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  • Epigenetic clock measuring age acceleration via DNA methylation levels in blood is associated with decreased oocyte yield. Journal of assisted reproduction and genetics Monseur, B., Murugappan, G., Bentley, J., Teng, N., Westphal, L. 2020

    Abstract

    PURPOSE: To investigate how biologic age (phenotypic age at which your body functions) greater than chronologic age, (age acceleration (AgeAccel)), correlates with oocyte yield.METHODS: Thirty-nine women undergoing ovarian stimulation, inclusive of all infertility diagnoses, were included in this pilot study. Methylome analysis of peripheral blood was utilized to determine biologic age. AgeAccel was defined as biologic age >2years older than chronologic age. A negative binomial model was used to obtain the crude association of AgeAccel with number of oocytes. A parsimonious adjusted model for the number of oocytes was obtained using backwards selection (p<0.05).RESULTS: Measures of age were negatively correlated with number of oocytes (chronological age Pearson rho=-0.45, biologic age Pearson rho=-0.46) and AMH was positively correlated with number of oocytes (Pearson rho=0.91). Patients with AgeAccel were noted to have lower AMH values (1.29ng/mL vs. 2.29, respectively (p=0.049)) and lower oocyte yield (5.50 oocytes vs. 14.50 oocytes, respectively (p=0.0030)). A crude association of a 7-oocyte reduction in the age-accelerated group was found (-6.9 oocytes (CI -11.6, -2.4)). In a model with AMH and antral follicle count, AgeAccel was associated with a statistically significant 3.3 reduction in the number of oocytes (-3.1; 95% CI -6.5, -0.1; p=0.036).CONCLUSIONS: In this small pilot study, AgeAccel is associated with a lower AMH and lower oocyte yield providing preliminary evidence that biologic age, specifically AgeAccel, may serve as an epigenetic biomarker to improve the ability of predictive models to assess ovarian reserve.

    View details for DOI 10.1007/s10815-020-01763-0

    View details for PubMedID 32285295

  • INCREASED RISK OF SEVERE MATERNAL MORBIDITY AMONG INFERTILE WOMEN: ANALYSIS OF US CLAIMS DATA. American journal of obstetrics and gynecology Murugappan, G., Li, S., Lathi, R. B., Baker, V. L., Luke, B., Eisenberg, M. L. 2020

    Abstract

    Severe maternal morbidity continues to be an issue of national and global concern and is increasing in incidence. The incidence of infertility is also on the rise, and infertile women experience a higher risk of incident chronic medical disease and cancer, suggesting that fertility may serve as a window to a woman's overall health.To investigate the risk of severe maternal morbidity by maternal fertility status.Retrospective cohort analysis using Optum's de-identifed Clinformatics® Data Mart Database between 2003-2015. Infertile women stratified by infertility diagnosis, testing or treatment were compared to fertile women seeking routine gynecologic care. In both groups, only women who underwent pregnancy and delivery of a singleton during the follow up period were included. Main outcomes were severe maternal morbidity indicators, defined by the CDC, and identified by ICD-10 and CPT codes within 6 weeks of each delivery. Results were adjusted for maternal age, race, education, nulliparity, race, smoking, obesity, delivery mode, preterm birth, number of prenatal visits, and year of delivery.19,658 women comprised the infertile group and 525,695 women comprised the fertile group. The overall incidence of any severe maternal morbidity indicator was 7.0% among women receiving fertility treatment, 6.4% among women receiving a fertility diagnosis, 5.5% among women receiving fertility testing and 4.3% among fertile women.. Overall, infertile women had a significantly higher risk of developing any severe maternal morbidity indicator (AOR 1.22, CI 1.14-1.31, p<0.01) as well as a significantly higher risk of disseminated intravascular coagulation (DIC) (AOR 1.48, CI 1.26 - 1.73, p<0.01), eclampsia (AOR 1.37, CI 1.05 - 1.79, p<0.01), heart failure during procedure or surgery (AOR 1.54, CI 1.21 - 1.97, p<0.01), internal injuries of the thorax, abdomen or pelvis (AOR 1.59, CI 1.12 - 2.26, p<0.01), intracranial injuries (AOR 1.77, CI 1.20- 2.61, p<0.01), pulmonary edema (AOR 2.18, CI 1.54 - 3.10, p<0.01), thrombotic embolism (AOR 1.58, CI 1.14 - 2.17, p<0.01), and blood transfusion (AOR 1.50, CI 1.30 - 1.72, p<0.01) compared to fertile women. Fertile women did not face a significantly higher risk of any maternal morbidity indicator compared to infertile women. In subgroup analysis by maternal race/ethnicity, the likelihood of severe morbidity was significantly higher among fertile Black women compared to fertile Caucasian women. There was no difference between infertile Black and Caucasian women after multivariable adjustment.Using an insurance claims database, we report that women diagnosed with infertility and women receiving fertility treatment experience a significantly higher risk of multiple indicators of severe maternal morbidity compared to fertile women. The increased risk of severe maternal morbidity noted among fertile Black women compared to fertile Caucasian women is attenuated among infertile Black women, who face similar risks as infertile Caucasian women.

