one third of the infants with meningitis had meningitis in the absence of sepsis. Because CSF cultures were performed only half as often as BCs, this discordance in blood and CSF culture results suggests that meningitis may be underdiagnosed among VLBW infants.

    View details for Web of Science ID 000221169200002

    View details for PubMedID 15121927

  • End tidal carbon monoxide levels are lower in women with gestational hypertension and pre-eclampsia. Journal of perinatology Kreiser, D., Baum, M., Seidman, D. S., Fanaroff, A., Shah, D., Hendler, I., Stevenson, D. K., Schiff, E., Druzin, M. L. 2004; 24 (4): 213-217

    Abstract

    The possible role of heme oxygenase and its byproduct carbon monoxide (CO) in the regulation of blood pressure is under investigation. The aim of this study was to compare end tidal breath CO (ETCO) levels in women with gestational hypertension (GH) or pre-eclampsia to the levels in healthy pregnant and nonpregnant women.We prospectively performed ETCO measurements corrected for ambient CO (ETCOc) in two medical centers (Stanford, CA and Cleveland, OH). A Natus CO-Stat End Tidal Breath Analyzer (Natus Medical Inc., San Carlos, CA) was used. The study group included a convenience sample of 31 women with GH/pre-eclampsia (PE). Control groups included 46 nonpregnant healthy women, 44 first-trimester and 48 third-trimester pregnant healthy women.Mean+/-SD ETCOc measurements were significantly lower in the GH/PE group compared to first-trimester (p=0.004) and third-trimester (p=0.001) normotensive pregnant and nonpregnant women (p=0.002) (1.36+/-0.30 vs 1.76+/-0.47, 1.72+/-0.42 and 1.78+/-0.54 ppm, respectively). The ETCOc values were < or =1.6 ppm in 89% of GH/PE women compared with, respectively, only 45, 54, and 46% of nonpregnant, first- and third-trimester normotensive pregnant women (p<0.05). ETCO measurements were not influenced by maternal age, parity, ethnicity, body mass index, gestational age or presence of household smokers. In the two centers, the controls had a similar mean ETCOc and the differences found remained significant when results for each center were analyzed separately.ETCOc levels were found to be significantly lower in women with GH/PE. Further investigation is required to determine if the lower CO levels reflect a deficient compensatory response to the increase in blood pressure or whether these are primary changes of significance to our understanding of the pathogenesis of GH/PE.

    View details for PubMedID 15014533

  • Induction of heme oxygenase-1 in transgenic mouse fibroblast cells following successive exposures to heme Annual Meeting of the Pediatric-Academic-Societies DeSandre, G. H., Wong, R. J., Vreman, H. J., Stevenson, D. K. NATURE PUBLISHING GROUP. 2004: 473A–473A
  • Characterization of coelenterazine analogs for measurements of Renilla luciferase activity in live cells and living animals. Molecular imaging Zhao, H., Doyle, T. C., Wong, R. J., Cao, Y., Stevenson, D. K., Piwnica-Worms, D., Contag, C. H. 2004; 3 (1): 43-54

    Abstract

    In vivo imaging of bioluminescent reporters relies on expression of light-emitting enzymes, luciferases, and delivery of chemical substrates to expressing cells. Coelenterazine (CLZN) is the substrate for a group of bioluminescent enzymes obtained from marine organisms. At present, there are more than 10 commercially available CLZN analogs. To determine which analog is most suitable for activity measurements in live cells and living animals, we characterized 10 CLZN analogs using Renilla luciferase (Rluc) as the reporter enzyme. For each analog, we monitored enzyme activity, auto-oxidation, and efficiency of cellular uptake. All CLZN analogs tested showed higher auto-oxidation signals in serum than was observed in phosphate buffer or medium, mainly as a result of auto-oxidation by binding to albumin. CLZN-f, -h, and -e analogs showed 4- to 8-fold greater Rluc activity, relative to CLZN-native, in cells expressing the enzyme from a stable integrant. In studies using living mice expressing Rluc in hepatocytes, administration of CLZN-e and -native produced the highest signal. Furthermore, distinct temporal differences in signal for each analog were revealed following intravenous or intraperitoneal delivery. We conclude that the CLZN analogs that are presently available vary with respect to hRluc utilization in culture and in vivo, and that the effective use of CLZN-utilizing enzymes in living animals depends on the selection of an appropriate substrate.

    View details for PubMedID 15142411

  • Induction of heme oxygenase-1 in mouse fibroblast cells after successive exposures to heme. Western Regional Meeting of the American-Federation-for-Medical-Research DeSandre, G. H., Wong, R. J., Vreman, H. J., Stevenson, D. K. LIPPINCOTT WILLIAMS & WILKINS. 2004: S122–S122
  • Gestational pattern of heme oxygenase expression in the rat PEDIATRIC RESEARCH Kreiser, D., Kelly, D. K., Seidman, D. S., Stevenson, D. K., Baum, M., Dennery, P. A. 2003; 54 (2): 172-178

    Abstract

    Fetal growth is influenced by many intrinsic and extrinsic factors. Our objective was to determine the pattern of heme oxygenase (HO) expression in the pregnant rat and to study its association with fetal growth and growth factors. Uterine tissues were obtained from nonpregnant and from time-mated rats at 7, 13, 16, 19, and 21 d of pregnancy. Placental tissue was obtained on d 13, 16, 19 and 21 of pregnancy. Tissues were evaluated for HO activity, HO-1, HO-2, leptin and vascular endothelial growth factor protein, and HO-1 and HO-2 mRNA. HO activity in both the uterus and placenta peaked on d 21 of pregnancy. In the uterus, HO-1 and HO-2 protein and total mRNA levels peaked on d 16 of pregnancy, whereas, in the placenta, HO-1 and HO-2 protein levels peaked on d 19. Additionally, placental HO-1 mRNA peaked on d 16, but placental HO-2 mRNA declined toward the end of pregnancy. Placental leptin and vascular endothelial growth factor protein levels followed a similar pattern to placental HO-1 and peaked on d 16. We conclude that there is a clear uterine and placental gestational pattern of HO expression in the rat. This pattern is comparable to that of vascular endothelial growth factor and leptin.

    View details for DOI 10.1203/01.PDR.0000072516.83498.07

    View details for Web of Science ID 000184407700005

    View details for PubMedID 12736392

  • Effect of parenteral glutamine supplementation on plasma amino acid concentrations in extremely low-birth-weight infants AMERICAN JOURNAL OF CLINICAL NUTRITION Poindexter, B. B., Ehrenkranz, R. A., Stoll, B. J., Koch, M. A., Wright, L. L., Oh, W., Papile, L. A., Bauer, C. R., Carlo, W. A., Donovan, E. F., Fanaroff, A. A., Korones, S. B., Laptook, A. R., Shankaran, S., Stevenson, D. K., TYSON, J. E., Lemons, J. A. 2003; 77 (3): 737-743

    Abstract

    Glutamine is one of the most abundant amino acids in both plasma and human milk and may be conditionally essential in premature infants. However, glutamine is not provided by standard intravenous amino acid solutions.We assessed the effect of parenteral glutamine supplementation on plasma amino acid concentrations in extremely low-birth-weight infants receiving parenteral nutrition (PN).A total of 141 infants with birth weights of 401-1000 g were randomly assigned to receive a standard intravenous amino acid solution that did not contain glutamine or an isonitrogenous amino acid solution with 20% of the total amino acids as glutamine. Blood samples were obtained just before initiation of study PN and again after the infants had received study PN (mean intake: 2.3 +/- 1.0 g amino acids x kg(-1) x d(-1)) for approximately 10 d.Infants randomly assigned to receive glutamine had mean plasma glutamine concentrations that increased significantly and were approximately 30% higher than those in the control group in response to PN (425 +/- 182 and 332 +/- 148 micromol/L for the glutamine and control groups, respectively). There was no significant difference between the 2 groups in the relative change in plasma glutamate concentration between the baseline and PN samples. In both groups, there were significant decreases in plasma phenylalanine and tyrosine between the baseline and PN samples; the decrease in tyrosine was greater in the group that received glutamine.In extremely low-birth-weight infants, parenteral glutamine supplementation can increase plasma glutamine concentrations without apparent biochemical risk. Currently available amino acid solutions are likely to be suboptimal in their supply of phenylalanine, tyrosine, or both for these infants.

    View details for Web of Science ID 000181210600034

    View details for PubMedID 12600870

  • Direct intestinal administration of metalloporphyrins and heme oxygenase expression. Western Regional Meeting of the American-Federation-for-Medical-Research Wong, R. J., Abate, A., Dennery, P. A., Vreman, H. J., Contag, C. H., Stevenson, D. K. LIPPINCOTT WILLIAMS & WILKINS. 2003: S140–S141
  • Ethical considerations in neuroimaging and its impact on decision-making for neonates BRAIN AND COGNITION Stevenson, D. K., Goldworth, A. 2002; 50 (3): 449-454

    Abstract

    Neuroimaging can now provide information about structure and function. Despite new and improved neuroimaging technologies applicable to the newborn, predictions about later cognition, learning, social and emotional behavior, and neuromuscular capabilities, based on images of a fetus inside or a newborn outside the womb, are fraught with difficulties that go beyond technical ones. The interpretation of neuroimages may be necessary but it is not sufficient for decision-making related to the withholding or withdrawing of medical support for neonates. As the explanatory reach of neuroimaging increases, there will still need to be consideration of ethical issues as they relate to the best interests of the neonate and the neonate's parents, the quality of life of the neonate and non-beneficial treatment. Once this is appreciated, the boundary between the technical and the ethical will be less often disputed.

    View details for Web of Science ID 000180058100009

    View details for PubMedID 12480489

  • The jaundiced newborn. Understanding and managing transitional hyperbilirubinemia. Minerva pediatrica Stevenson, D. K., Wong, R. J., Hintz, S. R., Vreman, H. J. 2002; 54 (5): 373-382

    Abstract

    Neonatal jaundice is one of the most common conditions diagnosed by the pediatrician. This normally benign transitional phenomenon is a dynamic balance between the production and elimination of bilirubin. These processes can be exacerbated by a number of pathophysiologic conditions, which cause either an increase in bilirubin production rates, such as hemolysis, or a decrease in bilirubin elimination rates, such as bilirubin conjugation defects. The most dangerous circumstance for an infant is the combination of increased bilirubin production with impaired elimination. These infants are at considerable risk for developing excessive and potentially dangerous hyperbilirubinemia and subsequent kernicterus. Therefore, the importance of early recognition of the imbalance is paramount. In this review, we will discuss the various risk factors associated with hyperbilirubinemia and describe strategies for the diagnosis and management of transitional hyperbilirubinemia.

    View details for PubMedID 12244276

  • Late-onset sepsis in very low birth weight neonates: The experience of the NICHD Neonatal Research Network PEDIATRICS Stoll, B. J., Hansen, N., Fanaroff, A. A., Wright, L. L., Carlo, W. A., Ehrenkranz, R. A., Lemons, J. A., Donovan, E. F., Stark, A. R., TYSON, J. E., Oh, W., Bauer, C. R., Korones, S. B., Shankaran, S., Laptook, A. R., Stevenson, D. K., Papile, L. A., Poole, W. K. 2002; 110 (2): 285-291

    Abstract

    Late-onset sepsis (occurring after 3 days of age) is an important problem in very low birth weight (VLBW) infants. To determine the current incidence of late-onset sepsis, risk factors for disease, and the impact of late-onset sepsis on subsequent hospital course, we evaluated a cohort of 6956 VLBW (401-1500 g) neonates admitted to the clinical centers of the National Institute of Child Health and Human Development Neonatal Research Network over a 2-year period (1998-2000).The National Institute of Child Health and Human Development Neonatal Research Network maintains a prospective registry of all VLBW neonates admitted to participating centers within 14 days of birth. Expanded infection surveillance was added in 1998.Of 6215 infants who survived beyond 3 days, 1313 (21%) had 1 or more episodes of blood culture-proven late-onset sepsis. The vast majority of infections (70%) were caused by Gram-positive organisms, with coagulase-negative staphylococci accounting for 48% of infections. Rate of infection was inversely related to birth weight and gestational age. Complications of prematurity associated with an increased rate of late-onset sepsis included patent ductus arteriosus, prolonged ventilation, prolonged intravascular access, bronchopulmonary dysplasia, and necrotizing enterocolitis. Infants who developed late-onset sepsis had a significantly prolonged hospital stay (mean length of stay: 79 vs 60 days). They were significantly more likely to die than those who were uninfected (18% vs 7%), especially if they were infected with Gram-negative organisms (36%) or fungi (32%).Late-onset sepsis remains an important risk factor for death among VLBW preterm infants and for prolonged hospital stay among VLBW survivors. Strategies to reduce late-onset sepsis and its medical, social, and economic toll need to be addressed urgently.

    View details for Web of Science ID 000177274800021

    View details for PubMedID 12165580

  • Changes in pathogens causing early-onset sepsis in very-low-birth-weight infants NEW ENGLAND JOURNAL OF MEDICINE Stoll, B. J., Hansen, N., Fanaroff, A. A., Wright, L. L., Carlo, W. A., Ehrenkranz, R. A., Lemons, J. A., Donovan, E. F., Stark, A. R., TYSON, J. E., Oh, W., Bauer, C. R., Korones, S. B., Shankaran, S., Laptook, A. R., Stevenson, D. K., Papile, L. A., Poole, W. K. 2002; 347 (4): 240-247

    Abstract

    It is uncertain whether the rates and causes of early-onset sepsis (that occurring within 72 hours after birth) among very-low-birth-weight infants have changed in recent years, since antibiotics have begun to be used more widely during labor and delivery.We studied 5447 very-low-birth-weight infants (those weighing between 401 and 1500 g) born at centers of the Neonatal Research Network of the National Institute of Child Health and Human Development between 1998 and 2000 who had at least one blood culture in the first three days of life and compared them with 7606 very-low-birth-weight infants born at centers in the network between 1991 and 1993.Early-onset sepsis (as confirmed by positive blood cultures) was present in 84 infants in the more recent birth cohort (1.5 percent). As compared with the earlier birth cohort, there was a marked reduction in group B streptococcal sepsis (from 5.9 to 1.7 per 1000 live births of infants weighing 401 to 1500 g, P<0.001) and an increase in Escherichia coli sepsis (from 3.2 to 6.8 per 1000 live births, P=0.004); the overall rate of early-onset sepsis was not significantly changed. Most E. coli isolates from the recent birth cohort (85 percent) were resistant to ampicillin, and mothers of infants with ampicillin-resistant E. coli infections were more likely to have received intrapartum ampicillin than were those with ampicillin-sensitive strains (26 of 28 with sensitivity data vs. 1 of 5, P=0.01). Infants with early-onset sepsis were more likely to die than uninfected infants (37 percent vs. 13 percent, P<0.001), especially if they were infected with gram-negative organisms.Early-onset sepsis remains an uncommon but potentially lethal problem among very-low-birth-weight infants. The change in pathogens over time from predominantly gram-positive to predominantly gram-negative requires confirmation by ongoing surveillance.

    View details for Web of Science ID 000177665800003

    View details for PubMedID 12140299

  • Heme oxygenase-1 modulates fetal growth in the rat LABORATORY INVESTIGATION Kreiser, D., Nguyen, X., Wong, R., Seidman, D., Stevenson, D., Quan, S., Abraham, N., Dennery, P. A. 2002; 82 (6): 687-692

    Abstract

    Intrauterine growth restriction is associated with increased perinatal morbidity and mortality as well as with lifelong cardiovascular and metabolic complications. Deficiency of heme oxygenase 1 (HO-1) is associated with growth restriction in mice and in humans, suggesting a role for HO-1 in fetal growth and maintenance of pregnancy. We hypothesized that modulation of HO-1 in the pregnant rat would alter fetal growth. In pregnant dams, placental HO activity was significantly inhibited with zinc deuteroporphyrin IX 2,4 bis glycol, and HO-1 protein was increased by transducing adenoviral human HO-1. Inhibition of HO-1 by zinc deuteroporphyrin IX 2,4 bis glycol resulted in a significant decrease in pup size, whereas transfection with hHO-1 resulted in increased pup size. Furthermore, the expression of IGF binding protein-1 and its receptor paralleled the expression of HO-1 in the placenta and were significantly modulated by modification of HO-1 along with the expression of vascular endothelial growth factor. These observations demonstrate that HO-1 modulates fetal growth by its effects on placental growth factors.

    View details for DOI 10.1097/01.LAB.0000017167.26718.F2

    View details for Web of Science ID 000176317600002

    View details for PubMedID 12065678

  • Failure to detect elevated levels of carboxyhemoglobin in infants dying from SIDS JOURNAL OF FORENSIC SCIENCES Meny, R. G., Vreman, H. J., Stevenson, D. K., Hauck, F. R., Donoghue, E. R., Smialek, J. E., Fowler, D. R., Zielke, H. R. 2002; 47 (3): 660-662

    Abstract

    Carboxyhemoglobin (COHb) levels were determined in stored blood samples from 91 infants diagnosed to have died from the sudden infant death syndrome (SIDS) (0.59+/-0.41%, excluding one outlying value of 10.83%); 48 age-matched controls (0.53+/-0.38%); and three individuals who died from fire related causes (41+/-20%). No statistical differences in COHb levels were detected between blood from SIDS and control infants (p = 0.43).

