Suzan Carmichael

All Publications

• Opioid Prescription and Persistent Opioid Use After Ectopic Pregnancy. Obstetrics and gynecology Wall-Wieler, E., Shover, C. L., Hah, J. M., Carmichael, S. L., Butwick, A. J. 2020

  Abstract

  OBJECTIVE: To evaluate outpatient opioid dispensing and the incidence of persistent opioid use after ectopic pregnancy.METHODS: This cohort study used U.S. employer-based claims data to identify opioid-naive individuals experiencing ectopic pregnancy from November 1, 2008, to September 30, 2015. Treatment was categorized as surgical, medical (using methotrexate), or unknown. New opioid prescriptions were defined as prescriptions filled from 1 week before to 1 week after an ectopic pregnancy treatment. For those who filled a new opioid prescription, we calculated the incidence and risk factors for persistent opioid use, defined as having filled at least one opioid prescription both from 8 to 90 days after treatment and from 91 to 365 days after treatment.RESULTS: Of the 15,338 individuals in our study, 7,047 (45.9%, 95% CI 45.2-46.7%) filled an opioid prescription at the time of treatment, of whom 4.1% (95% CI 3.6-4.6%) developed persistent opioid use. The risk of persistent opioid use was lower among those who had surgical compared with medical treatment (3.7% and 6.8%, respectively; relative risk [RR] 0.54, 95% CI 0.38-0.77). Variables most strongly associated with persistent opioid use were a history of benzodiazepine use (RR 1.99; 95% CI 1.43-2.78; adjusted relative risk [aRR] 1.57, 95% CI 1.11-2.22), antidepressant use (RR 1.91, 95% CI 1.45-2.53; aRR 1.53, 95% CI 1.08-2.18), and a pre-existing pain disorder (RR 1.58, 95% CI 1.26-1.99; aRR 1.47, 95% CI 1.16-1.85) in the year before treatment.CONCLUSION: New opioid use is common after an ectopic pregnancy; approximately 4% of those with new opioid use develop persistent opioid use, with the rate higher in those treated medically. New pain-management guidelines need to be developed to prevent persistent opioid use after ectopic pregnancy.

  View details for DOI 10.1097/AOG.0000000000004015

  View details for PubMedID 32769649

• An Expanded Obstetric Comorbidity Scoring System for Predicting Severe Maternal Morbidity. Obstetrics and gynecology Leonard, S. A., Kennedy, C. J., Carmichael, S. L., Lyell, D. J., Main, E. K. 2020

  Abstract

  OBJECTIVE: To develop and validate an expanded obstetric comorbidity score for predicting severe maternal morbidity that can be applied consistently across contemporary U.S. patient discharge data sets.METHODS: Discharge data from birth hospitalizations in California during 2016-2017 were used to develop the score. The outcomes were severe maternal morbidity, defined using the Centers for Disease Control and Prevention index, and nontransfusion severe maternal morbidity (excluding cases where transfusion was the only indicator of severe maternal morbidity). We selected 27 potential patient-level risk factors for severe maternal morbidity, identified using International Classification of Diseases, Tenth Revision, Clinical Modification diagnosis codes. We used a targeted causal inference approach integrated with machine learning to rank the risk factors based on adjusted risk ratios (aRRs). We used these results to assign scores to each comorbidity, which sum to a single numeric score. We validated the score in California and national data sets and compared the performance to that of a previously developed obstetric comorbidity index.RESULTS: Among 919,546 births, the rates of severe maternal morbidity and nontransfusion severe maternal morbidity were 168 and 74 per 10,000 births, respectively. The highest risk comorbidity was placenta accreta spectrum (aRR of 30.5 for severe maternal morbidity and 54.7 for nontransfusion severe maternal morbidity) and the lowest was gestational diabetes mellitus (aRR of 1.06 for severe maternal morbidity and 1.12 for nontransfusion severe maternal morbidity). Normalized scores based on the aRR were developed for each comorbidity, which ranged from 1 to 59 points for severe maternal morbidity and from 1 to 36 points for nontransfusion severe maternal morbidity. The overall performance of the expanded comorbidity scores was good (C-statistics were 0.78 for severe maternal morbidity and 0.84 for nontransfusion severe maternal morbidity in California data and 0.82 and 0.87, respectively, in national data) and improved on prior comorbidity indices developed for obstetric populations. Calibration plots showed good concordance between predicted and actual risks of the outcomes.CONCLUSION: We developed and validated an expanded obstetric comorbidity score to improve comparisons of severe maternal morbidity rates across patient populations with different comorbidity case mixes.

  View details for DOI 10.1097/AOG.0000000000004022

  View details for PubMedID 32769656

• Congenital diaphragmatic hernia and maternal dietary nutrient pathways and diet quality. Birth defects research Carmichael, S. L., Ma, C., Witte, J. S., Yang, W., Rasmussen, S. A., Brunelli, L., Nestoridi, E., Shaw, G. M., Feldkamp, M. L., National Birth Defects Prevention Study 2020

  Abstract

  INTRODUCTION: We examined the association of congenital diaphragmatic hernia (CDH) with maternal dietary intake, using semi-Bayes hierarchical models and principal components analysis to consider intake of nutrients that contribute to one-carbon metabolism and oxidative stress pathways, and a diet quality index.METHODS: We included data on 825 cases and 11,108 nonmalformed controls born from 1997-2011 whose mother participated in the National Birth Defects Prevention Study (NBDPS), a multisite, population-based case-control study. Exposure data were from maternal telephone interviews, which included a food frequency questionnaire. Adjusted odds ratios (aOR) and 95% confidence intervals (CI) were generated from logistic regression models that included nutritional factors as continuous variables and were adjusted for maternal energy intake, race-ethnicity, parity, and vitamin supplement intake.RESULTS: In the semi-Bayes hierarchical model that included all nutrients and confounders, riboflavin was the only nutrient for which the 95% CI excluded 1.0; the aOR for a 1SD increase was 0.83. The aORs were 0.79 (95% CI 0.69-0.91) for the one-carbon metabolism pathway score, 0.90 (95% CI 0.80-1.01) for oxidative stress, and 0.85 (95% CI 0.77-0.93) for diet quality (the aORs correspond to a 1 SD increase).CONCLUSIONS: The findings from this study provide some support for the hypothesis that better prepregnancy nutrition is associated with reduced risk for CDH. These results provide etiologic clues but should be interpreted with caution given the novelty of the investigation.

  View details for DOI 10.1002/bdr2.1770

  View details for PubMedID 32744808

• Asthma Medication Use and Risk of Birth Defects: National Birth Defects Prevention Study, 1997-2011. The journal of allergy and clinical immunology. In practice Howley, M. M., Papadopoulos, E. A., Van Bennekom, C. M., Van Zutphen, A. R., Carmichael, S. L., Munsie, J. W., Herdt, M. L., Browne, M. L., National Birth Defects Prevention Study 2020

  Abstract

  BACKGROUND: Evidence regarding associations between maternal asthma medication use and birth defects is mixed.OBJECTIVE: Using National Birth Defects Prevention Study (NBDPS) data from 1997-2011, we estimated associations between asthma medication use and 52 specific birth defects.METHODS: We compared self-reported maternal asthma medication use for 28,481 birth defect cases and 10,894 non-malformed controls. We calculated adjusted odds ratios [95% confidence intervals] to estimate the risk of birth defects associated with early pregnancy asthma medication use (the month before through the third month of pregnancy), controlling for maternal age, race/ethnicity, body mass index, smoking, folic acid-containing supplement use, and parity. We calculated risks by medication groupings: bronchodilators, anti-inflammatories, and both.RESULTS: Overall, 1,304 (5%) case and 449 (4%) control women reported early pregnancy asthma medication use. We observed an association between asthma medication use and longitudinal limb deficiency (1.81 [1.27-2.58]). Early pregnancy bronchodilator only use was associated with cleft palate (1.50 [1.11-2.02]), cleft lip (1.58 [1.12-2.23]), longitudinal limb deficiency (2.35 [1.55-3.54]), and truncus arteriosus (2.48 [1.13-5.42]). While early pregnancy anti-inflammatory only use was not associated with the birth defects studied, use of both medications was associated with biliary atresia (3.60 [1.55-8.35]) and pulmonary atresia (2.50 [1.09-5.78]).CONCLUSION: Consistent with previous NBDPS analyses, asthma medication use was not associated with most birth defects examined, but we observed modest risks for bronchodilator use and several birth defects. Our findings support maintaining adequate asthma treatment during pregnancy, as early pregnancy asthma exacerbations have been associated with adverse birth outcomes, including birth defects.

  View details for DOI 10.1016/j.jaip.2020.07.033

  View details for PubMedID 32745701

• Benzodiazepine use before conception and risk of ectopic pregnancy. Human reproduction (Oxford, England) Wall-Wieler, E., Robakis, T. K., Lyell, D. J., Masarwa, R., Platt, R. W., Carmichael, S. L. 2020

  Abstract

  STUDY QUESTION: Are women who fill a benzodiazepine prescription before conception at increased risk of ectopic pregnancy?SUMMARY ANSWER: Risk of ectopic pregnancy is 50% higher among women who fill a benzodiazepine prescription before conception.WHAT IS KNOWN ALREADY: Benzodiazepine use in pregnancy increases the risk of miscarriage, adverse birth outcomes and adverse child development outcomes.STUDY DESIGN, SIZE, DURATION: Using data from US commercial insurance claims, we performed a cohort study of 1691366 pregnancies between 1 November 2008 and 30 September 2015.PARTICIPANTS/MATERIALS, SETTING, METHODS: We identified ectopic pregnancies using diagnosis and procedure codes and used unadjusted and inverse probability of treatment (IPT)-weighted log-binomial models to calculate relative risks (RR) of ectopic pregnancy for pregnant women who did and did not fill any prescriptions for benzodiazepines in the 90days before conception. Two sub-groups of women with specific indications for benzodiazepine use were also examined-women who had a least one diagnosis for anxiety disorder and women who had at least one diagnosis of insomnia in the year before conception.MAIN RESULTS AND THE ROLE OF CHANCE: Of the 1691366 pregnancies, 1.06% filled at least two benzodiazepine prescriptions totaling at least 10days supply in the 90days before conception. Among women with a benzodiazepine prescription, there was an excess of 80 ectopic pregnancies per 10000 pregnancies, and their IPT-weighted risk of ectopic pregnancies was 1.47 (95% CI 1.32 to 1.63) times greater relative to women without benzodiazepine prescriptions before conception. The IPT-weighted RR between ectopic pregnancy and benzodiazepine use was 1.34 (95% CI 1.18 to 1.53) among women with anxiety disorder diagnoses and 1.28 (95% CI 0.99 to 1.68) among women with an insomnia diagnosis.LIMITATIONS, REASONS FOR CAUTION: We relied on outpatient prescription data to identify benzodiazepine use before conception, which could result in over- or under-estimation of actual benzodiazepine consumption. We relied on medical claim codes to identify pregnancies and conception date, which may result in misclassification of pregnancy outcomes and gestational length.WIDER IMPLICATIONS OF THE FINDINGS: This study found that women who have a benzodiazepine prescription before conception are at an increased risk of ectopic pregnancy. This information can help women, and their healthcare providers make more fully informed decisions about benzodiazepine use in their reproductive years.STUDY FUNDING/COMPETING INTEREST(S): Funding for this project was provided by a Banting Postdoctoral Fellowship and a Stanford Maternal and Child Health Research Institute Postdoctoral Award. Data access for this project was provided by the Stanford Center for Population Health Sciences Data Core. The PHS Data Core is supported by a National Institutes of Health National Center for Advancing Translational Science Clinical and Translational Science Award (UL1 TR001085) and internal Stanford funding. The authors have no competing interest.TRIAL REGISTRATION NUMBER: N/A.

  View details for DOI 10.1093/humrep/deaa082

  View details for PubMedID 32485732

• Antidepressant Use around Conception, Prepregnancy Depression, and Risk of Ectopic Pregnancy. Canadian journal of psychiatry. Revue canadienne de psychiatrie Wall-Wieler, E., Robakis, T. K., Cesta, C. E., Masarwa, R., Lyell, D. J., Liu, C., Platt, R. W., Carmichael, S. L. 2020: 706743720927829

  Abstract

  OBJECTIVE: To compare the risk of ectopic pregnancy among women with and women without antidepressant prescriptions around conception and examine whether this risk differs by prepregnancy depression status.METHODS: We conducted a cohort study of all pregnancies between November 1, 2008, and September 30, 2015, identified in the nationwide (American) IBM MarketScan Databases. At least one day's supply of antidepressants in the 3 weeks after a woman's last menstrual period defined active antidepressant use around conception. At least one depression diagnosis in the year before the last menstrual period defined prepregnancy depression. Relative risk (RR) of ectopic pregnancy was estimated using unadjusted and inverse probability of treatment (IPT)-weighted log-binomial models.RESULTS: Of the 1,703,245 pregnancies, 106,788 (6.3%) women had a prepregnancy depression diagnosis. Among women with a depression diagnosis, 40,287 (37.7%) had an active antidepressant prescription around conception; the IPT-weighted risk of ectopic pregnancy was similar among women who did and did not fill an antidepressant prescription around conception (IPT-weighted RR = 1.01; 95% CI, 0.93 to 1.10). Overall, the risk of ectopic pregnancy was higher among women who had a prepregnancy depression diagnosis than women who did not have a prepregnancy depression diagnosis (IPT-weighted RR = 1.09; 95% CI, 1.04 to 1.15).CONCLUSIONS: This study's findings suggest that women who have a prepregnancy depression diagnosis are at a slightly increased risk of ectopic pregnancy, and among women who have a prepregnancy depression diagnosis, the use of antidepressants around conception does not increase the risk of ectopic pregnancy.

  View details for DOI 10.1177/0706743720927829

  View details for PubMedID 32436752

• Treating Center Volume and Congenital Diaphragmatic Hernia Outcomes in California. The Journal of pediatrics Apfeld, J. C., Kastenberg, Z. J., Gibbons, A. T., Carmichael, S. L., Lee, H. C., Sylvester, K. G. 2020

  Abstract

  OBJECTIVE: To examined outcomes for infants born with congenital diaphragmatic hernias (CDH), according to specific treatment center volume indicators.STUDY DESIGN: A population-based retrospective cohort study was conducted involving neonatal intensive care units in California. Multivariable analysis was used to examine the outcomes of infants with CDH including mortality, total days on ventilation, and respiratory support at discharge. Significant covariables of interest included treatment center surgical and overall neonatal intensive care unit volumes.RESULTS: There were 728 infants in the overall CDH cohort, and 541 infants (74%) in the lower risk subcohort according to a severity-weighted congenital malformation score and never requiring extracorporeal membrane oxygenation. The overall cohort mortality was 28.3% (n=206), and 19.8% (n=107) for the subcohort. For the lower risk subcohort, the adjusted odds of mortality were significantly lower at treatment centers with higher CDH repair volume (OR, 0.41; 95% CI, 0.23-0.75; P=.003), ventilator days were significantly lower at centers with higher thoracic surgery volume (OR, 0.56; 9 5% CI, 0.33-0.95; P=.03), and respiratory support at discharge trended lower at centers with higher neonatal intensive care unit admission volumes (OR, 0.51; 9 5% CI, 0.26-1.02; P=.06).CONCLUSIONS: Overall and surgery-specific institutional experience significantly contribute to optimized outcomes for infants with CDH. These data and follow-on studies may help inform the ongoing debate over the optimal care setting and relevant quality indicators for newborn infants with major surgical anomalies.

  View details for DOI 10.1016/j.jpeds.2020.03.028

  View details for PubMedID 32418817

• Defining maternal obesity in studies of birth outcomes: Comparing ICD-9 codes at delivery and measures on the birth certificate. Paediatric and perinatal epidemiology Wall-Wieler, E., Abrams, B., Snowden, J. M., Carmichael, S. L. 2020

  Abstract

  BACKGROUND: Using ICD-9 codes underestimates the prevalence of obesity in adults; however, the validity of these codes in studies of pregnancy-related outcomes is not known.OBJECTIVES: To compare classification of maternal obesity based on ICD-9 codes in hospital discharge records versus data from birth certificates in the same women, examine predictors of agreement, and assess how associations between obesity and two birth outcomes differ by source of weight data.METHODS: This population-based study included 2329145 California births between 2007 and 2012. We compared data on obesity from childbirth hospital discharge records (ICD-9 codes for obesity) and birth certificates (pre-pregnancy body mass index (BMI) calculated from weight and height) and identified predictors of agreement between the two sources. Logistic regression models assessed whether the two definitions of obesity resulted in different estimates of the associations of obesity with caesarean birth and large-for-gestational age.RESULTS: Overall, 464754 women (20.0%) had obesity based on their pre-pregnancy BMI while only 100002 (4.3%) had an obesity-related ICD-9 code. The sensitivity of ICD-9-based obesity was low at 16.2%; however, obesity codes were highly specific at 98.7%, with a negative predictive value of 82.5% and a positive predictive value of 75.2%. Among women with obesity identified by the birth certificate, those with pre-pregnancy and pregnancy-related complications (eg diabetes and hypertension) were more likely to have an obesity-related diagnosis in their delivery hospital discharge record. Using ICD-9 codes overestimated the association of obesity with caesarean birth and newborn large-for-gestational age.CONCLUSIONS: ICD-9 codes in childbirth discharge records captured only one in five women with pre-pregnancy obesity. Sensitivity varied by maternal characteristics and conditions. This misclassification resulted in bias when examining the association of obesity and pregnancy-related outcomes.

  View details for DOI 10.1111/ppe.12667

  View details for PubMedID 32180247

• Multilevel social factors and NICU quality of care in California. Journal of perinatology : official journal of the California Perinatal Association Padula, A. M., Shariff-Marco, S., Yang, J., Jain, J., Liu, J., Conroy, S. M., Carmichael, S. L., Gomez, S. L., Phibbs, C., Oehlert, J., Gould, J. B., Profit, J. 2020

  Abstract

  OBJECTIVE: Our objective was to incorporate social and built environment factors into a compendium of multilevel factors among a cohort of very low birth weight infants to understand their contributions to inequities in NICU quality of care and support providers and NICUs in addressing these inequitiesvia development of a health equity dashboard.STUDY DESIGN: We examined bivariate associations between NICU patient pool and NICU catchment area characteristics and NICU quality of care with data from a cohort of 15,901 infants from 119 NICUs in California, born 2008-2011.RESULT: NICUs with higher proportion of minority racial/ethnic patients and lower SES patients had lower quality scores. NICUs with catchment areas of lower SES, higher composition of minority residents, and more household crowding had lower quality scores.CONCLUSION: Multilevel social factors impact quality of care in the NICU. Their incorporation into a health equity dashboard can inform providers of their patients' potential resource needs.

  View details for DOI 10.1038/s41372-020-0647-8

  View details for PubMedID 32157221

• Maternal diet as a risk factor for primary congenital glaucoma and defects of the anterior segment of the eye in the National Birth Defects Prevention Study. Birth defects research Moore, K. J., Carmichael, S. L., Forestieri, N. E., Desrosiers, T. A., Meyer, R. E., Freedman, S. F., North, K. E., Olshan, A. F., National Birth Defects Prevention Study 2020

  Abstract

  Primary congenital glaucoma (PCG) and anterior segment defects (ASDs) are rare ocular malformations diagnosed early in life which can cause blindness. Pathogenic variants in several genes have been linked to these conditions, but little is known about nongenetic risk factors. We investigated the association between maternal nutrition and PCG and ASDs in the National Birth Defects Prevention Study, a large population-based, multicenter case-control study of major birth defects in the United States. Mothers of cases (n =152) and control infants without a birth defect (n =9,178) completed an interview which included a food frequency questionnaire capturing usual dietary intake in the year before pregnancy. Maternal nutrition was assessed through individual nutrient intake, calculating a Diet Quality Index for Pregnancy (DQI-P) score for each mother, and using latent class analysis to empirically derive four dietary patterns. We calculated adjusted odds ratios (aORs) and 95% confidence intervals (CI) using logistic regression. The results for individual nutrients varied, with some having an inverse or U-shaped pattern of association with increasing intake. The DQI-P was not associated with risk of PCG and ASDs (aOR 0.91; CI 0.49-1.66, highest vs. lowest quartile). The dietary pattern analysis suggested lower odds among women with a Prudent and Mexican dietary pattern (aOR 0.82, 95% CI 0.52-1.29; aOR 0.80, 95% CI 0.36-1.78, respectively) compared to those with a Western dietary pattern. We found that higher intake of some nutrients and certain dietary patterns may be inversely associated with PCG and ASDs, though caution is urged due to imprecision of estimates.

  View details for DOI 10.1002/bdr2.1664

  View details for PubMedID 32154673

• Maternal dietary fat intake and the risk of congenital heart defects in offspring. Pediatric research Collins, R. T., Yang, W., Carmichael, S. L., Bolin, E. H., Nembhard, W. N., Shaw, G. M., National Birth Defects Prevention Study 2020

  Abstract

  BACKGROUND: Fatty acids are crucial in embryologic development, including cardiogenesis. The impact of maternal periconceptional dietary fat intake on the risk of congenital heart defects (CHDs) has not been clearly elucidated. We hypothesized that maternal dietary fat intake during pregnancy is associated with risk of CHDs in offspring.METHODS: We analyzed CHD cases and nonmalformed controls from the National Birth Defects Prevention Study, a case-control, multicenter population-based study of birth defects. We used multivariable logistic regression to analyze the association between maternal periconceptional dietary fat intake and occurrence of CHDs.RESULTS: We examined 11,393 infants with CHDs (cases) and 11,029 infants without birth defects (controls). Multivariable analysis of maternal dietary fat intake adjusted for maternal energy intake demonstrated modest change in risk for 2 of the 25 CHDs analyzed; otherwise there was no association. Maternal dietary fat intake unadjusted for total energy was associated with increased risk for several CHDs.CONCLUSIONS: After adjusting for total energy intake, maternal periconceptional dietary fat intake has a modest association with risk of a few specific CHDs. If maternal dietary fat intake does impact CHD risk, the effect is minimal.IMPACT: In this large, case-control study, after adjusting for total caloric intake, maternal periconceptional dietary fat intake was not associated with increased odds of congenital heart defects.This study investigates the hypothesis that women's periconceptional fat intake alters the risk of congenital heart defects in offspring.Our results raise questions about the role maternal fat intake may play in cardiogenesis and risk of congenital heart defects. Additionally, they raise the question about whether maternal lipid metabolism, as opposed to fat intake, may influence cardiac development.

  View details for DOI 10.1038/s41390-020-0813-x

  View details for PubMedID 32120376

• Weight gain during pregnancy and the risk of severe maternal morbidity by prepregnancy BMI. The American journal of clinical nutrition Leonard, S. A., Abrams, B., Main, E. K., Lyell, D. J., Carmichael, S. L. 2020

  Abstract

  BACKGROUND: High and low prepregnancy BMI are risk factors for severe maternal morbidity (SMM), but the contribution of gestational weight gain (GWG) is not well understood.OBJECTIVES: We evaluated associations between GWG and SMM by prepregnancy BMI group.METHODS: We analyzed administrative records from 2,483,684 Californian births (2007-2012), utilizing z score charts to standardize GWG for gestational duration. We fit the z scores nonlinearly and categorized GWG as above, within, or below the Institute of Medicine (IOM) recommendations after predicting equivalent GWG at term from the z score charts. SMM was defined using a validated index. Associations were estimated using multivariable logistic regression models.RESULTS: We found generally shallow U-shaped relations between GWG z score and SMM in all BMI groups, except class 3 obesity (≥40kg/m2), for which risk was lowest with weight loss. The weight gain amount associated with the lowest risk of SMM was within the IOM recommendations for underweight and class 2 obesity, but above the IOM recommendations for normal weight, overweight, and class 1 obesity. The adjusted risk ratios (RRs) and 95% CIs for GWG below the IOM recommendations, compared with GWG within the recommendations, were the following for underweight, normal weight, overweight, class 1 obesity, class 2 obesity, and class 3 obesity: 1.13 (0.99, 1.29), 1.09 (1.04, 1.14), 1.10 (1.01, 1.19), 1.07 (0.95, 1.21), 1.03 (0.88, 1.22), and 0.89 (0.73, 1.08), respectively. For GWG above the recommendations, the corresponding RRs and 95% CIs were 0.99 (0.84, 1.15), 1.04 (0.99, 1.08), 0.98 (0.92, 1.04), 1.03 (0.95, 1.13), 1.07 (0.94, 1.23), and 1.08 (0.91, 1.30), respectively.CONCLUSIONS: High and low GWG may be modestly associated with increased risk of SMM across BMI groups, except in women with class 3 obesity, for whom low weight gain and weight loss may be associated with decreased risk of SMM.

  View details for DOI 10.1093/ajcn/nqaa033

  View details for PubMedID 32119734

• Differences in pre-pregnancy diet quality by occupation among employed women. Public health nutrition Zaganjor, I., Carmichael, S. L., Agopian, A. J., Olshan, A. F., Desrosiers, T. A., National Birth Defects Prevention Study 2020: 1–8

  Abstract

  OBJECTIVE: Maternal risk factors for pregnancy outcomes are known to vary by employment status. We evaluated whether pre-pregnancy diet quality varies by occupation in a population-based sample.DESIGN: We analysed interview data from 7341 mothers in a national case-control study of pregnancy outcomes. Self-reported job(s) held during the 3 months before pregnancy were classified using Standard Occupational Classification (SOC) codes. Usual diet in the year before conception was assessed with a semi-quantitative FFQ and evaluated using the Diet Quality Index for Pregnancy (DQI-P). Using logistic regression, we calculated adjusted OR and 95 % CI to estimate associations between low diet quality (defined as the lowest quartile of DQI-P scores) and occupation types.SETTING: The National Birth Defects Prevention Study: Arkansas, California, Georgia, Iowa, Massachusetts, North Carolina, New Jersey, New York, Texas, Utah.PARTICIPANTS: Employed mothers of infants born between 1997 and 2011.RESULTS: No occupation was strongly associated with low diet quality. Moderate but relatively imprecise associations were observed for women employed in management (OR: 1·3; 95 % CI: 1·1, 1·7); arts, design, entertainment, sports and media (OR: 1·4; 95 % CI: 0·9, 2·1); protective service (OR 1·3; 95 % CI: 0·7, 2·5) and farming, fishing, and forestry occupations (OR: 0·5; 95 % CI: 0·2, 1·1).CONCLUSIONS: Our analyses suggest that women in certain occupations may have lower diet quality in the months before pregnancy. Further research is needed to determine whether certain occupations could benefit from interventions to improve diet quality in the workplace for women of reproductive age.

  View details for DOI 10.1017/S1368980019003926

  View details for PubMedID 32100672

• Maternal genitourinary and wound infections: Early postpartum readmissions and emergency department visits Leonard, S. A., Girsen, A., Carmichael, S. L., Gibbs, R. S. MOSBY-ELSEVIER. 2020: S169

  View details for DOI 10.1016/j.ajog.2019.11.261

  View details for Web of Science ID 000504997300245

• Antepartum iron-deficiency anemia: An opportunity to reduce severe maternal morbidity Leonard, S. A., Main, E. K., Lyell, D. J., Butwick, A. J., Carmichael, S. L. MOSBY-ELSEVIER. 2020: S168–S169

  View details for DOI 10.1016/j.ajog.2019.11.260

  View details for Web of Science ID 000504997300244

• Pregnancy outcomes of american indian and alaskan native women residing in rural versus urban areas Estes, J., Girsen, A., Sie, L., Leonard, S. A., Carmichael, S. L., El-Sayed, Y. Y. MOSBY-ELSEVIER. 2020: S97

  View details for DOI 10.1016/j.ajog.2019.11.143

  View details for Web of Science ID 000504997300127

• Maternal Health after Stillbirth: Postpartum Hospital Readmission in California. American journal of perinatology Wall-Wieler, E., Butwick, A. J., Gibbs, R. S., Lyell, D. J., Girsen, A. I., El-Sayed, Y. Y., Carmichael, S. L. 2020

  Abstract

   The aim of this study is to assess whether the risk of postpartum readmission within 6 weeks of giving birth differs for women who had stillbirths compared with live births. Using data from the Office of Statewide Health Planning and Development in California, we performed a population-based cohort study of 7,398,640 births between 1999 and 2011. We identified diagnoses and procedures associated with the first postpartum hospital readmission that occurred within 6 weeks after giving birth. We used log-binomial models to estimate relative risk (RR) of postpartum readmission for women who had stillbirth compared with live birth deliveries, adjusting for maternal demographic, prepregnancy, pregnancy, and delivery characteristics. The rate of postpartum readmission was higher among women who had stillbirths compared with women who had live births (206 and 96 per 10,000 births, respectively). After adjusting for maternal demographic and medical characteristics, the risk of postpartum readmission for women who had stillbirths was nearly 1.5 times greater (adjusted RR = 1.47, 95% confidence interval: 1.35-1.60) compared with live births. Among women with stillbirths, the most common indications at readmission were uterine infection or pelvic inflammatory disease, psychiatric conditions, hypertensive disorder, and urinary tract infection. Based on our findings, women who have stillbirths are at higher risk of postpartum readmissions within 6 weeks of giving birth than women who have live births. Women who have stillbirths may benefit from additional monitoring and counseling after hospital discharge for potential postpartum medical and psychiatric complications.· Women who have stillbirths are at nearly 1.5 times greater risk of postpartum readmission than women who have live births.. · Uterine infections and pelvic inflammatory disease, and psychiatric conditions are the most common reasons for readmission among women who had a stillbirth.. · Women who have stillbirths may benefit from additional monitoring and counseling after hospital discharge for potential postpartum medical and psychiatric complications..

  View details for DOI 10.1055/s-0040-1708803

  View details for PubMedID 32365389

• Pre-pregnancy Obesity and the Risk of Peripartum Cardiomyopathy. American journal of perinatology Cho, S. H., Leonard, S. A., Lyndon, A., Main, E. K., Abrams, B., Hameed, A. B., Carmichael, S. L. 2020

  Abstract

   The aim of this study is to evaluate the contribution of pre-pregnancy obesity and overweight to peripartum cardiomyopathy. This population-based study used linked birth record and maternal hospital discharge data from live births in California during 2007 to 2012 (n = 2,548,380). All women who had a diagnosis of peripartum cardiomyopathy during the childbirth hospitalization or who were diagnosed with peripartum cardiomyopathy during a postpartum hospital readmission within 5 months of birth were identified as cases. Pre-pregnancy body mass index (BMI, kg/m2) was classified as normal weight (18.5-24.9), overweight (25.0-29.9), obesity class 1 (30.0-34.9), obesity class 2 (35.0-39.9), and obesity class 3 (≥40). Because of small numbers, we excluded women with underweight BMI, and in some analyses, we combined obesity classes into one group. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) expressing associations between BMI and peripartum cardiomyopathy, adjusted for maternal age, race/ethnicity, education, health care payer, parity, plurality, and comorbidities. The overall prevalence of peripartum cardiomyopathy during hospital admissions was 1.3 per 10,000 live births (n = 320). Unadjusted ORs were 1.32 (95% CI: 1.01-1.74) for women with overweight BMI and 2.03 (95% CI: 1.57-2.62) for women with obesity, compared with women with normal pre-pregnancy BMI. Adjusted ORs were 1.26 (95% CI: 0.95-1.66) for overweight women and 1.38 (95% CI: 1.04-1.84) for women with obesity. The ORs suggested a dose-response relationship with increasing levels of obesity, but the 95% CIs for the specific classes of obesity included 1.00. Pre-pregnancy obesity was associated with an increased risk of peripartum cardiomyopathy. These findings underscore the importance of BMI during pregnancy. There is a need to recognize the increased risk of peripartum cardiomyopathy in women with high BMI, especially in the late postpartum period.· Pre-pregnancy obesity affects maternal health.. · Effects may extend to peripartum cardiomyopathy.. · The risk includes peripartum cardiomyopathy that emerges postpartum..

  View details for DOI 10.1055/s-0040-1712451

  View details for PubMedID 32512606

• Severe Maternal Morbidity among US- and Foreign-born Asian and Pacific Islander women in California. Annals of epidemiology Wall-Wieler, E., Bane, S., Lee, H. C., Carmichael, S. L. 2020

  Abstract

  To examine risk of severe maternal morbidity (SMM) - a composite of serious, potentially life-threatening conditions related to childbirth - among subgroups of nulliparous women with Asian and Pacific Islander race/ethnicity.This study used linked hospital discharge and vital record data California to identify nulliparous Asian and Pacific Islander women from 1997 to 2012 (n = 453,525). We examined risk of SMM for 15 Asian and Pacific Islander subgroups and compared risk between US- and foreign-born women.Risk of SMM was higher among Pacific Islander women than Asian women (148 and 127 cases per 10,000 births, respectively). Among Asian women, risk of SMM ranged from 94 (Korean) to 165 (Filipina) cases per 10,000 births, and among Pacific Islander women, risk ranged from 125 (Hawaiian) to 162 (Other). With the exception of Korean and Filipina women, relative risks of SMM for US- versus foreign-born Asian and Pacific Islander women were similar.Differences in risk of SMM exist between subgroups of the Asian and Pacific Islander community. These differences should be considered when conducting research on racial and ethnic differences of SMM and when counselling Asian and Pacific Islander women regarding their risk of SMM.

  View details for DOI 10.1016/j.annepidem.2020.07.016

  View details for PubMedID 32795600

• Factors Associated with Early Neonatal and First-Year Mortality in Infants with Myelomeningocele in California from 2006 to 2011. American journal of perinatology Kancherla, V., Ma, C., Grant, G., Lee, H. C., Hintz, S. R., Carmichael, S. L. 2020

  Abstract

   The aim of this study is to examine factors associated with early neonatal (death within first 7 days of birth) and infant (death during the first year of life) mortality among infants born with myelomeningocele. We examined linked data from the California Perinatal Quality Care Collaborative, vital records, and hospital discharge records for infants born with myelomeningocele from 2006 to 2011. Survival probability was calculated using Kaplan-Meier Product Limit method and 95% confidence intervals (CI) using Greenwood's method; Cox proportional hazard models were used to estimate unadjusted and adjusted hazard ratios (HR) and 95% CI. Early neonatal and first-year survival probabilities among infants born with myelomeningocele were 96.0% (95% CI: 94.1-97.3%) and 94.5% (95% CI: 92.4-96.1%), respectively. Low birthweight and having multiple co-occurring birth defects were associated with increased HRs ranging between 5 and 20, while having congenital hydrocephalus and receiving hospital transfer from the birth hospital to another hospital for myelomeningocele surgery were associated with HRs indicating a protective association with early neonatal and infant mortality. Maternal race/ethnicity and social disadvantage did not predict early neonatal and infant mortality among infants with myelomeningocele; presence of congenital hydrocephalus and the role of hospital transfer for myelomeningocele repair should be further examined.· Mortality in myelomeningocele is a concern. · Social disadvantage was not associated with death. · Hospital-based factors should be further examined.

  View details for DOI 10.1055/s-0040-1712165

  View details for PubMedID 32473597

• Early postpartum readmissions or emergency department visits: Identifying risk factors Girsen, A., Leonard, S. A., Carmichael, S. L., Gibbs, R. S. MOSBY-ELSEVIER. 2020: S351–S352

  View details for DOI 10.1016/j.ajog.2019.11.562

  View details for Web of Science ID 000504997300545

• Survival of infants with congenital diaphragmatic hernia in California: impact of hospital, clinical, and sociodemographic factors. Journal of perinatology : official journal of the California Perinatal Association Carmichael, S. L., Ma, C., Lee, H. C., Shaw, G. M., Sylvester, K. G., Hintz, S. R. 2020

  Abstract

  To understand factors associated with care and survival among babies with congenital diaphragmatic hernia (CDH).We used data on California births (2006-2011) to examine birth hospital level of care, hospital transfer before repair, and survival.Among 577 infants, 25% were born at lower-level hospitals, 62% were transferred, and 31% died during infancy. Late or no prenatal care had the strongest association with birth at lower-level hospitals (adjusted relative risk (ARR) = 1.9, 95% confidence interval (CI) = 1.0-3.6). Birth at lower-level hospitals was associated with transfer (ARR = 1.2, CI = 1.1-1.4), and transferred infants tended to be less clinically complex. Infants with low birthweight, other birth defects, low Apgar scores, and late or no prenatal care had two- to fourfold higher risk of mortality than their comparison groups.These data support the importance of prenatal care and delivery planning into higher-level hospitals for optimal care and outcomes for newborns with CDH.

  View details for DOI 10.1038/s41372-020-0612-6

  View details for PubMedID 32086437

• Improved Referral of Very Low Birthweight Infants to High-Risk Infant Follow-Up in California. The Journal of pediatrics Pai, V. V., Kan, P., Bennett, M., Carmichael, S. L., Lee, H. C., Hintz, S. R. 2019

  Abstract

  OBJECTIVE: To examine changes in referral rates of very low birthweight (birthweight <1500g) infants to high-risk infant follow-up in California and identify factors associated with referral before and after implementation of a statewide initiative in 2013 to address disparities in referral.STUDY DESIGN: We included very low birthweight infants born 2010-2016 in the population-based California Perinatal Quality Care Collaborative who survived to discharge home. We used multivariable logistic regression to examine factors associated with referral and derive risk-adjusted referral rates by neonatal intensive care unit (NICU) and region.RESULTS: Referral rate improved from 83.0% (preinitiative period) to 94.9% (postinitiative period); yielding an OR of 1.48 (95% CI, 1.26-1.72) for referral in the postinitiative period after adjustment for year. Referral rates improved the most (≥15%) for infants born at ≥33weeks of gestation, with a birthweight of 1251-1500g, and born in intermediate and lower volume NICUs. After the initiative, Hispanic ethnicity, small for gestational age status, congenital anomalies, and major morbidities were no longer associated with a decreased odds of referral. Lower birthweight, outborn status, and higher NICU volume were no longer associated with increased odds of referral. African American race was associated with lower odds of referral, and higher NICU level with a higher odds of referral during both time periods. Referral improved in many previously poor-performing NICUs and regions.CONCLUSIONS: High-risk infant follow-up referral of very low birthweight infants improved substantially across all sociodemographic, perinatal, and clinical variables after the statewide initiative, although disparities remain. Our results demonstrate the benefit of a targeted initiative in California, which may be applicable to other quality collaboratives.

  View details for DOI 10.1016/j.jpeds.2019.08.050

  View details for PubMedID 31587859

• Risk Factors for Maternal Readmission with Sepsis. American journal of perinatology Foeller, M. E., Sie, L., Foeller, T. M., Girsen, A. I., Carmichael, S. L., Lyell, D. J., Lee, H. C., Gibbs, R. S. 2019

  Abstract

  OBJECTIVE: Our primary objective was to identify risk factors for maternal readmission with sepsis. Our secondary objectives were to (1) assess diagnoses and infecting organisms at readmission and (2) compare early (<6 weeks) and late (6 weeks to 9 months postpartum) maternal readmission with sepsis.STUDY DESIGN: We identified our cohort using linked hospital discharge data and birth certificates for California deliveries from 2008 to 2011. Consistent with the 2016 sepsis classification, we defined sepsis as septicemia plus acute organ dysfunction. We compared women with early or late readmission with sepsis to women without readmission with sepsis.RESULTS: Among 1,880,264 women, 494 (0.03%) were readmitted with sepsis, 61% after 6 weeks. Risk factors for readmission with sepsis included preterm birth, hemorrhage, obesity, government-provided insurance, and primary cesarean. For both early and late sepsis readmissions, the most common diagnoses were urinary tract infection and pyelonephritis, and the most frequently identified infecting organism was gram-negative bacteria. Women with early compared with late readmission with sepsis shared similar obstetric characteristics.CONCLUSION: Maternal risk factors for both early and late readmission with sepsis included demographic characteristics, cesarean, hemorrhage, and preterm birth. Risks for sepsis after delivery persist beyond the traditional postpartum period of 6 weeks.