    View details for DOI 10.1016/j.ajog.2020.02.027

    View details for PubMedID 32112734

  • BLASTOCYST GRADE PREDICTS OUTCOME AFTER FROZEN EUPLOID TRANSFER IN PATIENTS WITH RECURRENT PREGNANCY LOSS. Murugappan, G., Kim, J. G., Kort, J. D., Hanson, B. M., Neal, S. A., Tiegs, A. W., Osman, E. K., Scott, R., Lathi, R. B. ELSEVIER SCIENCE INC. 2019: E151
  • PREIMPLANTATION GENETIC TESTING FOR ANEUPLOIDY (PGT-A) REDUCES MISCARRIAGE AND IMPROVES LIVE BIRTH RATES IN RECURRENT PREGNANCY LOSS PATIENTS. Kim, J. G., Murugappan, G., Lathi, R. B., Kort, J. D., Hanson, B. M., Tiegs, A. W., Osman, E. K., Neal, S. A., Scott, R. ELSEVIER SCIENCE INC. 2019: E401
  • IS ANTIMULLERIAN HORMONE PREDICTIVE OF OUTCOMES AFTER PGT-A IN PATIENTS WITH RECURRENT PREGNANCY LOSS? Murugappan, G., Shahine, L. K., Lathi, R. B. ELSEVIER SCIENCE INC. 2019: E403
  • Risk of cancer in infertile women: analysis of US claims data HUMAN REPRODUCTION Murugappan, G., Li, S., Lathi, R. B., Baker, V. L., Eisenberg, M. L. 2019; 34 (5): 894?902
  • Increased risk of incident chronic medical conditions in infertile women: analysis of US claims data Murugappan, G., Li, S., Lathi, R. B., Baker, V. L., Eisenberg, M. L. MOSBY-ELSEVIER. 2019
  • ATTITUDES TOWARDS POSTHUMOUS REPRODUCTION IN PATIENTS UNDERGOING EMBRYO OR GAMETE CRYOPRESERVATION. Vyas, N. M., Murugappan, G., Westphal, L. M. ELSEVIER SCIENCE INC. 2019: E51
  • Risk of cancer in infertile women: analysis of us claims data. Human reproduction (Oxford, England) Murugappan, G., Li, S., Lathi, R. B., Baker, V. L., Eisenberg, M. L. 2019

    Abstract

    STUDY QUESTION: Is female infertility associated with higher risk of cancer?SUMMARY ANSWER: Although absolute risks are low, infertility is associated with higher risk of cancer compared to a group of non-infertile women.WHAT IS KNOWN ALREADY: Infertile women are at higher risk of hormone-sensitive cancers. Information on risk of non-gynecologic cancers is rare and conflicting, and the effect of pregnancy on these risk associations is known for only a minority of cancer types.STUDY DESIGN, SIZE, DURATION: Retrospective cohort analysis between 2003 and 2016 using an insurance claims database.PARTICIPANTS/MATERIALS, SETTING, METHODS: In all, 64 345 infertile women identified by infertility diagnosis, testing or treatment were compared to 3 128 345 non-infertile patients seeking routine gynecologic care. Women with prior diagnosis of cancer or within 6 months of index event were excluded. Main outcomes were development of any malignancy and individual cancers as identified by ICD-9/ICD-10 codes. Results were adjusted for age at index date, index year, nulliparity, race, smoking, obesity, number of visits per year and highest level of education.MAIN RESULTS AND THE ROLE OF CHANCE: Infertile women had an overall higher risk of developing cancer compared to non-infertile women (2.0 versus 1.7%, adjusted hazard ratio (aHR) = 1.18; CI: 1.12-1.24). In addition, the risk of uterine cancer (0.10 versus 0.06%, aHR = 1.78; CI: 1.39-2.28), ovarian cancer (0.14 versus 0.09%, aHR 1.64; CI: 1.33-2.01), lung cancer (0.21 versus 0.21%, aHR = 1.38; CI: 1.01-1.88), thyroid cancer (0.21 versus 0.16%, aHR = 1.29; CI: 1.09-1.53), leukemia (0.10 versus 0.06%, aHR = 1.55; CI: 1.21-1.98) and liver and gallbladder cancer (0.05 versus 0.03%, aHR = 1.59; CI: 1.11-2.30) were higher in infertile women compared to non-infertile women. In a subgroup analysis of women in each cohort who became pregnant and had a delivery during enrollment, the risk of uterine and ovarian cancer were similar between infertile and non-infertile women. In a subgroup analysis excluding women with PCOS and endometriosis from both cohorts, the risk of uterine cancer was similar between infertile and non-infertile women.LIMITATIONS, REASONS FOR CAUTION: Absolute risk of cancer was low, average follow up for each individual was limited, and average age at index date was limited. Insurance databases have known limitations.WIDER IMPLICATIONS OF THE FINDINGS: Using claims-based data, we report that infertile women may have a higher risk of certain cancers in the years after infertility evaluation; continued follow up should be considered after reproductive goals are achieved.STUDY FUNDING/COMPETING INTEREST(S): None.