    View details for Web of Science ID 000175734800039

    View details for PubMedID 12051358

  • Risk factors for early death among extremely low-birth-weight infants AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY Shankaran, S., Fanaroff, A. A., Wright, L. L., Stevenson, D. K., Donovan, E. F., Ehrenkranz, R. A., Langer, J. C., Korones, S. B., Stoll, B. J., TYSON, J. E., Bauer, C. R., Lemons, J. A., Oh, W., Papile, L. A. 2002; 186 (4): 796-802

    Abstract

    The purposes of this study were to compare the clinical characteristics of extremely low birth-weight infants (501-1000 g birth weight) who die early (<12 hours of age) with those of infants who die >12 hours after birth and infants who survive to neonatal intensive care unit discharge and to develop a model of risk for early death.Perinatal data were prospectively collected on 5986 infants in the 12 participating centers of the National Institute of Child Health and Human Development Neonatal Research Network from March 1993 through December 1997. Maternal and neonatal characteristics of infants who died early were compared with infants who survived and infants who died beyond 12 hours of age. A model for risk for early death was developed by logistic regression analysis, with results expressed as odds ratio with 95% CI.Mothers of infants who died early were more likely to be delivered in an inborn setting and experience labor and were less likely to have hypertension or preeclampsia, to receive antenatal corticosteroids, or to be delivered by cesarean birth than mothers of infants who died >12 hours after birth or infants who survived. Infants who died early were more likely to have lower Apgar scores and lower gestational age/birth weight and were less likely to be intubated at birth and to receive mechanical ventilation and surfactant therapy than infants who died >12 hours after birth or infants who survived. Greater risk for early death versus survival to neonatal intensive care unit discharge was associated with the lack of surfactant administration (odds ratio, 8.6; 95% CI, 6.3-11.9), lack of delivery room intubation (odds ratio, 5.3; 95% CI, 3.5-8.1), lack of antenatal corticosteroid use (odds ratio, 2.3; 95% CI, 1.6-3.2), lower 1-minute Apgar score (odds ratio, 2.0; 95% CI, 1.8-2.2), male sex (odds ratio, 1.7; 95% CI, 1.3-2.3), multiple gestation (odds ratio, 1.7; 95% CI, 1.2-2.5), no tocolytics (odds ratio, 1.7; 95% CI, 1.2-2.3), lower gestational age per week (odds ratio, 1.4; 95% CI, 1.3-1.6), and lower birth weight per 50 g (95% CI, 1.2-1.4).Early death (<12 hours of age) among extremely low-birth-weight infants may reflect an assessment of non-viability by obstetricians and neonatologists.

    View details for DOI 10.1067/mob.2002.121651

    View details for Web of Science ID 000175545300033

    View details for PubMedID 11967510

  • Role of carbon monoxide and nitric oxide in newborn infants with postasphyxial hypoxic-ischemic encephalopathy PEDIATRICS Vreman, H. J., Wong, R. J., Stevenson, D. K., Engel, R. R. 2002; 109 (4): 715-715

    View details for Web of Science ID 000174704000047

    View details for PubMedID 11927721

  • Prediction of hyperbilirubinemia in near-term and term infants. Journal of perinatology Stevenson, D. K., Fanaroff, A. A., Maisels, M. J., Young, B. W., Wong, R. J., Vreman, H. J., MacMahon, J. R., Yeung, C. Y., Seidman, D. S., Gale, R., Oh, W., Bhutani, V. K., Johnson, L. H., Kaplan, M., Hammerman, C., Nakamura, H. 2001; 21: S63-72

    Abstract

    The purpose of this study was to determine whether end-tidal carbon monoxide (CO) corrected for ambient CO (ETCOc), as a single measurement or in combination with serum total bilirubin (STB) measurements, can predict the development of hyperbilirubinemia during the first 7 days of life.From nine multinational clinical sites, 1370 neonates completed this cohort study from February 20, 1998 through February 22, 1999. Measurements of both ETCOc and STB were performed at 30+/-6 hours of life; STB also was measured at 96+/-12 hours and subsequently following a flow diagram based on a table of hours of age-specific STB. An infant was defined as hyperbilirubinemic if the hours of age-specific STB was greater than or equal to the 95th percentile as defined by the table at any time during the study.A total of 120 (8.8%) of the enrolled infants became hyperbilirubinemic. Mean STB in breast-fed infants was 8.92+/-4.37 mg/dl at 96 hours versus 7.63+/-3.58 mg/dl in those fed formula only. The mean ETCOc at 30+/-6 hours for the total population was 1.48+/-0.49 ppm, whereas those of nonhyperbilirubinemic and hyperbilirubinemic infants were 1.45+/-0.47 and 1.81+/-0.59 ppm, respectively. Seventy-six percent (92 of 120) of hyperbilirubinemic infants had ETCOc greater than the population mean. An ETCOc greater than the population mean at 30+/-6 hours yielded a 13.0% positive predictive value (PPV) and a 95.8% negative predictive value (NPV) for STB > or =95th percentile. When infants with STB > or =95th percentile at <36 hours of age were excluded, the STB at 30+/-6 hours yielded a 16.7% PPV and a 98.1% NPV for STB >75th percentile. The combination of these two measurements at 30+/-6 hours (either ETCOc more than the population mean or STB >75th percentile) had a 6.4% PPV with a 99.0% NPV.This prospective cohort study supports previous observations that measuring STB before discharge may provide some assistance in predicting an infant's risk for developing hyperbilirubinemia. The addition of an ETCOc measurement provides insight into the processes that contribute to the condition but does not materially improve the predictive ability of an hours of age-specific STB in this study population. The combination of STB and ETCOc as early as 30+/-6 hours may identify infants with increased bilirubin production (eg, hemolysis) or decreased elimination (conjugation defects) as well as infants who require early follow-up after discharge for jaundice or other clinical problems such as late anemia. Depending on the incidence of hyperbilirubinemia within an institution, the criteria for decision making should vary according to its unique population.

    View details for PubMedID 11803421

  • Understanding newborn jaundice. Journal of perinatology Stevenson, D. K., Dennery, P. A., Hintz, S. R. 2001; 21: S21-4

    View details for PubMedID 11803411

  • The biology of bilirubin production. Journal of perinatology Dennery, P. A., Weng, Y. H., Stevenson, D. K., Yang, G. 2001; 21: S17-20

    Abstract

    Heme oxygenase (HO), the rate-limiting enzyme in bilirubin production, has been identified from the late 1960s. This enzyme has been shown to have many other roles in recent years. The inducible form is regulated by oxidative stress, inflammation, and heavy metals, among others, and is cytoprotective in many instance. Nonetheless, there are instances when HO-1 can be deleterious due to the release of iron from the reaction. Another important by-product, carbon monoxide, is a vasodilator and a neurotransmitter and has been implicated in signal transduction pathways. More recently, nonenzymatic, signaling roles of HO have been suggested. This may serve to regulate the endogenous activity of this enzyme when cellular heme levels are low.

    View details for PubMedID 11803410

  • Just when you thought it was safe... PEDIATRIC RESEARCH Hintz, S. R., Stevenson, D. K. 2001; 50 (6): 676-677

    View details for Web of Science ID 000172398500004

    View details for PubMedID 11726720

  • In vivo patterns of heme oxygenase-1 transcription. Journal of perinatology Contag, C. H., Stevenson, D. K. 2001; 21: S119-24

    Abstract

    Gene fusions composed of specific promoters and bioluminescent reporter genes can be used to assess gene expression patterns using whole-body imaging in living animal models. A transgenic mouse model was developed using the regulatory elements of the heme oxygenase promoter to drive luciferase as the reporter gene. In these transgenic mice, heme oxygenase (HO)-1 expression was apparent in neuronal tissues of neonates but not adults as measured by whole-body imaging, and in adults transcription of the reporter gene was inducible by known inducers of HO-1 transcription. Whole-body imaging of luciferase activity was then used to evaluate the effects of metalloporphyrins (Mps) on the transcription of the reporter gene. Some of the Mps, which are potent inhibitors of HO activity, did not activate the reporter gene above background. These Mps are ideally suited as chemotherapeutics that may target bilirubin production rates by inhibiting HO activity, but not result in a net increase in output from the HO gene. In contrast, known inducers of HO transcription did increase luciferase activity as did some of the other Mps that have been examined. Using whole-body in vivo transcriptional assays may facilitate rapid screening of potential therapeutic compounds for both desired and untoward effects.

    View details for PubMedID 11803432

  • Alternative metalloporphyrins for the treatment of neonatal jaundice. Journal of perinatology Vreman, H. J., Wong, R. J., Stevenson, D. K. 2001; 21: S108-13

    View details for PubMedID 11803430

  • Endogenous carbon monoxide formation by chorionic villi of term human placenta PLACENTA McLaughlin, B. E., Lash, G. E., Graham, C. H., Smith, G. N., Vreman, H. J., Stevenson, D. K., Marks, G. S., Nakatsu, K., Brien, J. F. 2001; 22 (10): 886-888

    Abstract

    Carbon monoxide (CO) is a novel messenger that is proposed to play a complementary role with nitric oxide in the regulation of placental haemodynamics. In a previous study, CO formation from exogenous haem has been measured in the microsomal fraction of chorionic villi as an index of haem oxygenase activity. The objective of the present study was to determine whether endogenous CO is formed by dissected chorionic villi of term human placenta, to which no exogenous substrate or co-factor had been added. Each sample of freshly isolated chorionic villi (approximately 0.4 g) of term human placenta from caesarean delivery was incubated in a sealed vial containing 1 ml of Krebs' solution (pH 7.4) at 37 degrees C. CO formation was determined by quantitating, using a gas-chromatographic method, the amount of CO released into the headspace gas of the incubation vial. There was time-dependent formation of endogenous CO in chorionic villi incubated at 37 degrees C during a 60-min time course. CO formation was found to be minimal in chorionic villi samples incubated at 4 degrees C and was increased relative to tissue weight. The data demonstrate that there is endogenous CO formation by chorionic villi of term human placenta.

    View details for Web of Science ID 000172592500014

    View details for PubMedID 11718578

  • Differing pathogenesis of perinatal bilirubinemia in glucose-6-phosphate dehydrogenase-deficient versus -normal neonates PEDIATRIC RESEARCH Kaplan, M., Hammerman, C., Renbaum, P., Levy-Lahad, E., Vreman, H. J., Stevenson, D. K. 2001; 50 (4): 532-537

    Abstract

    The objective was to compare the contribution to perinatal bilirubinemia of hemolysis and UDP-glucuronosyltransferase (UGT) gene promoter polymorphism, seen in Gilbert's syndrome, between glucose-6-phosphate dehydrogenase (G-6-PD)-deficient and -normal neonates. Serum total bilirubin (STB) values from 52 G-6-PD-deficient and 166 G-6-PD-normal term, male neonates, sampled within 3 h of delivery (first sample) and on d 3 (second sample), were analyzed in relation to blood carboxyhemoglobin corrected for inspired CO (COHbc), an accurate index of hemolysis, and UGT promoter genotype. COHbc values (% total Hb) were greater in G-6-PD-deficient neonates than controls: first sample 1.00 +/- 0.25% versus 0.84 +/- 0.24%, p < 0.0001; second sample 0.83 +/- 0.20% versus 0.76 +/- 0.19%, p = 0.002. First sample COHbc and STB values did not correlate in either the G-6-PD-deficient or control groups, whereas second sample COHbc values correlated significantly with corresponding STB values in the control population only (r = 0.28, p = 0.0007). At second sampling, there was a higher allele frequency of the variant UGT promoter among those with STB values > or =75th percentile than those <75th among the G-6-PD-deficient neonates (0.60 versus 0.33, respectively, p = 0.025), but not controls (0.31 versus 0.40, respectively, p = 0.24). Among those infants with at least one variant UGT promoter allele, STB values were higher in the G-6-PD-deficient neonates than controls at second sampling only (181 +/- 56 microM versus 149 +/- 46 microM, respectively, p = 0.03). Both within and between the G-6-PD-deficient and control groups, our data demonstrate changing and differing contributions of hemolysis and UGT promoter polymorphism to bilirubinemia during the first 3 d of life.

    View details for Web of Science ID 000171092600018

    View details for PubMedID 11568299

  • Prediction of hyperbilirubinemia in near-term and term infants PEDIATRICS Stevenson, D. K., Fanaroff, A. A., Maisels, M. J., Young, B. W., Wong, R. J., Vreman, H. J., MacMahon, J. R., Yeung, C. Y., Seidman, D. S., Gale, R., Oh, W., Bhutani, V. K., Johnson, L. H., Kaplan, M., Hammerman, C., Nakamura, H. 2001; 108 (1): 31-39

    Abstract

    The purpose of this study was to determine whether end-tidal carbon monoxide (CO) corrected for ambient CO (ETCOc), as a single measurement or in combination with serum total bilirubin (STB) measurements, can predict the development of hyperbilirubinemia during the first 7 days of life.From 9 multinational clinical sites, 1370 neonates completed this cohort study from February 20, 1998, through February 22, 1999. Measurements of both ETCOc and STB were performed at 30 +/- 6 hours of life; STB also was measured at 96 +/- 12 hours and subsequently following a flow diagram based on a table of hours of age-specific STB. An infant was defined as hyperbilirubinemic if the hours of age-specific STB was greater than or equal to the 95th percentile as defined by the table at any time during the study.A total of 120 (8.8%) of the enrolled infants became hyperbilirubinemic. Mean STB in breastfed infants was 8.92 +/- 4.37 mg/dL at 96 hours versus 7.63 +/- 3.58 mg/dL in those fed formula only. The mean ETCOc at 30 +/- 6 hours for the total population was 1.48 +/- 0.49 ppm, whereas those of nonhyperbilirubinemic and hyperbilirubinemic infants were 1.45 +/- 0.47 ppm and 1.81 +/- 0.59 ppm, respectively. Seventy-six percent (92 of 120) of hyperbilirubinemic infants had ETCOc greater than the population mean. An ETCOc greater than the population mean at 30 +/- 6 hours yielded a 13.0% positive predictive value (PPV) and a 95.8% negative predictive value (NPV) for STB >/=95th percentile. When infants with STB >95th percentile at <36 hours of age were excluded, the STB at 30 +/- 6 hours yielded a 16.7% PPV and a 98.1% NPV for STB >75th percentile. The combination of these 2 measurements at 30 +/- 6 hours (either ETCOc more than the population mean or STB >75th percentile) had a 6.4% PPV with a 99.0% NPV. Conclusions. This prospective cohort study supports previous observations that measuring STB before discharge may provide some assistance in predicting an infant's risk for developing hyperbilirubinemia. The addition of an ETCOc measurement provides insight into the processes that contribute to the condition but does not materially improve the predictive ability of an hours of age-specific STB in this study population. The combination of STB and ETCOc as early as 30 +/- 6 hours may identify infants with increased bilirubin production (eg, hemolysis) or decreased elimination (conjugation defects) as well as infants who require early follow-up after discharge for jaundice or other clinical problems such as late anemia. Depending on the incidence of hyperbilirubinemia within an institution, the criteria for decision making should vary according to its unique population.

    View details for Web of Science ID 000169571400025

    View details for PubMedID 11433051

  • Acute hemolysis and severe neonatal hyperbilirubinemia in glucose-6-phosphate dehydrogenase-deficient heterozygotes JOURNAL OF PEDIATRICS Kaplan, M., Hammerman, C., Vreman, H. J., Stevenson, D. K., Beutler, E. 2001; 139 (1): 137-140

    Abstract

    Two premature female infants had severe hyperbilirubinemia caused by hemolysis. Both neonates were heterozygotes for the glucose-6-phosphate dehydrogenase Mediterranean mutation as determined by DNA analysis. Glucose-6-phosphate dehydrogenase-deficient heterozygotes may be susceptible to the complications of this enzyme deficiency.

    View details for DOI 10.1067/mpd.2001.115312

    View details for Web of Science ID 000169877100029

    View details for PubMedID 11445808

  • Serum bilirubin levels at 72 hours by selected characteristics in breastfed and formula-fed term infants delivered by cesarean section ACTA PAEDIATRICA Hintz, S. R., Gaylord, T. D., Oh, W., Fanaroff, A. A., Mele, L., Stevenson, D. K. 2001; 90 (7): 776-781

    Abstract

    The present multicenter study analysed the relative impact of maternal and infant factors on serum bilirubin levels at 72 +/- 12 h in exclusively breastfed vs formula-fed term infants. End-tidal carbon monoxide levels corrected for ambient air (ETCOc), an index of bilirubin production, were measured in exclusively breastfed (B = 66) or formula-fed (F = 210) term infants at 2-8 h of age. Inclusion criteria included cesarean section to ensure a 3 d hospitalization, birthweight > or = 2,500 g, gestational age >37 wk and absence of any illness. The ETCOc for B infants and F infants did not differ significantly (1.3 +/- 0.7 ppm vs 1.3 +/- 0.8 ppm). The serum bilirubin level at 72 +/- 12 h was significantly higher in B infants than in F infants (8.5 +/- 3.4mg dl(-1) vs 6.7 +/- 3.4mg dl(-1) p < 0.001), as was the percentage weight loss from birthweight. Serum bilirubin levels were significantly higher in infants who were male, who did not have meconium-stained amniotic fluid, and in those whose mothers were insulin-dependent diabetics or hypertensive. There was no difference between groups in the need for phototherapy or exchange transfusion.Although higher bilirubin levels were observed in group B at 72 +/- 12 h compared with group F, this finding was not of clinical or therapeutic consequence in this study. The lack of difference in ETCOc between the groups may be a factor of the timing of ETCOc measurement in this study, or may suggest that early increased bilirubin production is not a significant contributor to jaundice observed in exclusively breastfed infants. Key words: bilirubin, breastfeeding, jaundice

    View details for Web of Science ID 000170367700013

    View details for PubMedID 11519981

  • Detection of heme oxygenase activity by measurement of CO. Current protocols in toxicology / editorial board, Mahin D. Maines (editor-in-chief) ... [et al.] Vreman, H. J., Stevenson, D. K. 2001; Chapter 9: Unit 9 2-?