  View details for DOI 10.1055/s-0039-1696721

  View details for PubMedID 31529451

• Rate and causes of severe maternal morbidity at readmission: California births in 2008-2012. Journal of perinatology : official journal of the California Perinatal Association Girsen, A. I., Sie, L., Carmichael, S. L., Lee, H. C., Foeller, M. E., Druzin, M. L., Gibbs, R. S. 2019

  Abstract

  OBJECTIVE: To determine the rate, maternal characteristics, timing, and indicators of severe maternal morbidity (SMM) that occurs at postpartum readmission.STUDY DESIGN: Women with a birth in California during 2008-2012 were included in the analysis. Readmissions up to 42 days after delivery were investigated. SMM was defined as presence of any of the 21 indicators defined by ICD-9 codes.RESULTS: Among 2,413,943 women with a birth, SMM at readmission occurred in 4229 women. Of all SMM, 12.1% occurred at readmission. Over half (53.5%) of the readmissions with SMM occurred within the first week after delivery hospitalization. The most common indicators of SMM were blood transfusion, sepsis, and pulmonary edema/acute heart failure.CONCLUSION: Twelve percent of SMM was identified at readmission with the majority occurring within 1 week after discharge from delivery hospitalization. Because early readmission may reflect lack of discharge readiness, there may be opportunities to improve care.

  View details for DOI 10.1038/s41372-019-0481-z

  View details for PubMedID 31462721

• Asthma medication use and risk of birth defects: National Birth Defects Prevention Study 1997-2011 Howley, M. M., Papadopoulos, E. A., Van Bennekom, C., Van Zutphen, A. R., Carmichael, S. L., Munsie, J. W., Herdt, M. L., Browne, M. L. WILEY. 2019: 365–66

  View details for Web of Science ID 000481785602235

• Severe maternal morbidity and postpartum mental health-related outcomes in Sweden: a population-based matched-cohort study ARCHIVES OF WOMENS MENTAL HEALTH Wall-Wieler, E., Carmichael, S. L., Urquia, M. L., Liu, C., Hjern, A. 2019; 22 (4): 519–26

  View details for DOI 10.1007/s00737-018-0917-z

  View details for Web of Science ID 000475907900010

• Factors Associated with Timeliness of Surgical Repair among Infants with Myelomeningocele: California Perinatal Quality Care Collaborative, 2006 to 2011. American journal of perinatology Kancherla, V., Ma, C., Grant, G., Lee, H. C., Shaw, G. M., Hintz, S. R., Carmichael, S. L. 2019

  Abstract

  OBJECTIVE: To examine factors associated with timely (0-2 days after birth) myelomeningocele surgical repair.STUDY DESIGN: We examined 2006 to 2011 births from the California Perinatal Quality Care Collaborative, linking to hospital discharge and vital records. Selected maternal, infant, and delivery hospital characteristics were evaluated to understand disparities in timely repair. Poisson regression was used to estimate adjusted risk ratios (aRRs) and 95% confidence intervals (CIs).RESULTS: Overall, 399 of the 450 (89%) infants had a timely repair and approximately 80% of them were delivered in level III/IV hospitals. Infants with hydrocephalus were significantly less likely to have a delayed myelomeningocele repair compared with those without (aRR=0.22; 95% CI=0.13, 0.39); infants whose medical care was paid by Medi-Cal or other nonprivate insurance were 2.2 times more likely to have a delayed repair compared with those covered by a private insurance (aRR=2.23; 95% CI=1.17, 4.27). Low birth weight was a significant predictor for delayed repair (aRR=2.06; 95% CI=1.10, 3.83).CONCLUSION: There was a significant disparity in myelomenigocele repair based on medical care payer. Families and hospitals should work together for timely repair in hospitals having specialized multidisciplinary teams. Findings from the study can be used to follow best clinical practices for myelomeningocele repair.

  View details for DOI 10.1055/s-0039-1693127

  View details for PubMedID 31307103

• Severe Maternal Morbidity Among Stillbirth and Live Birth Deliveries in California. Obstetrics and gynecology Wall-Wieler, E., Carmichael, S. L., Gibbs, R. S., Lyell, D. J., Girsen, A. I., El-Sayed, Y. Y., Butwick, A. J. 2019

  Abstract

  OBJECTIVE: To assess the prevalence and risk of severe maternal morbidity among delivery hospitalization for stillbirth compared with live birth deliveries.METHODS: Using data from the Office of Statewide Health Planning and Development in California, we performed a population-based cross-sectional study of 6,459,842 deliveries between 1999 and 2011. We identified severe maternal morbidity using an algorithm comprising diagnoses and procedures developed by the Centers for Disease Control and Prevention and used log-binomial regression models to examine the relative risk (RR) of severe maternal morbidity for stillbirth compared with live birth deliveries, adjusting for maternal demographic, medical, and obstetric characteristics. We also examined severe maternal morbidity prevalence by cause of fetal death among stillbirth deliveries.RESULTS: The prevalence of severe maternal morbidity for stillbirth and live birth was 578 and 99 cases per 10,000 deliveries, respectively. After adjusting for maternal demographic, medical, and obstetric characteristics, the risk of severe maternal morbidity among stillbirth deliveries was more than fourfold higher (adjusted RR 4.77; 95% CI 4.53-5.02) compared with live birth deliveries. The severe maternal morbidity prevalence was highest among stillbirths caused by hypertensive disorders and placental conditions (24 and 19 cases/100 deliveries, respectively), and lowest among stillbirths caused by fetal malformations or genetic abnormalities (1 case per 100 deliveries).CONCLUSION: Women who have stillbirths are at substantially higher risk for severe maternal morbidity than women who have live births, regardless of cause of fetal death. The prevalence of severe maternal morbidity varies by cause of fetal death.

  View details for DOI 10.1097/AOG.0000000000003370

  View details for PubMedID 31306335

• The ARRIVE Trial: Interpretation from an Epidemiologic Perspective. Journal of midwifery & women's health Carmichael, S. L., Snowden, J. M. 2019

  Abstract

  The findings of the ARRIVE trial (A Randomized Trial of Induction Versus Expectant Management) were recently published. This multisite randomized trial was designed to provide evidence regarding whether labor induction or expectant management is associated with increased adverse perinatal outcomes and risk of cesarean birth among healthy nulliparous women at term. The trial reported that the primary outcome, a composite of adverse neonatal outcomes, was not significantly different between the 2 groups; the principal secondary outcome, cesarean birth, was significantly more common among women whose pregnancy was expectantly managed than among women whose labor was induced at 39weeks. These results have the potential to change existing practice. Several aspects of the study design may influence its potential internal and external validity and should be considered in order to make sound causal inferences from this trial, which will in turn affect how its findings are translated to practice. Although chance and confounding are of minimal concern, given the sample size and randomization used in the study, selection bias may be a concern. Studies are vulnerable to selection bias when the sample population differs from eligible nonparticipants, including in randomized controlled trials. External validity is defined as the extent to which the study population and setting are representative of the larger source population the study intends to represent. External validity may be limited given the characteristics of the women enrolled in the ARRIVE trial and the practice settings where the study was conducted. This brief report provides concrete suggestions for further analyses that could help solidify conclusions from the trial, and for further research questions that will continue advancement toward answering this complex question of how best to manage labor and birth decisions at full term among low-risk women.

  View details for DOI 10.1111/jmwh.12996

  View details for PubMedID 31264773

• Prenatal and postnatal inflammation-related risk factors for retinopathy of prematurity JOURNAL OF PERINATOLOGY Goldstein, G. P., Leonard, S. A., Kan, P., Koo, E. B., Lee, H. C., Carmichael, S. L. 2019; 39 (7): 964–73

  View details for DOI 10.1038/s41372-019-0357-2

  View details for Web of Science ID 000472630200010

• Sociodemographic, health behavioral, and clinical risk factors for anotia/microtia in a population-based case-control study INTERNATIONAL JOURNAL OF PEDIATRIC OTORHINOLARYNGOLOGY Ryan, M. A., Olshan, A. F., Canfield, M. A., Hoyt, A. T., Scheuerle, A. E., Carmichael, S. L., Shaw, G. M., Werler, M. M., Fisher, S. C., Desrosiers, T. A., Natl Birth Defects Prevention Stud 2019; 122: 18–26

  View details for DOI 10.1016/j.ijporl.2019.03.026

  View details for Web of Science ID 000471738900004

• The role of genetic variation in DGKK on moderate and severe hypospadias. Birth defects research Richard, M. A., Sok, P., Canon, S., Brown, A. L., Peckham-Gregory, E. C., Nembhard, W. N., Carmichael, S. L., Ehli, E. A., Kallsen, N. A., Peyton, S. A., Davies, G. E., Patel, A., Zamilpa, I., Wyatt, R. A., Hobbs, C. A., Scheurer, M. E., Lupo, P. J. 2019

  Abstract

  BACKGROUND: Recent genome-wide association studies of hypospadias have implicated the role of genetic variants in or near the diacylglycerol kinase kappa (DGKK) gene. However, these variants are largely identified among samples of mild and moderate hypospadias cases. Therefore, we evaluated previously identified DGKK variants among second- and third-degree hypospadias cases and controls recruited in Arkansas, a state characterized by a high birth prevalence of hypospadias.METHODS: Second- and third-degree hypospadias non-Hispanic white cases (n =36 and n = 9, respectively) and controls (n =45) were recruited at Arkansas Children's Hospital. Preputial tissue was collected on cases and controls between 2013 and 2017. Cases and controls were genotyped using the Illumina Infinium Global Screening Array. We used logistic regression models to assess the association of genotyped and imputed genetic variants mapped to the DGKK region with second- and third-degree hypospadias.RESULTS: All families self-reported as non-Hispanic white and genetic principal component analyses did not demonstrate evidence of population stratification. Five DGKK variants previously reported as associated with hypospadias were identified in the genotype data. None of the variants were associated with second- or third-degree hypospadias (range of odds ratios = 0.7-0.9, all p >.05).CONCLUSIONS: In our analyses, genetic variation in DGKK does not play a role in the development of moderate and severe hypospadias. Our findings provide support to the etiologic heterogeneity of hypospadias by all classifications of severity.

  View details for DOI 10.1002/bdr2.1522

  View details for PubMedID 31102501

• Racial and ethnic disparities in severe maternal morbidity prevalence and trends ANNALS OF EPIDEMIOLOGY Leonard, S. A., Main, E. K., Scott, K. A., Profit, J., Carmichael, S. L. 2019; 33: 30–36

  View details for DOI 10.1016/j.annepidem.2019.02.007

  View details for Web of Science ID 000469160800004

• 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. 2019; 36 (5): 537–44

  View details for DOI 10.1055/s-0038-1670633

  View details for Web of Science ID 000463944600016

• Sociodemographic, health behavioral, and clinical risk factors for anotia/microtia in a population-based case-control study. International journal of pediatric otorhinolaryngology Ryan, M. A., Olshan, A. F., Canfield, M. A., Hoyt, A. T., Scheuerle, A. E., Carmichael, S. L., Shaw, G. M., Werler, M. M., Fisher, S. C., Desrosiers, T. A., National Birth Defects Prevention Study 2019; 122: 18–26

  Abstract

  OBJECTIVE: Anotia and microtia are congenital malformations of the external ear with few known risk factors. We conducted a comprehensive assessment of a wide range of potential risk factors using data from the National Birth Defects Prevention Study (NBDPS), a population-based case-control study of non-chromosomal structural birth defects in the United States.METHODS: Mothers of 699 infants with anotia or microtia (cases) and 11,797 non-malformed infants (controls) delivered between 1997 and 2011 were interviewed to obtain information about sociodemographic, health behavioral, and clinical characteristics. Adjusted odds ratios (aORs) and 95% confidence intervals (CIs) were estimated with logistic regression.RESULTS: Infants with anotia/microtia were more likely to be male (aOR, 1.29; 95% CI, 1.10-1.50) and from a multifetal pregnancy (aOR, 1.68; 95% CI, 1.16-2.42). Cases were also more likely to have parents of Hispanic ethnicity (maternal aOR, 3.19; 95% CI, 2.61-3.91; paternal aOR, 2.11; 95% CI, 1.54-2.88), and parents born outside the United States (maternal aOR, 1.29; 95% CI, 1.06-1.57; paternal aOR, 1.92; 95% CI, 1.53-2.41). Maternal health conditions associated with increased odds of anotia/microtia included obesity (aOR, 1.31; 95% CI, 1.06-1.61) and pre-pregnancy diabetes (type I aOR, 9.89; 95% CI, 5.46-17.92; type II aOR, 4.70; 95% CI, 2.56-8.63). Reduced odds were observed for black mothers (aOR, 0.57; 95% CI, 0.38-0.85) and mothers reporting daily intake of folic acid-containing supplements (aOR, 0.59; 95% CI, 0.46-0.76).CONCLUSION: We identified several risk factors for anotia/microtia, some which have been previously reported (e.g., diabetes) and others which we investigate for perhaps the first time (e.g., binge drinking) that warrant further investigation. Our findings point to some potentially modifiable risk factors and provide further leads toward understanding the etiology of anotia/microtia.

  View details for PubMedID 30928866

• Comparing Usual Dietary Intakes Among Subgroups of Mothers in the Year Before Pregnancy PUBLIC HEALTH REPORTS Carmichael, S. L., Ma, C., Feldkamp, M. L., Shaw, G. M., Natl Birth Defects Prevention Stu 2019; 134 (2): 155–63

  View details for DOI 10.1177/0033354918821078

  View details for Web of Science ID 000460640500009

• Fish consumption prior to pregnancy and pregnancy outcomes in the National Birth Defects Prevention Study, 1997-2011 PUBLIC HEALTH NUTRITION Benjamin, R. H., Mitchell, L. E., Canfield, M. A., Hoyt, A. T., Lai, D., Ramadhani, T. A., Carmichael, S. L., Case, A. P., Waller, D., Natl Birth Defects Prevention Stud 2019; 22 (2): 336–43

  View details for DOI 10.1017/S1368980018002641

  View details for Web of Science ID 000458515400015

• Use of mobile technology by frontline health workers to promote reproductive, maternal, newborn and child health and nutrition: a cluster randomized controlled Trial in Bihar, India. Journal of global health Carmichael, S. L., Mehta, K., Srikantiah, S., Mahapatra, T., Chaudhuri, I., Balakrishnan, R., Chaturvedi, S., Raheel, H., Borkum, E., Trehan, S., Weng, Y., Kaimal, R., Sivasankaran, A., Sridharan, S., Rotz, D., Tarigopula, U. K., Bhattacharya, D., Atmavilas, Y., Pepper, K. T., Rangarajan, A., Darmstadt, G. L. 2019; 9 (2): 0204249

  Abstract

  mHealth technology holds promise for improving the effectiveness of frontline health workers (FLWs), who provide most health-related primary care services, especially reproductive, maternal, newborn, child health and nutrition services (RMNCHN), in low-resource - especially hard-to-reach - settings. Data are lacking, however, from rigorous evaluations of mHealth interventions on delivery of health services or on health-related behaviors and outcomes.The Information Communication Technology-Continuum of Care Service (ICT-CCS) tool was designed for use by community-based FLWs to increase the coverage, quality and coordination of services they provide in Bihar, India. It consisted of numerous mobile phone-based job aids aimed to improve key RMNCHN-related behaviors and outcomes. ICT-CCS was implemented in Saharsa district, with cluster randomization at the health sub-center level. In total, evaluation surveys were conducted with approximately 1100 FLWs and 3000 beneficiaries who had delivered an infant in the previous year in the catchment areas of intervention and control health sub-centers, about half before implementation (mid-2012) and half two years afterward (mid-2014). Analyses included bivariate and difference-in-difference analyses across study groups.The ICT-CCS intervention was associated with more frequent coordination of AWWs with ASHAs on home visits and greater job confidence among ASHAs. The intervention resulted in an 11 percentage point increase in FLW antenatal home visits during the third trimester (P = 0.04). In the post-implementation period, postnatal home visits during the first week were increased in the intervention (72%) vs the control (60%) group (P < 0.01). The intervention also resulted in 13, 12, and 21 percentage point increases in skin-to-skin care (P < 0.01), breastfeeding immediately after delivery (P < 0.01), and age-appropriate complementary feeding (P < 0.01). FLW supervision and other RMNCHN behaviors were not significantly impacted.Important improvements in FLW home visits and RMNCHN behaviors were achieved. The ICT-CCS tool shows promise for facilitating FLW effectiveness in improving RMNCHN behaviors.

  View details for DOI 10.7189/jogh.09.020424

  View details for PubMedID 31788233

  View details for PubMedCentralID PMC6875677

• Gestational Weight Gain and Severe Maternal Morbidity at Delivery Hospitalization. Obstetrics and gynecology Leonard, S. A., Carmichael, S. L., Abrams, B. 2019; 134 (2): 420

  View details for DOI 10.1097/AOG.0000000000003389

  View details for PubMedID 31348212

• Re: Unexpected term NICU admissions: a marker of obstetrical care quality? American journal of obstetrics and gynecology Snowden, J. M., Carmichael, S. L., Klebanoff, M. A. 2019

  View details for DOI 10.1016/j.ajog.2019.08.031

  View details for PubMedID 31469988

• Risk of Stillbirth for Fetuses With Specific Birth Defects. Obstetrics and gynecology Heinke, D., Nestoridi, E., Hernandez-Diaz, S., Williams, P. L., Rich-Edwards, J. W., Lin, A. E., Van Bennekom, C. M., Mitchell, A. A., Nembhard, W. N., Fretts, R. C., Roberts, D. J., Duke, C. W., Carmichael, S. L., Yazdy, M. M. 2019

  Abstract

  To estimate the risk of stillbirth (fetal death at 20 weeks of gestation or more) associated with specific birth defects.We identified a population-based retrospective cohort of neonates and fetuses with selected major birth defects and without known or strongly suspected chromosomal or single-gene disorders from active birth defects surveillance programs in nine states. Abstracted medical records were reviewed by clinical geneticists to confirm and classify all birth defects and birth defect patterns. We estimated risks of stillbirth specific to birth defects among pregnancies overall and among those with isolated birth defects; potential bias owing to elective termination was quantified.Of 19,170 eligible neonates and fetuses with birth defects, 17,224 were liveborn, 852 stillborn, and 672 electively terminated. Overall, stillbirth risks ranged from 11 per 1,000 fetuses with bladder exstrophy (95% CI 0-57) to 490 per 1,000 fetuses with limb-body-wall complex (95% CI 368-623). Among those with isolated birth defects not affecting major vital organs, elevated risks (per 1,000 fetuses) were observed for cleft lip with cleft palate (10; 95% CI 7-15), transverse limb deficiencies (26; 95% CI 16-39), longitudinal limb deficiencies (11; 95% CI 3-28), and limb defects due to amniotic bands (110; 95% CI 68-171). Quantified bias analysis suggests that failure to account for terminations may lead to up to fourfold underestimation of the observed risks of stillbirth for sacral agenesis (13/1,000; 95% CI 2-47), isolated spina bifida (24/1,000; 95% CI 17-34), and holoprosencephaly (30/1,000; 95% CI 10-68).Birth defect-specific stillbirth risk was high compared with the U.S. stillbirth risk (6/1,000 fetuses), even for isolated cases of oral clefts and limb defects; elective termination may appreciably bias some estimates. These data can inform clinical care and counseling after prenatal diagnosis.

  View details for DOI 10.1097/AOG.0000000000003614

  View details for PubMedID 31809437

• Effects of team-based goals and non-monetary incentives on front-line health worker performance and maternal health behaviours: a cluster randomised controlled trial in Bihar, India. BMJ global health Carmichael, S. L., Mehta, K., Raheel, H., Srikantiah, S., Chaudhuri, I., Trehan, S., Mohanty, S., Borkum, E., Mahapatra, T., Weng, Y., Kaimal, R., Sivasankaran, A., Sridharan, S., Rotz, D., Tarigopula, U. K., Bhattacharya, D., Atmavilas, Y., Munar, W., Rangarajan, A., Darmstadt, G. L., Ananya Study Group, Atmavilas, Y., Bhattacharya, D., Borkum, E., Carmichael, S. L., Chaudhuri, I., Creanga, A., Darmstadt, G. L., Dutt, P., Irani, L., Kaimal, R., Mahapatra, T., Mehta, K. M., Mitra, R., Munar, W., Pepper, K., Raheel, H., Rangarajan, A., Saggurti, N., Sastry, P., Schooley, J., Shah, H., Srikantiah, S., Kiran Tarigopula, U., Ward, V., Weng, Y., Wahid, S., Wilhelm, J. 2019; 4 (4): e001146

  Abstract

  Introduction: We evaluated the impact of a 'Team-Based Goals and Incentives' (TBGI) intervention in Bihar, India, designed to improve front-line (community health) worker (FLW) performance and health-promoting behaviours related to reproductive, maternal, newborn and child health and nutrition.Methods: This study used a cluster randomised controlled trial design and difference-in-difference analyses of improvements in maternal health-related behaviours related to the intervention's team-based goals (primary), and interactions of FLWs with each other and with maternal beneficiaries (secondary). Evaluation participants included approximately 1300 FLWs and 3600 mothers at baseline (May to June 2012) and after 2.5 years of implementation (November to December 2014) who had delivered an infant in the previous year.Results: The TBGI intervention resulted in significant increases in the frequency of antenatal home visits (15 absolute percentage points (PP), p=0.03) and receipt of iron-folic acid (IFA) tablets (7 PP, p=0.02), but non-significant changes in other health behaviours related to the trial's goals. Improvements were seen in selected attitudes related to coordination and teamwork among FLWs, and in the provision of advice to beneficiaries (ranging from 8 to 14 PP) related to IFA, cord care, breast feeding, complementary feeding and family planning.Conclusion: Results suggest that combining an integrated set of team-based coverage goals and targets, small non-cash incentives for teams who meet targets and team building to motivate FLWs resulted in improvements in FLW coordination and teamwork, and in the quality and quantity of FLW-beneficiary interactions. These improvements represent programmatically meaningful steps towards improving health behaviours and outcomes.Trial registration number: NCT03406221.

  View details for DOI 10.1136/bmjgh-2018-001146

  View details for PubMedID 31543982

• Prenatal and postnatal inflammation-related risk factors for retinopathy of prematurity. Journal of perinatology : official journal of the California Perinatal Association Goldstein, G. P., Leonard, S. A., Kan, P., Koo, E. B., Lee, H. C., Carmichael, S. L. 2019

  Abstract

  To evaluate the relationship between prenatal and postnatal inflammation-related risk factors and severe retinopathy of prematurity (ROP).The study included infants born <30 weeks in California from 2007 to 2011. Multivariable log-binomial regression was used to assess the association between prenatal and postnatal inflammation-related exposures and severe ROP, defined as stage 3-5 or surgery for ROP.Of 14,816 infants, 10.8% developed severe ROP. Though prenatal inflammation-related risk factors were initially associated with severe ROP, after accounting for the effect of these risk factors on gestational age at birth through mediation analysis, the association was non-significant (P = 0.6). Postnatal factors associated with severe ROP included prolonged oxygen exposure, sepsis, intraventricular hemorrhage, and necrotizing enterocolitis.Postnatal inflammation-related factors were associated with severe ROP more strongly than prenatal factors. The association between prenatal inflammation-related factors and ROP was explained by earlier gestational age in infants exposed to prenatal inflammation.

  View details for PubMedID 30932029

• The contribution of maternal characteristics and cesarean delivery to an increasing trend of severe maternal morbidity BMC Pregnancy and Childbirth Leonard, S. A., Main, E. K., Carmichael, S. L. 2019; 19 (16)

  View details for DOI 10.1186/s12884-018-2169-3

• Racial and ethnic disparities in severe maternal morbidity prevalence and trends. Annals of epidemiology Leonard, S. A., Main, E. K., Scott, K. A., Profit, J., Carmichael, S. L. 2019

  Abstract

  Racial/ethnic disparities in severe maternal morbidity (SMM) are substantial, but little is known about whether these disparities are changing over time or the role of maternal and obstetric factors.We examined disparities in SMM prevalence and trends using linked birth certificate and delivery discharge records from Californian births during 1997-2014 (n = 8,252,025).The prevalence of SMM was highest in non-Hispanic (NH) Black women (1.63%), lowest in NH White women (0.84%), and increased from 1997 to 2014 by approximately 170% in each racial/ethnic group. The magnitude of SMM disparities remained consistent over time. Compared with NH White women, the adjusted risk of SMM was higher in women who identified as Hispanic (RR 1.14; 95% CI 1.12, 1.16), Asian/Pacific Islander (RR 1.23; 95% CI 1.20, 1.26), NH Black (RR 1.27; 95% CI 1.23, 1.31), and American Indian/Alaska Native (RR 1.29; 95% CI 1.15, 1.44), accounting for comorbidities, anemia, cesarean birth, and other maternal characteristics.The prevalence of SMM varied considerably by race/ethnicity but increased at similarly high rates among all racial/ethnic groups. Comorbidities, cesarean birth, and other factors did not fully explain the disparities in SMM, which remained persistent over time.

  View details for PubMedID 30928320

• The contribution of maternal characteristics and cesarean delivery to an increasing trend of severe maternal morbidity. BMC pregnancy and childbirth Leonard, S. A., Main, E. K., Carmichael, S. L. 2019; 19 (1): 16

  Abstract

  Severe maternal morbidity - life-threatening childbirth complications - has more than doubled in the United States over the past 15 years, affecting more than 50,000 women (1.4% of deliveries) annually. During this time period, maternal age, obesity, comorbidities, and cesarean delivery also increased and may be related to the rise in severe maternal morbidity. We sought to evaluate: (1) the association of advanced maternal age, pre-pregnancy obesity, pre-pregnancy comorbidities, and cesarean delivery with severe maternal morbidity, and (2) whether changes in the prevalence of these risk factors affected the trend of severe maternal morbidity.This population-based cohort study used linked birth record and patient discharge data from live births in California during 2007-2014 (n = 3,556,206). We used multivariable logistic regression models to assess the association of advanced maternal age (≥35 years), pre-pregnancy obesity (body mass index ≥30 kg/m2), pre-pregnancy comorbidity (index of 12 conditions), and cesarean delivery with severe maternal morbidity prevalence and trends. Severe maternal morbidity was identified by an index of 18 diagnosis and procedure indicators. We estimated odds ratios, predicted prevalence, and population attributable risk percentages.The prevalence of severe maternal morbidity increased by 65% during 2007-2014. Advanced maternal age, pre-pregnancy obesity, and pre-pregnancy comorbidity also increased during this period, but cesarean delivery did not. None of these risk factors affected the increasing trend of severe maternal morbidity. However, the pre-pregnancy risk factors together were estimated to contribute to 13% (95% confidence interval: 12, 14%) of severe maternal morbidity cases in the study population overall, and cesarean delivery was estimated to contribute to 37% (95% confidence interval: 36, 38%) of cases.Pre-pregnancy health and cesarean delivery are important risk factors for severe maternal morbidity but do not explain an increasing trend of severe maternal morbidity in California during 2007-2014. Investigation of other potential contributors is needed in order to identify ways to reverse the trend of severe maternal morbidity.

  View details for PubMedID 30626349

• Risk of severe maternal morbidity in relation to prepregnancy body mass index: Roles of maternal co-morbidities and caesarean birth. Paediatric and perinatal epidemiology Leonard, S. A., Carmichael, S. L., Main, E. K., Lyell, D. J., Abrams, B. 2019

  Abstract

  An association between prepregnancy body mass index (BMI) and severe maternal morbidity (SMM) has been reported, but evidence has been mixed and potential explanations have not been examined.To evaluate the association between prepregnancy BMI and SMM in a large, diverse birth cohort and assess potential mediation by obesity-related co-morbidities and caesarean birth.This cohort study used linked birth certificate and hospitalisation discharge records from Californian births during 2007-2012. We assessed associations between prepregnancy BMI and SMM, and used inverse probability weighting for multiple mediators to estimate relative and absolute natural direct and indirect effects accounting for mediation by co-morbidities (hypertensive conditions, diabetes, asthma) and caesarean birth.Among 2 650 182 births, the prevalence of SMM was 1.42%. Adjusted risk ratios for the total association between prepregnancy BMI category and SMM were 1.12 (95% confidence interval [CI] 1.07, 1.18) for underweight, 1.02 (95% CI 0.99, 1.04) for overweight, 1.04 (95% CI 1.00, 1.07) for obesity class 1, 1.14 (95% CI 1.09, 1.20) for obesity class 2, and 1.28 (95% CI 1.22, 1.36) for obesity class 3 compared to women with normal weight. After accounting for mediation by co-morbidity and caesarean birth, the risk ratios were 1.19 (95% CI 1.14, 1.26) for underweight, 0.91 (95% CI 0.89, 0.94) for overweight, 0.86 (95% CI 0.84, 0.89) for obesity class 1, 0.88 (95% CI 0.84, 0.92) for obesity class 2, and 0.89 (95% CI 0.83, 0.95) for obesity class 3.Co-morbidities and caesarean birth explained an association between high prepregnancy BMI and SMM. These findings suggest that promotion of healthy prepregnancy weight, along with management of co-morbidities and support of vaginal birth in pregnant women with high BMI, could reduce the risk of SMM. However, these mediators did not reduce the elevated risk of SMM observed in women with low BMI.

  View details for DOI 10.1111/ppe.12555

  View details for PubMedID 31106879

• Survival of infants with spina bifida and the role of maternal prepregnancy body mass index. Birth defects research Pace, N. D., Siega-Riz, A. M., Olshan, A. F., Chescheir, N. C., Cole, S. R., Desrosiers, T. A., Tinker, S. C., Hoyt, A. T., Canfield, M. A., Carmichael, S. L., Meyer, R. E. 2019

  Abstract

  To investigate first-year survival of infants born with spina bifida, and examine the association of maternal prepregnancy body mass index (BMI) with infant mortality.This is a retrospective cohort study of 1,533 liveborn infants with nonsyndromic spina bifida with estimated dates of delivery from 1998 to 2011 whose mothers were eligible for the National Birth Defects Prevention Study (NBDPS). NBDPS data were linked to death records to conduct survival analyses. Kaplan-Meier survival functions estimated mortality risk over the first year of life. Cox proportional hazards models estimated hazard ratios (HRs) for maternal prepregnancy BMI categorized as underweight (<18.5), normal (18.5-24.9), overweight (25-29.9), and obese (≥30).Infant mortality risk among infants with spina bifida was (4.4% [3.52, 5.60%]). Infants with multiple co-occurring defects, very preterm delivery, multiple gestation, high-level spina bifida lesions, or non-Hispanic Black mothers had an elevated risk of infant mortality. Maternal prepregnancy underweight and obesity were associated with higher infant mortality (15.7% [7.20, 32.30%] and 5.82% [3.60, 9.35%], respectively). Adjusted HR estimates showed underweight and obese mothers had greater hazard of infant mortality compared to normal weight mothers (HR: 4.5 [1.08, 16.72] and 2.6 [1.36, 8.02], respectively).The overall risk of infant mortality for infants born with spina bifida was lower than most previously reported estimates. Infants born with spina bifida to mothers who were underweight or obese prepregnancy were at higher risk of infant mortality. This study provides additional evidence of the importance of healthy maternal weight prior to pregnancy.

  View details for DOI 10.1002/bdr2.1552

  View details for PubMedID 31322328

• Comparing Usual Dietary Intakes Among Subgroups of Mothers in the Year Before Pregnancy. Public health reports (Washington, D.C. : 1974) Carmichael, S. L., Ma, C., Feldkamp, M. L., Shaw, G. M. 2018: 33354918821078

  Abstract

  OBJECTIVE:: The quantity and quality of dietary intake among women of reproductive age has important public health implications for nutritional status during pregnancy. We described dietary intake during the year before pregnancy among a large, diverse group of US mothers.METHODS:: We examined data from 11109 mothers who gave birth from 1997 through 2011 and participated in a population-based case-control study, the National Birth Defects Prevention Study, as controls (mothers who had babies without major birth defects). We examined whether subgroups of mothers at elevated risk of adverse pregnancy outcomes were more likely than their reference groups to have high dietary intake (>90th percentile of intake) or low dietary intake (<10th percentile of intake). We examined dietary intake of 22 nutritional factors, which were estimated from responses to a food frequency questionnaire.RESULTS:: Participants who were aged <20, were nulliparous, had

  View details for PubMedID 30593261

• A machine learning approach to investigate potential risk factors for gastroschisis in California. Birth defects research Weber, K. A., Yang, W., Carmichael, S. L., Padula, A. M., Shaw, G. M. 2018

  Abstract

  BACKGROUND: To generate new leads about risk factors for gastroschisis, a birth defect that has been increasing in prevalence over time, we performed an untargeted data mining statistical approach.METHODS: Using data exclusively from the California Center of the National Birth Defects Prevention Study, we compared 286 cases of gastroschisis and 1,263 non-malformed, live-born controls. All infants had delivery dates between October 1997 and December 2011 and were stratified by maternal age at birth (<20 and ≥ 20years). Cases and controls were compared by maternal responses to 183 questions (219 variables) using random forest, a data mining procedure. Variables deemed important by random forest were included in logistic regression models to estimate odds ratios and 95% confidence intervals.RESULTS: Among women younger than 20, of variables deemed important, there were higher odds observed for higher consumption of chocolate, low intake of iron, acetaminophen use, and urinary tract infections during the beginning of pregnancy. After adjustment, the higher odds remained for low iron intake and a urinary tract infection in the first month of pregnancy. Among women aged 20 or older, of variables deemed important, higher odds were observed for US-born women of Hispanic ethnicity and for parental substance abuse. There were lower odds observed for obese women, women who ate any cereal the month before pregnancy, and those with higher parity.CONCLUSIONS: We did not discover many previously unreported associations, despite our novel approach to generate new hypotheses. However, our results do add evidence to some previously proposed risk factors.

  View details for PubMedID 30588769

• Teratology society position statement on surveillance and prevalence estimation of neural tube defects. Birth defects research Kancherla, V., Carmichael, S. L., Feldkamp, M. L., Berry, R. J. 2018

  View details for PubMedID 30569547

• Prepregnancy maternal body mass index and venous thromboembolism: A population based cohort study. BJOG : an international journal of obstetrics and gynaecology Butwick, A. J., Bentley, J., Leonard, S. A., Carmichael, S. L., El-Sayed, Y. Y., Stephansson, O., Guo, N. 2018

  Abstract

  OBJECTIVE: To assess the relationship between maternal body mass index (BMI) and pregnancy-related venous thromboembolism (VTE).DESIGN: Cross-sectional study.SETTING & POPULATION: 2,449,133 women with singleton pregnancies who underwent delivery hospitalization in California between 2008 and 2012.METHODS: Association of prepregnancy BMI and the risk of an antepartum and postpartum VTE was examined using logistic regression, with normal BMI as reference.MAIN OUTCOME MEASURES: Antepartum and postpartum VTE related hospitalization.RESULTS: The prevalences of antepartum and postpartum VTE increased with increasing BMI (antepartum: 2.3, 3.0, 3.8, 4.2, 4.7, and 10.6 per 10 000 women for underweight, normal BMI, overweight, obesity class I, II, and III, P<0.001. postpartum: 2.0, 3.1, 3.9, 5.6, 9.0, and 13.2 per 10 000 women, P<0.01). The adjusted odds of antepartum and postpartum VTE increased progressively with increasing BMI, and obese class III women being at highest risk of pregnancy-related VTE compared with normal BMI women: adjusted odds ratio (OR) for antepartum VTE: 2.9; 95% CI 2.2-3.8 and adjusted OR for postpartum VTE: 3.6; 95% CI 2.9-4.6.CONCLUSIONS: Our findings clearly demonstrate an increasing risk of pregnancy-related VTE with increasing BMI. This article is protected by copyright. All rights reserved.

  View details for PubMedID 30500109

• Impact of post-collection freezing delay on the reliability of serum metabolomics in samples reflecting the California mid-term pregnancy biobank METABOLOMICS La Frano, M. R., Carmichael, S. L., Ma, C., Hardley, M., Shen, T., Wong, R., Rosales, L., Borkowski, K., Pedersen, T. L., Shaw, G. M., Stevenson, D. K., Fiehn, O., Newman, J. W. 2018; 14 (11)

  View details for DOI 10.1007/s11306-018-1450-9

  View details for Web of Science ID 000450525400001

• Fish consumption prior to pregnancy and pregnancy outcomes in the National Birth Defects Prevention Study, 1997-2011. Public health nutrition Benjamin, R. H., Mitchell, L. E., Canfield, M. A., Hoyt, A. T., Lai, D., Ramadhani, T. A., Carmichael, S. L., Case, A. P., Waller, D. K., National Birth Defects Prevention Study 2018: 1–8

  Abstract

  OBJECTIVE: To evaluate the relationships between maternal fish consumption and pregnancy outcomes in a large, population-based sample of women in the USA.DESIGN: We collected average fish consumption prior to pregnancy using a modified version of the semi-quantitative Willett FFQ. We estimated adjusted OR (aOR) and 95 % CI for associations between different levels of fish consumption and preterm birth (<37 weeks), early preterm birth (<32 and <35 weeks) and small-for-gestational-age infants (SGA; <10th percentile).SETTING: The National Birth Defects Prevention Study (NBDPS).SUBJECTS: Control mother-infant pairs with estimated delivery dates between 1997 and 2011 (n 10 919).RESULTS: No significant associations were observed between fish consumption and preterm birth or early preterm birth (aOR = 0·7-1·0 and 0·7-0·9, respectively). The odds of having an SGA infant were elevated (aOR = 2·1; 95 % CI 1·2, 3·4) among women with daily fish consumption compared with women consuming fish less than once per month. No associations were observed between other levels of fish consumption and SGA (aOR = 0·8-1·0).CONCLUSIONS: High intake of fish was associated with twofold higher odds of having an SGA infant, while moderate fish consumption prior to pregnancy was not associated with preterm or SGA. Our study, like many other studies in this area, lacked information regarding preparation methods and the specific types of fish consumed. Future studies should incorporate information on nutrient and contaminant contents, preparation methods and biomarkers to assess these relationships.