    View details for PubMedID 30863841

  • Increased Risk of Incident Chronic Medical Conditions in Infertile Women: Analysis of Us Claims Data. American journal of obstetrics and gynecology Murugapppan, G., Li, S., Lathi, R. B., Baker, V. L., Eisenberg, M. L. 2019

    Abstract

    BACKGROUND: The risk of common chronic medical conditions among infertile women is not known.OBJECTIVE: To study the association between female infertility and risk of incident chronic disease.STUDY DESIGN: Retrospective cohort analysis using the Optum de-identified Clinformatics© Datamart from 2003-2016. 64,345 infertile women were identified by infertility diagnosis, testing or treatment and compared to 3,128,345 non-infertile patients seeking routine gynecologic care. Women with prior diagnosis of the relevant chronic disease or cancer or with either diagnosis within six months of index event were excluded. Main outcome was diagnosis of incident chronic disease as identified by ICD-9/ICD-10 codes. Results were adjusted for age, index year, nulliparity, race, smoking, obesity, number of visits per year and highest level of education.RESULTS: Infertile patients were more likely to develop diabetes (aHR 1.44, CI 1.38-1.49), renal disease (aHR 1.22, CI 1.12-1.32), liver disease (aHR 1.25, CI 1.20-1.30), cerebrovascular disease (aHR 1.26, CI 1.15-1.38), ischemic heart disease (aHR 1.16, CI 1.09-1.24), other heart disease (aHR 1.16, CI 1.12-1.20), and drug abuse (aHR 1.24, CI 1.15-1.33) compared to non-infertile patients. Infertile patients were significantly less likely to develop alcohol abuse (aHR 0.86, CI 0.79-0.95) compared to non-infertile patients. Risk associations were similar after excluding women with PCOS and POI. In subgroup analyses of women who underwent pregnancy and childbirth during enrollment, several previously noted risk associations were attenuated compared to the overall cohort.CONCLUSION: While the absolute risk of chronic disease is low, infertility is associated with increased risk of incident chronic disease compared to a group of non-infertile women.

    View details for PubMedID 30710512

  • Hormone replacement versus natural frozen embryo transfer for euploid embryos. Archives of gynecology and obstetrics Wang, A., Murugappan, G., Kort, J., Westphal, L. 2019

    Abstract

    The goal of this study is to investigate hormone replacement (HR) versus natural frozen embryo transfer outcomes for euploid embryos.This is a retrospective cohort study at an academic medical center of patients undergoing in vitro fertilization with 24-chromosome day 5/6 preimplantation genetic testing for aneuploidies (PGT-A), from 2014 to 2018 using euploid single embryo frozen transfer. Multivariable logistic regression was used to study the association between transfer outcomes (ongoing pregnancy and miscarriage) with type of frozen euploid embryo transfer (HR versus natural) while controlling for multiple patient and cycle confounders.From a total of 389 cycles, 45.0% utilized HR frozen embryo transfer and 55.0% were natural cycles. We found that when compared to HR frozen embryo transfer, natural cycle frozen embryo transfer had significantly higher ongoing pregnancy rates (aOR 2.05, 1.27-3.31, p?=?0.003). There was no significant difference in miscarriage rates between the two groups (aOR for natural 0.69, 95% CI 0.37-1.32, p?=?0.27). When limiting the analysis to only the first transfer at our institution, findings were similar of higher ongoing pregnancy rates and no difference in miscarriage rates.In our multivariate analysis, we found that natural cycle single euploid frozen embryo transfer was associated with significantly higher ongoing pregnancy rates than HR transfer, with no difference in miscarriage rates.