    Abstract

    Heme oxygenase (HO) is the first and rate-limiting step in degradation of heme, and in the presence of NADPH-cytochrome P-450 reductase it produces equimolar amounts of biliverdin and CO. CO produced in a closed system can be quantified as described in this unit by gas chromatography as a measure of HO activity in tissue slices, tissue homogenates, and tissue fractions.

    View details for DOI 10.1002/0471140856.tx0902s00

    View details for PubMedID 23045068

  • Unique effects of zinc protoporphyrin on HO-1 induction and apoptosis BLOOD Yang, G., Nguyen, X., Ou, J., Rekulapelli, P., Stevenson, D. K., Dennery, P. A. 2001; 97 (5): 1306-1313

    Abstract

    Zinc protoporphyrin (ZnPP), a naturally occurring molecule, is increased in iron deficiency and lead intoxication. ZnPP can also induce heme oxygenase (HO-1), the enzyme it competitively inhibits. In cultured cells (HA-1), ZnPP was the strongest HO-1 inducer of any metalloporphyrin (MP) tested. This was not due to increased oxidative stress, enhanced binding at metal response element, nor increased binding at activator protein-1 (AP-1) or SP-1 sites on HO-1. Only ZnPP, however, increased binding of nuclear proteins to early growth response-1 (Egr-1) protein consensus sequence. Pretreatment of HA-1 with cycloheximide inhibited ZnPP-induced HO-1 messenger RNA (mRNA) by 55%. Incubation with antisense Egr-1 oligomers decreased ZnPP-induced HO-1 expression by 47%. Furthermore, the level of HO-1 mRNA induction by ZnPP was 2-fold less in Egr-1-deficient fibroblasts than in wild-type cells. Because no Egr-1 binding site was previously identified on the HO-1 promoter, HA-1 cells were transfected with HO-1 CAT constructs containing segments of a 12.5-kb enhancer region of HO-1. A 196-bp fragment (RH) located approximately 9.5 kb upstream of the transcription start site mediated HO-1 induction by ZnPP alone. DNase I footprinting analysis further revealed that nuclear proteins bound to a 50-bp sequence in the RH. Within this sequence, a novel 9-bp region with 78% homology to the Egr-1 consensus sequence was identified further suggesting that Egr-1 partially mediates HO-1 induction by ZnPP. Lastly, increased apoptosis and nuclear localization were only seen with ZnPP, suggesting that increased ZnPP in disease states may serve as a cellular signaling mechanism.

    View details for Web of Science ID 000167117500019

    View details for PubMedID 11222374

  • Drug therapy: Neonatal hyperbilirubinemia. NEW ENGLAND JOURNAL OF MEDICINE Dennery, P. A., Seidman, D. S., Stevenson, D. K. 2001; 344 (8): 581-590
  • Rapid in vivo functional analysis of transgenes in mice using whole body imaging of luciferase expression TRANSGENIC RESEARCH Zhang, W. S., Feng, J. Q., Harris, S. E., Contag, P. R., Stevenson, D. K., Contag, C. H. 2001; 10 (5): 423-434

    Abstract

    The use of transgenic animals in biomedical research is increasing rapidly and may be the best means of determining gene function. Generating transgenic animals typically requires time-consuming screening processes, and gene function is assessed by an array of difficult phenotypic and biochemical assays performed ex vivo. To address the unmet need in transgenic research for functional assays performed with ease in living animals, we demonstrate here that in vivo detection of luciferase enzyme as a transcriptional reporter facilitates rapid screening for both the presence and function of transgenes in intact living mice. Using this approach we identified three bioluminescent transgenic founders where the transgene consisted of the heme oxygenase promoter fused to the modified coding sequence of the luciferase gene. These founders were identified from 183 pups and confirmed by PCR analysis. Identification of HO-1-luc homozygotes from back- crossed F2 littermates was then accelerated by in vivo imaging. In another transgenic mouse line, where the transgene was comprised of the bone morphogenic-4 (BMP4) promoter fused to the modified luciferase gene, we were able to identify transgenic animals and in each line we were able to visualize patterns of expression in living animals over time. The light production from these transgenic mice indicated that the desired DNA fragment was functional and different expression profiles apparent at different ages and after gene induction.

    View details for Web of Science ID 000171405600005

    View details for PubMedID 11708652

  • Term infants with fetal growth restriction are not at increased risk for low intelligence scores at age 17 years JOURNAL OF PEDIATRICS Paz, I., Laor, A., Gale, R., Harlap, S., Stevenson, D. K., Seidman, D. S. 2001; 138 (1): 87-91

    Abstract

    To assess the long-term cognitive outcome of small for gestational age (SGA) compared with appropriate for gestational age (AGA) infants.Data from the Jerusalem Perinatal Study was matched with information from the army draft medical board. SGA and severe SGA were defined as birth weight below the 10th and 3rd percentiles for gestational age, respectively. A multiple linear regression analysis was performed to control for clinical, perinatal, and socio-demographic confounding variables.A cohort of 13,454 consecutive singleton term infants born between 1974 and 1976.IQ at age 17 years.SGA infants had lower adjusted mean +/- SE IQ scores compared with their AGA peers: 102.2 +/- 0.9 versus 105.1 +/- 0.7 (P <.0001) for males and 102.5 +/- 0.9 versus 103.9 +/- 0.7 (P <.015) for females. SGA was not associated with lower academic achievements compared with AGA.After controlling for multiple confounders, being born SGA at term is associated with slightly lower intelligence test scores at age 17 years. However, the clinical significance of the small difference is not evident in academic achievements.

    View details for DOI 10.1067/mpd.2001.110131

    View details for Web of Science ID 000166478700016

    View details for PubMedID 11148518

  • Bedside functional imaging of the premature infant brain during passive motor activation JOURNAL OF PERINATAL MEDICINE Hintz, S. R., Benaron, D. A., Siegel, A. M., Zourabian, A., Stevenson, D. K., Boas, D. A. 2001; 29 (4): 335-343

    Abstract

    Changes in regional brain blood flow and hemoglobin oxygen saturation occur in the human cortex in response to neural activation. Traditional functional radiologic methods cannot provide continuous, portable measurements. Imaging methods, which use near-infrared light allow for non-invasive measurements by taking advantage of the fact that hemoglobin is a strong absorber at these wavelengths.To test the feasibility of a new optical functional imaging system in premature infants, and to obtain preliminary brain imaging of passive motor activation in this population.A new optical imaging system, the Diffuse Optical Tomography System (DOTS), was used to provide real-time, bedside assessments. Custom-made soft flexible fiberoptic probes were placed on two extremely ill, mechanically ventilated 24 week premature infants, and three healthier 32 week premature infants. Passive motor stimulation protocols were used during imaging.Specific movement of the arm resulted in reproducible focal, contralateral changes in cerebral absorption. The data suggest an overall increase in blood volume to the imaged area, as well as an increase in deoxyhemoglobin concentration. These findings in premature infants differ from those expected in adults.In the intensive care setting, continuous non-invasive optical functional imaging could be critically important and, with further study, may provide a bedside monitoring tool for prospectively identifying patients at high risk for brain injury.

    View details for Web of Science ID 000170867600010

    View details for PubMedID 11565203

  • Exhaled carbon monoxide in asthma JOURNAL OF PEDIATRICS Vreman, H. J., Wong, R. J., Stevenson, D. K. 2000; 137 (6): 889-890

    View details for Web of Science ID 000165876300029

    View details for PubMedID 11113853

  • Sex differences in outcomes of very low birthweight infants: the newborn male disadvantage ARCHIVES OF DISEASE IN CHILDHOOD Stevenson, D. K., Verter, J., Fanaroff, A. A., Oh, W., Ehrenkranz, R. A., Shankaran, S., Donovan, E. F., Wright, L. L., Lemons, J. A., TYSON, J. E., Korones, S. B., Bauer, C. R., Stoll, B. J. 2000; 83 (3): F182-F185

    Abstract

    To determine the differences in short term outcome of very low birthweight infants attributable to sex.Boys and girls weighing 501-1500 g admitted to the 12 centres of the National Institute of Child Health and Human Development Neonatal Research Network were compared. Maternal information and perinatal data were collected from hospital records. Infant outcome was recorded at discharge, at 120 days of age if the infant was still in hospital, or at death. Best obstetric estimate based on the last menstrual period, standard obstetric factors, and ultrasound were used to assign gestational age in completed weeks. Data were collected on a cohort that included 3356 boys and 3382 girls, representing all inborn births from 1 May 1991 to 31 December 1993.Mortality for boys was 22% and that for girls 15%. The prenatal and perinatal data indicate few differences between the sex groups, except that boys were less likely to have been exposed to antenatal steroids (odds ratio (OR) = 0.80) and were less stable after birth, as reflected in a higher percentage with lower Apgar scores at one and five minutes and the need for physical and pharmacological assistance. In particular, boys were more likely to have been intubated (OR = 1.16) and to have received resuscitation medication (OR = 1.40). Boys had a higher risk (OR > 1.00) for most adverse neonatal outcomes. Although pulmonary morbidity predominated, intracranial haemorrhage and urinary tract infection were also more common.Relative differences in short term morbidity and mortality persist between the sexes.

    View details for Web of Science ID 000165126200005

    View details for PubMedID 11040165

    View details for PubMedCentralID PMC1721180

  • End-tidal carbon monoxide measurements in women with pregnancy-induced hypertension and preeclampsia AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY Baum, M., Schiff, E., Kreiser, D., Dennery, P. A., Stevenson, D. K., Rosenthal, T., Seidman, D. S. 2000; 183 (4): 900-903

    Abstract

    We sought to compare the end-tidal carbon monoxide breath levels in pregnant women with and without pregnancy-induced hypertension and preeclampsia.We prospectively performed end-tidal carbon monoxide measurements corrected for ambient carbon monoxide in nonsmoking women during late gestation (>31 weeks). The study group included 22 women with pregnancy-induced hypertension or symptoms of preeclampsia and a control group of 20 normotensive pregnant women.The carbon monoxide measurements corrected for ambient carbon monoxide (mean +/- SD) were significantly lower (P <.01) in the hypertensive group than in the control group (1.17 +/- 0.35 vs 1.70 +/- 0.54 ppm). The study group had a significantly higher number of low (<1.2 ppm) end-tidal carbon monoxide measurements corrected for ambient carbon monoxide (13 [59.1%] vs 1 [5.0%]; P <.001). The end-tidal carbon monoxide measurements corrected for ambient carbon monoxide remained significantly lower in comparison with those found in the control group when the study group was divided into women with pregnancy-induced hypertension only (n = 11) and those with preeclampsia (n = 11) (1.19 +/- 0.37 ppm; P <.01; and 1.15 +/- 0.41 ppm; P <.01; respectively).Our findings suggest that carbon monoxide formation may be significantly lower in women with pregnancy-induced hypertension and preeclampsia. These data suggest that carbon monoxide could have a contributory role in the apparent paradox of the seemingly protective effect of smoking to decrease the risk of preeclampsia.

    View details for DOI 10.1067/mob.2000.109047

    View details for Web of Science ID 000089983200021

    View details for PubMedID 11035334

  • Reduction of the NO-mediated response in the rat aorta by metalloporphyrins CANADIAN JOURNAL OF PHYSIOLOGY AND PHARMACOLOGY Vreman, H. J., Haenen, G. R., Stevenson, D. K., Bast, A. 2000; 78 (6): 457-461

    Abstract

    Metalloporphyrins (MPs) have been found to affect the production of carbon monoxide (CO) and nitric oxide (NO). Unlike that for CO, little is known about the mechanism of action of MPs on the NO system. We determined the in vitro ability of ferrous protoporphyrin (heme, FePP), zinc protoporphyrin (ZnPP), and bilirubin (BR) to scavenge NO. Heme and ZnPP were studied in the rat aortic ring system for their ability to affect phenylephrine-induced contraction and methacholine-stimulated relaxation. Heme was found to be a good NO scavenger with a ks = 0.53 +/- 0.19 x 10(4) M(-1)xs(-1) (n = 6). ZnPP and BR did not scavenge NO. Neither heme nor ZnPP treatment affected the phenylephrine response as measured by -logEC50 and the maximal effect. However, heme and ZnPP treatments decreased the -logEC50 and the maximal effects of methacholine, therefore decreasing vasorelaxation. We conclude that when ZnPP is administered in vivo blood pressure should be carefully monitored.

    View details for Web of Science ID 000087770700003

    View details for PubMedID 10914634

  • Association of fetal and maternal carboxyhemoglobin levels in normal and Rh-alloimmune pregnancies EARLY HUMAN DEVELOPMENT Hayde, M., Pollak, A., Bernaschek, G., Weiner, C. P., Vreman, H. J., Stevenson, D. K., Widness, J. A. 2000; 58 (3): 205-212

    Abstract

    To compare paired antepartum fetal/maternal COHb ratios in whole blood from control and alloimmunized pregnancies and to examine the relationships between fetal and maternal COHb.COHb levels were measured in paired fetal and maternal blood samples obtained at cordocentesis in 47 control and 16 Rh-alloimmunized pregnancies. COHb was determined by gas chromatography. Results were analyzed by t-test, regression and analysis of covariance.Although fetal/maternal COHb ratios for control and alloimmunized pregnancies were not statistically significantly different, i.e. 1. 11+/-0.04 and 1.26+/-0.09, respectively (P=0.09), fetal COHb levels were higher in Rh-alloimmunized fetuses (P=0.0002). Fetal COHb levels were also higher than paired maternal levels among the alloimmunized group (P=0.011), but not among the control group (1. 04+/-0.04, P=ns). In univariate regression analysis, fetal and maternal COHb levels were significantly correlated with one another in both control (r=0.52, P=0.0002) and alloimmunized pregnancy groups (r=0.52, P=0.05). Comparison of the slopes of the fetal versus maternal COHb plots for the two groups showed a significant difference (P=0.02), with the alloimmunized group having the steeper slope.Differences in the antepartum fetal-maternal COHb relationships in control and alloimmunized groups likely reflect increased endogenous CO production among alloimmunized fetuses as a result of pathologic hemolysis.

    View details for Web of Science ID 000088889200004

    View details for PubMedID 10936440

  • Haem oxygenase activity in human umbilical cord and rat vascular tissues PLACENTA Vreman, H. J., Wong, R. J., Kim, E. C., Nabseth, D. C., Marks, G. S., Stevenson, D. K. 2000; 21 (4): 337-344

    Abstract

    Carbon monoxide (CO) has been shown to affect vascular tone in smooth muscle cells and thus, may regulate regional or systemic blood pressure as well as fetoplacental vascular tone and fetal blood delivery. To assess the potential of vascular tissue to produce CO, we determined haem oxygenase (HO) activity through in vitro quantitation of CO production with gas chromatography and its inhibition by 33-66 microm of chromium mesoporphyrin (CrMP) in homogenate preparations of rat aorta and vena cava and human umbilical cord tissues. We compared these results to HO activity in rat heart and liver. We also discuss normalization of HO activity on a per mg protein as well as per g fresh weight (FW) tissue basis. We found that both rat vascular tissue HO activities (per g FW) were equal, but greater than that of heart (x3) and less than that of liver (x0.2). For human cord tissues, HO activities of artery and vein were equal, but greater than that of Wharton's jelly. Also, HO activity in rat vascular tissues was 3x greater than that of the human cord tissues. HO activity was completely inhibited by CrMP in rat heart (90 per cent) and liver (96 per cent), but incompletely (50-66 per cent) in both rat and human vascular tissues. We established that it is unlikely that other non-haem CO-generating processes account for this unique insensitivity of HO to CrMP inhibition. In fact, high concentrations of other potent metalloporphyrin inhibitors affected vascular tissue HO even less. We found that the degree of in vitro HO inhibition appeared to be related to the concentration of haem in the reaction medium. We conclude that the presence of HO activity in cord tissues supports the possibility that CO plays a role in fetoplacental blood flow regulation.