  View details for PubMedID 30326983

• Severe maternal morbidity and postpartum mental health-related outcomes in Sweden: a population-based matched-cohort study. Archives of women's mental health Wall-Wieler, E., Carmichael, S. L., Urquia, M. L., Liu, C., Hjern, A. 2018

  Abstract

  We examined whether women experiencing severe maternal morbidity (SMM) are more likely to be treated for a psychiatric illness or be prescribed psychotropic medications in the postpartum year than mothers who did not experience SMM. We also examine the relationship between SMM and specific mental health-related outcomes, and the relationship between specific SMM diagnoses/procedures and postpartum mental-health-related outcomes. The national registers in Sweden were used to create a population-based matched cohort. Every delivery with SMM between July 1, 2006, and December 31, 2012 (n=8558), was matched with two deliveries without SMM (n=17,116). Conditional logistic regression models assessed the relationship between SMM and postpartum mental health-related outcomes. Women who experienced SMM had significantly greater odds of being treated for a psychiatric disorder (aOR 1.22; 95% CI 1.03-1.45) and being prescribed psychotropic medications (aOR 1.40; 95% CI 1.24-1.58) in the postpartum year. Specifically, they had significantly greater odds of being treated for neuroses (aOR 1.35; 95% CI 1.09-1.69) and having a prescription for anxiolytics/hypnotics (aOR 1.36; 95% CI 1.18-1.58) or antidepressants (aOR 1.35; 95% CI 1.17-1.55). Women who were diagnosed with shock or uterine rupture/obstetric laparotomy during delivery had the greatest odds of postpartum mental health-related outcomes. This study identified mothers with SMM as a group at high risk for postpartum mental illness. Postpartum mental health services should be provided to ensure the well-being of these high-risk mothers.

  View details for PubMedID 30334101

• An application of data mining to identify potential risk factors for anophthalmia and microphthalmia. Paediatric and perinatal epidemiology Weber, K. A., Yang, W., Carmichael, S. L., Lupo, P. J., Dukhovny, S., Yazdy, M. M., Lin, A. E., Van Bennekom, C. M., Mitchell, A. A., Shaw, G. M., National Birth Defects Prevention Study 2018

  Abstract

  BACKGROUND: We examined a large number of variables to generate new hypotheses regarding a wider range of risk factors for anophthalmia/microphthalmia using data mining.METHODS: Data were from the National Birth Defects Prevention Study, a multicentre, case-control study from 10 centres in the United States. There were 134 cases of "isolated" and 87 "nonisolated" (with other major birth defects) of anophthalmia/microphthalmia and 11052 nonmalformed controls with delivery dates October 1997-December 2011. Using random forest, a data mining procedure, we compared the two case types with controls for 201 variables. Variables considered important ranked by random forest were included in a multivariable logistic regression model to estimate odds ratios and 95% confidence intervals.RESULTS: Predictors for isolated cases included paternal race/ethnicity, maternal intake of certain nutrients and foods, and childhood health problems in relatives. Using regression, inverse associations were observed with greater maternal education and with increasing intake of folate and potatoes. Odds were slightly higher with greater paternal education, for increased intake of carbohydrates and beans, and if relatives had a childhood health problem. For nonisolated cases, predictors included paternal race/ethnicity, maternal intake of certain nutrients, and smoking in the home the month before conception. Odds were higher for Hispanic fathers and smoking in the home and NSAID use the month before conception.CONCLUSIONS: Results appear to support previously hypothesised risk factors, socio-economic status, NSAID use, and inadequate folate intake, and potentially provide new areas such as passive smoking pre-pregnancy, and paternal education and ethnicity, to explore for further understanding of anophthalmia/microphthalmia.

  View details for PubMedID 30300919

• 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 PubMedID 30208499

• Application of machine-learning to predict early spontaneous preterm birth among nulliparous non-Hispanic black and white women. Annals of epidemiology Weber, A., Darmstadt, G. L., Gruber, S., Foeller, M. E., Carmichael, S. L., Stevenson, D. K., Shaw, G. M. 2018

  Abstract

  PURPOSE: Spontaneous preterm birth is a leading cause of perinatal mortality in the United States, occurring disproportionately among non-Hispanic black women compared to other race-ethnicities. Clinicians lack tools to identify first-time mothers at risk for spontaneous preterm birth. This study assessed prediction of early (<32weeks) spontaneous preterm birth among non-Hispanic black and white women by applying state-of-the-art machine-learning to multilevel data from a large birth cohort.METHODS: Data from birth certificate and hospital discharge records for 336,214 singleton births to nulliparous women in California from 2007 to 2011 were used in cross-validated regressions, with multiple imputation for missing covariate data. Residential census tract information was overlaid for 281,733 births. Prediction was assessed with areas under the receiver operator characteristic curves (AUCs).RESULTS: Cross-validated AUCs were low (0.62 [min=0.60, max=0.63] for non-Hispanic blacks and 0.63 [min=0.61, max=0.65] for non-Hispanic whites). Combining racial-ethnic groups improved prediction (cross-validated AUC=0.67 [min=0.65, max=0.68]), approaching what others have achieved using biomarkers. Census tract-level information did not improve prediction.CONCLUSIONS: The resolution of administrative data was inadequate to precisely predict individual risk for early spontaneous preterm birth despite the use of advanced statistical methods.

  View details for PubMedID 30236415

• 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 PubMedID 29614386

• Dietary factors and pediatric multiple sclerosis: A case-control study MULTIPLE SCLEROSIS JOURNAL Pakpoor, J., Seminatore, B., Graves, J. S., Schreiner, T., Waldman, A. T., Lotze, T. E., Belman, A., Greenberg, B. M., Weinstock-Guttman, B., Aaen, G., Tillema, J., McDonald, J. C., Hart, J., Ness, J. M., Harris, Y., Rubin, J., Candee, M., Krupp, L., Gorman, M., Benson, L., Rodriguez, M., Chitnis, T., Mar, S., Kahn, I., Rose, J., Carmichael, S. L., Roalstad, S., Waltz, M., Casper, T., Waubant, E., US Network Pediat Multiple Scleros 2018; 24 (8): 1067–76

  Abstract

  The role of diet in multiple sclerosis (MS) is largely uncharacterized, particularly as it pertains to pediatric-onset disease.To determine the association between dietary factors and MS in children.Pediatric MS patients and controls were recruited from 16 US centers (MS or clinically isolated syndrome onset before age 18, <4 years from symptom onset and at least 2 silent lesions on magnetic resonance imaging). The validated Block Kids Food Screener questionnaire was administered 2011-2016. Chi-squared test compared categorical variables, Kruskal-Wallis test compared continuous variables, and multivariable logistic regression analysis was performed.In total, 312 cases and 456 controls were included (mean ages 15.1 and 14.4 years). In unadjusted analyses, there was no difference in intake of fats, proteins, carbohydrates, sugars, fruits, or vegetables. Dietary iron was lower in cases ( p = 0.04), and cases were more likely to consume below recommended guidelines of iron (77.2% of cases vs 62.9% of controls, p < 0.001). In multivariable analysis, iron consumption below recommended guidelines was associated with MS (odds ratio = 1.80, p < 0.01).Pediatric MS cases may be less likely to consume sufficient iron compared to controls, and this warrants broader study to characterize a temporal relationship. No other significant difference in intake of most dietary factors was found.

  View details for PubMedID 28608728

  View details for PubMedCentralID PMC5711616

• Nutrient intake in women before conception and risks of anophthalmia and microphthalmia in their offspring. Birth defects research Weber, K. A., Yang, W., Carmichael, S. L., Shaw, G. M., National Birth Defects Prevention Study 2018; 110 (10): 863–70

  Abstract

  BACKGROUND: We previously explored associations between nutrients including folate and other macro and micronutrients and risks of anophthalmia or microphthalmia in the National Birth Defects Prevention Study. In the current study, we expand those previous results with larger sample sizes and conduct analyses with an additional diet quality index using more recent data.METHODS: The National Birth Defects Prevention Study is a population-based, multicenter case-control study of over 30 major birth defects, with estimated due dates from October 1997 to December 2011. Cases were 224 infants diagnosed with anophthalmia or microphthalmia. Controls were 11,109 live-born, nonmalformed infants randomly selected by each study center. Mothers completed a standardized, computer-assisted telephone interview between 6 weeks and 24 months after delivery. Mothers responded to a shortened food frequency questionnaire, assessing their nutrient intake for the year before pregnancy, and questions about periconceptional (2 months before to 2 months after conception) vitamin supplement use. Nutrient intake quartiles were based on the intake among controls.RESULTS: Among vitamin supplement users, odds of anophthalmia/microphthalmia were decreased for women with intake levels in the highest quartile of folate (0.56, 95% confidence interval [CI] 0.32-0.98), magnesium (0.42, 95% CI 0.22-0.82), and vitamin E (0.50, 95% CI 0.29-0.89). Among women not reporting vitamin supplement use, the odds were significantly increased for beta-carotene (2.5, 95% CI 1.10-5.68) and decreased for retinol (0.37, 95% CI 0.19-0.73).CONCLUSIONS: In this expanded analysis, we observed associations for a few nutrients, specifically forms of vitamin A. However, the heterogeneity of results by form and vitamin use necessitates further inquiry.

  View details for PubMedID 29504274

• Women's periconceptional diet and risk of biliary atresia in offspring. Birth defects research Carmichael, S. L., Ma, C., Van Zutphen, A. R., Moore, C. A., Shaw, G. M., National Birth Defects Prevention Study 2018

  Abstract

  INTRODUCTION: We examined the association of biliary atresia with maternal dietary intake, using National Birth Defects Prevention Study (NBDPS) data from 152 cases and 11,112 nonmalformed controls born 1997-2011.METHODS: NBDPS is a multisite, population-based case-control study. Exposure data were from maternal telephone interviews, which included a food frequency questionnaire. Odds ratios (OR) and 95% confidence intervals (CI) were generated from logistic regression models that included nutritional factors as continuous variables and were adjusted for energy intake only or energy intake plus covariates (maternal race-ethnicity, education, age, prepregnancy body mass index, vitamin/mineral supplement intake, conception during summer). Models included a quadratic term for the nutrient if p<0.10. ORs reflect odds of having biliary atresia for nutrient values at the 75th compared to 25th percentile values of each nutrient, based on distributions among controls.RESULTS: ORs for which the 95% CI excluded 1.00 were energy-adjusted ORs for calcium (0.63), protein (0.65), riboflavin (0.71), and diet quality index (0.69), and fully adjusted ORs for calcium (0.68) and vitamin E (0.72). ORs that were fully adjusted for covariates tended to be closer to 1.0 than ORs adjusted only for energy intake. ORs for the other studied nutrients had 95% CIs that included 1.00.CONCLUSIONS: NBDPS is the first study to include detailed information on maternal dietary intake and risk of biliary atresia. Our results suggest reduced risks associated with some nutrients, which may provide etiologic clues but should be interpreted with caution given the small number of cases and novelty of the investigation.

  View details for PubMedID 29762915

• Chemical Contaminants in Raw and Pasteurized Human Milk JOURNAL OF HUMAN LACTATION Hartle, J. C., Cohen, R. S., Sakamoto, P., Barr, D., Carmichael, S. L. 2018; 34 (2): 340–49

  Abstract

  Environmental contaminants ranging from legacy chemicals like p,p'-dichlorodiphenyltrichloroethane (DDT) to emerging chemicals like phthalates are ubiquitous. Research aims/questions: This research aims to examine the presence and co-occurrence of contaminants in human milk and effects of pasteurization on human milk chemical contaminants.We analyzed human milk donated by 21 women to a milk bank for 23 chemicals, including the persistent organic pollutants (POPs) polychlorinated biphenyls (PCBs), polybrominated diphenyl ethers (PBDEs), dichlorodiphenyltrichloroethane (DDT), and dichlorodiphenyldichloroethylene (DDE) isomers that are known to sequester in adipose tissue, along with the current-use and nonpersistent pesticides chlorpyrifos and permethrin, phthalates, and bisphenol A (BPA). Human milk was analyzed raw and pasteurized for these chemicals using gas chromatography-tandem mass spectrometry for the POPs and high-performance liquid chromatography-tandem mass spectrometry for non-POPs.Within the different chemical classes, PBDE47, PCB153, ppDDE, and MEHHP (phthalate metabolite) had the highest median concentrations and were observed in all samples. We also observed chlorpyrifos and BPA in all samples and permethrin in 90% of the samples tested. Only two chemicals, chlorpyrifos and permethrin, were susceptible to substantial degradation from pasteurization, a standard method for processing donated human milk.We detected 19 of 23 chemicals in all of our prepasteurized milk and 18 of 23 chemicals in all of our pasteurized milk. Pasteurization did not affect the presence of most of the chemicals. Future research should continue to explore human milk for potential chemical contamination and as a means to surveil exposures among women and children.

  View details for PubMedID 29601252

• Maternal body mass index and risk of intraventricular hemorrhage in preterm infants. Pediatric research Pai, V. V., Carmichael, S. L., Kan, P., Leonard, S. A., Lee, H. C. 2018

  Abstract

  BACKGROUND: Intraventricular hemorrhage (IVH) and pre-pregnancy obesity and underweight have been linked to inflammatory states. We hypothesize that IVH in preterm infants is associated with pre-pregnancy obesity and underweight due to an inflammatory intrauterine environment.METHODS: Population-based study of infants born between 22 and 32 weeks' gestation from 2007 to 2011. Data were extracted from vital statistics and the California Perinatal Quality Care Collaborative. Results were examined for all cases (any IVH) and for severe IVH.RESULTS: Among 20,927 infants, 4,818 (23%) had IVH and 1,514 (7%) had severe IVH. After adjustment for confounders, there was an increased risk of IVH associated with pre-pregnancy obesity, relative risk 1.14 (95% CI 1.06, 1.32) for any IVH, and 1.25 (85% CI 1.10, 1.42) for severe IVH. The direct effect of pre-pregnancy obesity on any IVH was significant (P<0.001) after controlling for antenatal inflammation-related conditions, but was not significant after controlling for gestational age (P=0.56).CONCLUSION: Pre-pregnancy obesity was found to be a risk factor for IVH in preterm infants; however, this relationship appeared to be largely mediated through the effect of BMI on gestational age at delivery. The etiology of IVH is complex and it is important to understand contributing maternal factors.Pediatric Research accepted article preview online, 06 April 2018. doi:10.1038/pr.2018.47.

  View details for PubMedID 29624572

• 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 PubMedID 29020134

• 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

• Congenital heart disease complexity and childhood cancer risk. Birth defects research Collins, R. T., Von Behren, J., Yang, W., Carmichael, S. L., Reynolds, P., Fisher, P. G., Shaw, G. M. 2018; 110 (17): 1314–21

  Abstract

  Childhood cancer is increased in those with birth defects, including those with congenital heart disease (CHD). Lymphoma risk is increased in children with CHD. This study analyzes the effect of CHD and CHD severity on childhood cancer risk.We analyzed cancer risk in a population-based cohort of children with and without CHD born between 1988 and 2004 by linking data from the California Birth Defects Monitoring Program with data from the California Cancer Registry. We compared cancer risk in children with and without CHD, excluding children with chromosomal anomalies.Of >3 million children in the birth cohort, 65,585 had birth defects (2%), 25,981 with CHD. Cancer occurred in 4,781 (0.15%) children, 43 (0.17%) with CHD. Cancer risk in CHD was increased (hazard ratio [HR]) 2.63, 95% CI: 1.95, 3.55). Leukemia was the most common cancer in those without CHD (1,722/4,738, 36%), central nervous system tumors were second (1,073/4,738, 23%), and lymphoma third (410/4,738, 9%). Among children with CHD, lymphoma and leukemia occurred with the same frequency (12/43, 28% for each). HR for lymphoma was 8.37 (CI: 4.71, 14.86) with CHD versus without. HR for leukemia was 2.05 (CI: 1.16, 3.61) with CHD versus without. CHD complexity was higher in lymphoma (3, interquartile range [IQR]: 2-3) than those with leukemia (1, IQR, 1-2; p < .02).Cancer risk is increased in children with CHD. Lymphoma risk is increased in CHD and is correlated with more complex CHD. These results suggest a shared developmental origin for CHD and lymphoma may be present.

  View details for PubMedID 30328285

• Impact of post-collection freezing delay on the reliability of serum metabolomics in samples reflecting the California mid-term pregnancy biobank. Metabolomics : Official journal of the Metabolomic Society La Frano, M. R., Carmichael, S. L., Ma, C., Hardley, M., Shen, T., Wong, R., Rosales, L., Borkowski, K., Pedersen, T. L., Shaw, G. M., Stevenson, D. K., Fiehn, O., Newman, J. W. 2018; 14 (11): 151

  Abstract

  Population-based biorepositories are important resources, but sample handling can affect data quality.Identify metabolites of value for clinical investigations despite extended postcollection freezing delays, using protocols representing a California mid-term pregnancy biobank.Blood collected from non-pregnant healthy female volunteers (n = 20) underwent three handling protocols after 30 min clotting at room temperature: (1) ideal-samples frozen (- 80 °C) within 2 h of collection; (2) delayed freezing-samples held at room temperature for 3 days, then 4 °C for 9 days, the median times for biobank samples, and then frozen; (3) delayed freezing with freeze-thaw-the delayed freezing protocol with a freeze-thaw cycle simulating retrieved sample sub-aliquoting. Mass spectrometry-based untargeted metabolomic analyses of primary metabolism and complex lipids and targeted profiling of oxylipins, endocannabinoids, ceramides/sphingoid-bases, and bile acids were performed. Metabolite concentrations and intraclass correlation coefficients (ICC) were compared, with the ideal protocol as the reference.Sixty-two percent of 428 identified compounds had good to excellent ICCs, a metric of concordance between measurements of samples handled with the different protocols. Sphingomyelins, phosphatidylcholines, cholesteryl esters, triacylglycerols, bile acids and fatty acid diols were the least affected by non-ideal handling, while sugars, organic acids, amino acids, monoacylglycerols, lysophospholipids, N-acylethanolamides, polyunsaturated fatty acids, and numerous oxylipins were altered by delayed freezing. Freeze-thaw effects were assay-specific with lipids being most stable.Despite extended post-collection freezing delays characteristic of some biobanks of opportunistically collected clinical samples, numerous metabolomic compounds had both stable levels and good concordance.

  View details for PubMedID 30830400

• Antioxidant Consumption is Associated with Decreased Odds of Congenital Limb Deficiencies PAEDIATRIC AND PERINATAL EPIDEMIOLOGY Pace, N. D., Desrosiers, T. A., Carmichael, S. L., Shaw, G. M., Olshan, A. F., Siega-Riz, A., Natl Birth Defects Prevention Stud 2018; 32 (1): 90–99

  Abstract

  Approximately 1 in 2000 infants is born with a limb deficiency in the US. Research has shown that women's periconceptional diet and use of vitamin supplements can affect risk of birth defects. We investigated whether maternal consumption of nutritional antioxidants was associated with occurrence of transverse limb deficiency (TLD) and longitudinal limb deficiencies (LLD).We analysed case-control data from mothers and their singleton infants with TLD (n = 566), LLD (n = 339), or no malformation (controls; n = 9384) in the National Birth Defects Prevention Study (1997-2009). Using a modified food frequency, we estimated usual pre-pregnancy antioxidant consumption by total fruit and vegetable consumption (in grams) grouped into tertiles, and cumulative antioxidant score (ranging from 1 to 10) based on consumption of three antioxidants: beta-carotene, lycopene, and lutein. We estimated odds ratios (OR) adjusted for maternal age, race/ethnicity, education, smoking, alcohol use, body mass index, and total energy.Compared to women in the lowest tertile of fruit and vegetable consumption, women in the highest tertile were less likely to have infants with TLD (OR 0.74, 95% CI 0.57, 0.96) or LLD (OR 0.82, 95% CI 0.59, 1.13). Compared to the lowest antioxidant consumption score of 1, those with the highest score of 10 had ORs of 0.68 (95% CI 0.48, 0.95) for TLD and 0.77 (95% CI 0.50, 1.17) for LLD.Dietary intake of antioxidants was associated with reduced odds of limb deficiencies. These findings add further evidence for women's periconceptional diet reducing occurrence of some birth defects.

  View details for PubMedID 28869773

  View details for PubMedCentralID PMC5771883

• Contribution of dietary intake to relapse rate in early paediatric multiple sclerosis JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY Azary, S., Schreiner, T., Graves, J., Waldman, A., Belman, A., Guttman, B., Aaen, G., Tillema, J., Mar, S., Hart, J., Ness, J., Harris, Y., Krupp, L., Gorman, M., Benson, L., Rodriguez, M., Chitnis, T., Rose, J., Barcellos, L. F., Lotze, T., Carmichael, S. L., Roalstad, S., Casper, C. T., Waubant, E. 2018; 89 (1): 28–33

  Abstract

  The role of diet in multiple sclerosis (MS) course remains largely unknown. Children with MS have a higher relapse rate compared with MS in adults. Thus, studying the effect of diet on relapse rate in this age group is likely to provide more robust answers.This is a multicentre study done at 11 paediatric MS centres in the USA. Patients with relapsing-remitting MS (RRMS) or clinically isolated syndrome (CIS) with disease onset before 18 years of age and duration of less than 4 years were included in this study. Dietary intake during the week before enrolment was assessed with the validated Block Kids Food Screener. The outcome of the study was time from enrolment to the next relapse. 219 patients with paediatric RRMS or CIS were enrolled. Each 10% increase in energy intake from fat increased the hazard of relapse by 56% (adjusted HR 1.56, 95% CI 1.05 to 2.31, p=0.027), and in particular each 10% increase in saturated fat tripled this hazard (adjusted HR: 3.37, 95% CI 1.34 to 8.43, p=0.009). In contrast, each additional one cup equivalent of vegetable decreased the hazard of relapse by 50% (adjusted HR: 0.50, 95% CI 0.27 to 0.91, p=0.024). These associations remained with mutual adjustment and persisted when adjusting for baseline 25(OH) vitamin D serum level. Other studied nutrients were not associated with relapse.This study suggests that in children with MS, high energy intake from fat, especially saturated fat, may increase the hazard to relapse, while vegetable intake may be independently protective.

  View details for PubMedID 28993476

  View details for PubMedCentralID PMC5732893

• Characteristics of women with multiple postpartum hospital admissions Girsen, A. I., Sie, L., Carmichael, S., Foeller, M. E., Druzin, M. L., Lee, H. C., Gibbs, R. S. MOSBY-ELSEVIER. 2018: S461–S462

  View details for Web of Science ID 000423616600271

• Thyroid Medication Use and Birth Defects in the National Birth Defects Prevention Study BIRTH DEFECTS RESEARCH Howley, M. M., Fisher, S. C., Van Zutphen, A. R., Waller, D. K., Carmichael, S. L., Browne, M. L., Natl Birth Defects Prevention 2017; 109 (18): 1471–81

  Abstract

  Thyroid disorders are common among reproductive-aged women, with hypothyroidism affecting 2 to 3% of pregnancies, and hyperthyroidism affecting an additional 0.1 to 1%. We examined associations between thyroid medications and individual birth defects using data from the National Birth Defects Prevention Study (NBDPS).The NBDPS is a multisite, population-based, case-control study that included pregnancies with estimated delivery dates from 1997 to 2011. We analyzed self-reported thyroid medication use from mothers of 31,409 birth defect cases and 11,536 unaffected controls. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using logistic regression for birth defects with five or more exposed cases, controlling for maternal age, race/ethnicity, and study center. Crude ORs and exact 95% CIs were estimated for defects with 3 to 4 exposed cases.Thyroid hormone was used by 738 (2.3%) case and 237 (2.1%) control mothers, and was associated with anencephaly (OR = 1.68; 95% CI, 1.03-2.73), holoprosencephaly (OR = 2.48; 95% CI, 1.13-5.44), hydrocephaly (1.77; 95% CI, 1.07-2.95) and small intestinal atresia (OR = 1.81; 95% CI, 1.04-3.15). Anti-thyroid medication was used by 34 (0.1%) case and 10 (<0.1%) control mothers, and was associated with aortic valve stenosis (OR = 6.91; 95% CI, 1.21-27.0).While new associations were identified, our findings are relatively consistent with previous NBDPS analyses. Our findings suggest thyroid medication use is not associated with most birth defects studied in the NBDPS, but may be associated with some specific birth defects. These results should not be interpreted to suggest that medications used to treat thyroid disease are teratogens, as the observed associations may reflect effects of the underlying thyroid disease. Birth Defects Research 109:1471-1481, 2017.© 2017 Wiley Periodicals, Inc.

  View details for PubMedID 28758357

• Maternal Exposure to Nitrogen Dioxide, Intake of Methyl Nutrients, and Congenital Heart Defects in Offspring AMERICAN JOURNAL OF EPIDEMIOLOGY Stingone, J. A., Luben, T. J., Carmichael, S. L., Aylsworth, A. S., Botto, L. D., Correa, A., Gilboa, S. M., Langlois, P. H., Nembhard, W. N., Richmond-Bryant, J., Shaw, G. M., Olshan, A. F., Natl Birth Defects Prevention 2017; 186 (6): 719–29

  Abstract

  Nutrients that regulate methylation processes may modify susceptibility to the effects of air pollutants. Data from the National Birth Defects Prevention Study (United States, 1997-2006) were used to estimate associations between maternal exposure to nitrogen dioxide (NO2), dietary intake of methyl nutrients, and the odds of congenital heart defects in offspring. NO2 concentrations, a marker of traffic-related air pollution, averaged across postconception weeks 2-8, were assigned to 6,160 nondiabetic mothers of cases and controls using inverse distance-squared weighting of air monitors within 50 km of maternal residences. Intakes of choline, folate, methionine, and vitamins B6 and B12 were assessed using a food frequency questionnaire. Hierarchical regression models, which accounted for similarities across defects, were constructed, and relative excess risks due to interaction were calculated. Relative to women with the lowest NO2 exposure and high methionine intake, women with the highest NO2 exposure and lowest methionine intake had the greatest odds of offspring with a perimembranous ventricular septal defect (odds ratio = 3.23, 95% confidence interval: 1.74, 6.01; relative excess risk due to interaction = 2.15, 95% confidence interval: 0.39, 3.92). Considerable departure from additivity was not observed for other defects. These results provide modest evidence of interaction between nutrition and NO2 exposure during pregnancy.

  View details for DOI 10.1093/aje/kwx139

  View details for Web of Science ID 000410728500012

  View details for PubMedID 28520847

  View details for PubMedCentralID PMC5610640

• 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 PubMedID 28800643

• 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

• Air pollution, neighborhood acculturation factors, and neural tube defects among Hispanic women in California BIRTH DEFECTS RESEARCH Padula, A. M., Yang, W., Carmichael, S. L., Lurmann, F., Balmes, J., Hammond, S. K., Shaw, G. M. 2017; 109 (6): 403-422

  Abstract

  Neural tube defects (NTDs) are one of the most common types of birth defects. Environmental pollutants and acculturation have been associated with NTDs independently. The potential effect modification of acculturation in the relationship between ambient air pollution and risks of NTDs is not well understood.We investigated whether associations between traffic-related air pollutant exposure in early gestation and NTDs, and more specifically spina bifida, were modified by individual and neighborhood acculturation factors among 139 cases and 466 controls born in the San Joaquin Valley of California, 1997 to 2006. Five criteria pollutant exposures in tertiles, two outcomes, and seven neighborhood acculturation factors from the U.S. Census at the block group level were included for a total of 280 investigated associations. Estimates were adjusted for maternal education and multivitamin use in the first 2 months of pregnancy. Additional analyses were stratified by nativity.Increased odds of NTDs were observed for individuals who had high exposures to carbon monoxide, nitrogen oxide, or nitrogen dioxide and lived in neighborhoods that were more acculturated. Conversely, there were increased odds of NTDs for those who had high prenatal exposure to PM10 and lived in neighborhoods that were less acculturated. The results of spina bifida alone were generally stronger in magnitude. When stratified by individual nativity (U.S.- vs. foreign-born), carbon monoxide, nitrogen oxide, and nitrogen dioxide were more strongly associated with NTDs among U.S.-born Hispanic mothers.Neighborhood acculturation factors were modifiers of the relationship between air pollution and NTDs in California, though not in a consistent direction for all pollutants. Birth Defects Research 109:403-422, 2017. © 2017 Wiley Periodicals, Inc.

  View details for DOI 10.1002/bdra.23602

  View details for Web of Science ID 000398804400001

  View details for PubMedID 28398703

• 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

• Maternal underweight and obesity and risk of orofacial clefts in a large international consortium of population-based studies INTERNATIONAL JOURNAL OF EPIDEMIOLOGY Kutbi, H., Wehby, G. L., Uribe, L., Romitti, P. A., Carmichael, S., Shaw, G. M., Olshan, A. F., DeRoo, L., Rasmussen, S. A., Murray, J. C., Wilcox, A., Lie, R. T., Munger, R. G. 2017; 46 (1): 190–99

  Abstract

  Evidence on association of maternal pre-pregnancy weight with risk of orofacial clefts is inconsistent.Six large case-control studies of orofacial clefts from Northern Europe and the USA were included in analyses pooling individual-level data. Cases included 4943 mothers of children with orofacial clefts (cleft lip only: 1135, cleft palate with cleft lip: 2081, cleft palate only: 1727) and controls included 10 592 mothers of unaffected children. Association of orofacial cleft risk with pre-pregnancy maternal weight classified by level of body mass index (BMI, kg/m 2 ) was evaluated using logistic regression adjusting for multiple covariates.Cleft palate, both alone and with cleft lip (CP+/-CL), was associated with maternal class II+ pre-pregnancy obesity (≥ 35)compared with normal weight [adjusted odds ratio (aOR) = 1.36; 95% confidence interval (CI) = 1.16, 1.58]. CP+/-CL was marginally associated with maternal underweight (aOR = 1.16; 95% CI = 0.98, 1.36). Cleft lip alone was not associated with BMI.In this largest population-based study to date, we found an increased risk of cleft palate, with or without cleft lip, in class II+ obese mothers compared with normal-weight mothers; underweight mothers may also have an increased risk, but this requires further study. These results also suggest that extremes of weight may have a specific effect on palatal development.

  View details for PubMedID 27215617

  View details for PubMedCentralID PMC5837498

• Maternal Smoking, Alcohol, and Caffeine Exposures and Risk of Hypospadias. Birth defects research Carmichael, S. L., Ma, C., Shaw, G. M. 2017; 109 (14): 1127–33

  Abstract

  We examined the association of hypospadias risk with maternal smoking and consumption of alcohol and caffeine.We analyzed data from mothers of 2437 moderate/severe cases and 5472 nonmalformed controls born from 1997 to 2011 who participated in the National Birth Defects Prevention Study (NBDPS). Exposures were assessed by maternal telephone interviews. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (95% CIs) adjusted for mother's age, parity, race-ethnicity, education, vitamin/mineral supplement intake, obesity, and study center.Active smoking during the first month of pregnancy was associated with reduced risk, with smaller ORs for increasing quantity smoked; the OR for smoking >1/2 pack/day was 0.7 (95% CI, 0.5-0.9). Among nonsmokers, the OR for any secondhand smoke exposure was 0.8 (95% CI, 0.7-0.9). ORs for alcohol and caffeine consumption were near one and CIs included 1.0. In an analysis of joint exposures to smoking and alcohol and caffeine consumption, the only OR for which the 95% CI excluded 1.0 was for women who smoked, drank, and had low caffeine consumption (OR, 0.6; 95% CI, 0.4-0.8).Maternal exposure to cigarette smoke was associated with reduced risk, and women who smoked, drank, and had low caffeine intake were at lowest risk. We do not interpret these results to suggest that these exposures have overall benefit to a pregnant woman or developing fetus. They may, however, offer clues to help us understand mechanisms that lead to hypospadias. Birth Defects Research 109:1127-1133, 2017. © 2017 Wiley Periodicals, Inc.

  View details for PubMedID 28635116

• Temporal Relationship of Onset of Necrotizing Enterocolitis and Introduction of Enteric Feedings and Powdered Milk Fortifier. American journal of perinatology Vaks, Y., Birnie, K. L., Carmichael, S. L., Hernandez-Boussard, T., Benitz, W. E. 2017

  View details for PubMedID 29190848

• Postpartum readmission and severe maternal morbidity in California Girsen, A., Lee, L. C., Carmichael, S. L., Foeller, M., Druzin, M. L., Gibbs, R. MOSBY-ELSEVIER. 2017: S112

  View details for Web of Science ID 000414256401118

• An Investigation of Connections between Birth Defects and Cancers Arising in Adolescence and Very Young Adulthood. The Journal of pediatrics Von Behren, J., Fisher, P. G., Carmichael, S. L., Shaw, G. M., Reynolds, P. 2017; 185: 237–40

  Abstract

  This study investigated the relationship between birth defects and cancer in adolescents and very young adults using California's population-based registries. Although overall cancer risk was elevated among individuals with chromosomal birth defects, this was not observed in those with nonchromosomal birth defects, as was demonstrated previously in younger children.

  View details for PubMedID 28336146

• Maternal Stressors and Social Support and Risks of Delivering Babies With Gastroschisis or Hypospadias. American journal of epidemiology Carmichael, S. L., Ma, C., Tinker, S., Shaw, G. M. 2017; 185 (12): 1240–46

  Abstract

  We examined the association of maternal stressful life events and social support with risks of gastroschisis and hypospadias, using data from the National Birth Defects Prevention Study, a population-based case-control study of US births taking place in 2006-2011. We examined maternal self-reports of 7 life events and 3 sources of social support during the periconceptional period among mothers of 593 gastroschisis cases, 1,142 male hypospadias cases, and 4,399 nonmalformed controls. Responses to the questions on stressful life events were summed to form an index (higher is worse), as were responses to questions on social support (higher is better). We used logistic regression to estimate adjusted odds ratios and 95% confidence intervals. The adjusted odds ratios for gastroschisis for a 4-point increase in the stress index were 3.5 (95% confidence interval (CI): 2.6, 4.8) among nonteenage mothers (age ≥20 years) and 1.0 (95% CI: 0.5, 1.7) among teenage mothers (age <20 years). The odds ratio for hypospadias (among all mothers) was 0.8 (95% CI: 0.7, 1.1). Adjusted odds ratios for a social support score of 3 (versus 0) in the 3 respective groups were 0.6 (95% CI: 0.4, 1.0), 1.0 (95% CI: 0.5, 2.3), and 0.6 (95% CI: 0.4, 0.9). Given the lack of prior research on these outcomes and stress, results should be interpreted with caution.

  View details for PubMedID 28505275

• Folic acid fortification and prevalences of neural tube defects, orofacial clefts, and gastroschisis in California, 1989 to 2010. Birth defects research. Part A, Clinical and molecular teratology Yang, W., Carmichael, S. L., Shaw, G. M. 2016; 106 (12): 1032-1041

  Abstract

  We examined whether prevalences of neural tube defects (NTDs), orofacial clefts, and gastroschisis changed more rapidly after than before folic acid fortification in California.This population-based study used vital statistics and birth defects registry data. The study population included all live births and stillbirths delivered in central California counties from 1989 to 2010. Cases included deliveries with NTDs, orofacial clefts, and gastroschisis. Weighted least squares regression was used to estimate slopes during prefortification (before 1997) and postfortification (after 1998), respectively. The difference of the two slopes with the 95% confidence interval (CI) was calculated.For all NTDs combined, slopes indicated that NTD prevalence was decreasing by 8.7 (slope: -8.7; 95% CI, -13.5--3.9) cases per 100,000 deliveries per year before fortification and by 1.7 (slope: -1.7; 95% CI, -3.7-0.3) after fortification; thus the decline had slowed by 7.0 (95% CI, 2.7-11.3) cases per 100,000 deliveries per year. For orofacial clefts, slopes for cleft lip with/without palate as well as for cleft palate alone indicated that the postfortification slope was lower than the prefortification slope suggesting a more accelerated decrease in the postfortification time period. For gastroschisis, the slope after fortification was lower compared with prefortification, indicating a less accelerated prevalence increase in the postfortification time period. Stratification by race/ethnicity did not substantially alter results.We observed a slower decline in prevalence of NTDs, an emergence of a decline in orofacial clefts, and a slower increase in gastroschisis, during the postfortification period in central California, relative to the prefortification period. Birth Defects Research (Part A), 2016. © 2016 Wiley Periodicals, Inc. Birth Defects Research (Part A) 106:1032-1041, 2016. © 2016 Wiley Periodicals, Inc.

  View details for DOI 10.1002/bdra.23514

  View details for PubMedID 27191125

• 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

• Maternal Autoimmune Disease and Birth Defects in the National Birth Defects Prevention Study BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY Howley, M. M., Browne, M. L., Van Zutphen, A. R., Richardson, S. D., Blossom, S. J., Broussard, C. S., Carmichael, S. L., Druschel, C. M. 2016; 106 (11): 950-962

  Abstract

  Little is known about the association between maternal autoimmune disease or its treatment and the risk of birth defects. We examined these associations using data from the National Birth Defects Prevention Study, a multi-site, population-based, case-control study.Analyses included 25,116 case and 9897 unaffected control infants with estimated delivery dates between 1997 and 2009. Information on autoimmune disease, medication use, and other pregnancy exposures was collected by means of telephone interview. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were estimated for birth defects with five or more exposed cases; crude ORs and exact 95% CIs were estimated for birth defects with three to four exposed cases.Autoimmune disease was reported by 373 mothers (279 case and 94 control mothers). The majority of birth defects evaluated were not associated with autoimmune disease; however, a statistically significant association between maternal autoimmune disease and encephalocele was observed (OR, 4.64; 95% CI, 1.95-11.04). Eighty-two mothers with autoimmune disease used an immune modifying/suppressing medication during pregnancy; this was associated with encephalocele (OR, 7.26; 95% CI, 1.37-24.61) and atrial septal defects (OR, 3.01; 95% CI, 1.16-7.80).Our findings suggest maternal autoimmune disease and treatment are not associated with the majority of birth defects, but may be associated with some defects, particularly encephalocele. Given the low prevalence of individual autoimmune diseases and the rare use of specific medications, we were unable to examine associations of specific autoimmune diseases and medications with birth defects. Other studies are needed to confirm these findings. Birth Defects Research (Part A) 106:950-962, 2016. © 2016 Wiley Periodicals, Inc.