    View details for Web of Science ID 000087666000006

    View details for PubMedID 10833368

  • Noninvasive functional imaging of human brain using light JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM Benaron, D. A., Hintz, S. R., Villringer, A., Boas, D., Kleinschmidt, A., Frahm, J., Hirth, C., Obrig, H., van Houten, J. C., Kermit, E. L., Cheong, W. F., Stevenson, D. K. 2000; 20 (3): 469-477

    Abstract

    Analysis of photon transit time for low-power light passing into the head, and through both skull and brain, of human subjects allowed for tomographic imaging of cerebral hemoglobin oxygenation based on photon diffusion theory. In healthy adults, imaging of changes in hemoglobin saturation during hand movement revealed focal, contralateral increases in motor cortex oxygenation with spatial agreement to activation maps determined by functional magnetic resonance imaging; in ill neonates, imaging of hemoglobin saturation revealed focal regions of low oxygenation after acute stroke, with spatial overlap to injury location determined by computed tomography scan. Because such slow optical changes occur over seconds and co-localize with magnetic resonance imaging vascular signals whereas fast activation-related optical changes occur over milliseconds and co-localize with EEG electrical signals, optical methods offer a single modality for exploring the spatio-temporal relationship between electrical and vascular responses in the brain in vivo, as well as for mapping cortical activation and oxygenation at the bedside in real-time for clinical monitoring.

    View details for Web of Science ID 000085829700005

    View details for PubMedID 10724111

  • Carbon monoxide detection and biological investigations. Transactions of the American Clinical and Climatological Association Stevenson, D. K., Vreman, H. J., Wong, R. J., Dennery, P. A., Contag, C. H. 2000; 111: 61-75

    Abstract

    Even though the heme degradation pathway consists of only two reactions, it and its major enzyme (i.e. HO), nonetheless, impact other processes not only through the removal of excess heme, but also through the production of several metabolically active compounds. Thus CO and biliverdin along with reactive iron, Fe2, are the primordial products of this ancient, highly conserved reaction. That every component of the heme catabolic pathway is directly or indirectly related to other reactions involving oxygen or light is, perhaps, no accident of nature. That a fundamentally destructive event can be linked with a multiplicity of synthetic events and various biological effects, depending on the timing and location of the HO activity, is testament to the economy and the ultimate beauty of nature. Furthermore, the interaction of the heme catabolic pathway with that of the NOS system may lead to even more exciting avenues of research. It may be shown that the integrity of the heme catabolic pathway, which is ever present and plays a role in every tissue, is central to the existence of most complex organisms.

    View details for PubMedID 10881332

    View details for PubMedCentralID PMC2194377

  • Validation of the natus CO-Stat (TM) end tidal breath analyzer in children and adults JOURNAL OF CLINICAL MONITORING AND COMPUTING Vreman, H. J., Wong, R. J., Harmatz, P., Fanaroff, A. A., Berman, B., Stevenson, D. K. 1999; 15 (7-8): 421-427

    Abstract

    The performance of a point-of-care, noninvasive end tidal breath carbon monoxide analyzer (CO-Stat End Tidal Breath Analyzer, Natus Medical Inc.) that also reports end tidal carbon dioxide (ETCO2) and respiratory rate (RR), was compared to established, marketed (predicate) devices in children (n = 39) and adults (n = 48) who are normal or at-risk of elevated CO excretion.Concentrations of end tidal breath CO (ETCO), room air CO, ETCO corrected for inhaled CO (ETCOc), ETCO2, and RR were measured with the CO-Stat analyzer and the data compared to those obtained from the same subjects using the Vitalograph BreathCO monitor (Vitalograph, Inc.) for ETCOc and the Pryon CO2 monitor (SC210 and SC300, Pryon Corp) for ETCO2 and RR. Adults and children were studied at three medical centers. The data were analyzed by paired t-tests and linear regression. Bias and imprecision between the CO-Stat analyzer and the predicate devices was calculated by the method of Bland and Altman.Paired t-tests, performed on the three parameters measured with the CO-Stat analyzer and predicate devices showed that only the ETCOc values in the adults and the ETCO2 values in the children were significantly different (lower, p < or = 0.0001, and higher, p < or = 0.0001, respectively). The mean bias and imprecision of the CO-Stat analyzer for adult ETCOc and children ETCO2 measurements were -0.9 +/- 1.2 ppm and 0.4 +/- 0.6%, respectively. Linear regression analysis for the ETCOc results in children and adults had a high degree of correlation (r = 0.91 and 0.98, respectively).We conclude that in a clinical environment the Natus CO-Stat End Tidal Breath Analyzer performs at least as well as predicate devices for the measurements of ETCOc, ETCO2, and RR.

    View details for Web of Science ID 000086962600004

    View details for PubMedID 12578038

  • Zinc protoporphyrin: A metabolite with a mission CLINICAL CHEMISTRY Labbe, R. F., Vreman, H. J., Stevenson, D. K. 1999; 45 (12): 2060-2072

    Abstract

    Zinc protoporphyrin (ZnPP) is a normal metabolite that is formed in trace amounts during heme biosynthesis. The final reaction in the biosynthetic pathway of heme is the chelation of iron with protoporphyrin. During periods of iron insufficiency or impaired iron utilization, zinc becomes an alternative metal substrate for ferrochelatase, leading to increased ZnPP formation. Evidence suggests that this metal substitution is one of the first biochemical responses to iron depletion, causing increased ZnPP to appear in circulating erythrocytes. Because this zinc-for-iron substitution occurs predominantly within the bone marrow, the ZnPP/heme ratio in erythrocytes reflects iron status in the bone marrow. In addition, ZnPP may regulate heme catabolism through competitive inhibition of heme oxygenase, the rate-limiting enzyme in the heme degradation pathway that produces bilirubin and carbon monoxide. Physiological roles, especially relating to carbon monoxide and possibly nitric oxide production, have been suggested for ZnPP. Clinically, ZnPP quantification is valuable as a sensitive and specific tool for evaluating iron nutrition and metabolism. Diagnostic determinations are applicable in a variety of clinical settings, including pediatrics, obstetrics, and blood banking. ZnPP analytical methodologies for clinical studies are discussed. In addition to diagnostic tests and metabolic studies, ZnPP has a potential therapeutic application in controlling bilirubin formation in neonates as a preventive measure for hyperbilirubinemia. Biochemical research techniques, both in vivo and in vitro, are described for further studies into the role of ZnPP in metabolism and physiology.

    View details for Web of Science ID 000084071400003

    View details for PubMedID 10585337

  • Selective inhibition of heme oxygenase, without inhibition of nitric oxide synthase or soluble guanylyl cyclase, by metalloporphyrins at low concentrations DRUG METABOLISM AND DISPOSITION Appleton, S. D., Chretien, M. L., McLlaughlin, B. E., Vreman, H. J., Stevenson, D. K., Brien, J. F., Nakatsu, K., Maurice, D. H., Marks, G. S. 1999; 27 (10): 1214-1219

    Abstract

    Studies on the physiological role of heme oxygenase (HO) require an inhibitor that will selectively inhibit HO activity without inhibiting the activity of either nitric oxide synthase (NOS) or soluble guanylyl cyclase (sGC). The objective of this study was to test a series of metalloporphyrins that have previously been shown to inhibit HO activity, for their ability to inhibit HO without inhibiting NOS or sGC activities. Measurement of activity of HO in rat brain microsomes and NOS in rat brain cytosol was made for samples incubated with metalloporphyrins (0.15-50 microM), including zinc protoporphyrin IX, zinc deuteroporphyrin IX 2,4-bis-ethylene glycol (ZnBG), chromium mesoporphyrin IX (CrMP), tin protoporphyrin IX, and zinc N-methylprotoporphyrin IX. CrMP and ZnBG were found to be the most selective inhibitors of HO activity (i.e., caused the greatest inhibition of HO activity, 89 and 80%, respectively, without inhibition of NOS activity). Based on these results, sGC activity in rat lung cytosol incubated with CrMP or ZnBG (0.15-15 microM) was measured. ZnBG did not affect basal sGC activity but did potentiate S-nitroso-N-acetylpenicillamine (SNAP)-induced sGC activity. CrMP did not affect either basal or SNAP-induced activity. It was concluded that of the five metalloporphyrins studied, CrMP, at a concentration of 5 microM, was a selective inhibitor of HO activity and was the most useful metalloporphyrin for the conditions tested. Thus, CrMP would appear to be a valuable chemical probe in elucidating the physiological role of HO.

    View details for Web of Science ID 000082861700017

    View details for PubMedID 10497150

  • Effects of skin-to-skin holding on general movements of preterm infants CLINICAL PEDIATRICS Constantinou, J. C., Adamson-Macedo, E. N., Stevenson, D. K., Mirmiran, M., Fleisher, B. E. 1999; 38 (8): 467-471

    Abstract

    The study objective was to test the hypothesis that the effect of skin-to-skin (STS) holding increases the ratio of rest to activity in low birth weight preterm infants. Ten infants with birthweight < 2,000 grams were videotaped before and after STS holding. Video recordings were analyzed to determine the number of general movements. We found no statistically significant difference between the percentage of general movements over the two periods. We conclude that the ratio of rest-activity before and after STS holding does not change as measured by occurrence of general movements.

    View details for Web of Science ID 000081864400005

    View details for PubMedID 10456242

  • Neonatal bilirubin production, reflected by carboxyhaemoglobin concentrations, in Down's syndrome ARCHIVES OF DISEASE IN CHILDHOOD Kaplan, M., Vreman, H. J., Hammerman, C., Stevenson, D. K. 1999; 81 (1): F56-F60

    Abstract

    To determine whether increased bilirubin production, reflected by blood carboxyhaemoglobin (COHb) values, is responsible for hyperbilirubinaemia in cases of Down's syndrome with no obvious cause for excessive jaundice.Blood was sampled on the third day of life for COHb, total haemoglobin (tHb), and serum total bilirubin, from 19 consecutively born neonates with Down's syndrome (a subset of 34 term babies), who had developed hyperbilirubinaemia (serum bilirubin >/= 256 micromol), and from 32 term controls. COHb, measured by gas chromatography, was corrected for inspired CO (COHbc) and expressed as a percentage of tHb.Significantly more of the Down's syndrome subset developed hyperbilirubinaemia than the controls (10/19 (52%) vs 7/32 (22%), relative risk 2.4, 95% confidence intervals (CI) 1.10 to 5.26). Third day serum bilirubin values (mean (SD)) were higher in the Down's syndrome neonates than in controls (214 +- 63 micromol/l vs 172 +- 54 micromol/l, respectively, p=0.015). Mean (SD) COHbc values were significantly higher in the Down's syndrome neonates than in controls (0.92 +- 0. 24% vs 0.63 +- 0.17%; p<0.0001). However, Down's syndrome neonates who became hyperbilirubinaemic had similar COHbc values to those who did not (0.87 +- 0.26% and 0.95 +- 0.23%, respectively). These values contrast with those of the controls, in whom a significant increase in COHbc was associated with hyperbilirubinaemia (0.74 +- 0. 15% vs 0.60 +- 0.16%, respectively; p<0.05). tHb values were similar in both groups.Down's syndrome neonates had a greater risk of hyperbilirubinaemia, and higher COHbc values, than controls. However, excessive bilirubin production could not be exclusively responsible for the hyperbilirubinaemia. By inference, decreased bilirubin elimination probably plays a greater part in its pathogenesis than in controls. Down's syndrome neonates may have abnormal erythropoiesis, leading to increased haem turnover.

    View details for Web of Science ID 000081283900012

    View details for PubMedID 10375364

  • Vitamin A supplementation for extremely-low-birth-weight infants NEW ENGLAND JOURNAL OF MEDICINE TYSON, J. E., Wright, L. L., Oh, W. O., Kennedy, K. A., Mele, L., Ehrenkranz, R. A., Stoll, B. J., Lemons, J. A., Stevenson, D. K., Bauer, C. R., Korones, S. B., Fanaroff, A. A. 1999; 340 (25): 1962-1968

    Abstract

    Vitamin A supplementation may reduce the risk of chronic lung disease and sepsis in extremely-low-birth-weight infants. The results of our pilot study suggested that a dose of 5000 IU administered intramuscularly three times per week for four weeks was more effective than the lower doses given in past trials.We performed a multicenter, blinded, randomized trial to assess the effectiveness and safety of this regimen as compared with sham treatment in 807 infants in need of respiratory support 24 hours after birth. The mean birth weight was 770 g in the vitamin A group and 769 g in the control group, and the respective gestational ages were 26.8 and 26.7 weeks.By 36 weeks' postmenstrual age, 59 of the 405 infants (15 percent) in the vitamin A group and 55 of the 402 infants (14 percent) in the control group had died. The primary outcome - death or chronic lung disease at 36 weeks' postmenstrual age - occurred in significantly fewer infants in the vitamin A group than in the control group (55 percent vs. 62 percent; relative risk, 0.89; 95 percent confidence interval, 0.80 to 0.99). Overall, 1 additional infant survived without chronic lung disease for every 14 to 15 infants who received vitamin A supplements. The proportions of infants in the vitamin A group and the control group who had signs of potential vitamin A toxicity were similar. The proportion of infants with serum retinol values below 20 microg per deciliter (0.70 micromol per liter) was lower in the vitamin A group than in the control group (25 percent vs. 54 percent, P<0.001).Intramuscular administration of 5000 IU of vitamin A three times per week for four weeks reduced biochemical evidence of vitamin A deficiency and slightly decreased the risk of chronic lung disease in extremely-low-birth-weight infants.

    View details for Web of Science ID 000081088500005

    View details for PubMedID 10379020

  • Untitled PEDIATRIC RESEARCH Hintz, S. R., Stevenson, D. K., Benaron, D. A. 1999; 45 (5): 737-738
  • Bilirubin toxicity and differentiation of cultured astrocytes. Journal of perinatology Rhine, W. D., SCHMITTER, S. P., Yu, A. C., Eng, L. F., Stevenson, D. K. 1999; 19 (3): 206-211

    Abstract

    To study the toxicity of bilirubin in primary cultures of newborn rat cerebral cortical astrocytes.Primary cultures of newborn rat astrocytes were incubated at bilirubin concentrations of 0, 1, 5, 10, 25, 50, 100, 200, and 2000 microM, at a bilirubin:albumin molar ratio of 1.7. Bilirubin toxicity was determined by changes in cellular morphology, trypan blue staining, and lactate dehydrogenase (LDH) release into the culture medium at various times of incubation. To determine if differentiation of astrocytes affects bilirubin toxicity, cultures were treated with dibutyryl cyclic adenosine monophosphate.All three indices of toxicity showed a bilirubin concentration dependence. LDH release in experimental cultures was significantly elevated (p < 0.05) above that of control cultures by 24 hours at bilirubin concentrations of > or = 100 microM. The absolute amount of LDH release differed significantly between the 200 and 2000 microM cultures from 1.5 to 24 hours, after which duration of exposure appeared to take over and all cultures approached maximum. LDH release for the lower concentrations all reached maximum by 120 hours, except for the 1 microM cultures, which showed no significant elevation above control throughout the study period. At 100 and 200 microM bilirubin, LDH release by untreated cells was significantly higher (p < 0.05) than release by treated cells by 36 hours.Undifferentiated astrocytes appeared to be more sensitive to bilirubin toxicity, which may correlate with the greater susceptibility of newborns to kernicteric injury. Studies with primary astrocyte culture may provide insight into how bilirubin sensitivity changes with brain development as well as the cellular and biochemical mechanisms of bilirubin encephalopathy.

    View details for PubMedID 10685223

  • Antepartum fetal and maternal carboxyhemoglobin and cotinine levels among cigarette smokers ACTA PAEDIATRICA Hayde, M., Bernaschek, G., Stevenson, D. K., Knight, G. J., Haddow, J. E., Widness, J. A. 1999; 88 (3): 327-331

    Abstract

    The objective of this study was to examine the association of carboxyhemoglobin (COHb) and plasma cotinine levels among pregnant women who smoke cigarettes and their fetuses. Fifteen pregnant women who smoked and their fetuses undergoing cordocentesis had blood samples analysed simultaneously for COHb and cotinine. Linear regression was used to test for associations among study variables. Significant maternal-fetal associations were observed both with COHb (r = 0.72, p = 0.003) and with cotinine (r = 0.96, p = 0.003). Maternal cotinine levels were correlated with maternal and fetal COHb levels (r = 0.96, p = 0.003; r = 0.99, p = 0.0003, respectively). Fetal cotinine levels were correlated with COHb in maternal and in fetal blood (r = 0.81, p = 0.0003; r = 0.88, p<0.0001, respectively). The strong direct associations of maternal and fetal levels of COHb and cotinine indicate that maternal COHb and cotinine measurements may be interpreted as surrogates of fetal COHb levels. However, the specificity, ex vivo stability and ease of measurement of cotinine offer advantages over using COHb in quantifying fetal CO exposure following maternal cigarette smoking.