  View details for DOI 10.1002/bdra.23527

  View details for Web of Science ID 000392817500012

  View details for PubMedID 27891777

  View details for PubMedCentralID PMC5305117

• Gene variants as risk factors for gastroschisis. American journal of medical genetics. Part A Padula, A. M., Yang, W., Schultz, K., Tom, L., Lin, B., Carmichael, S. L., Lammer, E. J., Shaw, G. M. 2016; 170 (11): 2788-2802

  Abstract

  In a population-based case-control study in California of 228 infants, we investigated 75 genetic variants in 20 genes and risk of gastroschisis with regard to maternal age, race/ethnicity, vitamin use, and smoking exposure. We hypothesized that genes related to vascular compromise may interact with environmental factors to affect the risk of gastroschisis. Haplotypes were constructed for 75 gene variants using the HaploView program. Risk for gastroschisis associated with each gene variant was calculated for both the homozygotes and the heterozygotes, with the homozygous wildtypes as the referent. Risks were estimated as odds ratios (ORs) with 95% confidence intervals (CIs) by logistic regression. We found 11 gene variants with increased risk and four variants with decreased risk of gastroschisis for heterozygous (ORh ) or homozygous variants (ORv ) genotypes. These included NOS3 (rs1036145) ORh  = 0.4 (95% CI: 0.2-0.7); NOS3 (rs10277237) ORv  = 2.7 (95% CI: 1.3-6.0); ADD1 (rs12503220) ORh  = 2.9 (95% CI: 1.6-5.4), GNB3 (rs5443) ORh  = 0.2 (95% CI: 0.1-0.5), ORv  = 0.4 (95% CI: 0.2-0.9); ICAM1 (rs281428) ORv  = 6.9 (95% CI: 2.1-22.9), ICAM1 (rs3093030) ORv  = 2.6 (95% CI: 1.2-5.6); ICAM4 (rs281438) ORv  = 4.9 (95% CI: 1.4-16.6), ICAM5 (rs281417) ORh  = 2.1 (95% CI: 1.1-4.1), ORv  = 4.8 (95% CI: 1.7-13.6); ICAM5 (rs281440) ORh  = 23.7 (95% CI: 5.5-102.5), ORv  = 20.6 (95% CI: 3.4-124.3); ICAM5 (rs2075741) ORv  = 2.2 (95% CI: 1.1-4.4); NAT1 ORv  = 0.3 (95% CI: 0.1-0.9). There were additional associations between several gene variants and gastroschisis among women aged 20-24 and among mothers with and without vitamin use. NOS3, ADD1, ICAM1, ICAM4, and ICAM5 warrant further investigation in additional populations and with the interaction of additional environmental exposures. © 2016 Wiley Periodicals, Inc.

  View details for DOI 10.1002/ajmg.a.37883

  View details for PubMedID 27616475

  View details for PubMedCentralID PMC5096035

• 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

• Maternal diet quality before pregnancy and risk of childhood leukaemia BRITISH JOURNAL OF NUTRITION Singer, A. W., Carmichael, S. L., Selvin, S., Fu, C., Block, G., Metayer, C. 2016; 116 (8): 1469-1478

  Abstract

  Previous studies on maternal nutrition and childhood leukaemia risk have focused on the role of specific nutrients such as folate and have not considered broader measures of diet quality, which may better capture intake of diverse nutrients known to impact fetal development. We examined the relationship between maternal diet quality before pregnancy, as summarised by a diet quality index, and risk of childhood acute lymphoblastic leukaemia (ALL) and acute myeloid leukaemia (AML) in a case-control study in California. Dietary intake in the year before pregnancy was assessed using FFQ in 681 ALL cases, 103 AML cases and 1076 matched controls. Conditional logistic regression was used to estimate OR and 95 % CI for diet quality continuous score and quartiles (Q1-Q4). Higher maternal diet quality score was associated with reduced risk of ALL (OR 0·66; 95 % CI 0·47, 0·93 for Q4 v. Q1) and possibly AML (OR 0·42; 95 % CI 0·15, 1·15 for Q4 v. Q1). No single index component appeared to account for the association. The association of maternal diet quality with risk of ALL was stronger in children diagnosed under the age of 5 years and in children of women who did not report using vitamin supplements before pregnancy. These findings suggest that the joint effects of many dietary components may be important in influencing childhood leukaemia risk.

  View details for DOI 10.1017/S0007114516003469

  View details for Web of Science ID 000386912200016

  View details for PubMedID 27725005

• Gastroschisis and maternal intake of phytoestrogens AMERICAN JOURNAL OF MEDICAL GENETICS PART A Wadhwa, E. L., Ma, C., Shaw, G. M., Carmichael, S. L. 2016; 170 (8): 2078-2082

  Abstract

  The prevalence of gastroschisis has increased significantly in the past few decades. The strongest risks have been observed for women <25 years old or of low body mass index, and maternal diet also been proposed to be associated with risk. The objective of this study was to evaluate whether the risk of gastroschisis is associated with maternal dietary intake of phytoestrogens. The analysis includes data on mothers of 409 gastroschisis cases and 3,007 controls who delivered their infants from 2005 to 2010 and participated in the National Birth Defects Prevention Study, a multistate, population-based, case-control study. Detailed information was obtained from maternal telephone interviews that included a validated food frequency questionnaire. We conducted logistic regression analyses that included each phytoestrogen in its continuous form (to test for linearity) and quadratic form (to test for non-linearity), adjusted for maternal energy intake, age, BMI, race-ethnicity, and smoking in 1st trimester. Logistic regression analysis indicated that biochanin A, formonoetin, and coumestrol had a significant non-linear association with gastroschisis (P-value <0.05 for quadratic term). Lower intakes were associated with increased risk, with somewhat stronger but relatively modest associations at the lower end of the distribution; for example, the ORs for the 10th versus 50th percentiles ranged from 1.1 to 1.2. Associations were not significant for the other phytoestrogens. This study provides some evidence for association with certain phytoestrogens, after adjusting for covariates. The implications of our findings for clinical practice are uncertain pending other studies examining this association. © 2016 Wiley Periodicals, Inc.

  View details for DOI 10.1002/ajmg.a.37659

  View details for Web of Science ID 000379948400016

  View details for PubMedID 27232448

• Joint effects of genetic variants and residential proximity to pesticide applications on hypospadias risk. Birth defects research. Part A, Clinical and molecular teratology Carmichael, S. L., Yang, W., Ma, C., Roberts, E., Kegley, S., English, P., Lammer, E. J., Witte, J. S., Shaw, G. M. 2016; 106 (8): 653-658

  Abstract

  We examined risks associated with joint exposure of gene variants and pesticides.Analyses included 189 cases and 390 male controls born from 1991 to 2003 in California's San Joaquin Valley. We used logistic regression to examine risks associated with joint exposures of gene variants and pesticides that our previous work identified as associated with hypospadias. Genetic variables were based on variants in DGKK, genes involved in sex steroid synthesis/metabolism, and genes involved in genital tubercle development. Pesticide exposure was based on residential proximity to commercial agricultural pesticide applications.Odds ratios (ORs) were highest among babies with joint exposures, who had two- to fourfold increased risks; for example, the OR was 3.7 (95% confidence interval [CI], 0.8-16.5) among subjects with the risk-associated DGKK haplotype and pesticide exposure; OR, 1.5 (95% CI, 0.7-3.1) among subjects with the haplotype and no pesticide exposure; and OR, 0.9 (95% CI, 0.5-1.6) among subjects without the haplotype but with pesticide exposure, relative to subjects with neither. However, results did not provide statistical evidence that these risks were significantly greater than expected on an additive scale, relative to risks associated with one exposure at a time.We observed elevated risks associated with joint exposures to selected pesticides and genetic variants but no statistical evidence for interaction. Birth Defects Research (Part A) 106:653-658, 2016. © 2016 Wiley Periodicals, Inc.

  View details for DOI 10.1002/bdra.23508

  View details for PubMedID 27098078

  View details for PubMedCentralID PMC4983249

• 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

• Maternal prenatal intake of one-carbon metabolism nutrients and risk of childhood leukemia CANCER CAUSES & CONTROL Singer, A. W., Selvin, S., Block, G., Golden, C., Carmichael, S. L., Metayer, C. 2016; 27 (7): 929-940

  Abstract

  Folate, vitamins B12 and B6, riboflavin, and methionine are critical nutrients for the one-carbon metabolism cycle involved in DNA synthesis and epigenetic processes. We examined the association between maternal intake of these nutrients before pregnancy and risk of childhood acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) in a matched case-control study.Maternal dietary intake and vitamin supplement use in the year before pregnancy was assessed by food frequency questionnaire for 681 ALL cases, 103 AML cases, and 1076 controls. Principal component analysis was used to construct a variable representing combined nutrient intake, and conditional logistic regression estimated the odds ratio (OR) and 95% confidence interval (CI) for the association of ALL and AML with the principal component and each nutrient.Higher maternal intake of one-carbon metabolism nutrients from food and supplements combined was associated with reduced risk of ALL (OR for one-unit change in the principal component = 0.91, CI 0.84-0.99) and possibly AML (OR for the principal component = 0.83, CI 0.66-1.04). When analyzed separately, intake of supplements high in these nutrients was associated with a reduced risk of ALL in children of Hispanic women only.In conclusion, these data suggest that higher maternal intake of one-carbon metabolism nutrients may reduce risk of childhood leukemia.

  View details for DOI 10.1007/s10552-016-0773-y

  View details for Web of Science ID 000381121400010

  View details for PubMedID 27294727

  View details for PubMedCentralID PMC4939072

• Elevated body mass index and decreased diet quality among women and risk of birth defects in their offspring. Birth defects research. Part A, Clinical and molecular teratology Carmichael, S. L., Yang, W., Gilboa, S., Ailes, E., Correa, A., Botto, L. D., Feldkamp, M. L., Shaw, G. M. 2016; 106 (3): 164-171

  Abstract

  We examined whether risks of 32 birth defects were higher than expected in the presence of overweight or obese body mass index (BMI) and low diet quality, based on estimating individual and joint effects of these factors and calculating relative excess risk due to interaction.Analyses included mothers of 20,250 cases with birth defects and 8617 population-based controls without birth defects born from 1997 to 2009 and interviewed for the National Birth Defects Prevention Study. We used logistic regression to generate adjusted odds ratios (AORs) reflecting the combined effects of BMI and diet quality. We focused analyses on 16 birth defects (n = 11,868 cases, 8617 controls) for which initial results suggested an association with BMI or diet quality.Relative to the reference group (normal weight women with not low diet quality, i.e., >lowest quartile), AORs for low diet quality among normal weight women tended to be >1, and AORs for overweight and obese women tended to be stronger among women who had low diet quality than not low diet quality. For 9/16 birth defects, AORs for obese women who had low diet quality-the group we hypothesized to have highest risk-were higher than other stratum-specific AORs. Most relative excess risk due to interactions were positive but small (<0.5), with confidence intervals that included zero.These findings provide evidence for the hypothesis of highest birth defect risks among offspring to women who are obese and have low diet quality but insufficient evidence for an interaction of these factors in their contribution to risk. Birth Defects Research (Part A) 106:164-171, 2016. © 2015 Wiley Periodicals, Inc.

  View details for DOI 10.1002/bdra.23471

  View details for PubMedID 26663631

• Elevated body mass index and decreased diet quality among women and risk of birth defects in their offspring BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY Carmichael, S. L., Yang, W., Gilboa, S., Ailes, E., Correa, A., Botto, L. D., Feldkamp, M. L., Shaw, G. M. 2016; 106 (3): 164-171

  Abstract

  We examined whether risks of 32 birth defects were higher than expected in the presence of overweight or obese body mass index (BMI) and low diet quality, based on estimating individual and joint effects of these factors and calculating relative excess risk due to interaction.Analyses included mothers of 20,250 cases with birth defects and 8617 population-based controls without birth defects born from 1997 to 2009 and interviewed for the National Birth Defects Prevention Study. We used logistic regression to generate adjusted odds ratios (AORs) reflecting the combined effects of BMI and diet quality. We focused analyses on 16 birth defects (n = 11,868 cases, 8617 controls) for which initial results suggested an association with BMI or diet quality.Relative to the reference group (normal weight women with not low diet quality, i.e., >lowest quartile), AORs for low diet quality among normal weight women tended to be >1, and AORs for overweight and obese women tended to be stronger among women who had low diet quality than not low diet quality. For 9/16 birth defects, AORs for obese women who had low diet quality-the group we hypothesized to have highest risk-were higher than other stratum-specific AORs. Most relative excess risk due to interactions were positive but small (<0.5), with confidence intervals that included zero.These findings provide evidence for the hypothesis of highest birth defect risks among offspring to women who are obese and have low diet quality but insufficient evidence for an interaction of these factors in their contribution to risk. Birth Defects Research (Part A) 106:164-171, 2016. © 2015 Wiley Periodicals, Inc.

  View details for DOI 10.1002/bdra.23471

  View details for Web of Science ID 000372908700002

• Lower rate of selected congenital heart defects with better maternal diet quality: a population-based study. Archives of disease in childhood. Fetal and neonatal edition Botto, L. D., Krikov, S., Carmichael, S. L., Munger, R. G., Shaw, G. M., Feldkamp, M. L. 2016; 101 (1): 43-49

  Abstract

  To evaluate whether better diet quality in mothers is associated with lower risk for major non-syndromic congenital heart defects in their children.Multicentre population-based case-control study, the National Birth Defects Prevention Study.Ten sites in the USA.Mothers of babies with major non-syndromic congenital heart defects (n=9885) and mothers with unaffected babies (n=9468) with estimated date of delivery from 1997 to 2009.Adjusted ORs for specific major congenital heart defects by quartiles of maternal diet quality in the year before pregnancy, assessed by the Diet Quality Index for pregnancy (DQI-P) and the Mediterranean Diet Score. Quartile 1 (Q1) reflecting the worst diet quality and Q4 the best diet quality.Better diet quality was associated with reduced risk for some conotruncal and atrial septal heart defects. For DQI-P, estimated risks reductions (Q4 vs Q1) for conotruncal defects were 37% for tetralogy of Fallot (OR 0.63, 95% CI 0.49 to 0.80) and 24% overall (OR 0.76, 95% CI 0.64 to 0.91); and for septal defects, 23% for atrial septal defects (OR 0.77, 95% CI 0.63 to 0.94) and 14% overall (OR 0.86, 95% CI 0.75 to 1.00). Risk reductions were weaker or minimal for most other major congenital heart defects.Better diet quality is associated with a reduced occurrence of some conotruncal and septal heart defects. This finding suggests that a reduction in certain cardiac malformations may be an additional benefit of improved maternal diet quality, reinforcing current preconception care recommendations.

  View details for DOI 10.1136/archdischild-2014-308013

  View details for PubMedID 26304461

• Residential agricultural pesticide exposures and risks of selected birth defects among offspring in the San Joaquin Valley of California. Birth defects research. Part A, Clinical and molecular teratology Carmichael, S. L., Yang, W., Roberts, E., Kegley, S. E., Brown, T. J., English, P. B., Lammer, E. J., Shaw, G. M. 2016; 106 (1): 27-35

  Abstract

  We examined associations of birth defects with residential proximity to commercial agricultural pesticide applications in California. Subjects included 367 cases representing five types of birth defects and 785 nonmalformed controls born 1997 to 2006.Associations with any versus no exposure to physicochemical groups of pesticides and specific chemicals were assessed using logistic regression adjusted for covariates. Overall, 46% of cases and 38% of controls were classified as exposed to pesticides within a 500 m radius of mother's address during a 3-month periconceptional window.We estimated odds ratios (ORs) for 85 groups and 95 chemicals with five or more exposed cases and control mothers. Ninety-five percent confidence intervals (CI) excluded 1.0 for 11 ORs for groups and 22 ORs for chemicals, ranging from 1.9 to 3.1 for groups and 1.8 to 4.9 for chemicals except for two that were <1 (noted below).For groups, these ORs were for anotia/microtia (n = 95 cases) and dichlorophenoxy acids/esters and neonicotinoids; anorectal atresia/stenosis (n = 77) and alcohol/ethers and organophosphates (these ORs were < 1.0); transverse limb deficiencies (n = 59) and dichlorophenoxy acids/esters, petroleum derivatives, and triazines; and craniosynostosis (n = 79) and alcohol/ethers, avermectins, neonicotinoids, and organophosphates. For chemicals, ORs were: anotia/microtia and five pesticides from the groups dichlorophenoxy acids/esters, copper-containing compounds, neonicotinoids, organophosphates, and triazines; transverse limb deficiency and six pesticides - oxyfluorfen and pesticides from the groups copper-containing compounds, 2,6-dinitroanilines, neonicotinoids, petroleum derivatives and polyalkyloxy compounds; craniosynostosis and 10 pesticides - oxyfluorfen and pesticides from the groups alcohol/ethers, avermectins, n-methyl-carbamates, neonicotinoids, ogranophosphates (two chemicals), polyalkyloxy compounds (two chemicals), and pyrethroids; and congenital diaphragmatic hernia (n = 62) and a copper-containing compound.

  View details for DOI 10.1002/bdra.23459

  View details for PubMedID 26689858

• 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

• Air Pollution, Neighbourhood Socioeconomic Factors, and Neural Tube Defects in the San Joaquin Valley of California PAEDIATRIC AND PERINATAL EPIDEMIOLOGY Padula, A. M., Yang, W., Carmichael, S. L., Tager, I. B., Lurmann, F., Hammond, S. K., Shaw, G. M. 2015; 29 (6): 536-545

  Abstract

  Environmental pollutants and neighbourhood socioeconomic factors have been associated with neural tube defects, but the potential impact of interaction between ambient air pollution and neighbourhood socioeconomic factors on the risks of neural tube defects is not well understood.We used data from the California Center of the National Birth Defects Study and the Children's Health and Air Pollution Study to investigate whether associations between air pollutant exposure in early gestation and neural tube defects were modified by neighbourhood socioeconomic factors in the San Joaquin Valley of California, 1997-2006. There were 5 pollutant exposures, 3 outcomes, and 9 neighbourhood socioeconomic factors included for a total of 135 investigated associations. Estimates were adjusted for maternal race-ethnicity, education, and multivitamin use.We present below odds ratios (ORs) that exclude 1 and a chi-square test of homogeneity P-value of <0.05. We observed increased odds of spina bifida comparing the highest to lowest quartile of particulate matter <10 μm (PM10 ) among those living in a neighbourhood with: (i) median household income of less than $30 000 per year [OR 5.1, 95% confidence interval (CI) 1.7, 15.3]; (ii) more than 20% living below the federal poverty level (OR 2.6, 95% CI 1.1, 6.0); and (iii) more than 30% with less than or equal to a high school education (OR 3.2, 95% CI 1.4, 7.4). The ORs were not statistically significant among those higher socioeconomic status (SES) neighbourhoods.Our results demonstrate effect modification by neighbourhood socioeconomic factors in the association of particulate matter and neural tube defects in California.

  View details for DOI 10.1111/ppe.12244

  View details for Web of Science ID 000362723900009

  View details for PubMedID 26443985

  View details for PubMedCentralID PMC4646169

• 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

• 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 PubMedID 26466315

• 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 PubMedID 26265442

• Periconceptional changes in weight and risk of delivering offspring with conotruncal heart defects. Birth defects research. Part A, Clinical and molecular teratology Carter, E. H., Carmichael, S. L., Birnie, K., Yang, W., Lammer, E. J., Shaw, G. M. 2015; 103 (10): 843-846

  Abstract

  Maternal nutritional status has been recognized as a contributor to conotruncal heart defects, but there is limited understanding of the specific nutrition-related factors involved. In this California case-control study of 296 conotruncal cases and 695 nonmalformed controls we explored whether weight loss during early pregnancy was associated with an increased risk of d-transposition of the great arteries (dTGA) and tetralogy of Fallot (TOF) conotruncal defects.During telephone interviews women were asked whether they were dieting to lose weight or using weight loss remedies during 2 months before or 2 months after conception, and how much weight they gained or lost in the first 2 months of pregnancy or during the year before pregnancy.Odds ratios for dieting to lose weight and use of weight loss remedies for dTGA and TOF were not substantially elevated and all had confidence intervals that included 1.0. Mothers who had a loss of >5 lbs in the first 2 months of pregnancy as well as mothers who lost and gained >5 lbs in the first 2 months of pregnancy also did not show a significant increased risk of delivering case infants when compared with women with no weight change in the year before pregnancy.Given current recommendations about limited weight gain for obese pregnant women, these data indicate that dieting may not substantially increase a fetus' risk of having a conotruncal defect.

  View details for DOI 10.1002/bdra.23381

  View details for PubMedID 26033835

• Next steps for birth defects research and prevention: The birth defects study to evaluate pregnancy exposures (BD-STEPS). Birth defects research. Part A, Clinical and molecular teratology Tinker, S. C., Carmichael, S. L., Anderka, M., Browne, M. L., Caspers Conway, K. M., Meyer, R. E., Nembhard, W. N., Olney, R. S., Reefhuis, J. 2015; 103 (8): 733-740

  Abstract

  The Birth Defects Study To Evaluate Pregnancy exposureS (BD-STEPS) is a population-based, multi-Center case-control study of modifiable risk factors for selected birth defects in the United States. BD-STEPS is the second major research effort of the Centers for Birth Defects Research and Prevention, which extends and expands the initial research effort, the National Birth Defects Prevention Study (NBDPS).BD-STEPS focuses on 17 categories of structural birth defects selected based on severity, prevalence, consistent ascertainment, and previous findings that warrant additional research. Cases are identified through existing birth defects surveillance programs; controls are from vital records or birth hospital logs from the same catchment area. BD-STEPS uses a standardized computer-assisted telephone interview to collect information from case and control mothers on topics including demographics, health conditions, and medication use. Following the maternal interview, selected Centers request permission to sample residual newborn screening blood spots from state repositories for genetic analyses. New components planned for BD-STEPS include linkages with external datasets and use of online questionnaires to collect in-depth information on selected exposures.BD-STEPS extends NBDPS by continuing to collect data on many exposures that were assessed in NBDPS, allowing data from both studies to be combined and providing an unprecedented sample size to analyze rare exposures. BD-STEPS expands upon NBDPS by collecting more detailed information on existing exposures as well as new exposures.The goal of BD-STEPS is to provide women and healthcare providers with information they need to make decisions to promote the healthiest pregnancy possible. Birth Defects Research (Part A) 103:733-740, 2015. © 2015 Wiley Periodicals, Inc.

  View details for DOI 10.1002/bdra.23373

  View details for PubMedID 25846741

• Next steps for birth defects research and prevention: The birth defects study to evaluate pregnancy exposures (BD-STEPS) BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY Tinker, S. C., Carmichael, S. L., Anderka, M., Browne, M. L., Conway, K. M., Meyer, R. E., Nembhard, W. N., Olney, R. S., Reefhuis, J. 2015; 103 (8): 733-740

  Abstract

  The Birth Defects Study To Evaluate Pregnancy exposureS (BD-STEPS) is a population-based, multi-Center case-control study of modifiable risk factors for selected birth defects in the United States. BD-STEPS is the second major research effort of the Centers for Birth Defects Research and Prevention, which extends and expands the initial research effort, the National Birth Defects Prevention Study (NBDPS).BD-STEPS focuses on 17 categories of structural birth defects selected based on severity, prevalence, consistent ascertainment, and previous findings that warrant additional research. Cases are identified through existing birth defects surveillance programs; controls are from vital records or birth hospital logs from the same catchment area. BD-STEPS uses a standardized computer-assisted telephone interview to collect information from case and control mothers on topics including demographics, health conditions, and medication use. Following the maternal interview, selected Centers request permission to sample residual newborn screening blood spots from state repositories for genetic analyses. New components planned for BD-STEPS include linkages with external datasets and use of online questionnaires to collect in-depth information on selected exposures.BD-STEPS extends NBDPS by continuing to collect data on many exposures that were assessed in NBDPS, allowing data from both studies to be combined and providing an unprecedented sample size to analyze rare exposures. BD-STEPS expands upon NBDPS by collecting more detailed information on existing exposures as well as new exposures.The goal of BD-STEPS is to provide women and healthcare providers with information they need to make decisions to promote the healthiest pregnancy possible. Birth Defects Research (Part A) 103:733-740, 2015. © 2015 Wiley Periodicals, Inc.

  View details for DOI 10.1002/bdra.23373

  View details for Web of Science ID 000359740800012

  View details for PubMedCentralID PMC4537667

• 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 PubMedID 25760546

• Sex Ratios Among Infants with Birth Defects, National Birth Defects Prevention Study, 1997-2009 AMERICAN JOURNAL OF MEDICAL GENETICS PART A Michalski, A. M., Richardson, S. D., Browne, M. L., Carmichael, S. L., Canfield, M. A., VanZutphen, A. R., Anderka, M. T., Marshall, E. G., Druschel, C. M. 2015; 167A (5): 1071-1081

  Abstract

  A small number of population-based studies have examined sex differences among infants with birth defects. This study presents estimates of sex ratio for both isolated cases and those with multiple congenital anomalies, as well as by race/ethnicity. Male-female sex ratios and their 95% confidence intervals were calculated for 25,952 clinically reviewed case infants included in the National Birth Defects Prevention Study (1997-2009), a large population-based case-control study of birth defects. The highest elevations in sex ratios (i.e., male preponderance) among isolated non-cardiac defects were for craniosynostosis (2.12), cleft lip with cleft palate (2.01), and cleft lip without cleft palate (1.78); the lowest sex ratios (female preponderance) were for choanal atresia (0.45), cloacal exstrophy (0.46), and holoprosencephaly (0.64). Among isolated cardiac defects, the highest sex ratios were for aortic stenosis (2.88), coarctation of the aorta (2.51), and d-transposition of the great arteries (2.34); the lowest were multiple ventricular septal defects (0.52), truncus arteriosus (0.63), and heterotaxia with congenital heart defect (0.64). Differences were observed by race/ethnicity for some but not for most types of birth defects. The sex differences we observed for specific defects, between those with isolated versus multiple defects, as well as by race/ethnicity, demonstrate patterns that may suggest etiology and improve classification.

  View details for DOI 10.1002/ajmg.a.36865

  View details for Web of Science ID 000353171900015

  View details for PubMedID 25711982

• Genetic Polymorphisms in ESR1 and ESR2 Genes, and Risk of Hypospadias in a Multiethnic Study Population JOURNAL OF UROLOGY Choudhry, S., Baskin, L. S., Lammer, E. J., Witte, J. S., Dasgupta, S., Ma, C., Surampalli, A., Shen, J., Shaw, G. M., Carmichael, S. L. 2015; 193 (5): 1625-1631

  Abstract

  Estrogenic endocrine disruptors acting via estrogen receptors α (ESR1) and β (ESR2) have been implicated in the etiology of hypospadias, a common congenital malformation of the male external genitalia. We determined the association of single nucleotide polymorphisms in ESR1 and ESR2 genes with hypospadias in a racially/ethnically diverse study population of California births.We investigated the relationship between hypospadias and 108 ESR1 and 36 ESR2 single nucleotide polymorphisms in 647 cases and 877 population based nonmalformed controls among infants born in selected California counties from 1990 to 2003. Subgroup analyses were performed by race/ethnicity (nonHispanic white and Hispanic subjects) and by hypospadias severity (mild to moderate and severe).Odds ratios for 33 of the 108 ESR1 single nucleotide polymorphisms had p values less than 0.05 (p = 0.05 to 0.007) for risk of hypospadias. However, none of the 36 ESR2 single nucleotide polymorphisms was significantly associated. In stratified analyses the association results were consistent by disease severity but different sets of single nucleotide polymorphisms were significantly associated with hypospadias in nonHispanic white and Hispanic subjects. Due to high linkage disequilibrium across the single nucleotide polymorphisms, haplotype analyses were conducted and identified 6 haplotype blocks in ESR1 gene that had haplotypes significantly associated with an increased risk of hypospadias (OR 1.3 to 1.8, p = 0.04 to 0.00001). Similar to single nucleotide polymorphism analysis, different ESR1 haplotypes were associated with risk of hypospadias in nonHispanic white and Hispanic subjects. No significant haplotype association was observed for ESR2.The data provide evidence that ESR1 single nucleotide polymorphisms and haplotypes influence the risk of hypospadias in white and Hispanic subjects, and warrant further examination in other study populations.

  View details for DOI 10.1016/j.juro.2014.11.087

  View details for Web of Science ID 000353113200073

  View details for PubMedID 25463985

• Craniosynostosis and Risk Factors Related to Thyroid Dysfunction AMERICAN JOURNAL OF MEDICAL GENETICS PART A Carmichael, S. L., Ma, C., Rasmussen, S. A., Cunningham, M. L., Browne, M. L., Dosiou, C., Lammer, E. J., Shaw, G. M. 2015; 167A (4): 701-707

  View details for DOI 10.1002/ajmg.a.36953

  View details for Web of Science ID 000352019000007

• Lower rate of selected congenital heart defects with better maternal diet quality: a population-based study ARCHIVES OF DISEASE IN CHILDHOOD-FETAL AND NEONATAL EDITION Botto, L. D., Krikov, S., Carmichael, S. L., Munger, R. G., Shaw, G. M., Feldkamp, M. L. 2015; 101 (1): 43-49

  View details for DOI 10.1136/archdischild-2014-308013

  View details for Web of Science ID 000367479500010

• Society for Paediatric and Perinatal Epidemiology 2015 Annual Meeting: Present and Future. Paediatric and perinatal epidemiology Hernandez-Diaz, S., Carmichael, S. L. 2015; 29 (5): 373–75

  View details for PubMedID 26264567

• Residential agricultural pesticide exposures and risk of selected congenital heart defects among offspring in the San Joaquin Valley of California. Environmental research Carmichael, S. L., Yang, W., Roberts, E., Kegley, S. E., Padula, A. M., English, P. B., Lammer, E. J., Shaw, G. M. 2014; 135: 133-138

  Abstract

  Pesticide exposures are ubiquitous and of substantial public concern. We examined the potential association of congenital heart defects with residential proximity to commercial agricultural pesticide applications in the San Joaquin Valley, California.Study subjects included 569 heart defect cases and 785 non-malformed controls born from 1997 to 2006 whose mothers participated in a population-based case-control study. Associations with any versus no exposure to physicochemical groups of pesticides and specific chemicals were assessed using logistic regression adjusted for relevant covariates, for 8 heart defect phenotypes that included ≥50 cases and pesticide exposures with ≥5 exposed cases and controls, which resulted in 235 comparisons.38% of cases and controls were classified as exposed to pesticides within a 500m radius of mother׳s address during a 3-month periconceptional window. Adjusted odds ratios (AORs) with 95% CIs excluding 1.0 were observed for 18 comparisons; all were >1 and ranged from 1.9 to 7.1. They included tetralogy of Fallot (n=101 cases) and neonicotinoids; hypoplastic left heart syndrome (n=59) and strobins; coarctation of the aorta (n=74) and pyridazinones; pulmonary valve stenosis (n=53) and bipyridyliums and organophosphates; ventricular septal defects (n=93) and avermectins and pyrethroids; and atrial septal defects (n=132) and dichlorphenoxy acid or esters, organophosphates, organotins, and pyrethroids. No AORs met both of these criteria for d-transposition of the great arteries (n=58) or heterotaxia (n=53).Most pesticides were not associated with increased risk of specific heart defect phenotypes. For the few that were associated, results should be interpreted with caution until replicated in other study populations.

  View details for DOI 10.1016/j.envres.2014.08.030

  View details for PubMedID 25262086

• Better Diet Quality before Pregnancy Is Associated with Reduced Risk of Gastroschisis in Hispanic Women JOURNAL OF NUTRITION Feldkamp, M. L., Krikov, S., Botto, L. D., Shaw, G. M., Carmichael, S. L. 2014; 144 (11): 1781-1786

  Abstract

  Gastroschisis is unique because of its substantial risk in pregnancies of adolescent women. Adolescents may have poor diet quality, which places them at higher risk of gastroschisis.We investigated whether better maternal diet quality, measured by 2 different indices, reduced the risk of gastroschisis.We used case-control data from the National Birth Defects Prevention Study to investigate maternal diet quality among 1125 gastroschisis cases and 9483 controls (estimated delivery dates between 1997 and 2009). Cases were ascertained from 10 U.S. birth defect surveillance systems. Control subjects were randomly selected from birth certificates or hospital records. Using a 58-item food-frequency questionnaire, interviewers queried mothers about their average food and cereal intake during the year before conception. Diet quality scores [Diet Quality Index (DQI) and Mediterranean diet score (MDS)] were calculated using specific components. Women were excluded if they consumed <500 or >5000 kcal/d, reported pregestational diabetes, or had >1 missing food item. Quartile-specific adjusted ORs (aORs) were calculated, using as reference the lowest quartile.Overall, we observed a statistically significant decrease with increasing diet quality for both the DQI and MDS. When stratified by maternal race/ethnicity, this finding was confined to Hispanic women. Among Hispanic women, the risk of gastroschisis decreased significantly with increasing DQI quartiles: quartile 2, aOR = 0.58 (95% CI: 0.40, 0.86); quartile 3, aOR = 0.52 (95% CI: 0.36, 0.79); and quartile 4, aOR = 0.48 (95% CI: 0.32, 0.76). Increasing diet quality, as measured by the MDS, showed reduced risk of gastroschisis among women, mostly Hispanic, who were born outside the United States: quartile 2, aOR = 0.62 (95% CI: 0.33, 1.16); quartile 3, aOR = 0.51 (95% CI: 0.28, 0.94); and quartile 4, aOR = 0.50 (95% CI: 0.28, 0.90).Increasing diet quality was associated with a reduced risk of gastroschisis only among Hispanic and foreign-born women, but these findings require replication.

  View details for DOI 10.3945/jn.114.201376

  View details for Web of Science ID 000343681400016

  View details for PubMedID 25332477

• Birth Defects, Causal Attributions, and Ethnicity in the National Birth Defects Prevention Study JOURNAL OF GENETIC COUNSELING Case, A. P., Royle, M., Scheuerle, A. E., Carmichael, S. L., Moffitt, K., Ramadhani, T. 2014; 23 (5): 860-873

  Abstract

  In order to translate research findings into effective prevention strategies, it is important to understand people's beliefs about the causes of poor health outcomes. However, with the exception of knowledge and beliefs about folic acid supplementation, little is known regarding women's causal attributions women regarding birth defects. We employed Attribution Theory constructs to analyze open-text interview responses from 2,672 control mothers in the National Birth Defects Prevention Study who gave birth in 1997-2005. Common themes included use of alcohol, tobacco, illicit drugs, and medications during pregnancy. Stress and emotional upset were also suggested as possible causes of birth defects. Genetic- and heredity-related responses were more likely to be mentioned by Asian/Pacific Islander women compared to non-Hispanic Whites. Hispanic women were less likely to suggest several specific possible teratogens, such as paint, pesticides, or other chemicals, but were more likely to suggest events occurring during childbirth. Differences also emerged among ethnic groups for theoretical constructs, although most responses were categorized as controllable, changeable over time, and with an internal locus of causality.

  View details for DOI 10.1007/s10897-014-9708-5

  View details for Web of Science ID 000341840500018

  View details for PubMedID 24682893

• Early Pregnancy Agricultural Pesticide Exposures and Risk of Gastroschisis among Offspring in the San Joaquin Valley of California BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY Shaw, G. M., Yang, W., Roberts, E., Kegley, S. E., Padula, A., English, P. B., Carmichael, S. L. 2014; 100 (9): 686-694

  Abstract

  Prevalence of gastroschisis has inexplicably been increasing over the past few decades. Our intent was to explore whether early gestational exposures to pesticides were associated with risk of gastroschisis.We used population-based data, accompanied by detailed information from maternal interviews as well as information on residential proximity to a large number of commercial pesticide applications during early pregnancy. The study population derived from the San Joaquin Valley of California (). Cases were 156 infants/fetuses with gastroschisis and controls were 785 infants without birth defects.Among 22 chemical pesticide groups analyzed, none had an elevated odds ratio with an associated confidence interval that excluded 1.0, although exposure to the triazine group showed borderline significance. Among 36 specific pesticide chemicals analyzed, only exposure to petroleum distillates was associated with an elevated risk, odds ratio = 2.5 (1.1-5.6). In general, a substantially different inference was not derived when analyses were stratified by maternal age or when risk estimation included adjustment for race/ethnicity, body mass index, folic acid supplement use, and smoking.Our study rigorously adds to the scant literature on this topic. Our a priori expectation was that we would observe certain pesticide compounds to be particularly associated with young age owing to the disproportionate risk observed for young women to have offspring with gastroschisis. We did not observe an exposure profile unique to young women. Birth Defects Research (Part A), 100:686-694, 2014. © 2014 Wiley Periodicals, Inc.

  View details for DOI 10.1002/bdra.23263

  View details for Web of Science ID 000342625200006

• Early pregnancy agricultural pesticide exposures and risk of gastroschisis among offspring in the San Joaquin Valley of California. Birth defects research. Part A, Clinical and molecular teratology Shaw, G. M., Yang, W., Roberts, E., Kegley, S. E., Padula, A., English, P. B., Carmichael, S. L. 2014; 100 (9): 686-694

  Abstract

  Prevalence of gastroschisis has inexplicably been increasing over the past few decades. Our intent was to explore whether early gestational exposures to pesticides were associated with risk of gastroschisis.We used population-based data, accompanied by detailed information from maternal interviews as well as information on residential proximity to a large number of commercial pesticide applications during early pregnancy. The study population derived from the San Joaquin Valley of California (). Cases were 156 infants/fetuses with gastroschisis and controls were 785 infants without birth defects.Among 22 chemical pesticide groups analyzed, none had an elevated odds ratio with an associated confidence interval that excluded 1.0, although exposure to the triazine group showed borderline significance. Among 36 specific pesticide chemicals analyzed, only exposure to petroleum distillates was associated with an elevated risk, odds ratio = 2.5 (1.1-5.6). In general, a substantially different inference was not derived when analyses were stratified by maternal age or when risk estimation included adjustment for race/ethnicity, body mass index, folic acid supplement use, and smoking.Our study rigorously adds to the scant literature on this topic. Our a priori expectation was that we would observe certain pesticide compounds to be particularly associated with young age owing to the disproportionate risk observed for young women to have offspring with gastroschisis. We did not observe an exposure profile unique to young women. Birth Defects Research (Part A), 100:686-694, 2014. © 2014 Wiley Periodicals, Inc.

  View details for DOI 10.1002/bdra.23263

  View details for PubMedID 24910073

• Differences in Risk Factors for Second and Third Degree Hypospadias in the National Birth Defects Prevention Study BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY in 't Woud, S. G., van Rooij, I. A., van Gelder, M. M., Olney, R. S., Carmichael, S. L., Roeleveld, N., Reefhuis, J. 2014; 100 (9): 703-711

  View details for DOI 10.1002/bdra.23296

  View details for Web of Science ID 000342625200008

• Birth defects epidemiology EUROPEAN JOURNAL OF MEDICAL GENETICS Carmichael, S. L. 2014; 57 (8): 355-358

  Abstract

  This article provides background information about epidemiologic methods and how they can be used to further our understanding of what causes birth defects. It briefly describes basic study designs and advantages and disadvantages of each, provides examples of how epidemiologic studies contribute to our current understanding of the etiologies of birth defects, and makes recommendations for future research.

  View details for DOI 10.1016/j.ejmg.2014.03.002

  View details for Web of Science ID 000341362400002

  View details for PubMedID 24657225

• Maternal stressors and social support as risks for delivering babies with structural birth defects. Paediatric and perinatal epidemiology Carmichael, S. L., Ma, C., Tinker, S., Rasmussen, S. A., Shaw, G. M. 2014; 28 (4): 338-344

  Abstract

  We examined the association of maternal stressful life events and social support with risks of birth defects using National Birth Defects Prevention Study data, a population-based case-control study.We examined seven stressful life events and three social support questions applicable to the periconceptional period, among mothers of 552 cases with neural tube defects (NTDs), 413 cleft palate (CP), 797 cleft lip ± cleft palate (CLP), 189 d-transposition of the great arteries (dTGA), 311 tetralogy of Fallot (TOF), and 2974 non-malformed controls. A stressful life events index equalled the sum of 'yes' responses to the seven questions. Social support questions were also summed to form an index. Data were analyzed using logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CI), adjusted for maternal race-ethnicity, age, education, body mass index, smoking, drinking, and intake of vitamin supplements.Associations with the stress index tended to be higher with higher scores, but few 95% CIs excluded one. A four-point increase in the index was moderately associated with NTDs (OR 1.5, [95% CI 1.1, 2.0]) and CLP (OR 1.3, [95% CI 1.0, 1.7]). The social support index tended to be associated with reduced risk but most 95% CIs included one, with the exception of dTGA (OR for a score of 3 vs 0 was 0.5 [95% CI 0.3, 0.8]).Maternal periconceptional stressful life events, social support, and the two factors in combination were at most modestly, if at all, associated with risks of the studied birth defects.

  View details for DOI 10.1111/ppe.12123

  View details for PubMedID 24697924

  View details for PubMedCentralID PMC4057295

• 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

• Preconceptional Folic Acid-Containing Supplement Use in the National Birth Defects Prevention Study BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY Khodr, Z. G., Lupo, P. J., Agopian, A. J., Canfield, M. A., Case, A. P., Carmichael, S. L., Mitchell, L. E. 2014; 100 (6): 472-482

  View details for DOI 10.1002/bdra.23238

  View details for Web of Science ID 000338036300003

• Corticosteroid Use and Risk of Orofacial Clefts BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY Skuladottir, H., Wilcox, A. J., Ma, C., Lammer, E. J., Rasmussen, S. A., Werler, M. M., Shaw, G. M., Carmichael, S. L. 2014; 100 (6): 499-506

  View details for DOI 10.1002/bdra.23248

  View details for Web of Science ID 000338036300006

• Late Detection of Critical Congenital Heart Disease Among US Infants: Estimation of the Potential Impact of Proposed Universal Screening Using Pulse Oximetry. JAMA pediatrics Peterson, C., Ailes, E., Riehle-Colarusso, T., Oster, M. E., Olney, R. S., Cassell, C. H., Fixler, D. E., Carmichael, S. L., Shaw, G. M., Gilboa, S. M. 2014; 168 (4): 361-370

  Abstract

  IMPORTANCE Critical congenital heart disease (CCHD) was added to the Recommended Uniform Screening Panel for Newborns in the United States in 2011. Many states have recently adopted or are considering requirements for universal CCHD screening through pulse oximetry in birth hospitals. Limited previous research is directly applicable to the question of how many US infants with CCHD might be identified through screening. OBJECTIVES To estimate the proportion of US infants with late detection of CCHD (>3 days after birth) based on existing clinical practice and to investigate factors associated with late detection. DESIGN, SETTING, AND PARTICIPANTS Descriptive and multivariable analysis. Data were obtained from a multisite population-based study of birth defects in the United States, the National Birth Defects Prevention Study (NBDPS). We included all live-born infants with estimated dates of delivery from January 1, 1998, through December 31, 2007, and nonsyndromic, clinically verified CCHD conditions potentially detectable through screening via pulse oximetry. MAIN OUTCOMES AND MEASURES The main outcome measure was the proportion of infants with late detection of CCHD through echocardiography or at autopsy under the assumption that universal screening at birth hospitals might reduce the number of such late diagnoses. Secondary outcome measures included prevalence ratios for associations between selected demographic and clinical factors and late detection of CCHD. RESULTS Of 3746 live-born infants with nonsyndromic CCHD, late detection occurred in 1106 (29.5% [95% CI, 28.1%-31.0%]), including 6 (0.2%) (0.1%-0.4%) first receiving a diagnosis at autopsy more than 3 days after birth. Late detection varied by CCHD type from 9 of 120 infants (7.5% [95% CI, 3.5%-13.8%]) with pulmonary atresia to 497 of 801 (62.0% [58.7%-65.4%]) with coarctation of the aorta. In multivariable analysis, late detection varied significantly by CCHD type and study site, and infants with extracardiac defects were significantly less likely to have late detection of CCHD (adjusted prevalence ratio, 0.58 [95% CI, 0.49-0.69]). CONCLUSIONS AND RELEVANCE We estimate that 29.5% of live-born infants with nonsyndromic CCHD in the NBDPS received a diagnosis more than 3 days after birth and therefore might have benefited from routine CCHD screening at birth hospitals. The number of infants in whom CCHD was detected through screening likely varies by several factors, including CCHD type. Additional population-based studies of screening in practice are needed.

  View details for DOI 10.1001/jamapediatrics.2013.4779

  View details for PubMedID 24493342

• Residential Agricultural Pesticide Exposures and Risk of Neural Tube Defects and Orofacial Clefts Among Offspring in the San Joaquin Valley of California AMERICAN JOURNAL OF EPIDEMIOLOGY Yang, W., Carmichael, S. L., Roberts, E. M., Kegley, S. E., Padula, A. M., English, P. B., Shaw, G. M. 2014; 179 (6): 740-748

  Abstract

  We examined whether early gestational exposures to pesticides were associated with an increased risk of anencephaly, spina bifida, cleft lip with or without cleft palate (CLP), or cleft palate only. We used population-based data along with detailed information from maternal interviews. Exposure estimates were based on residential proximity to agricultural pesticide applications during early pregnancy. The study population derived from the San Joaquin Valley, California (1997-2006). Analyses included 73 cases with anencephaly, 123 with spina bifida, 277 with CLP, and 117 with cleft palate only in addition to 785 controls. A total of 38% of the subjects were exposed to 52 chemical groups and 257 specific chemicals. There were relatively few elevated odds ratios with 95% confidence intervals that excluded 1 after adjustment for relevant covariates. Those chemical groups included petroleum derivatives for anencephaly, hydroxybenzonitrile herbicides for spina bifida, and 2,6-dinitroaniline herbicides and dithiocarbamates-methyl isothiocyanate for CLP. The specific chemicals included 2,4-D dimethylamine salt, methomyl, imidacloprid, and α-(para-nonylphenyl)-ω-hydroxypoly(oxyethylene) phosphate ester for anencephaly; the herbicide bromoxynil octanoate for spina bifida; and trifluralin and maneb for CLP. Adjusted odds ratios ranged from 1.6 to 5.1. Given that such odds ratios might have arisen by chance because of the number of comparisons, our study showed a general lack of association between a range of agricultural pesticide exposures and risks of selected birth defects.

  View details for DOI 10.1093/aje/kwt324

  View details for Web of Science ID 000333246800011

  View details for PubMedID 24553680

• One-carbon metabolite levels in mid-pregnancy and risks of conotruncal heart defects. Birth defects research. Part A, Clinical and molecular teratology Shaw, G. M., Yang, W., Carmichael, S. L., Vollset, S. E., Hobbs, C. A., Lammer, E. J., Ueland, P. M. 2014; 100 (2): 107-115

  Abstract

  Evidence exists for an association between use of vitamin supplements with folic acid in early pregnancy and reduced risk for offspring with conotruncal heart defects. A few observations have been made about nutrients related to one-carbon metabolism other than folate. Our prospective study attempted to extend information on nutrition and conotruncal heart defects by measuring analytes in mid-pregnancy sera.This study included data from a repository of women's mid-pregnancy serum specimens based on screened pregnancies in California from 2002-2007. Each woman's specimen was linked with delivery information to determine whether her fetus had a conotruncal heart defect or another structural malformation, or was nonmalformed. We identified 140 conotruncal cases and randomly selected 280 specimens as nonmalformed controls. Specimens were tested for a variety of analytes, including homocysteine, methylmalonic acid, folate, vitamin B12 , pyridoxal phosphate, pyridoxal, pyridoxic acid, riboflavin, total choline, betaine, methionine, cysteine, cystathionine, arginine, asymmetric and symmetric dimethylarginine.We did not observe statistical evidence for substantial differences between cases and controls for any of the measured analytes. Analyses specifically targeting B-vitamins also did not reveal differences between cases and controls. Birth Defects Research (Part A) 100:107-115, 2014. © 2014 Wiley Periodicals, Inc.

  View details for DOI 10.1002/bdra.23224

  View details for PubMedID 24532477

• Hypospadias and variants in genes related to sex hormone biosynthesis and metabolism ANDROLOGY Carmichael, S. L., Witte, J. S., Ma, C., Lammer, E. J., Shaw, G. M. 2014; 2 (1): 130-137

  Abstract

  We examined whether variants in genes related to sex hormone biosynthesis and metabolism were associated with hypospadias in humans. We examined 332 relatively common tag single-nucleotide polymorphisms (tagSNPs) in 20 genes. Analyses included 633 cases (84 mild, 322 moderate, 212 severe and 15 undetermined severity) and 855 population-based non-malformed male controls born in California from 1990 to 2003. We used logistic regression models to estimate odds ratios (OR) and 95% confidence intervals (CI) for each SNP. Several of the 332 studied SNPs had p < 0.01: one in CYP3A4, four in HSD17B3, one in HSD3B1, two in STARD3, 10 in SRD5A2 and seven in STS. In addition, haplotype analyses gave several associations with p < 0.01. For HSD17B3, 14-SNP and 5-SNP blocks had ORs of 1.5 (95% CI 1.1, 2.0, p < 0.001) and 2.8 (95% CI 1.6, 4.8, p < 0.001) respectively. For SRD5A2, 9-SNP, 3-SNP and 8-SNP blocks had ORs of 1.7 (95% CI 1.3, 2.2, p < 0.001), 1.4 (95% CI 1.1, 1.8, p = 0.008) and 1.5 (95% CI 1.2, 1.9, p = 0.002) respectively. Our study indicates that several genes that contribute to sex hormone biosynthesis and metabolism are associated with hypospadias risk.

  View details for DOI 10.1111/j.2047-2927.2013.00165.x

  View details for Web of Science ID 000328729900019

  View details for PubMedID 24281767

• 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

• 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

• 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

• Hypospadias and Genes Related to Genital Tubercle and Early Urethral Development JOURNAL OF UROLOGY Carmichael, S. L., Ma, C., Choudhry, S., Lammer, E. J., Witte, J. S., Shaw, G. M. 2013; 190 (5): 1884-1892

  Abstract

  PURPOSE: We determined whether variants in genes associated with genital tubercle (the anlage for the penis) and early urethral development were associated with hypospadias in humans. MATERIALS AND METHODS: We examined 293 relatively common tagSNPs in BMP4, BMP7, FGF8, FGF10, FGFR2, HOXA13, HOXD13, HOXA4, HOXB6, SRY, WT1, WTAP, SHH, GLI1, GLI2, and GLI3. The analysis included 624 cases (81 mild, 319 moderate, 209 severe, 15 undetermined severity) and 844 population-based non-malformed male controls born in California from 1990-2003. RESULTS: There were 28 SNPs for which any of the comparisons (i.e., overall or for a specific severity) had a p-value <0.01. The homozygous variant genotypes for four SNPs in BMP7were associated with at least 2-fold increased risk of hypospadias, regardless of severity. Five SNPs for FGF10were associated with 3- to 4-fold increased risks, regardless of severity; for four of them, results were restricted to whites. For GLI1, GLI2and GLI3, there were 12 associated SNPs but results were inconsistent by severity and race-ethnicity. For SHH, one SNP was associated with 2.4-fold increased risk of moderate hypospadias. For WT1, six SNPs were associated with approximately 2-fold increased risks, primarily for severe hypospadias. CONCLUSIONS: This study provides evidence that SNPs in several genes that contribute to genital tubercle and early urethral development are associated with hypospadias risk.

  View details for DOI 10.1016/j.juro.2013.05.061

  View details for Web of Science ID 000325471400089

  View details for PubMedID 23727413

• Hypospadias and residential proximity to pesticide applications. Pediatrics Carmichael, S. L., Yang, W., Roberts, E. M., Kegley, S. E., Wolff, C., Guo, L., Lammer, E. J., English, P., Shaw, G. M. 2013; 132 (5): e1216-26

  Abstract

  Experimental evidence suggests pesticides may be associated with hypospadias.Examine the association of hypospadias with residential proximity to commercial agricultural pesticide applications.The study population included male infants born from 1991 to 2004 to mothers residing in 8 California counties. Cases (n = 690) were ascertained by the California Birth Defects Monitoring Program; controls were selected randomly from the birth population (n = 2195). We determined early pregnancy exposure to pesticide applications within a 500-m radius of mother's residential address, using detailed data on applications and land use. Associations with exposures to physicochemical groups of pesticides and specific chemicals were assessed using logistic regression adjusted for maternal race or ethnicity and age and infant birth year.Forty-one percent of cases and controls were classified as exposed to 57 chemical groups and 292 chemicals. Despite >500 statistical comparisons, there were few elevated odds ratios with confidence intervals that excluded 1 for chemical groups or specific chemicals. Those that did were for monochlorophenoxy acid or ester herbicides; the insecticides aldicarb, dimethoate, phorate, and petroleum oils; and adjuvant polyoxyethylene sorbitol among all cases; 2,6-dinitroaniline herbicides, the herbicide oxyfluorfen, and the fungicide copper sulfate among mild cases; and chloroacetanilide herbicides, polyalkyloxy compounds used as adjuvants, the insecticides aldicarb and acephate, and the adjuvant nonyl-phenoxy-poly(ethylene oxy)ethanol among moderate and severe cases. Odds ratios ranged from 1.9 to 2.9.Most pesticides were not associated with elevated hypospadias risk. For the few that were associated, results should be interpreted with caution until replicated in other study populations.

  View details for DOI 10.1542/peds.2013-1429

  View details for PubMedID 24167181

  View details for PubMedCentralID PMC3813401

• Hypospadias and residential proximity to pesticide applications. Pediatrics Carmichael, S. L., Yang, W., Roberts, E. M., Kegley, S. E., Wolff, C., Guo, L., Lammer, E. J., English, P., Shaw, G. M. 2013; 132 (5): e1216-26

  Abstract

  Experimental evidence suggests pesticides may be associated with hypospadias.Examine the association of hypospadias with residential proximity to commercial agricultural pesticide applications.The study population included male infants born from 1991 to 2004 to mothers residing in 8 California counties. Cases (n = 690) were ascertained by the California Birth Defects Monitoring Program; controls were selected randomly from the birth population (n = 2195). We determined early pregnancy exposure to pesticide applications within a 500-m radius of mother's residential address, using detailed data on applications and land use. Associations with exposures to physicochemical groups of pesticides and specific chemicals were assessed using logistic regression adjusted for maternal race or ethnicity and age and infant birth year.Forty-one percent of cases and controls were classified as exposed to 57 chemical groups and 292 chemicals. Despite >500 statistical comparisons, there were few elevated odds ratios with confidence intervals that excluded 1 for chemical groups or specific chemicals. Those that did were for monochlorophenoxy acid or ester herbicides; the insecticides aldicarb, dimethoate, phorate, and petroleum oils; and adjuvant polyoxyethylene sorbitol among all cases; 2,6-dinitroaniline herbicides, the herbicide oxyfluorfen, and the fungicide copper sulfate among mild cases; and chloroacetanilide herbicides, polyalkyloxy compounds used as adjuvants, the insecticides aldicarb and acephate, and the adjuvant nonyl-phenoxy-poly(ethylene oxy)ethanol among moderate and severe cases. Odds ratios ranged from 1.9 to 2.9.Most pesticides were not associated with elevated hypospadias risk. For the few that were associated, results should be interpreted with caution until replicated in other study populations.

  View details for DOI 10.1542/peds.2013-1429

  View details for PubMedID 24167181

  View details for PubMedCentralID PMC3813401

• Traffic-related air pollution and selected birth defects in the San Joaquin Valley of California. Birth defects research. Part A, Clinical and molecular teratology Padula, A. M., Tager, I. B., Carmichael, S. L., Hammond, S. K., Yang, W., Lurmann, F. W., Shaw, G. M. 2013; 97 (11): 730-735

  Abstract

  Birth defects are a leading cause of infant morbidity and mortality. Studies suggest associations between environmental contaminants and some structural anomalies, although evidence is limited and several anomalies have not been investigated previously.We used data from the California Center of the National Birth Defects Prevention Study and the Children's Health and Air Pollution Study to estimate the odds of 26 congenital birth defect phenotypes with respect to quartiles of seven ambient air pollutant and traffic exposures in California during the first 2 months of pregnancy, 1997 to 2006 (874 cases and 849 controls). We calculated odds ratios (adjusted for maternal race/ethnicity, education, and vitamin use; aOR) for 11 phenotypes that had at least 40 cases.Few odds ratios had confidence intervals that did not include 1.0. Odds of esophageal atresia were increased for the highest versus lowest of traffic density (aOR = 2.8, 95% confidence interval [CI], 1.1-7.4) and PM10 exposure (aOR 4.9; 95% CI, 1.4-17.2). PM10 was associated with a decreased risk of hydrocephaly (aOR= 0.3; 95% CI, 0.1-0.9) and CO with decreased risk of anotia/microtia (aOR = 0.4; 95% CI, 0.2-0.8) and transverse limb deficiency (aOR = 0.4; 95% CI, 0.2-0.9), again reflecting highest versus lowest quartile comparisons.Most analyses showed no substantive association between air pollution and the selected birth defects with few exceptions of mixed results. Birth Defects Research (Part A) 97:730-735, 2013. © 2013 Wiley Periodicals, Inc.

  View details for DOI 10.1002/bdra.23175

  View details for PubMedID 24108522

• Periconceptional nutrient intakes and risks of orofacial clefts in California. Pediatric research Wallenstein, M. B., Shaw, G. M., Yang, W., Carmichael, S. L. 2013; 74 (4): 457-465

  Abstract

  Background:Evidence indicates that maternal nutrient intake may play a role in the development of birth defects. We investigated the association of maternal periconceptional intake of vitamin supplements and dietary nutrients with risk of developing cleft palate (CP) and cleft lip with or without cleft palate (CLP).Methods:Data were from a population-based, case-control study of fetuses and liveborn infants delivered in California,1999-2003. Analyses included 170 cases with CP, 425 with CLP, and 534 nonmalformed controls. Dietary intake was estimated from a food frequency questionnaire.Results:Vitamin supplement intake was associated with a modestly decreased risk of clefts, but the confidence intervals include one. Among women who did not use vitamin supplements, dietary intake of several micronutrients was associated with risk of clefts. We found at least a two-fold elevated risk of CP with low intake of riboflavin, magnesium, calcium, vitamin B12, and zinc; all CIs excluded 1.0. For CLP, we found at least a two-fold elevated risk with low intake of niacin, riboflavin, vitamin B12, and calcium, and a decreased risk with high intake of folate and cryptoxanthin; all CIs excluded 1.0.Conclusion:Results suggest that periconceptional nutrient intake may be associated with risk of CP and CLP.Pediatric Research (2013); doi:10.1038/pr.2013.115.

  View details for DOI 10.1038/pr.2013.115

  View details for PubMedID 23823175

• Maternal Dietary Nutrient Intake and Risk of Preterm Delivery AMERICAN JOURNAL OF PERINATOLOGY Carmichael, S. L., Yang, W., Shaw, G. M. 2013; 30 (7): 579-588

  Abstract

  Objective To examine maternal dietary intake and preterm delivery.Study Design Data included 5738 deliveries from the National Birth Defects Prevention Study. Odds ratios (ORs) reflected risks of delivery at <32, 32-34, or 35-36 versus ≥37 weeks for maternal intake in the lowest or highest quartile of nutrient intake compared with the middle two.Results Among deliveries < 32 weeks, many ORs were ≥1.5 or ≤0.7, but few confidence intervals excluded one. ORs were ≥1.5 for lowest quartiles of protein, thiamin, riboflavin, choline, vitamin A, α-carotene, β-carotene, vitamin E, iron, copper, and zinc and for highest quartiles of carbohydrate, glycemic index, and Mediterranean Diet Score. ORs were ≤0.7 for lowest quartiles of glycemic index and betaine and for highest quartiles of protein, alanine, methionine, vitamin B6, betaine, and calcium. Few ORs met these criteria for later preterm deliveries.Conclusions Results suggested an association of nutrient intake with earlier preterm deliveries.

  View details for DOI 10.1055/s-0032-1329686

  View details for Web of Science ID 000322021900009

  View details for PubMedID 23208764

• Hypospadias and Maternal Intake of Phytoestrogens AMERICAN JOURNAL OF EPIDEMIOLOGY Carmichael, S. L., Cogswell, M. E., Ma, C., Gonzalez-Feliciano, A., Olney, R. S., Correa, A., Shaw, G. M. 2013; 178 (3): 434-440

  Abstract

  Experimental data indicate that gestational exposures to estrogenic compounds impact risk of hypospadias. We examined whether risk of hypospadias (i.e., a congenital malformation in which the opening of the penile urethra occurs on the ventral side of the penis) was associated with maternal intake of phytoestrogens, given their potential impact on estrogen metabolism. The analysis included data on mothers of 1,250 hypospadias cases and 3,118 controls who delivered their infants from 1997 to 2005 and participated in the National Birth Defects Prevention Study, a multistate, population-based, case-control study. After adjustment for several covariates, high intakes of daidzein, genistein, glycetin, secoisolariciresinol, total isoflavones, total lignans, and total phytoestrogens were associated with reduced risks; odds ratios comparing intakes ≥90th percentile with intakes between the 11th and 89th percentiles ranged from 0.6 to 0.8. For example, the odds ratio for total phytoestrogen intake was 0.7 (95% confidence interval: 0.5, 1.0). This study represents the first large-scale analysis of phytoestrogen intake and hypospadias. The observed associations merit investigation in additional populations before firm conclusions can be reached.

  View details for DOI 10.1093/aje/kws591

  View details for Web of Science ID 000322734500012

  View details for PubMedID 23752918

  View details for PubMedCentralID PMC3727340

• Ambient air pollution and traffic exposures and congenital heart defects in the san joaquin valley of california. Paediatric and perinatal epidemiology Padula, A. M., Tager, I. B., Carmichael, S. L., Hammond, S. K., Yang, W., Lurmann, F., Shaw, G. M. 2013; 27 (4): 329-339

  Abstract

  Congenital anomalies are a leading cause of infant morbidity and mortality. Studies suggest associations between environmental contaminants and some anomalies, although evidence is limited.We used data from the California Center of the National Birth Defects Prevention Study and the Children's Health and Air Pollution Study to estimate the odds of 27 congenital heart defects with respect to quartiles of seven ambient air pollutant and traffic exposures in California during the first 2 months of pregnancy, 1997-2006 (n = 822 cases and n = 849 controls).Particulate matter < 10 microns (PM10 ) was associated with pulmonary valve stenosis [adjusted odds ratio (aOR)Fourth Quartile  = 2.6] [95% confidence intervals (CI) 1.2, 5.7] and perimembranous ventricular septal defects (aORThird Quartile  = 2.1) [95% CI 1.1, 3.9] after adjusting for maternal race/ethnicity, education and multivitamin use. PM2.5 was associated with transposition of the great arteries (aORThird Quartile  = 2.6) [95% CI 1.1, 6.5] and inversely associated with perimembranous ventricular septal defects (aORFourth Quartile  = 0.5) [95% CI 0.2, 0.9]. Secundum atrial septal defects were inversely associated with carbon monoxide (aORFourth Quartile  = 0.4) [95% CI 0.2, 0.8] and PM2.5 (aORFourth Quartile  = 0.5) [95% CI 0.3, 0.8]. Traffic density was associated with muscular ventricular septal defects (aORFourth Quartile  = 3.0) [95% CI 1.2, 7.8] and perimembranous ventricular septal defects (aORThird Quartile  = 2.4) [95% CI 1.3, 4.6], and inversely associated with transposition of the great arteries (aORFourth Quartile  = 0.3) [95% CI 0.1, 0.8].PM10 and traffic density may contribute to the occurrence of pulmonary valve stenosis and ventricular septal defects, respectively. The results were mixed for other pollutants and had little consistency with previous studies.

  View details for DOI 10.1111/ppe.12055

  View details for PubMedID 23772934

  View details for PubMedCentralID PMC3694598

• Maternal medication and herbal use and risk for hypospadias: data from the National Birth Defects Prevention Study, 1997-2007 PHARMACOEPIDEMIOLOGY AND DRUG SAFETY Lind, J. N., Tinker, S. C., Broussard, C. S., Reefhuis, J., Carmichael, S. L., Honein, M. A., Olney, R. S., Parker, S. E., Werler, M. M. 2013; 22 (7): 783-793

  Abstract

  To investigate associations between maternal use of common medications and herbals during early pregnancy and risk for hypospadias in male infants.We used data from the National Birth Defects Prevention Study, a multi-site, population-based, case-control study. We analyzed data from 1537 infants with second-degree or third-degree isolated hypospadias and 4314 live-born male control infants without major birth defects, with estimated dates of delivery from 1997 to 2007. Exposure was reported use of prescription or over-the-counter medications or herbal products, from 1 month before to 4 months after conception. Adjusted odds ratios (aORs) and 95% confidence intervals (CIs) were estimated using multivariable logistic regression, adjusting for maternal age, race/ethnicity, education, pre-pregnancy body mass index, previous live births, maternal subfertility, study site, and year.We assessed 64 medication and 24 herbal components. Maternal uses of most components were not associated with an increased risk of hypospadias. A new associations was observed for venlafaxine (aOR 2.4; 95%CI 1.0, 6.0) [Correction made here after initial online publication.]. The previously reported association for clomiphene citrate was confirmed (aOR 1.9; 95%CI 1.2, 3.0). Numbers were relatively small for exposure to other specific patterns of fertility agents, but elevated aORs were observed for the most common of them.Overall, findings were reassuring that hypospadias is not associated with most medication components examined in this analysis. New associations will need to be confirmed in other studies. Increased risks for hypospadias associated with various fertility agents raise the possibility of confounding by underlying subfertility.

  View details for DOI 10.1002/pds.3448

  View details for Web of Science ID 000325867800013

  View details for PubMedID 23620412

• Maternal Dietary Patterns are Associated With Risk of Neural Tube and Congenital Heart Defects AMERICAN JOURNAL OF EPIDEMIOLOGY Sotres-Alvarez, D., Siega-Riz, A. M., Herring, A. H., Carmichael, S. L., Feldkamp, M. L., Hobbs, C. A., Olshan, A. F. 2013; 177 (11): 1279-1288

  Abstract

  Studying empirically derived dietary patterns is useful in understanding dietary practice. We classified women by their dietary patterns using latent class analysis of 66 foods and studied the association of these patterns with neural tube defects (NTDs) and congenital heart defects (CHDs) in the U.S. National Birth Defects Prevention Study (1997-2005). Logistic regression models used data from 1,047 with an NTD, 6,641 with a CHD, and 6,123 controls that were adjusted for maternal characteristics and tested the effect modification of multivitamin supplement use. Four latent dietary patterns were identified: prudent, Western, low-calorie Western, and Mexican. Among participants who did not use supplements, those in the Mexican, Western, and low-calorie Western classes were significantly more likely (odds ratios of 1.6, 1.5, and 1.4, respectively) to have offspring born with NTDs than were those in the prudent class after adjustment of for dietary folic acid intake. In contrast, among supplement users, there was no difference in the incidence of NTDs between classes. Associations between dietary class and CHD subgroups were not modified by supplement use except for tetralogy of Fallot; among supplement users, those in the Western class were twice as likely (95% confidence interval: 1.4, 2.8) as the prudent class to have offspring with tetralogy of Fallot. Women who adhered to a Western diet were 1.2 (95% confidence interval: 1.03, 1.35) times more likely to have an infant with septal heart defect than were women who adhered to a prudent diet. A prudent dietary pattern, even with folate fortification, may decrease the risk of NTDs and some heart defects.

  View details for DOI 10.1093/aje/kws349

  View details for Web of Science ID 000319752400014

  View details for PubMedID 23639938

• The Association of Ambient Air Pollution and Traffic Exposures With Selected Congenital Anomalies in the San Joaquin Valley of California AMERICAN JOURNAL OF EPIDEMIOLOGY Padula, A. M., Tager, I. B., Carmichael, S. L., Hammond, S. K., Lurmann, F., Shaw, G. M. 2013; 177 (10): 1074-1085

  Abstract

  Congenital anomalies are a leading cause of infant mortality and are important contributors to subsequent morbidity. Studies suggest associations between environmental contaminants and some anomalies, although evidence is limited. We aimed to investigate whether ambient air pollutant and traffic exposures in early gestation contribute to the risk of selected congenital anomalies in the San Joaquin Valley of California, 1997-2006. Seven exposures and 5 outcomes were included for a total of 35 investigated associations. We observed increased odds of neural tube defects when comparing the highest with the lowest quartile of exposure for several pollutants after adjusting for maternal race/ethnicity, education, and multivitamin use. The adjusted odds ratio for neural tube defects among those with the highest carbon monoxide exposure was 1.9 (95% confidence interval: 1.1, 3.2) compared with those with the lowest exposure, and there was a monotonic exposure-response across quartiles. The highest quartile of nitrogen oxide exposure was associated with neural tube defects (adjusted odds ratio = 1.8, 95% confidence interval: 1.1, 2.8). The adjusted odds ratio for the highest quartile of nitrogen dioxide exposure was 1.7 (95% confidence interval: 1.1, 2.7). Ozone was associated with decreased odds of neural tube defects. Our results extend the limited body of evidence regarding air pollution exposure and adverse birth outcomes.

  View details for DOI 10.1093/aje/kws367

  View details for Web of Science ID 000318801200006

  View details for PubMedID 23538941

  View details for PubMedCentralID PMC3697063

• 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

• Fever Literacy and Fever Phobia CLINICAL PEDIATRICS Wallenstein, M. B., Schroeder, A. R., Hole, M. K., Ryan, C., Fijalkowski, N., Alvarez, E., Carmichael, S. L. 2013; 52 (3): 254-259

  Abstract

  To identify the percentage of parents who define the threshold for fever between 38.0°C and 38.3°C, which has not been reported previously, and to describe parental attitudes toward fever and antipyretic use.Thirteen-question survey study of caregivers.Overall, 81% of participants defined the threshold for fever as <38.0°C, 0% correctly defined fever between 38.0°C and 38.3°C, and 19% defined fever as >38.3°C. Twenty percent of children brought to clinic for a chief complaint of fever were never truly febrile. Ninety-three percent of participants believed that high fever can cause brain damage. For a comfortable-appearing child with fever, 89% of caregivers reported that they would give antipyretics and 86% would schedule a clinic visit.Our finding that 0% of parents correctly defined fever is both surprising and unsettling, and it should inform future discussions of fever between parents and clinicians.

  View details for DOI 10.1177/0009922812472252

  View details for Web of Science ID 000317849900007

  View details for PubMedID 23349363

• Thymidylate synthase polymorphisms and risks of human orofacial clefts BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY Shaw, G. M., Yang, W., Perloff, S., Shaw, N. M., Carmichael, S. L., Zhu, H., Lammer, E. J. 2013; 97 (2): 95-100

  Abstract

  Underlying mechanisms are unknown by which folic acid use in early pregnancy may reduce risks of orofacial clefts. Thymidylate synthase (TYMS) is a folate-dependent enzyme that catalyzes reductive methylation of deoxyuridylate to thymidylate, thereby playing a central role in DNA synthesis and repair. We investigated two TYMS functional variants (a 28-bp tandem repeat in the promoter enhancer region of the 5'-UTR; and TYMS 1494del6 (rs16430): a 6-bp deletion in the 3'-UTR) for their risk of cleft palate (CP) and of cleft lip with/without CP (CLP). We investigated effect measure modification between these variants and maternal folate intake for cleft risk.This case-control study included deliveries from July 1999 to June 2003 from select areas of California. Case groups included CLP or CP alone. Nonmalformed, liveborn controls were randomly selected. Maternal interviews provided information on vitamin use and dietary folate intake. DNA was derived from newborn bloodspots.Data were available for 304 CLP cases, 123 CP cases, and 581 controls. 1496del6 variants did not appear to influence risk of CP or CLP. Homozygosity for the 28-bp VNTR variant influenced CP risk (odds ratios, OR = 1.8, 95% confidence interval, 1.1-3.1), particularly among Hispanic infants, OR 2.1 (1.0-4.6). Effect measure modification was observed between the 28-bp VNTR and combined folate intake for CP with an OR of 10.0 (1.6-60.9).Although these findings are consistent with biological mechanisms, they were based on relatively small sample sizes and may represent false-positive discoveries. Replication is warranted in other populations.

  View details for DOI 10.1002/bdra.23114

  View details for Web of Science ID 000314982400004

  View details for PubMedID 23404871

• Diacylglycerol Kinase K Variants Impact Hypospadias in a California Study Population JOURNAL OF UROLOGY Carmichael, S. L., Mohammed, N., Ma, C., Iovannisci, D., Choudhry, S., Baskin, L. S., Witte, J. S., Shaw, G. M., Lammer, E. J. 2013; 189 (1): 305-311

  Abstract

  A recent genome wide association study demonstrated the novel finding that variants in DGKK are associated with hypospadias. Our objectives were to determine whether this finding could be replicated in a more racially/ethnically diverse study population of California births and to provide a more comprehensive investigation of variants.We examined the association of 27 DGKK single nucleotide polymorphisms with hypospadias relative to population based nonmalformed controls born in selected California counties from 1990 to 2003. Analyses included a maximum of 928 controls and 665 cases (mild in 91, moderate in 336, severe in 221 and undetermined in 17). Results for mild and moderate cases were similar, so they were grouped together.For mild and moderate cases OR for 15 of the 27 single nucleotide polymorphisms had p values less than 0.05, with 2 less than 1 and the others ranging from 1.3 to 1.8. Among severe cases ORs tended to be closer to 1, and none of the p values were less than 0.05. Due to high linkage disequilibrium across the single nucleotide polymorphisms, haplotype analyses were conducted and 2 blocks were generated. These analyses identified a set of 8 variants associated with a threefold to fourfold increased risk relative to the most common haplotype, regardless of severity of the phenotype (OR 4.1, p <10(-4) for mild to moderate cases and 3.3, p = 0.001 for severe cases).This study confirms that DGKK variants are associated with hypospadias. Additional studies are needed to allow a more thorough investigation of DGKK variability and to delineate the mechanism by which DGKK contributes to urethral development.

  View details for DOI 10.1016/j.juro.2012.09.002

  View details for Web of Science ID 000312604800107

  View details for PubMedID 23177175

• Association between weight gain during pregnancy and neural tube defects and gastroschisis in offspring BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY Yang, W., Carmichael, S. L., Tinker, S. C., Shaw, G. M. 2012; 94 (12): 1019-1025

  Abstract

  Limited information is available about the association of maternal weight gain during pregnancy and birth defects. The objective of this study was to investigate the association of maternal weight gain with neural tube defects (NTDs) and gastroschisis among offspring.We used data from the National Birth Defects Prevention Study, an ongoing multicenter, population-based, case-control study. Mothers of cases and controls were interviewed by telephone. Analyses included 255 anencephaly, 577 spina bifida, 648 gastroschisis cases, and 5587 controls with deliveries from 1999 to 2005. After subtracting birth weight, the associations of total and average weekly weight gain (kg) with each phenotype were estimated, stratified by gestational age (<37 vs. ≥37 weeks) and adjusted for relevant covariates.Among deliveries <37 weeks gestation, mothers of infants with anencephaly and spina bifida had lower weight gains compared to control mothers; no association between weight gains and gastroschisis was observed. Among deliveries ≥37 weeks, mothers of infants with anencephaly had lower weight gains during pregnancy; a similar association was not observed for spina bifida; mothers of infants with gastroschisis were twice as likely to have weight gains in the highest quartile. Stratification by maternal age (gastroschisis) or body mass index (BMI) or race/ethnicity (all phenotypes) did not alter odds ratio estimates.Altered weight gain during pregnancy may be a consequence of carrying an NTD/gastroschisis affected fetus or a marker for underlying factors common to the etiology of these birth defects. It is possible that whatever mechanisms influence weight gain may also influence the development of NTDs and gastroschisis, but in opposite directions.

  View details for DOI 10.1002/bdra.23057

  View details for Web of Science ID 000312527100009

  View details for PubMedID 22847944

  View details for PubMedCentralID PMC3522774

• Association of microtia with maternal nutrition BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY Ma, C., Shaw, G. M., Scheuerle, A. E., Canfield, M. A., Carmichael, S. L. 2012; 94 (12): 1026-1032

  Abstract

  Few studies have investigated the potential association of maternal dietary intake and risk of microtia among offspring.The study included deliveries from 1997 to 2005 from the National Birth Defects Prevention Study. Nonsyndromic cases of microtia were compared to nonmalformed, population-based, live-born control infants by estimating adjusted odds ratios (ORs) and 95% confidence intervals (CIs) from logistic regression models that included maternal race or ethnicity, education, folic acid-containing supplement intake, fertility treatment, study site, and total energy intake.Comparing intake in the lowest 10th percentile versus the 10th to 90th percentiles, lower maternal intakes of carbohydrate (OR, 1.59; 95% CI, 1.07-2.38) and dietary folate (OR, 1.57; 95% CI, 1.09-2.25) were associated with elevated risk of microtia. In addition, results suggested that higher diet quality (as measured by the Diet Quality Index, and comparing the highest with the lowest quartile) was protective, but the CI did not exclude one (OR, 0.73; 95% CI, 0.50-1.07). Results were similar among obese and nonobese women.These data contribute to the limited body of evidence regarding the potential contribution of maternal nutrition to the etiology of microtia.

  View details for DOI 10.1002/bdra.23053

  View details for Web of Science ID 000312527100010

  View details for PubMedID 22821770

• Maternal and Infant Gene-Folate Interactions and the Risk of Neural Tube Defects AMERICAN JOURNAL OF MEDICAL GENETICS PART A Etheredge, A. J., Finnell, R. H., Carmichael, S. L., Lammer, E. J., Zhu, H., Mitchell, L. E., Shaw, G. M. 2012; 158A (10): 2439-2446

  Abstract

  Neural tube defects (NTDs) are common, serious malformations with a complex etiology that suggests involvement of both genetic and environmental factors. The authors evaluated maternal or offspring folate-related gene variants and interactions between the gene variants and maternal intake of folates on the risk of NTDs in their offspring. A case-control study was conducted on mothers and/or their fetuses and infants who were born in California from 1999 to 2003 with an NTD (cases n = 222, including 24 mother-infant pairs) or without a major malformation (controls n = 454, including 186 mother-infant pairs). Maternal intake of folates was assessed by food frequency questionnaire and genotyping was performed on samples from mothers and infants. For mothers in the lowest folate-intake group, risk of NTDs in offspring was significantly decreased for maternal MTHFR SNPs rs1476413, rs1801131, and rs1801133 (odds ratio [OR] = 0.55, 80% confidence interval [CI]: 0.20, 1.48; OR = 0.58, 80% CI: 0.24, 1.43; OR = 0.69, 80% CI: 0.41, 1.17, respectively), and TYMS SNPs rs502396 and rs699517 (OR = 0.91, 80% CI: 0.53, 1.56; OR = 0.70, 80% CI: 0.38, 1.29). A gene-only effect was observed for maternal SHMT1 SNP rs669340 (OR = 0.69, 95% CI: 0.49, 0.96). When there was low maternal folate intake, risk of NTDs was significantly increased for infant MTHFD1 SNPs rs2236224, rs2236225, and rs11627387 (OR = 1.58, 80% CI: 0.99, 2.51; OR = 1.53, 80% CI: 0.95, 2.47; OR = 4.25, 80% CI: 2.33, 7.75, respectively) and SHMT1 SNP rs12939757 (OR = 2.01, 80% CI: 1.20, 3.37), but decreased for TYMS SNP rs2847153 (OR = 0.73, 80% CI: 0.37, 1.45). Although power to detect interaction effects was low for this birth defects association study, the gene-folate interactions observed in this study represent preliminary findings that will be useful for informing future studies on the complex etiology of NTDs.