    View details for Web of Science ID 000079338200018

    View details for PubMedID 10229047

  • Bedside imaging of intracranial hemorrhage in the neonate using light: Comparison with ultrasound, computed tomography, and magnetic resonance imaging PEDIATRIC RESEARCH Hintz, S. R., Cheong, W. F., van Houten, J. P., Stevenson, D. K., Benaron, D. A. 1999; 45 (1): 54-59

    Abstract

    Medical optical imaging (MOI) uses light emitted into opaque tissues to determine the interior structure. Previous reports detailed a portable time-of-flight and absorbance system emitting pulses of near infrared light into tissues and measuring the emerging light. Using this system, optical images of phantoms, whole rats, and pathologic neonatal brain specimens have been tomographically reconstructed. We have now modified the existing instrumentation into a clinically relevant headband-based system to be used for optical imaging of structure in the neonatal brain at the bedside. Eight medical optical imaging studies in the neonatal intensive care unit were performed in a blinded clinical comparison of optical images with ultrasound, computed tomography, and magnetic resonance imaging. Optical images were interpreted as correct in six of eight cases, with one error attributed to the age of the clot, and one small clot not seen. In addition, one disagreement with ultrasound, not reported as an error, was found to be the result of a mislabeled ultrasound report rather than because of an inaccurate optical scan. Optical scan correlated well with computed tomography and magnetic resonance imaging findings in one patient. We conclude that light-based imaging using a portable time-of-flight system is feasible and represents an important new noninvasive diagnostic technique, with potential for continuous monitoring of critically ill neonates at risk for intraventricular hemorrhage or stroke. Further studies are now underway to further investigate the functional imaging capabilities of this new diagnostic tool.

    View details for Web of Science ID 000077706500009

    View details for PubMedID 9890608

  • Simultaneous production of carbon monoxide and thiobarbituric acid reactive substances in rat tissue preparations by an iron-ascorbate system CANADIAN JOURNAL OF PHYSIOLOGY AND PHARMACOLOGY Vreman, H. J., Wong, R. J., Sanesi, C. A., Dennery, P. A., Stevenson, D. K. 1998; 76 (12): 1057-1065

    Abstract

    Most of the carbon monoxide (CO) produced by mammals is a product of the heme oxygenase (HO) reaction, the rate-limiting step in the heme degradation pathway leading to the generation of bilirubin in man. However, some CO is derived from other sources. We studied the association of CO production with lipid peroxidation in tissue preparations from adult male Wistar rats. Supernatants, from 20% tissue homogenates in potassium phosphate buffer, centrifuged for 1 min at 13,000 x g, were incubated for 30 min at 37 degrees C in septum-sealed vials in the dark with ascorbate (100 microM) and Fe(II) (6 microM) and (or) Fe(III) (60 microM). Butylated hydroxytoluene (BHT, 100 microM) was added for the blank reaction. CO produced into the headspace was quantitated by gas chromatography. Thiobarbituric acid reactive substances (TBARS), conjugated dienes (CD), and lipid hydroperoxides (LOOH) in the reaction medium were quantitated by spectrophotometry. Of the tissues studied, CO and TBARS formation was greatest for brain, followed by kidney, lung, spleen, and blood, but no CO or TBARS formation was detected for testes, intestine, liver, and heart. Cell fractionation studies indicated that these differences might be due to the presence of endogenous soluble antioxidants in the latter tissues. Furthermore, these studies demonstrated that CO was exclusively generated by subcellular fractions that contained membranes. The magnitude of the rate of product formation in brain supernatants depended on the concentration of Fe(II) and (or) Fe(III). The formation of CO, TBARS, CD, and LOOH increased linearly with time for up to 30 min, but the rates of product formation were different. Product formation was completely inhibited by BHT (100 microM), biliverdin (50 microM), bilirubin (50 microM), citrate (100 microM), and the Fe(II) chelators, desferrioxamine mesylate (100 microM) and diethylenetriaminepentaacetate, but not by 10 microM of the HO inhibitor, zinc deuteroporphyrin bis glycol. We conclude that CO generation is associated with the process of in vitro lipid peroxidation in tissues with limited antioxidant reserves.

    View details for Web of Science ID 000079780100001

    View details for PubMedID 10326826

  • Very low birth weight outcomes of the National Institute of Child Health and Human Development Neonatal Research Network, January 1993 through December 1994 AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY Stevenson, D. K., Wright, L. L., Lemons, J. A., Oh, W., Korones, S. B., Papile, L. A., Bauer, C. R., Stoll, B. J., TYSON, J. E., Shankaran, S., Fanaroff, A. A., Donovan, E. F. 1998; 179 (6): 1632-1639

    Abstract

    Our purpose was to determine the mortality and morbidity rates for infants weighing 501 to 1500 g according to gestational age, birth weight, and gender.Perinatal data were collected prospectively on an inborn cohort from January 1993 through December 1994 by 12 participating centers of the National Institute of Child Health and Human Development Neonatal Research Network and were compared with the corresponding data from previous reports. Sociodemographic factors, perinatal events, and the neonatal course to 120 days of life, discharge, or death were evaluated.Eighty-three percent of infants survived until discharge to home or to a long- term care facility (compared with 74% in 1988). Survival to discharge was 49% for infants weighing 501 to 750 g at birth, 85% for those 751 to 1000 g, 93% for those 1001 to 1250 g, and 96% for those 1251 to 1500 g. The majority of deaths occurred within the first 3 days of life. Mortality rates were greater for male than for female infants. Respiratory distress syndrome was the most frequent pulmonary disease (52%). Chronic lung disease (defined as an oxygen requirement at 36 weeks after conception) developed in 19%. Thirty-two percent of infants had evidence of intracranial hemorrhage. Periventricular leukomalacia was noted in 6% of infants who had ultrasonography after 2 weeks. The average duration of hospitalization for survivors was 68 days (122 days for surviving infants weighing 501 to 750 g, compared with an average of 43 days for surviving infants 1251 to 1500 g). Among infants who died, the average length of stay was 19 days.The mortality rate for infants weighing between 501 and 1500 g at birth continues to decline. This increase in survival is not accompanied by an increase in medical morbidity. There are interactions between birth weight, gestational age, sex, and survival rates.

    View details for Web of Science ID 000077702500056

    View details for PubMedID 9855609

  • Light-emitting diodes: A novel light source for phototherapy PEDIATRIC RESEARCH Vreman, H. J., Wong, R. J., Stevenson, D. K., Route, R. K., Reader, S. D., Fejer, M. M., Gale, R., Seidman, D. S. 1998; 44 (5): 804-809

    Abstract

    High intensity light-emitting diodes (LEDs) are being studied as possible light sources for the phototherapy of hyperbilirubinemic neonates. These power-efficient, low heat-producing light sources have the potential to deliver high intensity light of narrow wavelength band in the blue-green portion of the visible light spectrum, which overlaps the absorption spectrum of bilirubin (BR). We compared the efficacy between single LEDs of different color and then constructed a prototype phototherapy device using 300 blue LEDs. The efficacy of this device was compared with that of conventional phototherapy devices by measuring the in vitro photodegradation of BR in human serum albumin. When blue, blue-green, green, and white LEDs were compared, the blue light was the most effective in degrading BR by 28% of dark control, followed by blue-green (18% of control), and then white light (14% of control). Green light was the least effective (11% of control). The prototype device with three focused arrays, each with 100 blue LEDs, generated greater irradiance (> 200 microW.cm-2.nm-1) than any of the conventional devices tested. It also supported the greatest rate of BR photodegradation. We conclude that light from LEDs should be considered a more effective treatment for hyperbilirubinemia than light from presently used phototherapy devices. Furthermore, the unique characteristics of this light source may make it especially suitable for use in safe and lightweight home phototherapy devices.

    View details for Web of Science ID 000076607700027

    View details for PubMedID 9803466

  • Strategy for lipid suppression in lactate imaging using STIR-DQCT: A study of hypoxic-ischemic brain injury MAGNETIC RESONANCE IN MEDICINE Nakai, T., Rhine, W. D., Okada, T., Stevenson, D. K., Spielman, D. M. 1998; 40 (4): 629-632

    Abstract

    In vivo lactate detection using gradient enhanced double quantum coherence transfer (DQCT) was significantly improved by addition of short-time-inversion-recovery (STIR). Phantom studies demonstrated lipid suppression down to the background noise level with 33% loss of lactate signal. In vivo studies using a rabbit model of hypoxic and unilateral-ischemic brain injury showed reduction down to 29 +/- 11% in lipids with inversion times between 140 and 170 ms. Lactate signals on the ischemic side were 51 +/- 53% higher than the nonischemic side at the peak of hypoxia. STIR-DQCT can be a useful robust method of obtaining metabolic maps of lactate in vivo.

    View details for Web of Science ID 000076080900015

    View details for PubMedID 9771580

  • Stationary headband for clinical time-of-flight optical imaging at the bedside PHOTOCHEMISTRY AND PHOTOBIOLOGY Hintz, S. R., Benaron, D. A., van Houten, J. P., Duckworth, J. L., Liu, F. W., Spilman, S. D., Stevenson, D. K., Cheong, W. F. 1998; 68 (3): 361-369

    Abstract

    Conventional brain-imaging modalities may be limited by high cost, difficulty of bedside use, noncontinuous operation, invasiveness or an inability to obtain measurements of tissue function, such as oxygenation during stroke. Our goal was to develop a bedside clinical device able to generate continuous, noninvasive, tomographic images of the brain using low-power nonionizing optical radiation. We modified an existing stage-based time-of-flight optical tomography system to allow imaging of patients under clinical conditions. First, a stationary head-band consisting of thin, flexible optical fibers was constructed. The headband was then calibrated and tested, including an assessment of fiber lengths, the existing system software was modified to collect headband data and to perform simultaneous collection of data and image reconstruction, and the existing hardware was modified to scan optically using this headband. The headband was tested on resin models and allowed for the generation of tomographic images in vitro; the headband was tested on critically ill infants and allowed for optical tomographic images of the neonatal brain to be obtained in vivo.

    View details for Web of Science ID 000075986500022

    View details for PubMedID 9747590

  • Outcomes of very low birth weight twins cared for in the National Institute of Child Health and Human Development Neonatal Research Network's intensive care units AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY Donovan, E. F., Ehrenkranz, R. A., Shankaran, S., Stevenson, D. K., Wright, L. L., Younes, N., Fanaroff, A. A., Korones, S. B., Stoll, B. J., TYSON, J. E., Bauer, C. R., Lemons, J. A., Oh, W., Papile, L. A. 1998; 179 (3): 742-749

    Abstract

    The study's aim was to compare outcomes of very low birth weight twins with those of matched singletons.With data from the Neonatal Research Network registry (May 1991 to December 1994), univariable and multivariable comparisons of very low birth weight twin pairs and singletons were performed in 2 subgroups: (1) all paired twins and singletons with birth weights between 401 and 1500 g and (2) all paired twins and singletons born at <28 weeks' gestation.Twins constituted 19% of infants admitted with very low birth weight. Mothers of twins were more likely to receive prenatal care, have labor, have cesarean delivery, and receive antenatal glucocorticoids. Twins were more likely to have respiratory disease and to receive surfactant. Second-born twins had more early respiratory disease but similar longer-term outcomes. The risks of death, chronic lung disease, and grade III or IV intracranial hemorrhage were similar in twins and singletons.Although very low birth weight twins compose a sizable proportion of admissions, in National Institute of Child Health and Human Development Neonatal Research Network intensive care units, twins and singletons have similar outcomes.

    View details for Web of Science ID 000076085500031

    View details for PubMedID 9757982

  • Diffusion and perfusion magnetic resonance imaging of the evolution of hypoxic ischemic encephalopathy in the neonatal rabbit JOURNAL OF MAGNETIC RESONANCE IMAGING D'Arceuil, H. E., de Crespigny, A. J., Rother, J., Seri, S., Moseley, M. E., Stevenson, D. K., Rhine, W. 1998; 8 (4): 820-828

    Abstract

    Hypoxic-ischemic encephalopathy (HIE) can result from neonatal asphyxia, the pathophysiology of which is poorly understood. We studied the acute evolution of this disease, using magnetic resonance imaging in an established animal model. HIE was induced in neonatal rabbits by a combination of common carotid artery (CCA) ligation and hypoxia. Serial diffusion and perfusion-weighted magnetic resonance images were acquired before, during, and after the hypoxic interval. Focal areas of decreased apparent diffusion coefficient (ADC) were detected initially in the cortex ipsilateral to CCA ligation within 62 +/- 48 min from the onset of hypoxia. Subsequently, these areas of decreased ADC spread to the subcortical white matter, basal ganglia (ipsilateral side), and then to the contralateral side. Corresponding perfusion-weighted images showed relative cerebral blood volume deficits which closely matched those regions of ADC change. Our results show that MRI diffusion and perfusion-weighted imaging can detect acute cell swelling post-hypoxia in this HIE model.

    View details for Web of Science ID 000080143600010

    View details for PubMedID 9702883

  • Ethical dilemmas in the delivery room SEMINARS IN PERINATOLOGY Stevenson, D. K., Goldworth, A. 1998; 22 (3): 198-206

    Abstract

    The decision to withhold or withdraw life support in the neonatal intensive care unit (NICU) is common but is never routine. Often, moral demands make such decisions difficult and emotionally exhausting. But, what is perhaps more challenging from the moral point of view is the transition from the delivery room to the NICU. A satisfactory analysis of the moral issues of delivery room practices must include a discussion of quality of life, the best interest of the infant, the best interests of the family members, and futile treatment. Although these topics are relevant in any discussion of the moral justification of the omission, withdrawal, or use of treatment for patients, they are especially telling when entertained in the context of the transition of the fetus to a newborn. This article uses these four topics as a moral compass for certain decisions made in the delivery room.

    View details for Web of Science ID 000074456600004

    View details for PubMedID 9650227

  • A multicenter trial of two dexamethasone regimens in ventilator-dependent premature infants NEW ENGLAND JOURNAL OF MEDICINE Papile, L. A., TYSON, J. E., Stoll, B. J., Wright, L. L., Donovan, E. F., Bauer, C. R., Krause-Steinrauf, H., Verter, J., Korones, S. B., Lemons, J. A., Fanaroff, A. A., Stevenson, D. K. 1998; 338 (16): 1112-1118

    Abstract

    Ventilator-dependent premature infants are often treated with dexamethasone. However, the optimal timing of therapy is unknown.We compared the benefits and hazards of initiating dexamethasone therapy at two weeks of age and at four weeks of age in 371 ventilator-dependent very-low-birth-weight infants (501 to 1500 g) who had respiratory index scores (mean airway pressure x the fraction of inspired oxygen) of 52.4 at two weeks of age. One hundred eighty-two infants received dexamethasone for two weeks followed by placebo for two weeks, and 189 infants received placebo for two weeks followed by either dexamethasone (those with a respiratory-index score of > or =2.4 on treatment day 14) or additional placebo for two weeks. Dexamethasone was given at a dose of 0.25 mg per kilogram of body weight twice daily intravenously or orally for five days, and the dose was then tapered.The median time to ventilator independence was 36 days in the dexamethasone-placebo group and 37 days in the placebo-dexamethasone group. The incidences of chronic lung disease (defined as the need for oxygen supplementation at 36 weeks' postconceptional age) were 66 percent and 67 percent, respectively. Dexamethasone was associated with an increased incidence of nosocomial bacteremia (relative risk, 1.5; 95 percent confidence interval, 1.1 to 2.1) and hyperglycemia (relative risk, 1.9; 95 percent confidence interval, 1.2 to 3.0) in the dexamethasone-placebo group, elevated blood pressure (relative risk, 2.9; 95 percent confidence interval, 1.2 to 6.9) in the placebo-dexamethasone group, and diminished weight gain and head growth (P< 0.001) in both groups.Treatment of ventilator-dependent premature infants with dexamethasone at two weeks of age is more hazardous and no more beneficial than treatment at four weeks of ages.

    View details for Web of Science ID 000073070100004

    View details for PubMedID 9545359

  • Combination of ABO blood group incompatibility and glucose-6-phosphate dehydrogenase deficiency: effect on hemolysis and neonatal hyperbilirubinemia ACTA PAEDIATRICA Kaplan, M., Vreman, H. J., Hammerman, J., Leiter, C., Rudensky, B., MacDonald, M. G., Stevenson, D. K. 1998; 87 (4): 455-457

    Abstract

    The incidence (%) of hyperbilirubinemia (serum bilirubin > or = 257 micromol/l) was similar in neonates with a combination of ABO incompatibility and glucose-6-phosphate dehydrogenase (G-6-PD) deficiency (45%), with ABO incompatibility (54%) or G-6-PD deficiency (37%), alone (ns). Carboxyhemoglobin values, corrected for inspired CO, were similarly elevated in all three groups (0.87 +/- 0.32%, 0.82 +/- 0.29%, 0.76 +/- 0.18%, respectively, ns), but correlated with bilirubin only in those with ABO incompatibility alone. ABO-incompatible/G-6-PD-deficient neonates, compared with those with either condition alone, are not at increased risk for hemolysis or hyperbilirubinemia.

    View details for Web of Science ID 000073985400023

    View details for PubMedID 9628306

  • Bioluminescent indicators in living mammals NATURE MEDICINE Contag, P. R., Olomu, I. N., Stevenson, D. K., Contag, C. H. 1998; 4 (2): 245-247

    View details for Web of Science ID 000072249800043

    View details for PubMedID 9461201

  • Neonatal hypoglycemia, part II: Pathophysiology and therapy International Symposium on Neonatal Hypoglycemia Halamek, L. P., Stevenson, D. K. SAGE PUBLICATIONS INC. 1998: 11–16

    Abstract

    Contemporary research is elucidating both the molecular mechanisms of hypoglycemia-induced neuronal injury and its corresponding clinical manifestations. Recognizing and screening those neonates at highest risk of hypoglycemia-induced injury is an important skill for all physicians responsible for the care of newborns. Appropriate therapy, consisting of either oral or intravenous glucose, should never be delayed while one is awaiting laboratory confirmation of a "low" glucose level.