  View details for DOI 10.1002/ajmg.a.35552

  View details for Web of Science ID 000310070700011

  View details for PubMedID 22903727

• Thymidylate Synthase Polymorphisms and Risk of Conotruncal Heart Defects AMERICAN JOURNAL OF MEDICAL GENETICS PART A Zhu, H., Yang, W., Shaw, N., Perloff, S., Carmichael, S. L., Finnell, R. H., Shaw, G. M., Lammer, E. J. 2012; 158A (9): 2194-2203

  Abstract

  In this study, we investigated whether the two TYMS functional variants (28 bp VNTR and 1494del6) (275 cases and 653 controls) and six selected SNPs (265 case infants, 535 control infants; 169 case mothers and 276 control mothers) were associated with risks of conotruncal heart defects. Further, we evaluated interaction effects between these gene variants and maternal folate intake for risk of CTD. Cases with diagnosis of single gene disorders or chromosomal aneusomies were excluded. Controls were randomly selected from area hospitals in proportion to their contribution to the total population of live-born infants. DNA samples were collected using buccal brushes or drawn from the repository of newborn screening blood specimens when available. Genetic variants were treated as categorical variables (homozygous referent, heterozygote, homozygous variant). Odds ratios and 95% confidence intervals (CI) were computed to estimate risks among all subjects, Hispanic and non-Hispanic whites, respectively, using logistic regression. Gene-folate interactions were assessed for these variants by adding an interaction term to the logistic model. A dichotomized composite variable, "combined folate intake," was created by combining maternal peri-conceptional use of folic acid-containing vitamin supplements with daily dietary intake of folate. In general, the results do not show strong gene-only effects on risk of CTD. We did, however, observe a 3.6-fold increase in CTD risk (95% CI: 1.1-11.9) among infants who were homozygotes for the 6 bp deletion in the 3'-untranslated region (UTR) (1694del6) and whose mothers had low folate intake during the peri-conceptional period.

  View details for DOI 10.1002/ajmg.a.35310

  View details for Web of Science ID 000310068700015

  View details for PubMedID 22887475

  View details for PubMedCentralID PMC3429723

• Nutritional Factors and Hypospadias Risks PAEDIATRIC AND PERINATAL EPIDEMIOLOGY Carmichael, S. L., Ma, C., Feldkamp, M. L., Munger, R. G., Olney, R. S., Botto, L. D., Shaw, G. M., Correa, A. 2012; 26 (4): 353-360

  Abstract

  We examined whether hypospadias was associated with several aspects of the diet, including intake of animal products, intake of several nutrients and food groups related to a vegetarian diet and oestrogen metabolism, and diet quality.The study included deliveries from 1997 to 2005 that were part of the National Birth Defects Prevention Study. Diet was assessed by food frequency questionnaire during maternal telephone interviews, and two diet quality indices were developed based on existing indices. Analyses included 1250 cases with second- or third-degree hypospadias (urethra opened at the penile shaft, scrotum or perineum) and 3118 male, liveborn, non-malformed controls. All odds ratios (OR) and 95% confidence intervals [CI] were estimated from logistic regression models that included several potential confounders, including energy intake.Intake of animal products was not associated with hypospadias; for example, the adjusted OR for any vs. no intake of meat was 1.0 [95% CI 0.6, 1.6]. Frequency of intake of meat or other animal products was also not associated with hypospadias, nor was intake of iron or several nutrients that are potentially related to oestrogen metabolism. Diet quality was also not associated with hypospadias; the OR for diet quality in the highest vs. lowest quartile for the two diet quality indices were 1.0 [95% CI 0.6, 1.6] and 0.9 [95% CI 0.7, 1.1].This large study does not support an association of a vegetarian diet or worse diet quality with hypospadias.

  View details for DOI 10.1111/j.1365-3016.2012.01272.x

  View details for Web of Science ID 000305121500013

  View details for PubMedID 22686387

  View details for PubMedCentralID PMC3376012

• Environmental and genetic contributors to hypospadias: A review of the epidemiologic evidence BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY Carmichael, S. L., Shaw, G. M., Lammer, E. J. 2012; 94 (7): 499-510

  Abstract

  This review evaluates current knowledge related to trends in the prevalence of hypospadias, the association of hypospadias with endocrine-disrupting exposures, and the potential contribution of genetic susceptibility to its etiology. The review focuses on epidemiologic evidence. Increasing prevalence of hypospadias has been observed, but such increases tend to be localized to specific regions or time periods. Thus, generalized statements that hypospadias is increasing are unsupported. Owing to the limitations of study designs and inconsistent results, firm conclusions cannot be made regarding the association of endocrine-disrupting exposures with hypospadias. Studies with more rigorous study designs (e.g., larger and more detailed phenotypes) and exposure assessment that encompasses more breadth and depth (e.g., specific endocrine-related chemicals) will be critical to make better inferences about these important environmental exposures. Many candidate genes for hypospadias have been identified, but few of them have been examined to an extent that enables solid conclusions. Further study is needed that includes larger sample sizes, comparison groups that are more representative of the populations from which the cases were derived, phenotype-specific analyses, and more extensive exploration of variants. In conclusion, examining the associations of environmental and genetic factors with hypospadias remain important areas of inquiry, although our actual understanding of their contribution to hypospadias risk in humans is currently limited.

  View details for DOI 10.1002/bdra.23021

  View details for Web of Science ID 000306186100001

  View details for PubMedID 22678668

  View details for PubMedCentralID PMC3393839

• Cancer in Children with Nonchromosomal Birth Defects JOURNAL OF PEDIATRICS Fisher, P. G., Reynolds, P., Von Behren, J., Carmichael, S. L., Rasmussen, S. A., Shaw, G. M. 2012; 160 (6): 978-983

  Abstract

  To examine whether the incidence of childhood cancer is elevated in children with birth defects but no chromosomal anomalies.We examined cancer risk in a population-based cohort of children with and without major birth defects born between 1988 and 2004, by linking data from the California Birth Defects Monitoring Program, the California Cancer Registry, and birth certificates. Cox proportional hazards models generated hazard ratios (HRs) and 95% CIs based on person-years at risk. We compared the risk of childhood cancer in infants born with and without specific types of birth defects, excluding infants with chromosomal anomalies.Of the 4869 children in the birth cohort with cancer, 222 had a major birth defect. Although the expected elevation in cancer risk was observed in children with chromosomal birth defects (HR, 12.44; 95% CI, 10.10-15.32), especially for the leukemias (HR, 28.99; 95% CI, 23.07-36.42), children with nonchromosomal birth defects also had an increased risk of cancer (HR, 1.58; 95% CI, 1.33-1.87), but instead for brain tumors, lymphomas, neuroblastoma, and germ cell tumors.Children with nonchromosomal birth defects are at increased risk for solid tumors, but not leukemias. Dysregulation of early human development likely plays an important role in the etiology of childhood cancer.

  View details for DOI 10.1016/j.jpeds.2011.12.006

  View details for Web of Science ID 000304377300019

  View details for PubMedID 22244463

• Gene variants in the folate-mediated one-carbon metabolism (FOCM) pathway as risk factors for conotruncal heart defects AMERICAN JOURNAL OF MEDICAL GENETICS PART A Zhu, H., Yang, W., Lu, W., Etheredge, A. J., Lammer, E. J., Finnell, R. H., Carmichael, S. L., Shaw, G. M. 2012; 158A (5): 1124-1134

  Abstract

  We evaluated 35 variants among four folate-mediated one-carbon metabolism pathway genes, MTHFD1, SHMT1, MTHFR, and DHFR as risk factors for conotruncal heart defects. Cases with a diagnosis of single gene disorders or chromosomal aneusomies were excluded. Controls were randomly selected from area hospitals in proportion to their contribution to the total population of live-born infants. Odds ratios (OR) and the 95% confidence intervals (CI) were computed for each genotype (homozygous variant or heterozygote, vs. homozygous wildtype) and for increase of each less common allele (log-additive model). Interactions between each variant and three folate intake variables (maternal multivitamin use, maternal dietary folate intake, and combined maternal folate intake) were also evaluated under the log-additive model. In general, we did not identify notable associations. The A allele of MTHFD1 rs11627387 was associated with a 1.7-fold increase in conotruncal defects risk in both Hispanic mothers (OR = 1.7, 95% CI = 1.1-2.5) and Hispanic infants (OR = 1.7, 95% CI = 1.2-2.3). The T allele of MTHFR rs1801133 was associated with a 2.8-fold increase of risk among Hispanic women whose dietary folate intake was ≤ 25th centile. The C allele of MTHFR rs1801131 was associated with a two-fold increase of risk (OR = 2.0, 95% CI = 1.0-3.9) only among those whose dietary folate intake was >25th centile. Our study suggested that MTHFD1 rs11627387 may be associated with risk of conotruncal defects through both maternal and offspring genotype effect among the Hispanics. Maternal functional variants in MTHFR gene may interact with dietary folate intake and modify the conotruncal defects risk in the offspring.

  View details for DOI 10.1002/ajmg.a.35313

  View details for Web of Science ID 000303000200022

  View details for PubMedID 22495907

  View details for PubMedCentralID PMC3331895

• Is Maternal Parity an Independent Risk Factor for Birth Defects? BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY Duong, H. T., Hoyt, A. T., Carmichael, S. L., Gilboa, S. M., Canfield, M. A., Case, A., McNeese, M. L., Waller, D. K. 2012; 94 (4): 230-236

  Abstract

  Although associations between maternal parity and birth defects have been observed previously, few studies have focused on the possibility that parity is an independent risk factor for birth defects. We investigated the relation between levels of parity and a range of birth defects, adjusting each defect group for the same covariates.We included infants who had an estimated delivery date between 1997 and 2007 and participated in the National Birth Defects Prevention Study, a multisite case-control study. Cases included infants or fetuses belonging to 38 phenotypes of birth defects (n = 17,908), and controls included infants who were unaffected by a major birth defect (n = 7173). Odds ratios (ORs) were adjusted for 12 covariates using logistic regression.Compared with primiparous mothers, nulliparous mothers were more likely to have infants with amniotic band sequence, hydrocephaly, esophageal atresia, hypospadias, limb reduction deficiencies, diaphragmatic hernia, omphalocele, gastroschisis, tetralogy of Fallot, and septal cardiac defects, with significant ORs (1.2 to 2.3). Compared with primiparous mothers, multiparous mothers had a significantly increased risk of omphalocele, with an OR of 1.5, but had significantly decreased risk of hypospadias and limb reduction deficiencies, with ORs of 0.77 and 0.77.Nulliparity was associated with an increased risk of specific phenotypes of birth defects. Most of the phenotypes associated with nulliparity in this study were consistent with those identified by previous studies. Research into biologic or environmental factors that are associated with nulliparity may be helpful in explaining some or all of these associations.

  View details for DOI 10.1002/bdra.22889

  View details for Web of Science ID 000302606600005

  View details for PubMedID 22371332

• Reduced Risks of Neural Tube Defects and Orofacial Clefts With Higher Diet Quality ARCHIVES OF PEDIATRICS & ADOLESCENT MEDICINE Carmichael, S. L., Yang, W., Feldkamp, M. L., Munger, R. G., Siega-Riz, A. M., Botto, L. D., Shaw, G. 2012; 166 (2): 121-126

  Abstract

  To examine whether better maternal diet quality was associated with reduced risk for selected birth defects.A multicenter, population-based case-control study, the National Birth Defects Prevention Study.Ten participating centers in the United States.Eligible subjects' estimated due dates were from October 1997 through December 2005. Telephone interviews were conducted with 72% of case and 67% of control mothers. Analyses included 936 cases with neural tube defects (NTDs), 2475 with orofacial clefts, and 6147 nonmalformed controls.Food-frequency data were used to calculate the Mediterranean Diet Score (MDS) and Diet Quality Index (DQI), modeled after existing indices.Adjusted odds ratios (ORs).After covariate adjustment, increasing diet quality based on either index was associated with reduced risks for the birth defects studied. The strongest association was between anencephaly and DQI; the OR for highest vs lowest quartile was 0.49 (95% CI, 0.31-0.75). The ORs for cleft lip with or without cleft palate and cleft palate and DQI were also notable (0.66 [95% CI, 0.54-0.81] and 0.74 [95%CI, 0.56-0.96], respectively).Healthier maternal dietary patterns, as measured by diet quality scores, were associated with reduced risks of NTDs and clefts. These results suggest that dietary approaches could lead to further reduction in risks of major birth defects and complement existing efforts to fortify foods and encourage periconceptional multivitamin use.

  View details for DOI 10.1001/archpediatrics.2011.185

  View details for Web of Science ID 000301211000002

  View details for PubMedID 21969361

• Paternal Age and Congenital Malformations in Offspring in California, 1989-2002 MATERNAL AND CHILD HEALTH JOURNAL Grewal, J., Carmichael, S. L., Yang, W., Shaw, G. M. 2012; 16 (2): 385-392

  Abstract

  This study examined the association between paternal age and a wide range of structural birth defects. Data were drawn from The California Birth Defects Monitoring Program, a population-based active surveillance system for collecting information on infants and fetuses with defects born between 1989 and 2002. The analysis included 46,114 cases with defects, plus a random sample of 36,838 non-malformed births. After adjustment for maternal age, risks of anomalies of the nervous system for 38 and 42 year-old fathers, as compared to 29 year-old fathers, were 1.05-fold [1.00, 1.11] and 1.10-fold [1.02, 1.18] higher, respectively. Similar results were observed for anomalies of the limbs, where 38 and 42 year-old fathers had a 1.06-fold [1.02, 1.11] and 1.11-fold [1.05, 1.18] higher risk, respectively. Risks of anomalies of the integument were 1.05-fold [1.00, 1.09] and 1.10-fold [1.03, 1.16] higher for 38 and 42 year olds, respectively. Young paternal age, i.e., less than 29 years, was associated with an increased risk of amniotic bands (OR: 0.87 [0.78, 0.97]), pyloric stenosis (OR: 0.93 [0.90, 0.96]) and anomalies of the great veins (OR: 0.93 [0.87, 1.00]). In sum, both advanced and young paternal age was associated with select birth defects in California between 1989 and 2002.

  View details for DOI 10.1007/s10995-011-0759-z

  View details for Web of Science ID 000299370400013

  View details for PubMedID 21344170

• A Genetic Signature of Spina Bifida Risk from Pathway-Informed Comprehensive Gene-Variant Analysis PLOS ONE Marini, N. J., Hoffmann, T. J., Lammer, E. J., Hardin, J., Lazaruk, K., Stein, J. B., Gilbert, D. A., Wright, C., Lipzen, A., Pennacchio, L. A., Carmichael, S. L., Witte, J. S., Shaw, G. M., Rine, J. 2011; 6 (11)

  Abstract

  Despite compelling epidemiological evidence that folic acid supplements reduce the frequency of neural tube defects (NTDs) in newborns, common variant association studies with folate metabolism genes have failed to explain the majority of NTD risk. The contribution of rare alleles as well as genetic interactions within the folate pathway have not been extensively studied in the context of NTDs. Thus, we sequenced the exons in 31 folate-related genes in a 480-member NTD case-control population to identify the full spectrum of allelic variation and determine whether rare alleles or obvious genetic interactions within this pathway affect NTD risk. We constructed a pathway model, predetermined independent of the data, which grouped genes into coherent sets reflecting the distinct metabolic compartments in the folate/one-carbon pathway (purine synthesis, pyrimidine synthesis, and homocysteine recycling to methionine). By integrating multiple variants based on these groupings, we uncovered two provocative, complex genetic risk signatures. Interestingly, these signatures differed by race/ethnicity: a Hispanic risk profile pointed to alterations in purine biosynthesis, whereas that in non-Hispanic whites implicated homocysteine metabolism. In contrast, parallel analyses that focused on individual alleles, or individual genes, as the units by which to assign risk revealed no compelling associations. These results suggest that the ability to layer pathway relationships onto clinical variant data can be uniquely informative for identifying genetic risk as well as for generating mechanistic hypotheses. Furthermore, the identification of ethnic-specific risk signatures for spina bifida resonated with epidemiological data suggesting that the underlying pathogenesis may differ between Hispanic and non-Hispanic groups.

  View details for DOI 10.1371/journal.pone.0028408

  View details for Web of Science ID 000298168100069

  View details for PubMedID 22140583

• Periconceptional Intake of Folic Acid and Food Folate and Risks of Preterm Delivery AMERICAN JOURNAL OF PERINATOLOGY Shaw, G. M., Carmichael, S. L., Yang, W., Siega-Riz, A. M. 2011; 28 (10): 747-751

  Abstract

  We investigated multiple sources of folate and folic acid to determine whether their periconceptional intakes were associated with preterm delivery. Studied were controls from the National Birth Defects Prevention Study delivered September 1998 to December 2005. Telephone interviews were conducted with 5952 (68% of eligible) mothers. Women were queried about intake of vitamin supplements in the 12 weeks before conception through delivery. A version of the Nurse's Health Study food frequency questionnaire was used to assess food sources. Eight percent of infants ( N = 487) were preterm (<37 weeks). Compared with women who began intake of supplements with folic acid before pregnancy, those who began any time during pregnancy had an ~20% lowered risk of preterm delivery. Lower dietary intakes showed a modest increased risk of preterm delivery: odds ratios were 1.44 (1.01 to 2.04) for lowest quartile intake of folate and 1.27 (0.95 to 1.69) for lowest quartile intake of folic acid compared with the highest. Findings suggest some evidence that folates influenced risks; however, an interpretation of results was also consistent with no association between intake of folates and preterm delivery.

  View details for DOI 10.1055/s-0031-1280855

  View details for Web of Science ID 000298200500002

  View details for PubMedID 21681695

• Estimated dietary phytoestrogen intake and major food sources among women during the year before pregnancy NUTRITION JOURNAL Carmichael, S. L., Gonzalez-Feliciano, A. G., Ma, C., Shaw, G. M., Cogswell, M. E. 2011; 10

  Abstract

  Phytoestrogens may be associated with a variety of different health outcomes, including outcomes related to reproductive health. Recently published data on phytoestrogen content of a wide range of foods provide an opportunity to improve estimation of dietary phytoestrogen intake.Using the recently published data, we estimated intake among a representative sample of 6,584 women of reproductive age from a multi-site, population-based case-control study, the National Birth Defects Prevention Study (NBDPS). The NBDPS uses a shortened version of the Willett food frequency questionnaire to estimate dietary intake during the year before pregnancy. We estimated intake among NBDPS control mothers.Lignans contributed 65% of total phytoestrogen intake; isoflavones, 29%; and coumestrol, 5%. Top contributors to total phytoestrogen intake were vegetables (31%) and fruit (29%); for isoflavones, dairy (33%) and fruit (21%); for lignans, vegetables (40%) and fruit (29%); and for coumestans, fruit (55%) and dairy (18%). Hispanic women had higher phytoestrogen intake than non-Hispanic white or black women. Associations with maternal age and folic acid-containing supplements were more modest but indicated that older mothers and mothers taking supplements had higher intake.The advantage of the approach used for the current analysis lies in its utilization of phytoestrogen values derived from a single laboratory that used state-of-the-art measurement techniques. The database we developed can be applied directly to other studies using food frequency questionnaires, especially the Willett questionnaire. The database, combined with consistent dietary intake assessment, provides an opportunity to improve our ability to understand potential associations of phytoestrogen intake with health outcomes.

  View details for DOI 10.1186/1475-2891-10-105

  View details for Web of Science ID 000295960300001

  View details for PubMedID 21978267

  View details for PubMedCentralID PMC3196693

• Maternal nutrition and gastroschisis: findings from the National Birth Defects Prevention Study AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY Feldkamp, M. L., Carmichael, S. L., Shaw, G. M., Panichello, J. D., Moore, C. A., Botto, L. D. 2011; 204 (5)

  Abstract

  Gastroschisis is increasing in many countries, especially among young women. Because young women may have inadequate nutrition, we assessed the relationship between individual nutrients and the risk for gastroschisis.We analyzed data from the National Birth Defects Prevention Study, a population-based case-control study. Cases were ascertained from 10 birth defect surveillance systems. Controls were randomly selected from birth certificates or hospital records. Nutrient intake was estimated for the year prior to conception from maternal interviews based on a 58-item food frequency questionnaire and cereal consumption reported. A total of 694 cases and 6157 controls were available for analysis.Reported intake of individual nutrients did not substantially affect the risk for gastroschisis. Stratification by maternal age, preconception body mass index, folic acid-containing supplements, or energy intake (kilocalories) did not alter risk estimates.This study does not support an increased risk for gastroschisis with decreasing tertiles of individual nutrients.

  View details for DOI 10.1016/j.ajog.2010.12.053

  View details for Web of Science ID 000290206200025

  View details for PubMedID 21396620

• Craniosynostosis and Nutrient Intake during Pregnancy BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY Carmichael, S. L., Rasmussen, S. A., Lammer, E. J., Ma, C., Shaw, G. M. 2010; 88 (12): 1032-1039

  Abstract

  To examine the association of craniosynostosis with maternal intake of folic acid-containing supplements and dietary nutrients.The study included deliveries from 1997 to 2005 from the National Birth Defects Prevention Study. Nonsyndromic infants with craniosynostosis (n = 815) were compared to nonmalformed, population-based liveborn control infants (n = 6789), by estimating adjusted odds ratios (AORs) and 95% confidence intervals (CIs) from logistic regression models that included mother's age, parity, race-ethnicity, education, body mass index, smoking, alcohol, fertility treatments, plurality, and study center. We compared quartiles of intake and specified nutrients as continuous.Intake of folic acid-containing supplements was not associated with craniosynostosis (AORs were close to 1). Analyses of dietary nutrients were restricted to mothers who took supplements during the first trimester (i.e., most women). Based on continuous specifications of nutrients, sagittal synostosis risk was significantly lower among women with higher intake of riboflavin and vitamins B₆, E, and C; metopic synostosis risk was significantly higher among women with higher intakes of choline and vitamin B₁₂; and coronal synostosis risk was significantly lower among women with higher intake of methionine and vitamin C. As examples, AORs for sagittal synostosis among women with intakes of vitamin B₆ and riboflavin in the highest versus lowest quartiles were 0.4 (95% CI, 0.2-0.6) and 0.5 (95% CI, 0.3-0.7), respectively.This analysis suggests that dietary intake of certain nutrients may be associated with craniosynostosis, and results may vary by suture type.

  View details for DOI 10.1002/bdra.20717

  View details for Web of Science ID 000285396200006

  View details for PubMedID 20842649

• Association of Microtia With Maternal Obesity and Periconceptional Folic Acid Use AMERICAN JOURNAL OF MEDICAL GENETICS PART A Ma, C., Carmichael, S. L., Scheuerle, A. E., Canfield, M. A., Shaw, G. M. 2010; 152A (11): 2756-2761

  Abstract

  The study objective was to examine the association of microtia with maternal intake of folic-acid-containing supplements and obesity. The study data included deliveries from 1997 to 2005 from the National Birth Defects Prevention Study. Non-syndromic cases of microtia were compared to non-malformed, population-based liveborn control infants, by estimating adjusted odds ratios (AORs) and 95% confidence intervals (CIs) from logistic regression models that included maternal race/ethnicity, education, and study site. Maternal obesity was only weakly associated with microtia. Maternal periconceptional intake of folic-acid-containing vitamin supplements reduced the risk for microtia, but only among non-obese women (OR: 0.63; 95% CI: 0.44-0.91). The reduced risk was stronger when analyses were restricted to isolated cases (OR: 0.51; 95% CI: 0.34-0.77), and it was independent of the level of maternal dietary folate intake. Adjusting for maternal race/ethnicity did not reveal alternative interpretations of this association. This analysis suggests that maternal periconceptional intake of folic-acid-containing supplements may provide protection from microtia for non-obese women.

  View details for DOI 10.1002/ajmg.a.33694

  View details for Web of Science ID 000284005700013

  View details for PubMedID 20949601

• Prepregnancy Obesity: A Complex Risk Factor for Selected Birth Defects BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY Carmichael, S. L., Rasmussen, S. A., Shaw, G. M. 2010; 88 (10): 804-810

  Abstract

  Obesity is associated with increased risk of many adverse health conditions. During pregnancy, obesity presents particularly important challenges for both mother and baby. Over the last 20 years, studies have emerged indicating an association between prepregnancy weight and risks of birth defects. However, few studies have examined the mechanisms through which this association occurs. Understanding the underlying mechanisms may provide clues to public health strategies for the prevention of birth defects associated with maternal obesity. This article briefly reviews existing literature on the association between maternal obesity and birth defects, discusses potential underlying mechanisms, and suggests research needed to improve our understanding of this important association.

  View details for DOI 10.1002/bdra.20679

  View details for Web of Science ID 000283638500006

  View details for PubMedID 20973050

• Periconceptional Nutrient Intakes and Risks of Neural Tube Defects in California 6th International Conference on Neural Tube Defects Carmichael, S. L., Yang, W., Shaw, G. M. WILEY-LISS. 2010: 670–78

  Abstract

  This study investigated the association of neural tube defects (NTDs) with maternal periconceptional intake of folic acid-containing supplements and dietary nutrients, including folate, among deliveries that occurred after folic acid fortification in selected California counties.The population-based case-control study included fetuses and live born infants with spina bifida (189) or anencephaly (141) and 625 nonmalformed, live born controls delivered from 1999 to 2003. Mothers reported supplement use during telephone interviews, which included a 107-item food frequency questionnaire. For dietary nutrients, intakes <25th, 25th to <75th (reference), and > or =75th percentile were compared, based on control distributions.After adjustment for potential confounders, any versus no supplement intake resulted in ORs of 0.8 (95% CI, 0.5-1.3) for anencephaly and 0.8 (95% CI, 0.6-1.2) for spina bifida. After stratification by maternal intake of vitamin supplements, most factors in the glycemic pathway were not associated with either NTD, with the exception of low levels of fructose and glucose that were significantly associated with anencephaly. Some nutrients that contribute to one-carbon metabolism showed lowered risks (folate, riboflavin, vitamins B(6) and B(12)); others did not (choline, methionine, zinc). Antioxidant nutrients tended to be associated with lowered risks (vitamins C, E, A, beta-carotene, lutein).Mothers' intake of vitamin supplements was modestly if at all associated with a lowered risk of NTDs. Dietary intake of several nutrients contributing to one-carbon metabolism and oxidative stress were associated with reduced NTD risk.

  View details for DOI 10.1002/bdra.20675

  View details for Web of Science ID 000281529700009

  View details for PubMedID 20740594

  View details for PubMedCentralID PMC2929981

• Hypospadias and halogenated organic pollutant levels in maternal mid-pregnancy serum samples CHEMOSPHERE Carmichael, S. L., Herring, A. H., Sjoedin, A., Jones, R., Needham, L., Ma, C., Ding, K., Shaw, G. M. 2010; 80 (6): 641-646

  Abstract

  Environmental contaminants that disrupt endocrine function may contribute to hypospadias etiology.To compare levels of selected halogenated organic pollutants in women delivering infants with and without hypospadias.This study examined levels of nine polybrominated flame retardants (PBDEs), 30 polychlorinated biphenyls (PCBs) and nine persistent pesticides in mid-pregnancy serum samples from 20 women who delivered infants with hypospadias and 28 women who delivered unaffected infants, in California. Analytes were measured using isotope dilution high-resolution mass spectrometry. Values below individual limits of detection (LOD) for each analyte were imputed based on a truncated multivariate normal distribution. Levels of 17 analytes for which at least 50% of cases and controls had values above the LOD were compared using t-tests and by generating odds ratios from logistic regression analyses.Means were greater for cases than controls for 11 of the 17 reported analytes (4 of 5 PBDEs, 7 of 9 PCBs, and 0 of 3 other persistent pesticides), but none of the differences were statistically significant. Eleven of the 17 odds ratios exceeded one (the same analytes that had greater means), but none of the confidence intervals excluded one. After adjustment for sample processing time and foreign-born Hispanic race-ethnicity, only four of the odds ratios exceeded one.Levels of the PBDEs and PCBs were not statistically significantly different, but the sample size was small. The current study adds to a relatively limited knowledge base regarding the potential association of specific contaminants with hypospadias or other birth defects.

  View details for DOI 10.1016/j.chemosphere.2010.04.055

  View details for Web of Science ID 000280749500005

  View details for PubMedID 20494400

• Patterns of tobacco exposure before and during pregnancy ACTA OBSTETRICIA ET GYNECOLOGICA SCANDINAVICA Anderka, M., Romitti, P. A., Sun, L., Druschel, C., Carmichael, S., Shaw, G. 2010; 89 (4): 505-514

  Abstract

  To describe maternal exposure to tobacco in the three months before conception and throughout pregnancy, examine risk factors associated with tobacco exposure in pregnancy and smoking cessation, assess use of pharmacotherapy for smoking cessation and evaluate birth outcomes by smoking status.A cohort of women from a multi-site United States study were asked retrospectively about their exposure to tobacco.The study population was comprised of 4,667 mothers of non-malformed control infants who participated in the National Birth Defects Prevention Study from 1997 to 2003.Using computer-assisted telephone interview responses from this population-based sample, we assessed patterns of maternal smoking and exposure to environmental tobacco smoke (ETS) as well as use of pharmacotherapy for quitting smoking during pregnancy.Overall, 961 (20.6%) mothers reported any smoking and 1,401 (30.0%) reported any exposure to ETS at home or work during the three months before conception through pregnancy. Of the 961 smokers, 512 (53.3%) reportedly quit smoking before or during pregnancy, including 379 (74% of quitters) in the first trimester, and 420 (43.7%) continued to smoke throughout the pregnancy. Only 2.1% of smokers reportedly used pharmacotherapy to quit smoking anytime from three months before conception through pregnancy. Low birthweight and preterm delivery rates were lowest among offspring of non-smokers and highest in offspring of those who continued to smoke throughout pregnancy.About one-half of mothers who reported preconceptional smoking quit before or during pregnancy. Use of pharmacotherapy to quit smoking during pregnancy was not common.

  View details for DOI 10.3109/00016341003692261

  View details for Web of Science ID 000277094700011

  View details for PubMedID 20367429

• Fetal Constraint as a Potential Risk Factor for Craniosynostosis AMERICAN JOURNAL OF MEDICAL GENETICS PART A Sanchez-Lara, P. A., Carmichael, S. L., Graham, J. M., Lammer, E. J., Shaw, G. M., Ma, C., Rasmussen, S. A. 2010; 152A (2): 394-400

  Abstract

  Non-syndromic craniosynostosis is multifactorial, and fetal head constraint has been hypothesized as one factor thought to play a role. Data from the National Birth Defects Prevention Study (NBDPS), a large multi-site case-control study of birth defects, were used to evaluate associations between four selected factors related to fetal constraint and craniosynostosis: plurality (twins or higher), macrosomia (birth weight >4,000 g), post-term gestational age (> or =42 weeks), and nulliparity (no previous live births). Case infants (n = 675) had craniosynostosis documented either by radiographic evidence or by surgical intervention. Infants with a recognized or strongly suspected single-gene conditions or chromosomal abnormalities were excluded. Control infants (n = 5,958) had no major birth defects and were randomly selected from the same population as case infants. Logistic regression was used to estimate odds ratios for the association between these four factors and craniosynostosis, while adjusting for several covariates. We found that plurality and nulliparity were associated with a twofold increased risk for metopic craniosynostosis, and macrosomia had almost twice the risk of developing coronal craniosynostosis. Contrary to our hypothesis, prematurity and low birth weight were also associated with craniosynostosis. In conclusion, these four constraint-related factors were not found to be associated with craniosynostosis when all suture types were combined, though some types of craniosynostosis were associated with individual constraint-related factors.

  View details for DOI 10.1002/ajmg.a.33246

  View details for Web of Science ID 000274508300019

  View details for PubMedID 20101684

• Socioeconomic Measures, Orofacial Clefts, and Conotruncal Heart Defects in California BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY Carmichael, S. L., Ma, C., Shaw, G. M. 2009; 85 (10): 850-857

  Abstract

  To examine the association of multiple measures of socioeconomic status (SES) with risks of orofacial clefts and conotruncal heart defects.Data were from a recent population-based case-control study conducted in California that included 608 patients with orofacial clefts, 277 patients with conotruncal heart defects, and 617 nonmalformed controls.The odds ratio for the worst versus best score on a household-level SES index was strongest for cleft lip with or without palate, at 1.7 (95% confidence interval, 0.9-3.4); the odds ratios for this comparison were closer to 1 and less precise for the other defect groups. An index based on neighborhood-level SES was also not associated with increased risk of the studied defects.This detailed analysis of SES and selected birth defects did not suggest worse SES was associated with increased risk of the studied defects, with the possible exception of cleft lip with or without cleft palate.

  View details for DOI 10.1002/bdra.20614

  View details for Web of Science ID 000271348700006

  View details for PubMedID 19645048

• Maternal Nutrient Intake and Risks for Transverse and Longitudinal Limb Deficiencies: Data from the National Birth Defects Prevention Study, 1997-2003 48th Annual Meeting of the Teratology-Society Robitaille, J., Carmichael, S. L., Shaw, G. M., Olney, R. S. WILEY-BLACKWELL. 2009: 773–79

  Abstract

  The association between periconceptional intake of supplements containing folic acid with specific subtypes of limb deficiencies has been inconsistent. The objective was to investigate whether intake of nutrients involved in one-carbon metabolism (folate, vitamin B(6), vitamin B(12), riboflavin, choline, betaine, zinc, and methionine) through diet alone or in combination with a supplement containing folic acid influenced the risk for transverse limb deficiency (TLD) and longitudinal limb deficiency (LLD).We analyzed 1997-2003 data from the National Birth Defects Prevention Study and included 324 case infants with TLD, 158 case infants with LLD, and 4982 nonmalformed control infants. A food frequency questionnaire was used to estimate nutrient intakes. Use of supplements containing folic acid 1 month before through 2 months after conception was recorded.Use of a supplement containing folic acid was not associated with LLD or TLD. For nonsupplement users, within (1) the lowest quartile of dietary folate intake or vitamin B(6) intake, adjusted odds ratios (aORs) for LLD were, respectively, 3.86 (95% confidence interval [CI]: 1.08-13.78) and 4.36 (95% CI: 0.93-20.48); and (2) the lowest quartile for riboflavin intake, the aOR for TLD was 2.94 (95% CI: 1.04-8.32). For supplement users within the lowest quartile of folate intake or riboflavin intake, the aORs for TLD were, respectively, 1.52 (95% CI: 0.91-2.54) and 1.54 (95% CI: 1.00-2.37).TLD and LLD were not associated with supplement use, but TLD was associated with low intakes of riboflavin from diet.

  View details for DOI 10.1002/bdra.20587

  View details for Web of Science ID 000270586400004

  View details for PubMedID 19350655

• Maternal Thyroid Disease, Thyroid Medication Use, and Selected Birth Defects in the National Birth Defects Prevention Study BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY Browne, M. L., Rasmussen, S. A., Hoyt, A. T., Waller, D. K., Druschel, C. M., Caton, A. R., Canfield, M. A., Lin, A. E., Carmichael, S. L., Romitti, P. A. 2009; 85 (7): 621-628

  Abstract

  Although thyroid disorders are present in approximately 3% of pregnant women, little is known about the association between maternal thyroid disease and birth defects.We assessed the association between maternal thyroid disease, thyroid medication use, and 38 types of birth defects among 14,067 cases and 5875 controls in the National Birth Defects Prevention Study, a multisite, population-based, case-control study. Infants in this study were born between October 1997 and December 2004. Information on exposures including maternal diseases and use of medications was collected by telephone interview.We found statistically significant associations between maternal thyroid disease and left ventricular outflow tract obstruction heart defects (1.5; 95% CI, 1.0-2.3), hydrocephaly (2.9; 95% CI, 1.6-5.2), hypospadias (1.6; 95% CI, 1.0-2.5), and isolated anorectal atresia (2.4; 95% CI, 1.2-4.6). Estimates for the association between periconceptional use of thyroxine and specific types of birth defects were similar to estimates for any thyroid disease. Given that antithyroid medication use was rare, we could not adequately assess risks for their use for most case groups.Our results are consistent with the positive associations between maternal thyroid disease or thyroid medication use and both hydrocephaly and hypospadias observed in some previous studies. New associations with left ventricular outflow tract obstruction heart defects and anorectal atresia may be chance findings.

  View details for DOI 10.1002/bdra.20573

  View details for Web of Science ID 000268426000005

  View details for PubMedID 19215015

• Maternal Corticosteroid Use and Hypospadias JOURNAL OF PEDIATRICS Carmichael, S. L., Ma, C., Werler, M. M., Olney, R. S., Shaw, G. M. 2009; 155 (1): 39-44

  Abstract

  To explore whether women who reported corticosteroid use during pregnancy were more likely to deliver an infant with hypospadias than women who did not.The analysis encompassed data on deliveries with an estimated due date between 1997 and 2004 from the National Birth Defects Prevention Study, a large population-based, case-control study conducted in the United States. Included were 1165 cases of moderate to severe hypospadias and 3000 nonmalformed male controls.The mothers of 39 cases (3.3%) and 62 controls (2.1%) reported using a corticosteroid medication during the period extending from 4 weeks before conception to 14 weeks after conception. The odds ratio (OR) for any corticosteroid exposure versus no corticosteroid exposure was 1.6 (95% confidence interval [CI] = 1.1 to 2.5); after adjustment for maternal race/ethnicity, education, age, and study site, it was 1.3 (95% CI = 0.8 to 2.0). Analyses by route of administration and specific component suggest that elevated ORs occurred only for nasal spray/inhaled corticosteroids (OR = 1.5; 95% CI = 0.9 to 2.6).Maternal use of corticosteroid medications was weakly associated with risk of hypospadias, but the association was negligible after adjustment for potential confounders.

  View details for DOI 10.1016/j.jpeds.2009.01.039

  View details for Web of Science ID 000267672600013

  View details for PubMedID 19394038

• Anencephaly and Spina Bifida among Hispanics: Maternal, Sociodemographic, and Acculturation Factors in the National Birth Defects Prevention Study 21st Annual Meeting of the Society-for-Pediatric-Epidemiology-Research Canfield, M. A., Ramadhani, T. A., Shaw, G. M., Carmichael, S. L., Waller, D. K., Mosley, B. S., Royle, M. H., Olney, R. S. WILEY-BLACKWELL. 2009: 637–46

  Abstract

  We used data from the multisite National Birth Defects Prevention Study for expected delivery dates from October 1997 through 2003, to determine whether the increased risk in anencephaly and spina bifida (neural tube defects (NTDs)) in Hispanics was explained by selected sociodemographic, acculturation, and other maternal characteristics.For each type of defect, we examined the association with selected maternal characteristics stratified by race/ethnicity and the association with Hispanic parents' acculturation level, relative to non-Hispanic whites. We used logistic regression and calculated crude odds ratios (ORs) and their 95% confidence intervals (CIs).Hispanic mothers who reported the highest level of income were 80% less likely to deliver babies with spina bifida. In addition, highly educated Hispanic and white mothers had 76 and 35% lower risk, respectively. Other factors showing differing effects for spina bifida in Hispanics included maternal age, parity, and gestational diabetes. For spina bifida there was no significant elevated risk for U.S.-born Hispanics, relative to whites, but for anencephaly, corresponding ORs ranged from 1.9 to 2.3. The highest risk for spina bifida was observed for recent Hispanic immigrant parents from Mexico or Central America residing in the United States <5 years (OR = 3.28, 95% CI = 1.46-7.37).Less acculturated Hispanic parents seemed to be at highest risk of NTDs. For anencephaly, U.S.-born and English-speaking Hispanic parents were also at increased risk. Finally, from an etiologic standpoint, spina bifida and anencephaly appeared to be etiologically heterogeneous from these analyses.

  View details for DOI 10.1002/bdra.20582

  View details for Web of Science ID 000268426000007

  View details for PubMedID 19334286

• Increased Prevalence of Cardiovascular Defects Among 56,709 California Twin Pairs AMERICAN JOURNAL OF MEDICAL GENETICS PART A Hardin, J., Carmichael, S. L., Selvin, S., Lammer, E. J., Shaw, G. M. 2009; 149A (5): 877-886

  Abstract

  This study compared the prevalence of cardiovascular defects in twin and singleton births and explored the influences of zygosity (monozygotic and dizygotic) and maternal age (<35 and >or=35 years of age) on concordance. Data on twin and singleton infants with (n = 628 twin pairs and n = 14,078 singletons) and without (n = 53,974 twin pairs and n = 4,858,255 singletons) cardiovascular defects were obtained from the California Birth Defects Monitoring Program and the California vital statistics birth and fetal death records during the period 1983-2003. Prevalence ratios (PR) (prevalence of twin/singleton) and approximate 95% confidence intervals were calculated for 16 congenital cardiovascular categories. Poisson regression techniques using log-linear models were employed to assess whether the probability of concordance of defects within each cardiovascular category varied by zygosity or maternal age. An increased prevalence was observed in twins compared to singletons in all 16 cardiovascular categories. Seven of the cardiovascular categories had at least double the prevalence in twins compared to singletons. Like-sex twins, as a proxy of monozygosity, had an increased prevalence of cardiovascular defects compared to unlike sex twins. Probabilities of concordance for flow lesions were higher among monozygotic than dizygotic twins. Our study provides evidence that twinning is associated with more cardiovascular defects than singletons. Increased concordance for flow lesions in monozygotic twins was observed, an observation that is in agreement with findings from familial recurrence studies of cardiovascular defects.

  View details for DOI 10.1002/ajmg.a.32745

  View details for Web of Science ID 000265805900010

  View details for PubMedID 19353581

• Neural tube defects: an analysis of neighbourhood- and individual-level socio-economic characteristics PAEDIATRIC AND PERINATAL EPIDEMIOLOGY Grewal, J., Carmichael, S. L., Song, J., Shaw, G. M. 2009; 23 (2): 116-124

  Abstract

  Several studies have reported that neural tube defects (NTD) occur more frequently among children born to women of lower socio-economic status (SES). This study investigated the relationship between individual- and neighbourhood-level SES and the risk of an NTD-affected pregnancy. Data were drawn from a population-based case-control study of fetuses and infants among a cohort of California births between July 1999 and June 2003. Information on individual SES was obtained via telephone interviews with mothers of 337 (76% of eligible) cases and 626 (79% of eligible) non-malformed liveborn controls. Respondents' addresses were linked to the 2000 US Census to characterise six measures of neighbourhood SES (education, poverty, unemployment, occupation, crowding and rental occupancy). The analyses indicated that relative to women with a high school education, those with less than a high school education had a 1.7-fold increased risk of delivering infants with NTDs [95% CI 1.2, 2.6]. Twofold elevated risks for NTDs were observed for women with less than a high school education who lived in neighbourhoods where a majority of residents had not graduated from high school [95% CI 1.3, 3.1]. No consistent risk gradients were observed between NTD-affected pregnancies and indicators of lower neighbourhood SES. Results for phenotype subgroups were similar to those for all cases. Low maternal education was associated with an elevated risk of NTD in offspring. This risk varied by the education profile of the neighbourhood: women who did not graduate from high school and lived in less educated neighbourhoods exhibited a higher risk.

  View details for DOI 10.1111/j.1365-3016.2008.00992.x

  View details for Web of Science ID 000262645600003

  View details for PubMedID 19159398

• The Estimated Probability of Dizygotic Twins: A Comparison of Two Methods TWIN RESEARCH AND HUMAN GENETICS Hardin, J., Selvin, S., Carmichael, S. L., Shaw, G. M. 2009; 12 (1): 79-85

  Abstract

  This study presents a general model of two binary variables and applies it to twin sex pairing data from 21 twin data sources to estimate the frequency of dizygotic twins. The purpose of this study is to clarify the relationship between maximum likelihood and Weinberg's differential rule zygosity estimation methods. We explore the accuracy of these zygosity estimation measures in relation to twin ascertainment methods and the probability of a male. Twin sex pairing data from 21 twin data sources representing 15 countries was collected for use in this study. Maximum likelihood estimation of the probability of dizygotic twins is applied to describe the variation in the frequency of dizygotic twin births. The differences between maximum likelihood and Weinberg's differential rule zygosity estimation methods are presented as a function of twin data ascertainment method and the probability of a male. Maximum likelihood estimation of the probability of dizygotic twins ranges from 0.083 (95% approximate CI: 0.082, 0.085) to 0.750 (95% approximate CI: 0.749, 0.752) for voluntary ascertainment data sources and from 0.374 (95% approximate CI: 0.373, 0.375) to 0.987 (95% approximate CI: 0.959, 1.016) for active ascertainment data sources. In 17 of the 21 twin data sources differences of 0.01 or less occur between maximum likelihood and Weinberg zygosity estimation methods. The Weinberg and maximum likelihood estimates are negligibly different in most applications. Using the above general maximum likelihood estimate, the probability of a dizygotic twin is subject to substantial variation that is largely a function of twin data ascertainment method.

  View details for Web of Science ID 000263635000009

  View details for PubMedID 19210182

• Trends in the Probability of Twins and Males in California, 1983-2003 TWIN RESEARCH AND HUMAN GENETICS Hardin, J., Carmichael, S. L., Selvin, S., Shaw, G. M. 2009; 12 (1): 93-102

  Abstract

  This study examines the probability of twins by birth year, maternal race-ethnicity, age, and parity and the influences of these demographic factors on the probability of male in twins and singletons in a large, racially diverse population. Recent publications note steep increases in twin births while the probability of male births has been reported to vary by parental race-ethnicity and age and birth order. Probability of male stratified by plurality has not been investigated in California prior to this study. Cubic spline estimates and Poisson regression techniques were employed to describe trends in twins and males using California vital statistics birth and fetal death records over the period from 1983-2003. This study includes 127,787 twin pair and 11,025,106 singleton births. The probability of twins varied by birth year, maternal race-ethnicity, age, and parity. The probability of twins increased by 10.1% from 1983-1992 and increased by 20.1% from 1993-2003, nearly doubling the previous increase. All maternal race-ethnicity groups showed increases in probability of twins with increasing maternal age. Parous women compared to nulliparous women had larger increases in the probability of twins. The probability of males in twins decreased from 1983-1992 and increased from 1993-2003; while in singletons the probability appeared unchanged. These findings show increases in the probability of twins in California from 1983-2003 and identify maternal age, race-ethnicity, and parity groups most likely to conceive twins. The cause of the increase in twins is unknown but coincides with trends towards delayed childbearing and increased use of subfertility treatments.

  View details for Web of Science ID 000263635000011

  View details for PubMedID 19210184

• Hypospadias and Intake of Nutrients Related to One-Carbon Metabolism JOURNAL OF UROLOGY Carmichael, S. L., Yang, W., Correa, A., Olney, R. S., Shaw, G. M. 2009; 181 (1): 315-321

  Abstract

  We examined whether hypospadias is associated with maternal intake of folic acid containing vitamin/mineral supplements or dietary intake of nutrients related to one-carbon metabolism (folate, choline, vitamins B12 and B6, thiamine, riboflavin, methionine and zinc).The study included births from October 1997 to December 2003 that were part of the National Birth Defects Prevention Study. Diet was assessed by food frequency questionnaire during maternal telephone interviews. Analyses included 915 cases with second or third degree hypospadias (urethra opened at the penile shaft, scrotum or perineum) and 2,266 male, liveborn, nonmalformed controls. All ORs and 95% CIs were estimated from logistic regression models that included several potential confounders. Nutrient based analyses also included energy intake.Hypospadias risk was not associated with supplement use (adjusted ORs were 1.2, 95% CI 0.9-1.6 for intake beginning in the month before or the first month of pregnancy and 1.1, 95% CI 0.8-1.4 for intake beginning in the second or third month, relative to no intake). Among women who took supplements reduced hypospadias risk was associated with higher dietary intakes of choline, methionine and vitamin B12. The respective ORs (CIs) for the highest vs lowest quartiles were 0.7 (0.5-1.1), 0.6 (0.4-0.9) and 0.7 (0.5-1.0). Among women who did not take supplements increased risk of hypospadias was associated with higher vitamin B12 intake. The OR (CI) for the highest vs lowest quartile was 3.1 (1.1-9.0).This study suggests an association of hypospadias with intake of certain nutrients related to one-carbon metabolism.

  View details for DOI 10.1016/j.juro.2008.09.041

  View details for Web of Science ID 000261705900175

  View details for PubMedID 19013591

• Mid-Pregnancy Cotinine and Risks of Orofacial Clefts and Neural Tube Defects JOURNAL OF PEDIATRICS Shaw, G. M., Carmichael, S. L., Vollset, S. E., Yang, W., Finnell, R. H., Blom, H., Midttun, O., Ueland, P. M. 2009; 154 (1): 17-19

  Abstract

  Past studies of cigarette smoking as a contributor to orofacial clefts and neural tube defects (NTDs) used self-reports of smoke exposures. We have correlated measurements of cotinine (a nicotine metabolite) in mid-pregnancy sera with clefts and NTDs.From a repository of >180 000 mid-pregnancy serum specimens collected in California from 2003 to 2005 and linked to delivery outcome information, we identified 89 orofacial cleft-associated pregnancies, 80 NTD-affected pregnancies, and randomly selected 409 pregnancy specimens that corresponded to infants without malformations as control subjects. Cotinine was measured by liquid chromatography-mass spectrometry. No smoke exposure was defined as cotinine values <2 ng/mL, and any exposure was defined as >or=2 ng/mL.We observed odds ratios of 2.1 (95% CI, 1.0-4.4) for clefts and 0.4 (95% CI, 0.1-1.7) for NTDs associated with exposure. After adjusting for race/ethnicity, age, and serum folate levels, odds ratios were 2.4 (95% CI, 1.1-5.3) and 0.6 (95% CI, 0.1-2.5). We explored 2 cotinine levels, 2 to 10 ng/mL and >10 ng/mL for clefts (data were too sparse for NTDs). Odds ratios for these levels were 3.3 (95% CI, 0.9-11.9) and 1.7 (95% CI, 0.7-4.2), respectively.Smoking exposures, as measured with cotinine levels during mid-pregnancy, were associated with increased risks of clefts and possibly reduced risks of NTDs.

  View details for DOI 10.1016/j.jpeds.2008.08.006

  View details for Web of Science ID 000262272500006

  View details for PubMedID 18990410

• Nutrient Pathways and Neural Tube Defects A Semi-Bayesian Hierarchical Analysis EPIDEMIOLOGY Carmichael, S. L., Witte, J. S., Shaw, G. M. 2009; 20 (1): 67-73

  Abstract

  We used conventional and hierarchical logistic regression to examine the association of neural tube defects (NTDs) with intake of 26 nutrients that contribute to the mechanistic pathways of methylation, glycemic control, and oxidative stress, all of which have been implicated in NTD etiology. The hierarchical approach produces more plausible, more stable estimates than the conventional approach, while adjusting for potential confounding by other nutrients.Analyses included 386 cases and 408 nonmalformed controls with complete data on nutrients and potential confounders (race/ethnicity, education, obesity, and intake of vitamin supplements) from a population-based case-control study of deliveries in California from 1989 to 1991. Nutrients were specified as continuous, and their units were standardized to have a mean of zero and standard deviation (SD) of 1 for comparability of units across pathways. ORs reflect a 1-SD increase in the corresponding nutrient.Among women who took vitamin supplements, semi-Bayesian hierarchical modeling results suggested no associations between nutrient intake and NTDs. Among women who did not take supplements, both conventional and hierarchical models (HM) suggested an inverse association between lutein intake and NTD risk (HM odds ratio [OR] = 0.6; 95% confidence interval = 0.5-0.9) and a positive association with sucrose (HM OR 1.4; 1.1-1.8) and glycemic index (HM OR 1.3; 1.0-1.6).Our findings for lutein, glycemic index, and sucrose suggest that further study of NTDs and the glycemic control and oxidative stress pathways is warranted.

  View details for DOI 10.1097/EDE.0b013e31818f6375

  View details for Web of Science ID 000261930800013

  View details for PubMedID 19234400

• Chromosomal Abnormalities among Children Born with Conotruncal Cardiac Defects BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY Lammer, E. J., Chak, J. S., Iovannisci, D. M., Schultz, K., Osoegawa, K., Yang, W., Carmichael, S. L., Shaw, G. M. 2009; 85 (1): 30-35

  Abstract

  Conotruncal heart defects compose 25% to 30% of nonsyndromic congenital heart defects. This study describes the frequency of chromosome abnormalities and microdeletion of 22q11 associated among infants and fetuses delivered with conotruncal heart malformations.From a population base of 974,579 infants/fetuses delivered, 622 California infants/fetuses were ascertained with a defect of aortopulmonary septation. Infants whose primary cardiac defect was tetralogy of Fallot (n = 296) or d-transposition of the great arteries (n = 189) were screened for microdeletion of 22q11.Of the infants who had routine karyotypes, 5% had chromosomal abnormalities, including four with extra sex chromosomes. Thirty infants had chromosome 22q11 microdeletions, providing a cause for 10% of infants whose primary defect was tetralogy of Fallot. Right aortic arch, abnormal branching patterns of the major arteries arising from the thoracic aorta, and pulmonary artery abnormalities were observed more frequently among infants with tetralogy of Fallot caused by 22q11 microdeletion.We found an unusual number of infants with an extra sex chromosome and a conotruncal defect. Infants with tetralogy of Fallot owing to 22q11 microdeletion showed more associated vascular anomalies than infants with tetralogy without a 22q11 microdeletion. Although these associated vascular anomalies provide clues as to which infants with tetralogy of Fallot are more likely to carry the microdeletion, the overall risk of 10% among infants with tetralogy of Fallot warrants chromosome analysis and fluorescent in situ hybridization (FISH) testing routinely, which may be supplanted by genome-wide copy number testing as it becomes more widely utilized.

  View details for DOI 10.1002/bdra.20541

  View details for Web of Science ID 000262904800005

  View details for PubMedID 19067405

• Periconceptional glycaemic load and intake of sugars and their association with neural tube defects in offspring PAEDIATRIC AND PERINATAL EPIDEMIOLOGY Shaw, G. M., Carmichael, S. L., Laurent, C., Siega-Riz, A. M. 2008; 22 (6): 514-519

  Abstract

  In a California population, we previously observed increased neural tube defect (NTD) risks associated with maternal intakes of periconceptional diets predicting higher glycaemic responses and higher sucrose. Our objective here was to replicate these results in a larger study of multiple regions within the United States. This population-based case-control study included deliveries from 1997 to 2003 from the National Birth Defects Prevention Study. NTD cases were infants or fetuses born with spina bifida or anencephaly. Infants without malformations were eligible as controls. Interview participation was 71% among case mothers and 68% among control mothers. There were 720 NTD case and 4699 control mothers with completed interviews included in analyses. Diet was assessed using a 58-item food frequency questionnaire focusing on the year before conception, whereas cereals, beverages and supplement use was assessed periconceptionally. We found no increased risks of NTD-affected pregnancies with increased intakes (adjusted for kcal/day) of sucrose, glucose, fructose or with maternal diets with a higher glycaemic load. The reasons for current findings to be inconsistent with previous findings are unknown.

  View details for DOI 10.1111/j.1365-3016.2008.00964.x

  View details for Web of Science ID 000259818200003

  View details for PubMedID 19000288

• Markers of Acculturation and Risk of NTDs among Hispanic Women in California BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY Carmichael, S. L., Shaw, G. M., Song, J., Abrams, B. 2008; 82 (11): 755-762

  Abstract

  Prevalences of NTDs are typically 50-100% greater among Hispanic women compared to non-Hispanic Whites. This article examines whether markers of acculturation such as "language preference" allow the identification of high-risk groups within the Hispanic population. It also examines whether known NTD risk factors explain observed differences in risk among Hispanic women who are more and less acculturated.This population-based case-control study of deliveries in selected California counties from 1999-2003 included 337 NTD cases and 626 nonmalformed, liveborn controls.Relative to less acculturated US-born Hispanic women (i.e., women who preferred reading and speaking Spanish), other subgroups (i.e., US-born Hispanic women who preferred English, foreign-born Hispanic women regardless of "language preference", and non-Hispanic White women) had approximately twofold increased risks of spina bifida. Only the less acculturated foreign-born women (i.e., women with a preference for Spanish) had substantially increased risk of anencephaly (OR 1.7; 95% CI 0.9, 3.4). Adjustment for several NTD risk factors (maternal intake of folic acid-containing supplements, dietary folate intake, body mass index, food insecurity, stressful life events, smoking, alcohol intake, education, income, and neighborhood education and poverty) resulted in modest or no reductions in most of the ORs.The explanation for variability in NTD risks among Hispanic and non-Hispanic White women therefore likely extends beyond most known NTD risk factors.

  View details for DOI 10.1002/bdra.20517

  View details for Web of Science ID 000261567200004

  View details for PubMedID 18985703

• Autoantibodies to folate receptor during pregnancy and neural tube defect risk JOURNAL OF REPRODUCTIVE IMMUNOLOGY Cabrera, R. M., Shaw, G. M., Ballard, J. L., Carmichael, S. L., Yang, W., Lammer, E. J., Finnell, R. H. 2008; 79 (1): 85-92

  Abstract

  Periconceptional folic acid can reduce the occurrence of neural tube defects (NTDs) by up to 70%, and autoantibodies for folate receptors (FRs) have been observed in serum from women with a pregnancy complicated by an NTD. This population-based cohort study has examined serum from pregnant mothers for autoantibodies to FRs, antibodies to bovine folate binding protein (FBP), and inhibition of folic acid binding to FR and FBP in association with NTD risk. The mid-gestational maternal serum specimens used for this study were collected during the 15-18th week of pregnancy. Samples were obtained from the California Birth Defects Monitoring Program; 29 mothers had a pregnancy complicated by spina bifida and 76 mothers had unaffected children. The presence of IgG and IgM antibodies to human FR, bovine FBP, and inhibition of folic acid binding to FR and FBP was determined. Higher activity of IgM to FBP in cases verses controls was observed (P=0.04). Higher activity of IgM and IgG autoantibodies to FR was observed (P<0.001 and P=0.04, respectively). Risk estimates at two standard deviations above average control antibody concentrations were OR=2.07 (CI=1.02, 4.06) for anti-FBP IgM, OR=2.15 (CI=1.02, 4.69) for anti-FR IgG and OR=3.19 (CI=1.47, 6.92) for anti-FR IgM. These data support the hypothesis that high titers of antibodies and blocking of folic acid binding to FRs by maternal serum should be regarded as risk factors for NTDs.

  View details for DOI 10.1016/j.jri.2008.08.002

  View details for Web of Science ID 000260989000012

  View details for PubMedID 18804286

• NTD prevalences in central California before and after folic acid fortification International Neural Tube Defect Meeting Chen, B. H., Carmichael, S. L., Selvin, S., Abrams, B., Shaw, G. M. WILEY-BLACKWELL. 2008: 547–52

  Abstract

  In many regions, NTD prevalences were already declining prior to folic acid fortification. This study examined whether the declining prefortification (1989-1996) NTD prevalences continued into the postfortification period (1998-2003) in selected California counties.This population-based study used vital statistics data and birth defects registry data that were actively ascertained from medical records. The study population included all live births and stillbirths delivered in central California counties from 1989 to 2003. Cases included deliveries with NTDs during the same time period.For all NTDs combined, the slopes indicated that NTD prevalence was decreasing by 7.5 (slope: -7.5; 95% CI: -12.4, -2.5) cases per 100,000 deliveries per year before fortification, whereas NTD prevalence was no longer decreasing after fortification. Comparison of the difference in the two slopes indicated that the postfortification slope exceeded the prefortification slope by 12.6 (95% CI: 2.6, 22.6) cases per 100,000 deliveries per year.Annual NTD prevalences in central California did not continue to decrease after implementation of folic acid fortification.

  View details for DOI 10.1002/bdra.20466

  View details for Web of Science ID 000258763500001

  View details for PubMedID 18496833

• Maternal periconceptional smoking and alcohol consumption and risk for select congenital anomalies 20th Annual Meeting of the Society-for-Pediatric-and-Perinatal-Epidemiologic-Research Grewal, J., Carmichael, S. L., Ma, C., Lammer, E. J., Shaw, G. M. WILEY-BLACKWELL. 2008: 519–26

  Abstract

  This study examined the association between maternal smoking and alcohol use (including binge drinking) during the periconceptional period (i.e., 2 months before through 2 months after conception) and the risk of orofacial clefts, NTDs, and conotruncal heart defects in offspring.Data were drawn from a population-based case-control study of fetuses and live-born infants among a cohort of California births between July 1999 and June 2003. The 1,355 cases comprised of 701 orofacial clefts, 337 NTDs, and 323 conotruncal heart defects. Information on smoking and alcohol consumption was obtained via telephone interviews with mothers of 1,355 (80% of eligibles) cases and 700 (77% of eligibles) nonmalformed, live-born controls.Maternal smoking of five cigarettes or less per day was associated with reduced risks of NTDs (OR 0.7; 95% CI: 0.3, 1.4), whereas the risk associated with higher cigarette consumption was lower for conotruncal heart defects (OR 0.5; 95% CI: 0.2, 1.2). Maternal intake of alcohol less than 1 day per week was associated with a 1.6- to 2.1-fold higher risk of NTDs (95% CI: 0.9, 2.6), d-transposition of the great arteries (95% CI: 1.1, 3.2), and multiple cleft lip with or without cleft palate (CLP) (95% CI: 0.8, 4.5). Risks associated with more frequent alcohol intake were 2.1 for NTDs (95% CI: 1.1, 4.0) and 2.6 for multiple CLP (95% CI: 1.1, 6.1).This study observed that maternal alcohol intake increased the risk for d-transposition of the great arteries, NTDs, and multiple CLP in infants. By contrast, smoking was associated with a lower risk of NTDs and conotruncal heart defects.

  View details for DOI 10.1002/bdra.20461

  View details for Web of Science ID 000257906800004

  View details for PubMedID 18481814

• Nutrient intakes in women and congenital diaphragmatic hernia in their offspring BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY Yang, W., Shaw, G. M., Carmichael, S. L., Rasmussen, S. A., Waller, D. K., Pober, B. R., Anderka, M. 2008; 82 (3): 131-138

  Abstract

  Congenital diaphragmatic hernia (CDH) is a severe birth defect where there is an opening in the diaphragm through which a portion of the abdominal contents protrudes into the thoracic cavity. The etiologies of CDH remain unknown, although experimental animal data suggest dietary factors might play a role. This study examined whether maternal nutrient intakes were associated with delivering infants with CDH.We analyzed infants with isolated CDH who were born from 1997 to 2003 and recruited into the National Birth Defects Prevention Study (NBDPS), a multisite, population-based case-control study. Exposure data were obtained from telephone interviews, which were completed within 24 months after delivery, and were available for 377 case mothers and 5,008 control mothers. A food frequency questionnaire was used to derive nutrient intakes during the year before pregnancy.A crude OR of 0.6 (95% CI: 0.3-1.0) was observed for higher intake of choline. Elevated ORs (1.4 to 1.7) were found for lower intakes of choline, cysteine, methionine, and protein. Among women who took vitamin supplements, higher intakes of B vitamins (i.e., folate, vitamin B1, B2, B6, and B12), minerals (i.e., calcium, iron, magnesium, and zinc), and vitamin E were inversely associated with CDH (ORs from 0.7-0.3). Moreover, among women who did not take vitamin supplements, lower intakes of calcium, retinol, selenium, vitamin B12, and vitamin E had positive associations with CDH (ORs from 1.4 to 2.1).Our observations contribute to a limited body of evidence suggesting a woman's periconceptional diet might be associated with CDH in her offspring.

  View details for DOI 10.1002/bdra.20436

  View details for Web of Science ID 000254601400002

  View details for PubMedID 18181217

• Craniosynostosis and maternal smoking 47th Annual Meeting of the Teratology-Society Carmichael, S. L., Ma, C., Rasmussen, S. A., Honein, M. A., Lammer, E. J., Shaw, G. M. WILEY-BLACKWELL. 2008: 78–85

  Abstract

  Several previous studies suggested increased risk of craniosynostosis among infants born to women who smoked.This study used data from the National Birth Defects Prevention Study, a multi-state, population-based case-control study of infants delivered from 1997-2003. Nonmalformed, liveborn controls were selected randomly from birth certificates or birth hospitals. Data from maternal telephone interviews were available for 531 cases and 5008 controls.Smoking during the first month of pregnancy was not associated with craniosynostosis. Smoking later in pregnancy was associated with increased risk, but only among mothers who smoked at least one pack/day. For example, during the second trimester, the odds ratio for smoking <5 cigarettes/day was 1.0 (95% confidence interval [CI] 0.6, 1.8), but the odds ratio (OR) for smoking 15 or more cigarettes/day was 1.6 (95% CI 0.9, 2.8), after adjustment for maternal age, education, race-ethnicity, sub-fertility, parity, folic acid supplement intake, body mass index, and study center. Among women who did not smoke, adjusted odds ratios suggested that secondhand smoke exposure at home, but not at work/school, was associated with modestly increased risk; the OR for home exposure was 1.3 (95% CI 0.9, 1.9). Results followed a similar pattern for some, but not all, specific suture types, but numbers for some groupings were small.The results suggest moderately increased risk of craniosynostosis among mothers who were the heaviest smokers and who continued to smoke after the first trimester. Results are somewhat equivocal, given that most confidence intervals included one.

  View details for DOI 10.1002/bdra.20426

  View details for Web of Science ID 000253624800002

  View details for PubMedID 18050313

• Socioeconomic status in relation to selected birth defects in a large multicentered US case-control study AMERICAN JOURNAL OF EPIDEMIOLOGY Yang, J., Carmichael, S. L., Canfield, M., Song, J., Shaw, G. M. 2008; 167 (2): 145-154

  Abstract

  This study examined individual and household socioeconomic status (SES) in relation to phenotypes of neural tube defects, orafacial clefts, and conotruncal heart defects using data from the National Birth Defects Prevention Study with 2,551 nonmalformed liveborn controls and 1,841 cases delivered in 1997-2000. The individual SES was measured by maternal and paternal education, occupation, and household income. All individual SES measures were combined to create a household SES index. Elevated risks were found for maternal low education in association with anencephaly and dextrotransposition of the great arteries (dTGA) (adjusted odds ratios (AORs) > or = 1.4); paternal low education in association with anencephaly, cleft palate, tetralogy of Fallot (TOF), and dTGA (AORs > or = 1.4); low household income in association with TOF (AOR = 1.4, 95% confidence interval (CI): 0.8, 2.5); maternal operator/laborer occupation in association with cleft palate, TOF, and dTGA (AORs > or = 1.4); paternal operator/laborer occupation in association with spina bifida (AOR = 1.4, 95% CI: 1.0, 2.0); and either parent's unemployment in association with dTGA (AOR > or = 1.4). Subjects with the lowest household SES index had the greatest risks of all selected birth defects except TOF. This study reveals consistently increased risks of selected birth defects in association with household SES index but not individual SES measures.

  View details for DOI 10.1093/aje/kwm283

  View details for Web of Science ID 000252498200003

  View details for PubMedID 17947220

• Maternal corticosteroid use and orofacial clefts AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY Carmichael, S. L., Shaw, G. M., Ma, C., Werler, M. M., Rasmussen, S. A., Lammer, E. J. 2007; 197 (6)

  Abstract

  The purpose of this study was to examine whether maternal corticosteroid use during pregnancy is associated with delivering an infant with an orofacial cleft.This study included data on deliveries from the National Birth Defects Prevention Study, which is a population-based case-control study. Exposures were assessed by telephone interviews for mothers of 1141 cases with cleft lip +/- cleft palate (CLP), 628 with cleft palate (CP), and 4143 controls.Mothers of 33 infants with CLP (2.9%), mothers of 6 infants with CP (1.0%), and 72 control subjects (1.7%) reported corticosteroid use from 4 weeks before through 12 weeks after conception. The crude odds ratio for "any" vs "no" use was 1.7 (95% CI, 1.1-2.6) for CLP and 0.5 (0.2-1.3) for CP. When analyzed by route of administration and medication components, odds ratios for CLP tended to be elevated, and odds ratios for CP tended to be close to 1.Our results suggest a moderately increased risk of CLP among women who use corticosteroids during early pregnancy.

  View details for DOI 10.1016/j.ajog.2007.05.046

  View details for Web of Science ID 000251675700008

  View details for PubMedID 18060943

• Nutrient intakes in women and risks of anophthalmia and microphthalmia in their offspring BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY Shaw, G. M., Carmichael, S. L., Laurent, C., Louik, C., Finnell, R. H., Lammer, E. J. 2007; 79 (10): 708-713

  Abstract

  There is a paucity of information about risk factors for the human eye anomalies anophthalmia and microphthalmia. In this population-based case-control study we investigated whether periconceptional intakes of supplemental folic acid, dietary folate, vitamin A, and several other nutrients were associated with these eye defects.This study included data on deliveries that had estimated due dates from 1997-2002 and were part of the National Birth Defects Prevention Study (the National Birth Defects Prevention Study is a population-based case-control study of a wide spectrum of birth defects, incorporating data from 10 birth defects surveillance systems in the United States [Arkansas, California, Georgia/Centers for Disease Control and Prevention, Iowa, Massachusetts, New Jersey, New York, North Carolina, Texas, and Utah]). Cases were those infants or fetuses born with either anophthalmia or microphthalmia. Liveborn infants without major malformations were eligible as controls. Maternal interviews were conducted, primarily by telephone, in English or Spanish. Participation in the interview was 71% among case mothers and 68% among control mothers. Interviews were completed with 89 case mothers and 4,143 control mothers. A shortened version of the food frequency questionnaire from the Nurse's Health Study was used to assess frequency of intake of 58 food items during the year before pregnancy.Our results did not indicate reduced risks for these eye malformations associated with maternal intake of vitamin supplements containing folic acid. The data did not show an association between malformation risk and higher or lower intakes of vitamin A. We also did not observe strong evidence that an abundance or a lack of dietary intake of any other nutrient was associated with increased risk of the studied eye malformations.Our observations contribute to a limited body of findings on these rare eye defects.

  View details for DOI 10.1002/bdra.20398

  View details for Web of Science ID 000250222400007

  View details for PubMedID 17847120

• Association between 49 infant gene polymorphisms and preterm delivery AMERICAN JOURNAL OF MEDICAL GENETICS PART A Chen, B. H., Carmichael, S. L., Shaw, G. M., Iovannisci, D. M., Lammer, E. J. 2007; 143A (17): 1990-1996

  Abstract

  The occurrence of preterm delivery has been increasing in the U.S. Previous studies have identified risk factors for preterm delivery that may have genetic influences. We conducted a case-control study comparing the frequencies of 49 genetic polymorphisms among 62 preterm infants and 553 term infants. The polymorphisms that we examined were involved in xenobiotic-metabolism, blood pressure, coagulation, the inflammatory response, cell-cell interaction, or folate-homocysteine metabolism. Univariate analyses on the individual polymorphisms revealed a statistically significant effect for the variant genotypes compared to the wildtype genotypes in SERPINE1 11053G > T (OR = 0.4, 95% CI = 0.2-0.8). This finding suggests the coagulation/thrombophilic pathway may influence the development of preterm delivery.

  View details for DOI 10.1002/ajmg.a31868

  View details for Web of Science ID 000249173900007

  View details for PubMedID 17676631

• Maternal food insecurity is associated with increased risk of certain birth defects JOURNAL OF NUTRITION Carmichael, S. L., Yang, W., Herring, A., Abrams, B., Shaw, G. M. 2007; 137 (9): 2087-2092

  Abstract

  Food insecurity represents a lack of access to enough food to meet basic needs. We hypothesized that food insecurity may increase birth defect risks, because it is an indicator of increased stress or compromised nutrition, which are both implicated in birth defect etiologies. This study used population-based case-control data. Included in the analysis were 1,189 case mothers and 695 control mothers who were interviewed by telephone. We calculated a food insecurity score as the number of affirmative responses to 5 questions from a shortened instrument designed to measure food insecurity. OR for the food insecurity score specified as a linear term indicated that a higher score was associated with increased risk of cleft palate, d-transposition of the great arteries, tetralogy of Fallot, spina bifida, and anencephaly, but not with cleft lip with or without cleft palate, after adjustment for maternal race-ethnicity, education, BMI, intake of folic acid-containing supplements, dietary intake of folate and energy, neighborhood crime, and stressful life events. In addition, several models suggested effect modification by certain factors. For example, for anencephaly, among women with the worst score for neighborhood crime (i.e. 6), the OR associated with a 1-unit change in the food insecurity score was 1.57 (95% CI 1.06, 2.33), whereas among women with a low crime score (i.e. 2), the corresponding OR was 1.16 (95% CI 0.96, 1.38). This study suggests that increased risks of certain birth defects may be included among the negative consequences of food insecurity.

  View details for Web of Science ID 000249110600016

  View details for PubMedID 17709447

• Maternal thyroid disease as a risk factor for craniosynostosis 27th David W Smith Workshop on Malformations and Morphogenesis Rasmussen, S. A., Yazdy, M. M., Carmichael, S. L., Jamieson, D. J., Canfield, M. A., Honein, M. A. LIPPINCOTT WILLIAMS & WILKINS. 2007: 369–77

  Abstract

  To study the relationship between maternal thyroid disease and craniosynostosis using data from the National Birth Defects Prevention Study, a multisite, case-control study.Case infants (n=431) were identified through population-based birth defects surveillance systems at eight sites and had craniosynostosis verified by radiographic imaging. Control infants (n=4,094) consisted of a random sample of live births with no major birth defects from the same population as the case infants. Information on thyroid disease was based on self-report: mothers who reported either a thyroid disorder or use of a medication to treat a thyroid disorder during pregnancy were considered to have thyroid disease. Using an unconditional logistic regression model, we considered potential confounding factors (maternal age, race or ethnicity, smoking, body mass index, preexisting diabetes, plurality, gravidity, family history, infant sex).Among case mothers, 19 (4.4%) were classified as having thyroid disease, compared with 65 (1.6%) of control mothers. Maternal thyroid disease was associated with craniosynostosis after controlling for maternal age (adjusted odds ratio 2.47, 95% confidence interval 1.46-4.18), the only factor that remained significant in the final model.These data provide additional evidence that maternal thyroid disease (most likely Graves' disease) or its treatment is associated with craniosynostosis. Given the frequency of maternal thyroid disease, this association warrants further investigation.II.

  View details for Web of Science ID 000248290500021

  View details for PubMedID 17666613

• Maternal stressful life events and risks of birth defects EPIDEMIOLOGY Carmichael, S. L., Shaw, G. M., Yang, W., Abrams, B., Lammer, E. J. 2007; 18 (3): 356-361

  Abstract

  Several previous studies suggest that maternal stress may be associated with increased risk of certain birth defects. This study examined the association of maternal stressful life events with risks of several birth defects.The data are from a recent, population-based case-control study. Telephone interviews were conducted with 1355 eligible case mothers and 700 control mothers. Maternal stress was measured by responses to 18 yes/no questions about life events that occurred from 2 months before through 2 months after conception.An increase in the stressful life events index (ie, number of "yes" responses to the 18 life-events questions) was associated with increased risk of cleft palate, cleft lip with or without cleft palate, d-transposition of the great arteries, and tetralogy of Fallot, after adjustment for maternal race-ethnicity, education, obesity, age, smoking, drinking, intake of folic acid-containing supplements, neighborhood crime, and food insecurity. For example, the odds ratio for a 3-unit change in the stress index was 1.45 (95% confidence interval = 1.03-2.06) for cleft palate. Increased stress was associated with an increased risk of spina bifida and anencephaly particularly among women who did not take folic acid supplements. A 3-unit change in stress was associated with a 2.35-fold increased risk of anencephaly among women who did not take supplements (CI =1.47-3.77) and a 1.42-fold increased risk among women who did (CI = 0.89-2.25).The adverse health effects of stress may include increased risks of certain birth defects.