    View details for Web of Science ID 000071577400002

    View details for PubMedID 9475694

  • Macrosomia does not predict overweight in late adolescence in infants of diabetic mothers ACTA OBSTETRICIA ET GYNECOLOGICA SCANDINAVICA Seidman, D. S., Laor, A., Stevenson, D. K., Sivan, E., Gale, R., Shemer, J. 1998; 77 (1): 58-62

    Abstract

    To determine the predictive value of macrosomia for overweight later in adult life in infants of diabetic mothers.Data from the computerized records of the Jerusalem Perinatal Study were matched to measurements made at age 17 obtained from the military draft medical examination records.10,891 infants born in Jerusalem between November 1974 and February 1976.Macrosomia based on 90th percentile birth weight for gestational age and overweight defined as the 90th percentile for body mass index at age 17.Diabetes was diagnosed in 87 (0.8%) of the mothers. Thirty-one (35.6%) of the infants of the diabetic mothers were macrosomic compared to 1012 (9.4%) of the siblings of nondiabetic mothers (p < 0.001). At 17 years of age 10.3% vs. 9.4% of the siblings of diabetic vs. nondiabetic mothers were overweight (p > 0.05). The rate of adolescent overweight in macrosomic vs. nonmacrosomic subjects was 12.3% vs. 9.7% (p < 0.01) in siblings of nondiabetic mothers, and 16.1% vs. 7.1% (p > 0.05) for diabetic mothers. The sensitivity and specificity, in diabetic mothers, of macrosomia for overweight at age 17 was 44.4% and 66.7%, respectively. The positive and negative predictive value of macrosomia for overweight at age 17 was 16.1% and 92.9%, respectively.The risk of adolescent overweight was significantly increased among macrosomic infants, although this trend did not reach statistical significance in the smaller group of infants born to diabetic mothers. Macrosomia among infants of diabetic mothers had little predictive value for overweight in late adolescence.

    View details for Web of Science ID 000071812100013

    View details for PubMedID 9492720

  • Neonatal hypoglycemia .1. Background and definition International Symposium on Neonatal Hypoglycemia Halamek, L. P., Benaron, D. A., Stevenson, D. K. SAGE PUBLICATIONS INC. 1997: 675–80

    Abstract

    Hypoglycemia in the neonate remains a common problem. The association of low blood glucose concentrations and abnormal development has prompted extensive research into the anticipation, evaluation, and treatment of neonatal hypoglycemia. Glucose homeostasis in the fetus and neonate is a developmentally regulated dynamic process involving a number of intricate physiologic mechanisms. In addition, the determination of glucose concentrations is dependent upon both the type of tissue analyzed and the limitations of the specific method employed. The complexity of glucose metabolism makes it difficult to precisely define "normal" and "abnormal" glucose levels in preterm and term neonates.

    View details for Web of Science ID A1997YK31400001

    View details for PubMedID 9415833

  • Supplemental oxygen may decrease progression of prethreshold disease to threshold retinopathy of prematurity. Journal of perinatology Gaynon, M. W., Stevenson, D. K., Sunshine, P., Fleisher, B. E., Landers, M. B. 1997; 17 (6): 434-438

    Abstract

    The optimum level of oxygen saturation for infants with prethreshold retinopathy of prematurity (ROP) is unknown. We reviewed our conversion rate from prethreshold to threshold ROP between 1985 and 1993 during which time target levels of oxygen saturation rose in a stepwise fashion. A retrospective study of 153 infants with prethreshold ROP was performed at Stanford University between 1985 and 1993 that showed that target minimum oxygen saturation rose from 92% (1985-1987) to 95% (1988) to 96% (1989) to 99% (1990-1993). In addition, we looked at 26 infants between 1994 and 1996 who were excluded from the STOP-ROP study and who were not receiving supplemental oxygen in an effort to maintain equipoise for that study. Infant characteristics were tabulated, and rates of progression from prethreshold to threshold ROP were calculated. Rates of progression to threshold varied little between 1985 and 1989 (average 37%), but dropped to 7% for the period between 1990 and 1993. From 1994 through 1996 the rate of progression to threshold disease rose again, to 38%. Moderate supplemental oxygen (target saturation 99% with PO2 no higher than 100 mm Hg) was associated with regression of prethreshold ROP, without appearing to arrest retinal vascular maturation.

    View details for PubMedID 9447528

  • Visualizing gene expression in living mammals using a bioluminescent reporter PHOTOCHEMISTRY AND PHOTOBIOLOGY Contag, C. H., Spilman, S. D., Contag, P. R., Oshiro, M., Eames, B., Dennery, P., Stevenson, D. K., Benaron, D. A. 1997; 66 (4): 523-531

    Abstract

    Control of gene expression often involves an interwoven set of regulatory processes. As information regarding regulatory pathways may be lost in ex vivo analyses, we used bioluminescence to monitor gene expression in living mammals. Viral promoters fused to firefly luciferase as transgenes in mice allowed external monitoring of gene expression both superficially and in deep tissues. In vivo bioluminescence was detectable using either intensified or cooled charge-coupled device cameras, and could be detected following both topical and systemic delivery of substrate. In vivo control of the promoter from the human immunodeficiency virus was demonstrated. As a model for DNA-based therapies and vaccines, in vivo transfection of a luciferase expression vector (SV-40 promoter and enhancer controlling expression) was detected. We conclude that gene regulation, DNA delivery and expression can now be noninvasively monitored in living mammals using a luciferase reporter. Thus, real-time, noninvasive study of gene expression in living animal models for human development and disease is possible.

    View details for Web of Science ID A1997YC04200026

    View details for PubMedID 9337626

  • Size at birth, maternal nutritional status in pregnancy, and blood pressure at age 17: population based analysis BRITISH MEDICAL JOURNAL Laor, A., Stevenson, D. K., Shemer, J., Gale, R., Seidman, D. S. 1997; 315 (7106): 449-453

    Abstract

    To assess the effect of size at birth, maternal nutrition, and body mass index on blood pressure in late adolescence.Population based analysis of birth weight corrected for gestational age, mother's weight before pregnancy and weight gain in pregnancy, obtained from the Jerusalem perinatal study, and blood pressure and body mass index at age 17, available from military draft records.Jerusalem, Israel.10,883 subjects (6684 men and 4199 women) born in Jerusalem during 1974-6 and subsequently drafted to the army.Systolic and diastolic blood pressures measured at age 17 and their correlation with birth weight, size at birth, mother's body mass index and weight gain during pregnancy, and height and weight at age 17.Systolic and diastolic blood pressures were significantly and positively correlated with body weight, height, body mass index at age 17, and with mother's body weight and body mass index before pregnancy, but not with birth weight or mother's weight gain in pregnancy.Variables reflecting poor intrauterine nutrition, including low maternal body mass index before pregnancy, poor maternal weight gain in pregnancy, and being born small for gestational age, were not associated with a higher blood pressure in late adolescence.

    View details for Web of Science ID A1997XT71400014

    View details for PubMedID 9284660

  • The effect of antenatal phenobarbital therapy on neonatal intracranial hemorrhage in preterm infants NEW ENGLAND JOURNAL OF MEDICINE Shankaran, S., Papile, L. A., Wright, L. L., Ehrenkranz, R. A., Mele, L., Lemons, J. A., Korones, S. B., Stevenson, D. K., Donovan, E. F., Stoll, B. J., Fanaroff, A. A., Oh, W. 1997; 337 (7): 466-471

    Abstract

    The administration of phenobarbital to pregnant women before delivery has been thought to decrease the frequency of intracranial hemorrhage in preterm infants. To evaluate this potential neuroprotective therapy further, we determined the effect of antenatal administration of phenobarbital on the frequency of neonatal intracranial hemorrhage and early death.We studied 610 women who were 24 to 33 weeks pregnant and who were expected to deliver their infants within 24 hours. The women were randomly assigned to receive either phenobarbital (10 mg per kilogram of body weight) or placebo intravenously, followed by maintenance doses until delivery or 34 weeks of gestation. The infants born to these women underwent cranial ultrasonography to detect the presence of intracranial hemorrhage.There were 309 women in the phenobarbital group and 301 in the placebo group. A total of 247 women (80 percent) in the phenobarbital group and 235 (78 percent) in the placebo group delivered within 24 hours after infusion of the study drug or administration of the last maintenance dose. Intracranial hemorrhage or early death occurred in 83 of the 344 infants born to the women in the phenobarbital group (24 percent) and in 74 of the 324 born to the women in the placebo group (23 percent; risk ratio for the infants in the phenobarbital group, 1.1; 95 percent confidence interval, 0.8 to 1.4). Among infants born before 34 weeks' gestation in whom ultrasonographic studies were performed, intracranial hemorrhage was diagnosed in 70 of 311 infants in the phenobarbital group (23 percent) and 64 of 279 in the placebo group (23 percent; risk ratio, 1.0; 95 percent confidence interval, 0.8 to 1.4).Antenatal administration of phenobarbital does not decrease the risk of intracranial hemorrhage or early death in preterm infants.

    View details for Web of Science ID A1997XQ49900005

    View details for PubMedID 9250849

  • Carbon monoxide and bilirubin production in neonates Japan-Society-for-Premature-and-Newborn-Medicine Stevenson, D. K., Vreman, H. J. AMER ACAD PEDIATRICS. 1997: 252–54

    View details for Web of Science ID A1997XP05000015

    View details for PubMedID 9240808

  • Vitamin A to prevent bronchopulmonary dysplasia in very-low-birth-weight infants: Has the dose been too low? EARLY HUMAN DEVELOPMENT Kennedy, K. A., Stoll, B. J., Ehrenkranz, R. A., Oh, W., Wright, L. L., Stevenson, D. K., Lemons, J. A., Sowell, A., Mele, L., TYSON, J. E., Verter, J. 1997; 49 (1): 19-31

    Abstract

    Inconsistent effects of vitamin A supplementation on prevention of bronchopulmonary dysplasia have been reported. Meta-analysis of these reports resulted in a relative risk of 0.69-1.02 for death or bronchopulmonary dysplasia associated with vitamin A supplementation. Effective dosage regimens or serum retinol concentrations have not been determined in previous reports. The purpose of this pilot study was to define a vitamin A regimen that produces serum retinol concentrations of 25-55 micrograms/dl.In this three-phase study, 91 infants (mean birth weight 799-864 g) were enrolled. Vitamin A was administered three times/week for 4 weeks at an average daily dose of 986-2143 IU/day. Physical examinations were performed and serum retinol specimens were collected weekly to assess clinical signs of toxicity.The majority of serum retinol concentrations remained < 25 micrograms/dl until an intramuscular vitamin A dose of 5000 IU/dose three times/week was used. No clinical signs of toxicity were associated with the higher dosage and higher serum concentrations of vitamin A.A large clinical trial of vitamin A supplementation with 5000 IU/dose three times/week (25-114% more than the dose used in the three published clinical trials) is needed to assess whether vitamin A supplementation safely reduces the risk of bronchopulmonary dysplasia in very-low-birth-weight infants.

    View details for Web of Science ID A1997XC43800003

    View details for PubMedID 9179535

  • Carbon monoxide formation in the guinea pig hippocampus: Ontogeny and effect of in vitro ethanol exposure DEVELOPMENTAL BRAIN RESEARCH Cook, M. N., Marks, G. S., Vreman, H. J., McLaughlin, B. E., Nakatsu, K., Stevenson, D. K., Brien, J. F. 1997; 101 (1-2): 283-286

    Abstract

    Carbon monoxide (CO) is considered to be a novel neuronal messenger in the brain, similar to nitric oxide. The ontogeny of CO formation in transverse hippocampal slices of the guinea pig was elucidated at selected prenatal and postnatal ages, and the effect of in vitro ethanol exposure on hippocampal CO formation was determined. There was a higher rate of hippocampal CO formation in the fetus at gestational day (GD) 50 and GD 62 (term, about GD 68) compared with the adult. In vitro ethanol exposure (50 and 100 mM) decreased hippocampal CO formation in the GD 62 fetus, which was prevented by incubation with 500 microM L-glutamate.

    View details for Web of Science ID A1997XP15200030

    View details for PubMedID 9263603

  • Heme oxygenase activity and immunohistochemical localization in bovine pulmonary artery and vein JOURNAL OF CARDIOVASCULAR PHARMACOLOGY Marks, G. S., McLaughlin, B. E., Vreman, H. J., Stevenson, D. K., Nakatsu, K., Brien, J. F., Pang, S. C. 1997; 30 (1): 1-6

    Abstract

    Recent studies suggest that carbon monoxide (CO) derived from heme oxygenase (HO)-catalyzed metabolism of heme plays a role in the regulation of cell function and communication. In blood vessels, CO may regulate vascular smooth-muscle tone through the activation of soluble guanylyl cyclase, in a manner similar to that of nitric oxide. The objective of this study was to determine the relation between HO enzymatic activity and localization of HO protein in bovine pulmonary blood vessels. HO enzymatic activity was determined by quantitating the rate of CO formation in the microsomal fraction of homogenates of bovine pulmonary artery (BPA) and vein (BPV). HO protein was localized by immunohistochemical analysis of paraformaldehyde-fixed tissue by using polyclonal antibodies to inducible HO (HO-1) and noninducible HO (HO-2). HO enzymatic activity was measured in BPA and BPV, which correlated with the presence of HO protein. In BPA, HO enzymatic activity was found in the adventitia and medial layer; HO protein was localized in the nerves and vasa vasorum of the adventitia and was found throughout the smooth-muscle cells in the medial layer. The data clearly demonstrate the presence of HO enzymatic activity for the formation of CO in blood vessels that contain HO protein.

    View details for Web of Science ID A1997YK70100001

    View details for PubMedID 9268214

  • Imaging - Tissue optics SCIENCE Benaron, D. A., Cheong, W. F., Stevenson, D. K. 1997; 276 (5321): 2002-2003

    View details for Web of Science ID A1997XG74800051

    View details for PubMedID 9221510

  • Development of jaundice in Korean neonates after Cesarean section ACTA PAEDIATRICA JAPONICA Lee, C. S., Vreman, H. J., Choi, J. H., Yun, C. K., Stevenson, D. K. 1997; 39 (3): 309-311

    Abstract

    The aim of the project was to determine the physiologic mechanisms of later- and higher-peak transitional plasma bilirubin levels in Korean infants. Blood carboxyhemoglobin, corrected for inhaled CO (COHbc), as an index of bilirubin production, and plasma total bilirubin levels in 40 healthy term Korean infants delivered by Cesarean section were measured throughout the first week of life. The COHbc levels were significantly higher in the Korean neonates than in previously studied Caucasian neonates. Moreover, COHbc levels decreased by 28% during the first 7 days of life from 0.85 +/- 0.20 to 0.61 +/- 0.34% (P < 0.025). This pattern parallels a 15% decrease in total hemoglobin from 181 +/- 23 to 154 +/- 53 g/L (P < 0.05). In contrast, plasma bilirubin concentrations more than doubled from 80 +/- 32 to 172 +/- 48 mumol/L (4.7 +/- 1.8 to 10.0 +/- 2.8 mg/dL; P < 0.001), remaining unchanged between days 4 and 7. Both increased production and decreased elimination of bilirubin contribute to physiologic jaundice in Korean infants.

    View details for Web of Science ID A1997XM62300003

    View details for PubMedID 9241890

  • Hypoxia-ischemia, but not hypoxia alone, induces the expression of heme oxygenase-1 (HSP32) in newborn rat brain JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM Bergeron, M., Ferriero, D. M., Vreman, H. J., Stevenson, D. K., Sharp, F. R. 1997; 17 (6): 647-658

    Abstract

    Heme oxygenase (HO) is the rate-limiting enzyme in the degradation of heme to produce bile pigments and carbon monoxide. The HO-1 isozyme is induced by a variety of agents such as heat, heme, and hydrogen peroxide. Evidence suggests that the bile pigments serve as antioxidants in cells with compromised defense mechanisms. Because hypoxia-ischemia (HI) increases the level of oxygen free radicals, the induction of HO-1 expression in the brain during ischemia could modulate the response to oxidative stress. To study the possible involvement of HO-1 in neonatal hypoxia-induced ischemic tolerance, we examined the brains of newborn rat pups exposed to 8% O2 (for 2.5 to 3 hours), and the brain of chronically hypoxic rat pups with congenital cardiac defects (Wistar Kyoto; WKY/ NCr). Heme oxygenase-1 immunostaining did not change after either acute or chronic hypoxia, suggesting that HO-1 is not a good candidate for explaining hypoxia preconditioning in newborn rat brain. To study the role of HO-1 in neonatal HI, 1-week-old rats were subjected to right carotid coagulation and exposure to 8% O2/92% N2 for 2.5 hours. Whereas HO enzymatic activity was unchanged in ipsilateral cortex and subcortical regions compared with the contralateral hemisphere or control brains, immunocytochemistry and Western blot analysis showed increased HO-1 staining in ipsilateral cortex, hippocampus, and striatum at 12 to 24 hours up to 7 days after HI. Double fluorescence immunostaining showed that HO-1 was expressed mostly in ED-1 positive macrophages. Because activated brain macrophages have been associated with the release of several cytotoxic molecules, the presence of HO-1 positive brain macrophages may determine the tissue vulnerability after HI injury.