  View details for DOI 10.1097/01.ede.0000259986.85239.87

  View details for Web of Science ID 000245993300010

  View details for PubMedID 17435445

• Maternal reproductive and demographic characteristics as risk factors for hypospadias PAEDIATRIC AND PERINATAL EPIDEMIOLOGY Carmichael, S. L., Shaw, G. M., Laurent, C., Olney, R. S., Lammer, E. J. 2007; 21 (3): 210-218

  Abstract

  This study examined the association of hypospadias risk with several maternal reproductive and demographic characteristics: age, parity, body mass index (BMI), nausea and vomiting of pregnancy (NVP), multiple pregnancy, fertility treatments and procedures, education and race-ethnicity. The study included data on deliveries with estimated due dates from October 1997 to December 2000 that were part of the National Birth Defects Prevention Study, a multi-state case-control study of many birth defects. The analysis included 502 cases with second or third degree hypospadias (i.e. the urethra opened at the penile shaft, scrotum or perineum) and 1286 male, liveborn, non-malformed controls. Risks were estimated from a multivariable logistic regression model that included all exposures of interest. Results indicated particularly elevated risks among births to women who were primiparae, aged >or=35 years and had a BMI of >26, compared with women who were multiparae, aged <30 years and had a BMI of

  View details for Web of Science ID 000245676100003

  View details for PubMedID 17439529

• Risks of human limb deficiency anomalies associated with 29 SNPs of genes involved in homocysteine metabolism, coagulation, cell-cell interactions, inflammatory response, and blood pressure regulation AMERICAN JOURNAL OF MEDICAL GENETICS PART A Carmichael, S. L., Shaw, G. M., Iovannisci, D. M., Yang, W., Finnell, R. H., Cheng, S., Lammer, E. J. 2006; 140A (22): 2433-2440

  View details for DOI 10.1002/ajmg.a.31505

  View details for Web of Science ID 000241746200006

• Risk of limb deficiency defects associated with NAT1, NAT2, GSTT1, GSTM1, and NOS3 genetic variants, maternal smoking, and vitamin supplement intake AMERICAN JOURNAL OF MEDICAL GENETICS PART A Carmichael, S. L., Shaw, G. M., Yang, W., Iovannisci, D. M., Lammer, E. 2006; 140A (18): 1915-1922

  View details for DOI 10.1002/ajmg.a.31402

  View details for Web of Science ID 000240391800005

• Risk of limb deficiency defects associated with NAT1, NAT2, GSTT1, GSTM1, and NOS3 genetic variants, maternal smoking, and vitamin supplement intake. American journal of medical genetics. Part A Carmichael, S. L., Shaw, G. M., Yang, W., Iovannisci, D. M., Lammer, E. 2006; 140 (18): 1915-1922

  Abstract

  Increasing epidemiologic evidence suggests that genetic susceptibilities contribute to birth defects risks, especially in combination with other environmental exposures. This analysis examines the association of risk of limb deficiency defects with infant genotypes for N-acetyltranferases (NAT1, NAT2), glutathione-S-tranferases (GSTT1, GSTM1), and endothelial nitric oxide synthase (NOS3). The combined effects of infant genotype with maternal smoking and supplement intake were also examined. The authors genotyped 92 cases and 201 non-malformed controls from a California population-based case-control study (1987-1988 birth cohort). Several of the infant genotypes were associated with an at least 1.5-fold increased risk for limb deficiency defects: homozygosity for the NAT1 1088 and 1095 polymorphisms, heterozygosity and homozygosity for the NOS3 A(-922)G polymorphism, and heterozygosity (but not homozygosity) for the NOS3 G894T polymorphism. The authors hypothesized that the effects of selected variant genotypes in the presence of maternal smoking, or in the absence of supplement intake, may exceed effects of any of these factors alone. A few observations suggested that risks were greatest among infants with variant genotypes, whose mothers also smoked or did not take supplements, but most did not, and risk estimates were imprecise. Further studies exploring genetic susceptibility and combined gene-environment effects with respect to limb development will be important to continued improvement of our understanding of the etiology of limb anomalies.

  View details for PubMedID 16906563

• Maternal nutrient intakes and risk of orofacial clefts EPIDEMIOLOGY Shaw, G. M., Carmichael, S. L., Laurent, C., Rasmussen, S. A. 2006; 17 (3): 285-291

  Abstract

  Information about nutritional factors as potential risks of orofacial clefts is limited.In this population-based case-control study, we investigated whether periconceptional intakes of supplemental folic acid, dietary folate, and several other nutrients were associated with orofacial clefts. We included data on deliveries from 1997 through 2000 in the National Birth Defects Prevention Study. Orofacial cleft cases were infants or fetuses born with cleft palate (CP) or with cleft lip with or without cleft palate (CLP). Infants without malformations were eligible as controls. Interview participation was 71% among case mothers and 68% among control mothers. Interviews were completed for 704 CLP cases, 404 CP cases, and 2594 controls.The odds ratio (OR) for CLP associated with use of vitamin supplements containing folic acid was 0.88 (95% confidence interval = 0.73-1.07) and for CP was 1.09 (0.84-1.40). Adjusting for maternal race/ethnicity, age, and education produced an OR of 1.01 (0.82-1.24) for CLP and 1.02 (0.77-1.34) for CP. We found some evidence for decreased CLP risks (>or=30% reduction in risk) with increasing intakes of total protein, choline, and methionine. Decreased CP risk was associated with increased intake of cysteine. Intakes of only 2 micronutrients, iron and riboflavin, were found to reduce CLP risk when adjusted for other nutrients.Our observations contribute to the limited body of evidence suggesting a woman's periconceptional diet may influence clefting risks in her offspring. Our finding of no reduction in clefting risk with periconceptional use of supplements containing folic acid is inconsistent with many previous observations but not all.

  View details for DOI 10.1097/01.ede.0000208348.30012..35

  View details for Web of Science ID 000236926500014

  View details for PubMedID 16570024

• Correlates of intake of folic acid-containing supplements among pregnant women AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY Carmichael, S. L., Shaw, G. M., Yang, W., Laurent, C., Herring, A., Royle, M. H., Canfield, M. 2006; 194 (1): 203-210

  Abstract

  This study describes the timing and correlates of folic acid supplement intake among pregnant women.Data from 2518 women with estimated delivery dates from 1997 to 2000, collected for the National Birth Defects Prevention Study, a population-based case-control study, were analyzed. Multinomial logistic regression was used to identify correlates of supplement intake.Fifty-three percent of women began taking folic acid supplement during the periconceptional period, 35% during early pregnancy, and 8% during late pregnancy (ie, 3 months before through 1 month after conception, 2-3 months after conception, or more than 3 months after conception, respectively). Women who did not take folic acid supplement periconceptionally tended to be nonwhite, speak Spanish, have low education, be younger than 25 years old, be nulliparous, smoke, have no previous miscarriage and no fertility treatments, begin prenatal care and become aware of their pregnancy after the first trimester, have nonplanned pregnancies, and eat less breakfast cereal.This study identifies correlates of folic acid supplement intake, which may contribute to the design of interventions to improve intake during early pregnancy.

  View details for DOI 10.1016/j.ajog.2005.06.018

  View details for Web of Science ID 000234386200031

  View details for PubMedID 16389033

• Endothelial nitric oxide synthase (NOS3) genetic variants, maternal smoking, vitamin use, and risk of human orofacial clefts AMERICAN JOURNAL OF EPIDEMIOLOGY Shaw, G. M., Iovannisci, D. M., Yang, W., Finnell, R. H., Carmichael, S. L., Cheng, S., Lammer, E. J. 2005; 162 (12): 1207-1214

  Abstract

  Orofacial clefts have been associated with maternal cigarette smoking and lack of folic acid supplementation (which results in higher plasma homocysteine concentrations). Because endothelial nitric oxide synthase (NOS3) activity influences homocysteine concentration and because smoking compromises NOS3 activity, genetic variation in NOS3 might interact with smoking and folic acid use in clefting risk. The authors genotyped 244 infants with isolated cleft lip with or without cleft palate (CL/P), 99 with isolated cleft palate, and 588 controls from a California population-based case-control study (1987-1989 birth cohort) for two NOS3 polymorphisms: A(-922)G and G894T. Analyses of gene-only effects for each polymorphism revealed a 60% increased risk of CL/P among NOS3 A(-922)G homozygotes (odds ratio (OR) = 1.6, 95% confidence interval (CI): 1.0, 2.6). There was some evidence for higher risk of CL/P with maternal periconceptional smoking in infants with an NOS3 -922G allele (for homozygotes, OR = 2.5, 95% CI: 1.2, 5.6) but not in those with an 894T allele. For CL/P risk, odds ratios were over 4 among mothers who smoked, who did not use vitamins, and whose infants had at least one variant allele for each NOS3 polymorphism (for A(-922)G, OR = 4.6, 95% CI: 2.1, 10.2; for 894T, OR = 4.4, 95% CI: 1.8, 10.7). No similar patterns were observed for risk of cleft palate.

  View details for DOI 10.1093/aje/kwi336

  View details for Web of Science ID 000233850400009

  View details for PubMedID 16269583

• Hypospadias and maternal exposures to cigarette smoke PAEDIATRIC AND PERINATAL EPIDEMIOLOGY Carmichael, S. L., Shaw, G. M., Laurent, C., Lammer, E. J., Olney, R. S. 2005; 19 (6): 406-412

  Abstract

  The few previous studies of hypospadias and smoking have suggested either no association or a reduced risk. This study, which uses data from the National Birth Defects Prevention Study, a multi-state, population-based case-control study, includes data on males born with severe hypospadias (i.e. the urethra opens at the penile shaft, scrotum or perineum) from 1997 to 2000. Non-malformed, liveborn male controls were selected randomly from birth certificates or from birth hospitals. Maternal interviews were completed by telephone with 453 case mothers and 1267 control mothers. Maternal smoking was not associated with hypospadias risk. For example, during the third month of pregnancy, smoking < 0.5 pack/day had an odds ratio (OR) of 1.1 [95% CI 0.6, 1.9]; 0.5 pack/day, 0.6 [0.4, 1.1]; and > or = 1 pack/day, 0.8 [0.4, 1.6]. Exposure to any secondhand smoke at home during the third month of pregnancy showed an OR of 0.6 [95% CI 0.4, 1.0], and exposure at work or school, an OR of 0.7 [0.5, 1.1]. Similar risks were observed for other months during the periconceptional period, and adjustment for several potential confounders did not substantially alter results. This analysis does not confirm a recent report suggesting that maternal smoking is associated with a reduced risk of having offspring with hypospadias.

  View details for Web of Science ID 000233020700002

  View details for PubMedID 16269066

• Maternal progestin intake and risk of hypospadias ARCHIVES OF PEDIATRICS & ADOLESCENT MEDICINE Carmichael, S. L., Shaw, G. M., Laurent, C., Croughan, M. S., Olney, R. S., Lammer, E. J. 2005; 159 (10): 957-962

  Abstract

  Previous studies have suggested that maternal intake of progestins during early pregnancy may be associated with an increased risk of hypospadias. Progesterone and its derivatives are commonly prescribed during early pregnancy, for example, in cases of luteal phase dysfunction and in conjunction with ovulation stimulation drugs.To examine whether risk of hypospadias was associated with periconceptional progestin intake.The National Birth Defects Prevention Study, a population-based, multistate, case-control study including deliveries that had estimated due dates from October, 1997 to December, 2000.Participation in the study was 71% among case mothers and 68% among control mothers. This analysis included 502 subjects diagnosed with second- or third-degree hypospadias (ie, the urethra opened at the penile shaft, scrotum, or perineum) and 1286 male, live-born, nonmalformed control subjects.Forty-two case mothers (8.4%) and 31 control mothers (2.4%) reported any pregnancy-related progestin intake from 4 weeks before through 14 weeks after conception, resulting in an odds ratio of 3.7 (95% confidence interval [CI], 2.3-6.0). Analyses stratified by several potential covariates also suggested elevated risks. For example, among the 10 cases and 13 controls who did not report any fertility-related procedures or treatments other than progestins, the odds ratio was 2.2 (95% CI, 1.0-5.0). Progestin intake for the purpose of contraception was not associated with increased risk.This study found that pregnancy-related intake of progestins was associated with increased hypospadias risk.

  View details for Web of Science ID 000232322000008

  View details for PubMedID 16203941

• Risks of human conotruncal heart defects associated with 32 single nucleotide polymorphisms of selected cardiovascular disease-related genes AMERICAN JOURNAL OF MEDICAL GENETICS PART A Shaw, G. M., Iovannisci, D. M., Yang, W., Finnell, R. H., Carmichael, S. L., Cheng, S., Lammer, E. J. 2005; 138A (1): 21-26

  View details for DOI 10.1002/ajmg.a.30924

  View details for Web of Science ID 000231635400005

• Epidemiologic characteristics of anophthalmia and bilateral microphthalmia among 2.5 million births in California, 1989-1997 AMERICAN JOURNAL OF MEDICAL GENETICS PART A Shaw, G. M., Carmichael, S. L., Yang, W., Harris, J. A., Finnell, R. H., Lammer, E. J. 2005; 137A (1): 36-40

  View details for DOI 10.1002/ajmg.a.30840

  View details for Web of Science ID 000231009900006

• Periconceptional dietary intake of myo-inositol and neural tube defects in offspring BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY Shaw, G. M., Carmichael, S. L., Yang, W., Schaffer, D. M. 2005; 73 (3): 184-187

  Abstract

  Periconceptional intake of nutrients in addition to folic acid may contribute to neural tube defect (NTD) etiologies; a likely candidate is myo-inositol. We investigated whether maternal periconceptional dietary intake of myo-inositol influenced NTD risk.Data were derived from a case-control study of fetuses and infants with NTDs among 1989-1991 California births. Interviews were conducted with mothers of 454 NTD cases and with mothers of 462 nonmalformed controls. A standard 100-item food frequency questionnaire was used to assess nutrient intake.We observed small increases in risk, with increases slightly more evident for anencephaly, associated with intakes of myo-inositol less than the highest intake quartile, e.g., risk of anencephaly was 1.3 (0.7-2.4) among fetuses whose mothers consumed lowest versus highest intakes of myo-inositol. These small increases, however, were imprecise, and also did not indicate increasing risk with decreasing level of myo-inositol intake. Adjusted risk estimates did not differ considerably from their unadjusted counterparts.Our results do not indicate that myo-inositol intake, as measured in this study, is strongly associated with risk of human NTDs.

  View details for DOI 10.1002/bdra.20112

  View details for Web of Science ID 000228049200010

  View details for PubMedID 15744734

• Risks of selected congenital malformations among offspring of mixed race-ethnicity BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY Yang, J., Carmichael, S. L., Kaidarova, Z., Shaw, G. M. 2004; 70 (10): 820-824

  Abstract

  Little is known about the occurrence of specific congenital malformations among offspring of mixed race-ethnicity.Using data from a population-based registry, we explored the occurrence of selected malformation phenotypes in offspring to parents who were of different race-ethnicity. Data were derived from the California Birth Defects Monitoring Program, a population-based active surveillance system for collecting information on infants and fetuses with congenital malformations using multiple source ascertainment. Approximately 2.6 million live births and stillbirths occurred during 1989-2000. Information on parental race-ethnicity (non-Hispanic white, Hispanic, black, and Asian) was obtained from birth certificates and fetal death files. Malformation phenotypes studied were spina bifida, anencephaly, cleft lip, cleft palate, tetralogy of Fallot, d-transposition of great arteries, hypospadias, small intestinal atresia, preaxial polydactyly, microtia, and hypertrophic pyloric stenosis.A total of 11.2% of births were to parents of mixed race-ethnicity. Compared to births of parents who were both white, moderately increased risks (risk ratio >/= 1.7) of anencephaly, polydactyly, and microtia, and decreased risks (risk ratio

  View details for DOI 10.1002/bdra.20025

  View details for Web of Science ID 000224970800005

  View details for PubMedID 15390318

• Gene-nutrient interactions: importance of folates and retinoids during early embryogenesis TOXICOLOGY AND APPLIED PHARMACOLOGY Finnell, R. H., Shaw, G. M., Lammer, E. J., Brandl, K. L., Carmichael, S. L., Rosenquist, T. H. 2004; 198 (2): 75-85

  Abstract

  The role that nutritional factors play in mammalian development has received renewed attention over the past two decades, as the scientific literature exploded with reports of retinoid compounds disrupting craniofacial development, and with other reports that folic acid supplementation in the periconceptional period can protect embryos from highly significant malformations. As was often the case, the situation became far more complicated, as the interaction between nutritional factors with selected genes was recognized. In this review, we attempt to summarize a complex clinical and experimental literature of nutritional factors, their biological transport mechanisms, and the impact that they have during early embryogenesis. Although not exhaustive, our goal was to provide an overview of important gene-nutrient interactions and a framework for their investigation.

  View details for DOI 10.1016/j.taap.2003.09.031

  View details for Web of Science ID 000222713900001

  View details for PubMedID 15236946

• Periconceptional dietary intake of choline and betaine and neural tube defects in offspring AMERICAN JOURNAL OF EPIDEMIOLOGY Shaw, G. M., Carmichael, S. L., Yang, W., Selvin, S., Schaffer, D. M. 2004; 160 (2): 102-109

  Abstract

  Periconceptional intake of folic acid prevents some neural tube defects (NTDs). Other nutrients may also contribute to NTD etiologies; a likely candidate is choline. Similar to folic acid, choline is involved in one-carbon metabolism for methylation of homocysteine to methionine. The authors investigated whether maternal periconceptional dietary intakes of choline and its metabolite betaine influence NTD risk. Data were derived from a case-control study of fetuses and infants with NTDs among 1989-1991 California births. In-person interviews were conducted with mothers of 424 NTD cases and with mothers of 440 nonmalformed controls. A standard 100-item food frequency questionnaire was used to assess nutrient intake. Dietary intakes of choline were associated with reduced NTD risks. Controlling for intake of supplemental folic acid, dietary folate, dietary methionine, and other covariates did not substantially influence risk estimates for choline. NTD risk estimates were lowest for women whose diets were rich in choline, betaine, and methionine. That is, for women whose intake was above the 75th percentile compared with below the 25th percentile for all three nutrients, the odds ratio was 0.17 (95% confidence interval: 0.04, 0.76). Study findings for dietary components other than folic acid offer additional clues about the complex etiologies of NTDs.

  View details for DOI 10.1093/aje/kwh187

  View details for Web of Science ID 000222556600002

  View details for PubMedID 15234930

• Epidemiologic characteristics of anotia and microtia in California, 1989-1997 BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY Shaw, G. M., Carmichael, S. L., Kaidarova, Z., Harris, J. A. 2004; 70 (7): 472-475

  Abstract

  There is a paucity of epidemiologic information about the external ear malformations anotia and microtia.Using data from a large population-based registry, we explored prevalences and maternal/infant characteristics associated with anotia and microtia. Data were derived from the California Birth Defects Monitoring Program, a population-based active surveillance system for collecting information on infants and fetuses with congenital malformations using multiple source ascertainment. Approximately 2.5 million births (live-born and stillborn) occurred during the ascertainment period, 1989-1997. Information on maternal and infant/fetal characteristics was obtained from California birth certificate and fetal death files.The prevalence of anotia/microtia was 2.50 per 10,000 live births and stillbirths. Isolated cases, i.e., those live births and stillbirths with no other accompanying anomaly diagnoses, revealed a prevalence of 0.63 per 10,000, whereas among nonisolated cases, the prevalence was 1.53 per 10,000 live births and stillbirths. Prevalences of isolated anotia/microtia were substantially higher among U.S.-born Hispanics, foreign-born Hispanics, and Asians compared to non-Hispanic whites, with relative risks ranging from three- to seven-fold. Similar prevalences for maternal race/ethnicity (except for Asians) were observed for live births and stillbirths with nonisolated cases of anotia/microtia, but the magnitude of risks were lower than those observed for isolated cases. Prevalence of nonisolated anotia/microtia was substantially lower among women whose education was 12 years or more.These data reveal descriptive epidemiologic features of anotia/microtia most notably substantial risks associated with race/ethnic groups and lower maternal education. Additional study for factors associated with these characteristics could reveal clues for the etiology of these ear anomalies.

  View details for DOI 10.1002/bdra.20042

  View details for Web of Science ID 000222987400006

  View details for PubMedID 15259037

• Congenital malformations in offspring of Hispanic and African-American women in California, 1989-1997 BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY Carmichael, S. L., Shaw, G. M., Kaidarova, Z. 2004; 70 (6): 382-388

  Abstract

  Little is known about risks of most specific birth defects among infants born to U.S.-born and foreign-born Hispanic or African-American women.Using data from a large population-based registry, we explored risks of selected congenital malformation phenotypes in offspring of U.S.-born and foreign-born Hispanic and African-American women, relative to non-Hispanic white women, in California. Approximately 2.2 million live births and stillbirths occurred during the ascertainment period, 1989-1997. Information on maternal racial-ethnic background and other covariates was obtained from birth certificate and fetal death files.Adjusted relative risks (ARRs) for the 20 groupings of malformations designated by three-digit British Pediatric Association (BPA) codes ranged from 0.6 (genital organ malformations, among infants born to foreign-born Hispanics) to 1.7 (anencephaly, also among infants born to foreign-born Hispanics). Grouping by four-digit BPA codes revealed that among infants born to U.S.-born Hispanics, 46 of the ARRs were < or = 0.8 and 12 were > or = 1.3; among infants born to foreign-born Hispanics, 75 of the ARRs were < or = 0.8 and 15 were > or = 1.3; and among infants born to African-American women, 45 ARRs were < or = 0.8 and 25 were > or = 1.3. For each racial-ethnic group of women, the observed variability in risks covered most organ systems.Although the results suggested that (in comparison with non-Hispanic whites) each racial-ethnic group was more likely to have reduced risk for specific defects (rather than elevated risk), in general, the range of the relative risks was comparatively narrow.

  View details for DOI 10.1002/bdra.20012

  View details for Web of Science ID 000222419100002

  View details for PubMedID 15211706

• Limb deficiency defects, MSX1, and exposure to tobacco smoke AMERICAN JOURNAL OF MEDICAL GENETICS PART A Carmichael, S. L., Shaw, G. M., Yang, W., Lammer, E. J., Zhu, H. P., Finnell, R. H. 2004; 125A (3): 285-289

  Abstract

  There is increasing evidence from epidemiologic studies that genetic susceptibilities may modify the teratogenic effects of smoking. A previous study suggested that maternal smoking in the presence of a dinucleotide repeat polymorphism for MSX1 produced an almost fivefold increased risk for limb anomalies, providing evidence for a gene-environment interaction. The current study examined this potential interaction, using case-control data with several methodologic improvements, including a larger sample size and more detailed information on cigarette smoke exposures. Cases (n = 92) were ascertained from pregnancies ending in 1987-1989, and controls (n = 180) were randomly selected from eligible liveborn infants. In telephone interviews, women reported smoking behaviors during the month before pregnancy through the end of the first trimester. Odds ratios (OR) for maternal and paternal smoking ranged from 1.0 to 1.4, risk estimates were imprecise; for example, the OR for maternal smoking >or=20 cigarettes per day, versus none, was 1.3 (95% confidence interval (CI) 0.5-3.4). Relative to the homozygous wildtype, the OR was 1.5 (95% CI 0.7-3.5) for the homozygous variant genotype and 0.8 (95% CI 0.5-1.4) for the heterozygous variant genotype. There was no evidence that maternal smoking or both parents smoking, in combination with a susceptible MSX1 genotype, conferred an additional increase in risk of limb defects. This study did not find a gene-environment interaction between maternal smoking, infant MSX1 CA repeat polymorphism, and risk of limb deficiency defects. This finding contrasts with results of a previous study, which provided initial evidence for such an interaction. Several important methodological differences may have contributed to the differences in findings between the two studies.

  View details for DOI 10.1002/ajmg.a.20517

  View details for Web of Science ID 000189316800011

  View details for PubMedID 14994238

• Congenital malformations in births with orofacial clefts among 3.6 million California births, 1983-1997 AMERICAN JOURNAL OF MEDICAL GENETICS PART A Shaw, G. M., Carmichael, S. L., Yang, W., Harris, J. A., Lammer, E. J. 2004; 125A (3): 250-256

  Abstract

  Few population-based epidemiologic data are available on malformation phenotypes that co-occur with orofacial clefts. We explored the occurrence of structural congenital malformations in offspring with cleft palate (CP) and in offspring with cleft lip with or without CP (CLP), using data from a population-based active surveillance system. Ascertainment was performed among 3548991 liveborn and 23239 stillborn offspring of California women who delivered in nonmilitary hospitals during the period, 1983-1997. Structural congenital malformations were found in 91888 births. Among them, 2343 had CP and 4072 had CLP. Malformations were grouped according to 3- and 4-digit codes of the British Pediatric Association (BPA). Prevalences of each malformation grouping, defined by these codes, were calculated among: (1). all births with CP; (2). all births with CLP; (3). all births without CP or CLP but with another structural malformation; and (4). all births in the population at risk. These various prevalence measures were the basis of estimating relative risks. Observed relative risks indicated that some phenotypes were more likely and some were less likely to co-occur with either CP or CLP, with relative risks ranging from 0.5 to 2.4. For both CP and CLP, estimated relative risks were highest for malformations involving the respiratory system and lowest for spina bifida. The exclusion of all births (n = 10702) with chromosomal anomalies from comparisons did not materially alter observed relative risk estimates. Computations extended to 4-digit level BPA codes revealed elevated risks for a number of more specific diagnoses seen within the larger (3-digit level) groupings defined as eye, ear, respiratory, upper alimentary tract, and other musculoskeletal anomalies. In this large population-based cohort of infants and fetuses with CLP or CP, we observed several noncleft malformation groupings to be more common and others to be less common in their co-occurrence with orofacial clefts relative to their co-occurrence with any other malformation. These observed patterns tended to be similar for CP and for CLP.

  View details for DOI 10.1002/ajmg.a.20508

  View details for Web of Science ID 000189316800005

  View details for PubMedID 14994232

• Occurrence of low birthweight and preterm delivery among California infants before and after compulsory food fortification with folic acid PUBLIC HEALTH REPORTS Shaw, G. M., Carmichael, S. L., Nelson, V., Selvin, S., Schaffer, D. M. 2004; 119 (2): 170-173

  Abstract

  Studies suggest that folic acid intake influences the occurrence of low birthweight and preterm delivery. Since 1998, there has been compulsory fortification of flour and other grains with folic acid in the U.S. The objective of this study was to investigate the frequencies of low birthweight and preterm delivery after mandatory folic acid fortification among approximately six million California births.The authors investigated prevalences of low birthweight and preterm delivery before and after compulsory fortification among 5,916,630 singleton California live births that occurred from January 1990 through December 2000.The unadjusted prevalences of very low birthweight, low birthweight, and preterm delivery did not substantially vary across birth years. That is, substantial decreased prevalences during the fortification period relative to the period preceding it were not observed. However, analyses that simultaneously adjusted for maternal age, parity, race/ethnicity, education, year of birth, and fortification period revealed the following relative risk ratios (RR) and 95% confidence intervals (CI): RR = 0.91, CI 0.88, 0.94 for very low birthweight, RR = 0.94; 95% CI 0.93, 0.96 for low birthweight, and RR = 0.96; 95% CI 0.94, 0.97 for preterm delivery.Findings indicate small reductions in prevalences of these outcomes associated with the timing of fortification of the U.S. food supply.

  View details for Web of Science ID 000226363500011

  View details for PubMedID 15192904

• Differential risks to males and females for congenital malformations among 2.5 million California births, 1989-1997 BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY Shaw, G. M., Carmichael, S. L., Kaidarova, Z., Harris, J. A. 2003; 67 (12): 953-958

  Abstract

  Although many studies have observed variations in the prevalence of specific malformations by sex, there is a lack of population-based data on potential malformation prevalence differences by sex at birth.Our objective was to explore differences in the prevalence of structural congenital malformation phenotypes between sexes in a California population of 2.5 million live- and stillbirths, using data from a population-based active surveillance system. Ascertainment was performed among offspring of California women who delivered in nonmilitary hospitals during the period of 1989-1997. Malformations were grouped according to the four-digit malformation codes of the British Pediatric Association.Overall, 32,619 males and 21,835 females were considered to have structural congenital malformations, with prevalences of 2.52% and 1.76%, respectively. Thus, males demonstrated a malformation prevalence that was 22% higher than that in females. Using a criterion of a 40% increase or decrease in the relative risk for males, increased risks for 15 and decreased risks for 17 specific malformation categories were observed. Increased risks were associated with most organ systems, with the notable exception of the nervous system (increased risks for nervous system malformations were observed among female births). Risks were not substantially influenced by adjusting for maternal age, race/ethnicity, parity, or education.Our observations extend the relatively few studies that have investigated differential prevalences of a large number of specific structural malformations between male and female births.

  View details for DOI 10.1002/bdra.10129

  View details for Web of Science ID 000187445400001

  View details for PubMedID 14745913

• Socio-economic status and risk of conotruncal heart defects and orofacial clefts PAEDIATRIC AND PERINATAL EPIDEMIOLOGY Carmichael, S. L., Nelson, V., Shaw, G. M., Wasserman, C. R., Croen, L. A. 2003; 17 (3): 264-271

  Abstract

  Studies of socio-economic status (SES) have figured prominently in research related to a variety of health outcomes, although the question remains as to whether SES contributes to the aetiologies of congenital anomalies. This study examines the association of SES with risks of conotruncal heart defects and orofacial clefts, using interview data from 696 case mothers (86% of eligible) and 734 (78%) control mothers from a population-based case-control study. Socio-economic measures from maternal interview included mother's education and employment. Reported addresses were linked with the US census to characterise six measures of neighbourhood SES (education, poverty, unemployment, occupation, crowding and rental occupancy). Results were adjusted for race-ethnicity, multivitamin/mineral supplement intake, cigarette smoking and binge drinking. Results for individual and neighbourhood measures suggested that low SES was associated with increased risk of d-transposition of the great arteries (dTGA), reduced risk of tetralogy of Fallot (TOF), but was not associated with risk of orofacial clefts. For example, when examining odds ratios (OR) that compared risks among women whose neighbourhoods were in the lowest vs. highest quartile of the census-based SES measures, ORs for five of the six measures were> 1.4 for dTGA, and ORs for all six measures were < 0.7 for TOF. ORs for clefts tended to be closer to 1. This study suggests that SES risks are birth defect specific.

  View details for Web of Science ID 000184158900007

  View details for PubMedID 12839538

• Diet quality and risk of neural tube defects MEDICAL HYPOTHESES Carmichael, S. L., Shaw, G. M., Selvin, S., Schaffer, D. M. 2003; 60 (3): 351-355

  Abstract

  Many studies have examined the impact of single nutrients on neural tube defect (NTD) risk, particularly folate. The impact of dietary patterns or nutrients in combination has received much less attention. This study examines the association of diet quality with NTD risk, using food frequency data from a population-based case-control study of NTDs (n=454 cases and 462 controls). The diet quality score was based on low (<10th percentile among controls) versus high (>90th percentile) values for intakes of iron, vitamins B(6) and A, calcium, folate, and percentage of kilocalories from fat and from sweets (range=0-14). Women with a low score (i.e., <4, or <10th percentile) had an elevated risk of an NTD-affected pregnancy (odds ratio 1.6, 95% CI 1.0-2.6). Stratified analyses suggested that the effect may be restricted to certain groups of women who may be at greater nutritional risk (i.e., women who did not take vitamin supplements or regularly consume breakfast cereals before pregnancy).

  View details for DOI 10.1016/S0306-9877(02)00402-4

  View details for Web of Science ID 000181152100012

  View details for PubMedID 12581611

• Social networks and risk of neural tube defects EUROPEAN JOURNAL OF EPIDEMIOLOGY Carmichael, S. L., Shaw, G. M., Neri, E., Schaffer, D. M., Selvin, S. 2003; 18 (2): 129-133

  Abstract

  The contribution of social support and social networks to risk of neural tube defects (NTDs) has not been explored, despite evidence that various aspects of the social environment contribute to their etiology. Using data from a population-based case-control study of deliveries occurring in California from 1989 to 1991, this study investigates whether social networks, as measured by the presence and frequency of various types of social contacts, are associated with NTD risk. In-person interviews were conducted with 538 (88% of eligible) mothers of NTD cases and with mothers of 539 non-malformed controls (88%) on average 5 months from the term delivery date. Unadjusted results indicate that women who reported having close friends, close relatives, or monthly contacts with close friends or relatives had 30-70% lower risks of having NTD-affected pregnancies, relative to women reporting 'none' to any of these measures. Only the presence of close friends was associated with reduced NTD risk after adjustment for other aspects of the social network and several potential covariates. This study is the first to investigate the association between social networks and risk of NTDs. Stronger inferences await replication and extension of these results.

  View details for Web of Science ID 000182005200006

  View details for PubMedID 12733834

• Maternal periconceptional vitamins: Interactions with selected factors and congenital anomalies? EPIDEMIOLOGY Shaw, G. M., Nelson, V., Carmichael, S. L., Lammer, E. J., Finnell, R. H., Rosenquist, T. H. 2002; 13 (6): 625-630

  Abstract

  The mechanisms by which folic acid may contribute to reductions in risk of several congenital anomalies are unknown. The data gap includes a lack of information on possible effect modification between maternal folic acid use and other maternal exposures. We hypothesized that effects of congenital anomalies associated with maternal fever, cigarette smoking or alcohol use would be modified by intake of vitamins.We explored case-control data that showed risk reductions among infants and fetuses whose mothers consumed vitamins. Data were from California deliveries of infants and fetuses in the period 1987-1989. Maternal telephone interviews were completed for 207 (87%) conotruncal cases, 489 (85%) orofacial cleft cases, 265 (84%) neural tube defect cases, 165 (82%) limb anomaly cases, and 734 controls (nonmalformed infants).Considering women who reported vitamin use and no periconceptional fever as referents, for each anomaly group we observed elevated effects for the combinations of maternal vitamin use/fever, no use/no fever and no use/fever. Effects were most elevated for the combination of no vitamin use and fever. Adjusted for maternal body mass index, education and race/ethnicity, odds ratios were 2.4 (95% confidence inter-val = 1.0-5.9) for conotruncal defects, 2.9 (1.4-5.8) for cleft lip with or without cleft palate, 1.3 (0.4-3.9) for cleft palate, 3.1 (1.4-6.8) for neural tube defects, and 2.6 (1.0-6.4) for limb-deficiency defects. These interactions were further investigated relative to maternal use of fever-reducing medications. Effects tended to be highest among those women who did not use vitamins, had fevers, and did not use fever-reducing medications. Compared with women who used vitamins and did not smoke periconceptionally, anomaly risks tended to be highest among women who did not use vitamins and smoked. No specific pattern emerged involving alcohol intake.These data further suggest that the underlying mechanisms of folic acid associated with congenital anomalies may be complex.

  View details for DOI 10.1097/01.EDE.0000032431.83648.8D

  View details for Web of Science ID 000178637200005

  View details for PubMedID 12410002

• Congenital malformations in offspring of Vietnamese women in California, 1985-97 TERATOLOGY Shaw, G. M., Carmichael, S. L., Nelson, V. 2002; 65 (3): 121-124

  Abstract

  Little is known about reproductive outcome risks for Vietnamese women delivering infants and fetuses in the U.S.Using data from a large population-based registry, we explored risks of selected congenital malformation phenotypes in offspring of Vietnamese women in California. Data were derived from the California Birth Defects Monitoring Program, a population-based active surveillance system for collecting information on infants and fetuses with congenital malformations using multiple source ascertainment. Approximately 3.4 million births (liveborn and stillborn) occurred during the ascertainment period, 1985-97. Information on maternal race/ethnic background was obtained from California birth certificate and fetal death files. Vietnamese women delivered 45,453 births and 1,257,853 births were delivered to non-Hispanic white women.The overall prevalence of structural congenital malformations was 1.92 among Vietnamese and 2.63 among non-Hispanic whites per 100 births and fetal deaths. Grouping by 20 3-digit malformation codes of the International Classification of Diseases-Ninth Revision revealed relative risks of 0.8 or less for spina bifida, eye, upper alimentary, genital, urinary, musculoskeletal, "other" limb, and "other" musculoskeletal anomalies, and relative risks of 1.3 or more for anencephaly and chromosomal anomalies. Grouping by the more specific 4-digit malformation codes revealed 50, among 178, malformation groupings with associated relative risks of >or=1.3 or

  View details for DOI 10.1002/tera.10020

  View details for Web of Science ID 000174119100007

  View details for PubMedID 11877775

• Assessing combined chemical exposures as risk factors for neural tube defects REPRODUCTIVE TOXICOLOGY Shaw, G. M., Selvin, S., Carmichael, S. L., Schaffer, D. M., Nelson, V., Neri, E. 2001; 15 (6): 631-635

  Abstract

  Many studies have investigated whether chemical exposures early in pregnancy increase risks to women of delivering offspring with congenital anomalies. We investigated whether periconceptional exposures to chemicals in combination increased risks to women of having neural tube defect (NTD)-affected pregnancies. Women were asked about occupational tasks performed during the periconceptional period. These tasks were assigned by an industrial hygienist to a priori defined exposure categories. The exposure categories included 74 chemical groups. Two population-based case control studies were analyzed. Information on tasks was obtained from mothers of 538 NTD cases and their 539 controls in one study, and mothers of 265 NTD cases and 481 controls from another study. We used data from the first study to identify clues. Specifically, we estimated NTD risks for maternal occupational exposures to all possible pairs, triplets, and quadruplets of 74 chemical groups. Chemical combinations revealing elevated NTD risks in these "clue generation" analyses were then investigated in the second population-based case-control study for their contribution to risk of NTDs. We computed odds ratios for each of the total 192,374 possible comparisons and identified all combinations that produced odds ratios of 5 or more. A 5-fold elevated risk criterion revealed 53 combinations. These 53 reflected various combinations of exposures exclusive to 12 of 74 chemical groups. Analyses of data from the second study did not identify odds ratios of 2.0 or greater for maternal exposures to the 12 chemical groups that resulted in 5-fold elevated risks in the first study. Despite the use of a labor-intensive method to categorize exposures, we were unable to substantiate clues associated with combined chemical exposures identified in one large case-control study as NTD risk factors in a second case-control study.

  View details for Web of Science ID 000172676400004

  View details for PubMedID 11738516

• Clinical anatomy and the physical examination part I: Thorax, abdomen, perineum, and pelvis - Educational Affairs Committee, American Association of Clinical Anatomists CLINICAL ANATOMY Leonard, R. J., Hoos, P. C., Lozanoff, S., MARKS, S. C., Mathers, L. H., Page, D. W., Pawlina, W., Petterborg, L. J., Abrahams, P., Akesson, E. J., Aker, F. D., Bedell, A. W., Carmichael, S., Cheng, J. C., Haukoos, J. S., Heller, R. F., Huddleston, H. T., Liang, A., Mau, C. K., Nguyen, C., Patwardhan, R., Schlunt, K., Seifert, M. F., Serrao, R., The, T. L., Weiglein, A. H., Williams, V. F., Blevins, C. E., Cahill, D. R. 2001; 14 (5): 332-348

  View details for Web of Science ID 000170811400005

• FACTORS ASSOCIATED WITH THE PATTERN OF MATERNAL WEIGHT-GAIN DURING PREGNANCY OBSTETRICS AND GYNECOLOGY Abrams, B., Carmichael, S., Selvin, S. 1995; 86 (2): 170-176

  Abstract

  To examine the pattern of maternal weight gain using maternal characteristics and pregnancy outcome.We used maternal weight data measured prospectively from all deliveries between 1980-1990 at the University of California, San Francisco. Piecewise linear regression was used to estimate the rate of maternal weight gain in each trimester. Bivariate techniques were used to examine associations between maternal weight gain per trimester and maternal characteristics and pregnancy outcomes. We also used multiple regression analysis to examine the relationship between maternal characteristics and trimester weight gain.Weight data for at least one trimester were available for 10,418 women. The average rate of weight gain (kg/week) was lowest during the first trimester (0.169 +/- 0.268, n = 7587), peaked during the second trimester (0.563 +/- 0.236, n = 8000), and slowed slightly in the third trimester (0.518 +/- 0.234, n = 10,052). Maternal height, hypertension, cesarean delivery, and fetal size correlated positively with the rate of gain in each trimester, but pre-pregnancy body size, age, parity, smoking status, race-ethnicity, and diabetes were associated differently with gain, depending on which trimester was examined. The most important maternal predictors of weight gain per trimester were age and Asian race-ethnicity in the first trimester; pre-pregnancy body mass, parity, and height in the second; and hypertension, age, and parity in the third.Maternal weight gain per trimester is associated with a number of maternal characteristics and pregnancy outcomes, and these relationships vary according to which trimester is being examined.

  View details for Web of Science ID A1995RK50500003

  View details for PubMedID 7617345