    View details for Web of Science ID A1997XL36800006

    View details for PubMedID 9236721

  • Rhesus isoimmunization: Increased hemolysis during early infancy PEDIATRIC RESEARCH Hayde, M., Widness, J. A., Pollak, A., KohlhauserVollmuth, C., Vreman, H. J., Stevenson, D. K. 1997; 41 (5): 716-721

    Abstract

    The objective of the present study was to determine whether whole blood carboxyhemoglobin (COHb) and plasma bilirubin, two indicators of hemolysis, are elevated in infants with severe Rh isoimmune hemolytic disease during the first months of life. Beginning at 2 wk of age and continuing monthly for 3 mo, serial blood samples were obtained for COHb, plasma bilirubin, Hb, reticulocyte count, plasma erythropoietin, plasma enzymes, and plasma iron. Because control infants (n = 13) and infants with ABO hemolytic disease (n = 5) did not differ from one another in any of the study parameters, these two groups were combined and compared with infants with the Rh isoimmunization. Infants with severe Rh isoimmune hemolytic disease (n = 13) were found to have significantly lower Hb and significantly higher bilirubin, the COHb fraction divided by the Hb concentration (COHb/Hb), and plasma erythropoietin levels at 2 and 6 wk of age, and reticulocyte counts at 6 wk. The remaining parameters were not different between the control-ABO group and Rh-isoimmune group at any of the study intervals. The study's two primary indicators of hemolysis, plasma bilirubin and COHb/Hb, were significantly correlated with one another in the Rh-immunized group (r = 0.66, p < 0.0001), but not in the combined control-ABO group. Serial Rh antibody concentrations measured in the serum of four neonates with Rh isoimmunization demonstrated a mean half-life of 14.3 d. We speculate that, among infants with severe Rh isoimmune hemolytic disease, elevated total bilirubin levels and COHb/Hb ratios identified in the early weeks of life indicate continuing hemolysis due to persistence of maternal Rh antibodies.

    View details for Web of Science ID A1997WV66300018

    View details for PubMedID 9128296

  • Neonatal severity of illness scoring systems: A comparison CLINICAL PEDIATRICS Fleisher, B. E., Murthy, L., Lee, S., Constantinou, J. C., Benitz, W. E., Stevenson, D. K. 1997; 36 (4): 223-227

    Abstract

    Several different scoring systems have been developed to predict neonatal morbidity and mortality. In this investigation we compared the utility of four severity of illness scoring systems (SISS) as predictors of days on ventilatory (DOV), length of hospital stay (LOS), and mortality in very-low-birth weight (VLBW) premature infants who required mechanical ventilation. The SISS assessed were the Score for Neonatal Acute Physiology (SNAP); the Score for Neonatal Acute Physiology-Perinatal Extension (SNAP + PE); Clinical Risk Index for Babies (CRIB), and the Sinkin Score at 12 hours (SS12). Results revealed significant correlations among the SS12, SNAP, SNAP + PE, CRIB, birth weight (BW), DOV, and LOS. However, none of the systems we assessed offered striking advantage over BW in a VLBW ventilated group.

    View details for Web of Science ID A1997WU89500007

    View details for PubMedID 9114994

  • The value of neurophysiologic approaches in the anticipation and evaluation of neonatal hypoglycemia. Acta paediatrica Japonica; Overseas edition Halamek, L. P., Benaron, D. A., Stevenson, D. K. 1997; 39: S33-43

    Abstract

    The association of low blood glucose with central nervous system (CNS) injury was first described in 1937 by Hartmann and Jaudon. In the early 60 years since publication of these observations the effects of hypoglycemia upon the brain remain poorly understood. Technology capable of accurately determining plasma glucose concentrations has been developed. Investigators have sought to establish critical values below which glucose levels should not be allowed to fall. Despite these efforts the definitive level of glucose capable of producing brain injury in any particular patient remains unknown. Glucose homeostasis within the neonatal CNS represents a dynamic process consisting of many interrelated variables including gestational and chronologic age, genotype, relative health, blood flow, metabolic rate and availability of other suitable substrates. New technique for assessing the glucose delivery: consumption ratio and directly monitoring the cellular consequences of glucose deprivation within discrete regions of the brain will help to answer the question 'How long is too low and how long is too long?'

    View details for PubMedID 9200877

  • Heme oxygenase activity and acute and chronic ethanol exposure in the hippocampus, frontal cerebral cortex, and cerebellum of the near-term fetal guinea pig ALCOHOL Cook, M. N., Marks, G. S., Vreman, H. J., Nakatsu, K., Stevenson, D. K., Brien, J. F. 1997; 14 (2): 117-124

    Abstract

    Heme oxygenase (HO) catalyzes the oxidation of heme to produce carbon monoxide, which is considered to be a novel neuronal messenger in the brain and may play a role in neuronal development. The objective of this study was to determine the effects of in vitro, acute in vivo, and chronic in vivo ethanol exposure on HO activity in the hippocampus, frontal cerebral cortex, and cerebellum of the near-term fetal guinea pig. HO activity was determined using a gas chromatographic method to quantitate CO formation in the microsomal fraction of the homogenate of each selected brain region, incubated with saturating concentrations of heme, NADPH, and O2. Fetal body, brain, hippocampal, and cerebellar weights were recorded. In vitro ethanol exposure (25-100 mM) did not affect hippocampal, cerebral cortical, or cerebellar HO activity of the fetal guinea pig at gestational day (GD) 62 (term, about GD 68). Acute maternal oral administration of 4 g ethanol/kg maternal body weight at GD 62 did not affect HO activity in these three fetal brain areas compared with control fetuses (maternal administration of isocaloric sucrose or water). For chronic daily maternal oral administration of 4 g ethanol/kg maternal body weight throughout gestation, fetal body, brain, hippocampal, and cerebellar weights were decreased at GD 62 compared with isocaloric-sucrose/pair-fed and water treatment control groups. Furthermore, isocaloric-sucrose/pair-feeding treatment decreased fetal body and brain weights compared with water treatment. Chronic in vivo ethanol exposure did not alter HO activity in the near-term fetal hippocampus, frontal cerebral cortex, or cerebellum. This is the first study of the effect of ethanol exposure on HO activity in the developing brain of any species. The data demonstrate, for ethanol CNS teratogenesis in the guinea pig manifesting as fetal brain growth restriction, there is no associated change in HO activity in the hippocampus, frontal cerebral cortex, or cerebellum.

    View details for Web of Science ID A1997WP44200003

    View details for PubMedID 9085711

  • Carbon monoxide formation in the ductus arteriosus in the lamb: Implications for the regulation of muscle tone BRITISH JOURNAL OF PHARMACOLOGY Coceani, F., Kelsey, L., Seidlitz, E., Marks, G. S., McLaughlin, B. E., Vreman, H. J., Stevenson, D. K., RABINOVITCH, M., Ackerley, C. 1997; 120 (4): 599-608

    Abstract

    1. We have previously shown that carbon monoxide (CO) potently relaxes the lamb ductus arteriosus and have ascribed this response to inhibition of a cytochrome P450-based mono-oxygenase reaction controlling the formation of endothelin-1 (ET-1). In the present study, we have examined whether CO is formed naturally in the vessel. 2. The CO-forming enzyme, haem oxygenase (HO), was identified in ductal tissue in its constitutive (HO-2) and inducible (HO-1) isoforms by Western immunoblotting and immunological staining procedures (both light and electron microscopy). HO-1 was localized to endothelial and muscle cells, while HO-2 was found only in muscle cells. Inside the muscle cells, HO-1 and HO-2 immunoreactivity was limited to the perinuclear region, and the Golgi apparatus in particular. However, upon exposure to endotoxin, HO-1 became more abundant, and both HO isoforms migrated towards the outer region of the cytoplasm close to the sarcolemma. 3. CO was formed enzymatically from added substrate (hemin, 50 microM) in the 10,000 g supernatant of the ductus and its formation was inhibited by zinc protoporphyrin IX (ZnPP, 200 microM). 4. ZnPP (10 microM) had no effect on the tone of the ductus under normal conditions (2.5 to 95% O2), but it contracted the endotoxin-treated ductus (at 2.5% O2). At the same concentration, ZnPP also tended to contract the hypoxic vessel (zero O2). 5. ZnPP (10 microM) curtailed the relaxant response of the oxygen (30%)/indomethacin (2.8 microM)-contracted ductus to bradykinin (35 nM), while it left the sodium nitroprusside (35 nM) relaxation unchanged. 6. We conclude that CO is formed in the ductus and may exert a relaxing influence when its synthesis is upregulated by an appropriate stimulus.

    View details for Web of Science ID A1997WJ00500011

    View details for PubMedID 9051297

  • The risk of carbon monoxide poisoning after prolonged laparoscopic surgery OBSTETRICS AND GYNECOLOGY Nezhat, C., Seidman, D. S., Vreman, H. J., Stevenson, D. K., Nezhat, F., Nezhat, C. 1996; 88 (5): 771-774

    Abstract

    To evaluate whether thermal energy produced by laser and bipolar electrosurgery during laparoscopic procedures significantly elevates blood carboxyhemoglobin levels.We prospectively studied 27 healthy nonsmoking patients, mean +/- standard deviation (SD) age 39.1 +/- 8.0 years (range 22-56), scheduled for laparoscopic procedures in which smoke was generated. Prolonged operative laparoscopy involved high-flow carbon dioxide insufflation, intensive evacuation of intra-abdominal smoke, and controlled hyperventilation with 50-100% oxygen. Laser and bipolar electrosurgery were used in all cases. Blood samples were drawn before and after surgery. Carboxyhemoglobin concentrations were measured using a highly accurate gas chromatography method.The mean +/- SD duration of surgery was 141 +/- 72 minutes (range 45-300). The mean +/- SD carboxyhemoglobin levels were 0.70 +/- 0.15% (range 0.44-1.20%) before surgery and 0.58 +/- 0.20% (range 0.30-1.33%) after surgery. A significant decrease (P < .001) in carboxyhemoglobin concentrations occurred during surgery (mean +/- SD, 20 +/- 11%; range 3-46%). The carboxyhemoglobin level was increased at the end of surgery in only one woman. In only one patient did the levels exceed 1% (1.33%), still well below the human threshold tolerance level of 2%. The Spearman correlation coefficient between carboxyhemoglobin concentrations and duration of surgery was r = 0.308 (P = .12).Carbon monoxide (CO) poisoning is not associated with even prolonged laparoscopic surgical procedures. This may be attributed to aggressive smoke evacuation that minimizes exposure to CO, and to active elimination of CO by ventilation with high oxygen concentrations.

    View details for Web of Science ID A1996VP61400006

    View details for PubMedID 8885911

  • Intravenous immune globulin in neonatal immune hemolytic disease: Does it reduce hemolysis? ACTA PAEDIATRICA Hammerman, C., Vreman, H. J., Kaplan, M., Stevenson, D. K. 1996; 85 (11): 1351-1353

    Abstract

    We studied the effect of intravenous immune globulin (IVIG) on hemolysis in term, hyperbilirubinemic, Coomb's positive infants utilizing measurement of carboxyhemoglobin fraction corrected for inhaled carbon monoxide (COHbc), a sensitive indicator of hemolysis. COHbc values were determined before and after IVIG infusion. In those babies who responded with a decrease in serum total bilirubin (n = 19), no exchange transfusions were required and COHbc levels decreased significantly by 24 h post-IVIG from 1.37 +/- 0.31 to 1.12 +/- 0.26% tHb (p < 0.0001). There were no corresponding decreases in COHbc levels (1.989 +/- 0.54 to 1.82 +/- 0.48% tHb; p > 0.05) among those whose serum bilirubin levels did not decrease in response in to IVIG (n = 7), and all of these infants required exchange transfusions. Furthermore, the extent of the decrease in COHbc was related to the degree of decrease in serum bilirubin levels, such that the percentage decrease of bilirubin at 24 h was directly correlated with the percentage decrease of COHbc at 24 h (p = 0.007). We conclude that IVIG, when successful, inhibits hemolysis in these infants.

    View details for Web of Science ID A1996VT95200017

    View details for PubMedID 8955465

  • Nitrovasodilator therapy for severe respiratory distress syndrome. Journal of perinatology Benitz, W. E., Rhine, W. D., Van Meurs, K. P., Stevenson, D. K. 1996; 16 (6): 443-448

    Abstract

    Improved gas exchange in infants with severe respiratory distress syndrome has been reported in association with infusion of nitroprusside and during inhalation of nitric oxide. To evaluate the association between nitrovasodilator therapy and clinical improvement in premature neonates with severe respiratory distress syndrome, we reviewed the courses of 22 infants with severe respiratory distress syndrome who were treated with sodium nitroprusside for at least 24 hours. These infants had birth weights of 2049 +/- 828 gm (range 720 to 3430 gm), gestational ages of 32.5 +/- 3.5 weeks (range 25 to 38 weeks), high ventilator settings before treatment (FIO2 of 100%, peak inspiratory pressures of 37.8 +/- 6.1 cm H2O [range 30 to 50 cm H2O], and mean airway pressures of 18.0 +/- 3.3 cm H2O [range 12.3 to 26 cm H2O]), and low pretreatment PaO2 of 49.3 +/- 9.4 mm Hg (range 27 to 69 mm Hg). Baseline oxygenation indexes were 39.4 +/- 12.1 (range 18.6 to 66.7). Nitroprusside infusion was temporally associated with increased PaO2, decreased PaCO2, and reduced oxygenation index. Potentially beneficial changes were inconsistent in infants with pulmonary interstitial emphysema and were greatest in infants treated with end-expiratory pressures of at least 4 cm H2O. These observations provide a basis for the hypothesis that nitrovasodilator therapy produces improvement in gas exchange in premature infants with severe respiratory distress syndrome.

    View details for PubMedID 8979182

  • Hepatic heme oxygenase is inducible in neonatal rats during the early postnatal period PEDIATRIC RESEARCH Tom, D. J., Rodgers, P. A., Shokoohi, V., Stevenson, D. K., Dennery, P. A. 1996; 40 (2): 288-293

    Abstract

    Heme oxygenase (HO) is the rate-limiting enzyme in the catabolism of heme to bilirubin. Cobalt chloride (CoCl2) and many other agents that generate oxidant stresses induce the HO-1 isoform. Furthermore, HO-1 has been shown to protect against oxidant stress in vitro and in vivo by mechanisms involving increased ferritin synthesis. However, little is known about the inducibility of hepatic HO-1 during the very early postnatal period, and whether HO-1 induction is associated with increased ferritin synthesis in neonates. Therefore, we studied hepatic HO-1 mRNA, HO-1 protein concentration, total HO activity, and ferritin protein levels in neonatal rats. Neonatal rats 0-5 d of age were injected with 250 mumol/kg body weight of CoCl2. 6H2O in saline or with an equal volume of saline in age-matched controls. Liver samples were collected 4 h after injection for HO-1 mRNA analysis and 20 h after injection for analysis of HO-1 protein concentration, total HO activity, and ferritin protein levels. In CoCl2-treated rats, hepatic HO-1 mRNA was 3-10 times the levels in control rats (p < 0.05), HO-1 protein concentration was 2-5 times the levels in control rats (p < 0.05), and total HO activity was higher by 20-80% than in control rats (p < 0.05). There were no differences in hepatic ferritin protein levels between CoCl2-treated neonatal rats and controls; however, in CoCl2-treated adult rats, hepatic ferritin protein levels were 1.6 times the levels in controls (p < 0.05). Thus, neonatal rats can up-regulate hepatic HO-1 mRNA, HO-1 protein concentration, and total HO activity in response to CoCl2; however, no upregulation of hepatic ferritin protein levels was observed in neonatal rats after CoCl2 administration or subsequent HO-1 induction. We speculate that neonatal rats induce hepatic HO-1 and up-regulate ferritin by different mechanisms than do adult rats.

    View details for Web of Science ID A1996UY05100016

    View details for PubMedID 8827779

  • Intravenous immune globulin in neonatal ABO isoimmunization: Factors associated with clinical efficacy BIOLOGY OF THE NEONATE Hammerman, C., Kaplan, M., Vreman, H. J., Stevenson, D. K. 1996; 70 (2): 69-74

    Abstract

    Intravenous immune globulin (IVIG) reduces jaundice in many but not all cases of neonatal isoimmunization. We sought to elucidate the type of infant most likely to benefit from IVIG administration by attempting to define pretreatment parameters associated with both clinical symptomatology and therapeutic responsiveness to IVIG.Term, healthy Coombs-positive infants were studied prospectively. IVIG was administered if, despite phototherapy, serum bilirubin reached > or = 222 mumol/l (13 mg/dl) at < or = 24 h of age and/or > or = 274 mumol/l (16 mg/dl) at > 24 h of age. Clinical data including serial serum total bilirubin levels, rate of bilirubin rise on day 1 of life, serial corrected carboxyhemoglobin levels (a sensitive indicator of hemolysis) and total hemoglobin (tHb) levels were collected.Infants were classified as IVIG responders (n = 18), those in whom total serum bilirubin levels either remained stable or decreased following IVIG administration; IVIG nonresponders (n = 5), those who developed a total serum bilirubin of > or = 2 mg/dl greater than pre-IVIG bilirubin levels within the first 24 h after IVIG administration, or nontreated, those not meeting IVIG treatment criteria (n = 13). Four of the five nonresponders proceeded to require exchange transfusion vs. none of the others (p < 0.001). Four of the five nonresponders had a pretreatment rate of bilirubin rise of > or = 1 mg/dl/h as compared with only 1 of 18 responders and none of the nontreated (p < 0.001). Pretreatment tHb levels were also different (13.2 +/- 1.3 vs. 15.5 +/- 2.3 vs. 17.7 +/- 2.4 g/dl for nonresponders vs. responders vs. nontreated infants, respectively; p < 0.005). The highest pretreatment COHbc levels were seen in the nonresponders (1.8 +/- 0.7 vs. 1.4 +/- 0.3 vs. 0.9 +/- 0.3% tHb, respectively).Our 3 groups represent a spectrum of hemolysis, ranging from severe to moderate to mild. This spectrum appears to relate not only to the severity of hemolysis, but also to the therapeutic responsiveness to IVIG. We speculate that some or all of the factors identified can be used prospectively to predict the subsequent clinical course of ABO-incompatible infants and to facilitate optimal management.

    View details for Web of Science ID A1996VD14700001

    View details for PubMedID 8864425

  • Early-onset sepsis in very low birth weight neonates. A report from the National Institute of Child Health and Human Development Neonatal Research Network JOURNAL OF PEDIATRICS Stoll, B. J., Gordon, T., Korones, S. B., Shankaran, S., TYSON, J. E., Bauer, C. R., Fanaroff, A. A., Lemons, J. A., Donovan, E. F., Oh, W., Stevenson, D. K., Ehrenkranz, R. A., Papile, L. A., Verter, J., Wright, L. L. 1996; 129 (1): 72-80

    Abstract

    Early-onset sepsis (occurring within 72 hours of birth) is included in the differential diagnosis of most very low birth weight (VLBW) neonates. To determine the current incidence of early-onset sepsis, risk factors for disease, and the impact of early-onset sepsis on subsequent hospital course, we studied a cohort of 7861 VLBW neonates (401 to 1500 gm) admitted to the 12 National Institute of Child Health and Human Development (NICHD) Neonatal Research Network centers during a 32-month period (1991-1993).The NICHD Neonatal Research Network maintains a prospectively collected registry on all VLBW neonates born or cared for at participating centers. Data from this registry were analyzed retrospectively.Blood culture-proven early-onset sepsis was uncommon, occurring in only 1.9% of VLBW neonates. Group B streptococcus was the most frequent pathogen associated with early-onset sepsis (31%), followed by Escherichia coli (16%) and Haemophilus influenzae (12%). Decreasing gestational age was associated with increased rates of infection. Antibiotic therapy for suspected sepsis is frequently initiated at birth in VLBW neonates. Almost half of the infants in this cohort were considered to have clinical sepsis and continued to receive antibiotics for 5 or more days, despite a negative blood culture result in 98% of cases. These findings underscore the difficulty of ruling out sepsis in the symptomatic immature neonate and the special concern for culture-negative clinical sepsis in the face of maternal antibiotic use. Neonates with early-onset sepsis were significantly more likely to have subsequent comorbidities, including severe intraventricular hemorrhage, patent ductus arteriosus, and prolonged assisted ventilation. Although 26% of VLBW neonates with early-onset sepsis died, only 4% of the 950 deaths that occurred in the first 72 hours of life were attributed to infection. For those infants discharged alive, early-onset sepsis was associated with a significantly prolonged hospital stay (86 vs 69 days; p <0.02).Early-onset sepsis remains an important but uncommon problem among VLBW preterm infants. Improved diagnostic strategies are needed to enable the clinician to distinguish between the infected and the uninfected VLBW neonate with symptoms and to target continued antibiotic therapy to those who are truly infected.

    View details for Web of Science ID A1996UY27200011

    View details for PubMedID 8757565

  • Late-onset sepsis in very low birth weight neonates: A report from the National Institute of Child Health and Human Development Neonatal Research Network JOURNAL OF PEDIATRICS Stoll, B. J., Gordon, T., Korones, S. B., Shankaran, S., TYSON, J. E., Bauer, C. R., Fanaroff, A. A., Lemons, J. A., Donovan, E. F., Oh, W., Stevenson, D. K., Ehrenkranz, R. A., Papile, L. A., Verter, J., Wright, L. L. 1996; 129 (1): 63-71

    Abstract

    Late-onset sepsis (occurring after 3 days of age) is an important problem in very low birth weight (VLBW) infants. To determine the current incidence of late-onset sepsis, risk factors for disease, and the impact of late-onset sepsis on subsequent hospital course, we evaluated a cohort of 7861 VLBW (401 to 1500 gm) neonates admitted to the 12 National Institute of Child Health and Human Development (NICHD) Neonatal Research Network centers during a 32-month period (1991 to 1993).The NICHD Neonatal Research Network maintains a prospectively collected registry of all VLBW neonates cared for at participating centers. Data from this registry were analyzed retrospectively.Of 6911 infants who survived beyond 3 days, 1696 (25%) had one or more episodes of blood culture-proven sepsis. The vast majority of infection (73%) were caused by gram-positive organisms, with coagulase-negative staphylococci accounting for 55% of all infections. Rate of infection was inversely related to birth weight and gestational age. Complications of prematurity associated with an increased rate of infection included intubation, respiratory distress syndrome, prolonged ventilation, bronchopulmonary dysplasia, patent ductus arteriosus, severe intraventricular hemorrhage, and necrotizing enterocolitis. Among infants with bronchopulmonary dysplasia, those with late-onset sepsis had a significantly longer duration of mechanical ventilation (45 vs 33 days; p <0.01). Late-onset sepsis prolonged hospital stay: the mean number of days in the hospital for VLBW neonates with and without late-onset sepsis was 86 and 61 days, respectively (p <0.001). Even after adjustment for other complications of prematurity, including intraventricular hemorrhage, necrotizing enterocolitis, and bronchopulmonary dysplasia, infants with late-onset sepsis had a significantly longer hospitalization (p <0.001). Moreover, neonates in whom late-onset sepsis developed were significantly more likely to die than those who were uninfected (17% vs 7%; p <0.000 1), especially if they were infected with gram-negative organisms (40%) or fungi (28%). Deaths attributed to infection increased with increasing chronologic age. Whereas only 4% of deaths in the first 3 days of life were attributed to infection, 45% of deaths after 2 weeks were related to infection.Late-onset sepsis is a frequent and important problem among VLBW preterm infants. Successful strategies to decrease late-onset sepsis should decrease VLBW mortality rates, shorten hospital stay, and reduce costs.

    View details for Web of Science ID A1996UY27200010

    View details for PubMedID 8757564

  • Interlaboratory variability of bilirubin measurements CLINICAL CHEMISTRY Vreman, H. J., Verter, J., Oh, W., Fanaroff, A. A., Wright, L. L., Lemons, J. A., Shankaran, S., TYSON, J. E., Korones, S. B., Bauer, C. R., Stoll, B. J., Papile, L. A., Donovan, E. F., Ehrenkranz, R. A., Stevenson, D. K. 1996; 42 (6): 869-873

    Abstract

    During an 8-month study, 14 laboratories used automated analytical systems to measure total bilirubin concentrations in lyophilized bovine specimens containing 38, 169, and 253 micromol/L bilirubin (2.2, 9.9, and 14.8 mg/dL, respectively). The measured mean +/- SD (n, range) were: 39 +/- 7 micromol/L (n = 90, 31-53) [2.3 +/- 0.4 mg/dL (1.8-3.1)]; 176 +/- 29 micromol/L (n = 89, 146-222) [10.3 +/- 1.7 mg/dL (8.5-13.0)]; and 260 +/- 43 micromol/L (n = 103, 208-316) [15.2 +/- 2.5 mg/dL (12.1-18.5)]. In comparison with target values, measurements were consistently lower at 4, higher at 6, and within +/- 4% at 4 laboratories for each of the three concentrations. The measured values for each concentration remained fairly constant during the study at each laboratory. We conclude that bilirubin measurements differed significantly from the established target values at most of the participating laboratories.

    View details for Web of Science ID A1996UQ78300007

    View details for PubMedID 8665677

  • Contribution of haemolysis to jaundice in Sephardic Jewish glucose-6-phosphate dehydrogenase deficient neonates BRITISH JOURNAL OF HAEMATOLOGY Kaplan, M., Vreman, H. J., Hammerman, C., Leiter, C., Abramov, A., Stevenson, D. K. 1996; 93 (4): 822-827

    Abstract

    We determined the contribution of haemolysis to the development of hyperbilirubinaemia in glucose-6-phosphate dehydrogenase (G-6-PD) deficient neonates and G-6-PD normal controls. Blood carboxyhaemoglobin (COHb), sampled on the third day of life, was measured by gas chromatography, corrected for inhaled carbon monoxide (COHbC), and expressed as a percentage of total haemoglobin concentration (Hb). Serum bilirubin was tested as clinically necessary. 37 non-jaundiced (peak serum total bilirubin (PSTB) < or = 255 mumol/l) and 20 jaundiced (PSTB > or = 257 mumol/l) G-6-PD-deficient neonates were compared to 31 non-jaundiced and 24 jaundiced controls with comparable PSTB values, respectively. COHbC values for the entire G-6-PD deficient group were higher than in the controls (0.75 +/- 0.17% v 0.62 +/- 0.19%, P < 0.001). COHbC and PSTB values did not correlate in the G-6-PD-deficient group (r = 0.15, P > 0.05) but did in the controls (r = 0.58, P < 0.001). COHbC values were increased to a similar extent in the G-6-PD-deficient, non-jaundiced (0.72 +/- 0.16%), the G-6-PD-deficient, jaundiced (0.80 +/- 0.19%) and the control, jaundiced (0.75 +/- 0.18%) subgroups, compared to the control, non-jaundiced subgroup (0.53 +/- 0.13%) (P < 0.05). Although present in G-6-PD deficient neonates, increased haemolysis was not directly related to the PSTB.

    View details for Web of Science ID A1996UU82400013

    View details for PubMedID 8703811

  • Duration of action and tissue distribution of zinc protoporphyrin in neonatal rats PEDIATRIC RESEARCH Rodgers, P. A., Seidman, D. S., Wei, P. L., Dennery, P. A., Stevenson, D. K. 1996; 39 (6): 1041-1049

    Abstract

    Zinc protoporphyrin IX (ZnPP) has been shown to inhibit heme oxygenase (HO) activity effectively in vivo and has potential in the treatment of neonatal jaundice. Because this is a transitional or temporary condition lasting only several days, an effective chemopreventive agent with a relatively short duration of action would be desirable for the treatment of severe neonatal jaundice. To determine the effective duration of action of ZnPP, we administered either 40 nmol/g of body weight ZnPP or 5 microL/g body weight diluent intraperitoneally to neonatal rats 24-36 h after birth. Between 0 and 21 d after ZnPP dosing, the duration of action was investigated through measurements of serum bilirubin and hepatic and splenic HO inhibition, which were correlated to measurements of ZnPP distribution. Significant (p < 0.05) hepatic HO inhibition, ranging from 27 to 51%, was observed in the liver between 1 and 4 d after dosing, concurrent with a 23-28% reduction in serum bilirubin levels, and was associated with ZnPP tissue concentrations of 27-38 nmol/g. Splenic HO was not inhibited measurably by the much lower concentrations of ZnPP found in the spleen (2.8-20.1 nmol/g) between 0 and 21 d after dosing. Furthermore, HO isoform 1 (HO-1) induction was apparently not a confounding factor in the duration of action of ZnPP, because the modest increases in HO-1 protein levels were not sustained longer than 24 h after ZnPP administration. Our findings demonstrated that the duration of action of ZnPP in neonatal rats is less than 1 wk. The reduction in serum bilirubin levels, the short duration of action and minimal confounding effects suggest that ZnPP may be an effective chemopreventive agent for the treatment of severe neonatal jaundice.

    View details for Web of Science ID A1996UN55500018

    View details for PubMedID 8725267

  • A model for detecting early metabolic changes in neonatal asphyxia by 1H-MRS JOURNAL OF MAGNETIC RESONANCE IMAGING Nakai, T., Rhine, W. D., Enzmann, D. R., Stevenson, D. K., Spielman, D. M. 1996; 6 (3): 445-452

    Abstract

    In newborn rabbits, the early cerebral metabolic changes caused by hypoxic-ischemic (H-I) insult was examined by using volume localized 1H-MRS (STEAM). Partial ischemia was caused by unilateral carotid artery ligation, and hypoxia was induced by 10% oxygen inspiration for 150 minutes. Lactate immediately increased after hypoxia induction and almost disappeared 120 to 150 minutes after removal of hypoxia in both H-I and hypoxia-only experiments. Lactate production correlated well with decrease of the blood oxygen saturation. More lactate was produced on ischemic side 50 minutes post-hypoxia induction in H-I study. Ischemia alone did not cause any significant lactate production. Lactate caused by hypoxia can be dynamically monitored by localized 1H-MRS. Existence of regional ischemia can induce greater anaerobic glycolysis and may affect the pattern of brain injury under hypoxia. 1H-MRS is a sensitive tool to detect the acute metabolic change caused by H-I insult.

    View details for Web of Science ID A1996UM58400004

    View details for PubMedID 8724409

  • Evaluation of neonatal jaundice: monitoring the transition in bilirubin metabolism. Journal of perinatology Stevenson, D. K., Vreman, H. J., Benaron, D. A. 1996; 16 (3): S62-7

    View details for PubMedID 8817441

  • Neonatal intracranial ischemia and hemorrhage: Diagnosis with US, CT, and MR imaging RADIOLOGY Blankenberg, F. G., Norbash, A. M., Lane, B., Stevenson, D. K., Bracci, P. M., Enzmann, D. R. 1996; 199 (1): 253-259

    Abstract

    To assess the usefulness of ultrasound (US), computed tomography (CT), and magnetic resonance (MR) imaging in the detection of intracranial hemorrhage and ischemia in newborns.Seventy-six neonates who underwent US within 72 hours of CT or MR examination were studied. Four observers rated images for the presence of germinal matrix hemorrhage (GMH), intraventricular hemorrhage (IPH), extraaxial hemorrhage, and hypoxic-ischemic encephalopathy.In 39% of neonates, CT and MR imaging provided greater confidence than US for the diagnosis or exlusion of neonatal ischemia or hemorrhage. Kappa analysis revealed significantly better interobserver agreement with CT than with US for the detection of GMH, IVH, IPH, and cortical infarction or ischemia (P <.005). Interobserver agreement was significantly better with MR imaging than with US for the detection of GMH, IVH, and cortical infarction or ischemia (P < .005).Sensitivity and interobserver agreement are better with MR imaging and CT than with US for the detection of neonatal cortical ischemia or infarction.

    View details for Web of Science ID A1996UB58400040

    View details for PubMedID 8633155

  • Ontogeny of heme oxygenase activity in the hippocampus, frontal cerebral cortex, and cerebellum of the guinea pig DEVELOPMENTAL BRAIN RESEARCH Cook, M. N., Marks, G. S., Vreman, H. J., Nakatsu, K., Stevenson, D. K., Brien, J. F. 1996; 92 (1): 18-23

    Abstract

    Heme oxygenase (HO) catalyzes the oxidation of heme to produce carbon monoxide (CO), biliverdin and iron. CO is considered to function as a novel neuronal messenger in the brain analogous to nitric oxide. The ontogeny of microsomal HO activity in the hippocampus, frontal cerebral cortex, and cerebellum of the immature fetal, mature fetal and adult guinea pig was determined using an optimized assay which quantitated heme-derived CO formation by a gas chromatographic method. There was a distinct developmental profile of HO activity that was similar for all three brain regions. In particular, HO activity was maximal in the mature fetus compared with the immature fetus and the adult. These data demonstrate that HO activity is developmentally regulated and that there is similar ontogeny of HO activity in the hippocampus, frontal cerebral cortex, and cerebellum of the guinea pig.

    View details for Web of Science ID A1996UG30200003

    View details for PubMedID 8861718

  • Characterization of porphyrin heme oxygenase inhibitors CANADIAN JOURNAL OF PHYSIOLOGY AND PHARMACOLOGY Vreman, H. J., Cipkala, D. A., Stevenson, D. K. 1996; 74 (3): 278-285

    Abstract

    Synthetic metalloporphyrin derivatives of heme have been identified as competitive inhibitors of heme oxygenase, the rate-limiting enzyme in the heme degradation pathway that produces equimolar quantities of carbon monoxide, biliverdin, and bilirubin. Therefore, administration of metalloporphyrin has been proposed as one means to prevent excessive hyperbilirubinemia in human neonates. Tin proto- and meso-porphyrin have been studied for the suppression of neonatal jaundice. However, these compounds are also photosensitizers. This property may limi