    View details for DOI 10.1007/s00404-019-05251-4

    View details for PubMedID 31338657

  • Antimullerian hormone is a predictor of live birth in patients with recurrent pregnancy loss. Fertility research and practice Murugappan, G., Shahine, L., Lathi, R. B. 2019; 5: 2

    Abstract

    Background: Ovarian reserve testing is not routinely performed in the evaluation of recurrent pregnancy loss (RPL). The objective of this study was to determine if AMH levels are predictive of live birth rate in RPL patients pursuing expectant management (EM).Methods: Retrospective cohort study of RPL patients. Patients tried to conceive spontaneously for 12 calendar months or until they achieved a live birth, whichever occurred first. All patients with the intent to conceive were included regardless of final outcome.Results: One hundred fifty-five RPL patients treated from 2009 to 2017 were included. In a univariate logistic regression, AMH<1ng/mL was associated with decreased likelihood of live birth (OR 0.38; CI 0.16-0.87, p=0.03) and increasing age (OR 0.91; CI 0.83-0.99, p=0.04). Likelihood of live birth was not significantly associated with BMI (OR 1.21; CI 0.83-1.77, p=0.31), three or four or more prior pregnancy losses (OR 0.93; CI 0.40-2.22, p=0.87 and OR 0.52; CI 0.19-1.42, p=0.20, respectively) and prior live births (OR 1.00; CI 0.48-2.08, p=0.99). AMH <1ng/mL was shown to be a stronger predictor of live birth than age using a multivariate model adjusting for age, AMH, and time to conception.Conclusions: AMH<1ng/mL is associated with decreased likelihood of live birth among RPL patients pursuing EM, and may be a stronger predictor of live birth than age in this population.

    View details for DOI 10.1186/s40738-019-0054-z

    View details for PubMedID 30923623

  • IS ANTIMULLERIAN HORMONE (AMH) PREDICTIVE OF REPRODUCTIVE POTENTIAL IN PATIENTS WITH RECURRENT PREGNANCY LOSS (RPL)? Murugappan, G., Shahine, L., Lathi, R. B. ELSEVIER SCIENCE INC. 2018: E39?E40
  • Gestational carrier in assisted reproductive technology FERTILITY AND STERILITY Murugappan, G., Farland, L. V., Missmer, S. A., Correia, K. F., Anchan, R. M., Ginsburg, E. S. 2018; 109 (3): 420?28

    Abstract

    To compare clinical outcomes of in vitro fertilization (IVF) cycles with the use of gestational carriers (GCs) with non-GC IVF cycles.Retrospective cohort study of assisted reproductive technology (ART) cycles performed with (24,269) and without (1,313,452) the use of a GC.ART centers.Infertile patients seeking IVF with or without use of a GC.Autologous and donor oocyte cycles, fresh and cryopreserved embryo transfer cycles.Live birth rate (LBR), twin and high-order multiple birth rates.Approximately 2% of embryo transfers used a GC. Per embryo transfer, GCs had greater pregnancy rate and LBR across all IVF types compared with non-GC cycles in crude models and models adjusted a priori for potential confounders. For women with uterine-factor infertility, embryo transfer with the use of a GC resulted in a higher odds of live birth for autologous fresh embryos and for cryopreserved embryos compared with patients with non-uterine-factor infertility diagnoses.GC benefits LBRs for some patients seeking ART. The highest LBRs occurred when the indication for GC was uterine-factor infertility.

    View details for PubMedID 29428314

  • Reply: PGS for recurrent pregnancy loss-still an open question HUMAN REPRODUCTION Murugappan, G., Lathi, R. 2017; 32 (2): 478?79

    View details for PubMedID 27974441

  • Reply: The value of cytogenetic analysis of the product of conception before preimplantation genetic screening HUMAN REPRODUCTION Murugappan, G., Lathi, R. 2017; 32 (2): 479?80

    View details for PubMedID 27974444

  • Intent to treat analysis of in vitro fertilization and preimplantation genetic screening versus expectant management in patients with recurrent pregnancy loss. Human reproduction Murugappan, G., Shahine, L. K., Perfetto, C. O., Hickok, L. R., Lathi, R. B. 2016; 31 (8): 1668-1674

    Abstract

    In an intent to treat analysis, are clinical outcomes improved in recurrent pregnancy loss (RPL) patients undergoing IVF and preimplantation genetic screening (PGS) compared with patients who are expectantly managed (EM)?Among all attempts at PGS or EM among RPL patients, clinical outcomes including pregnancy rate, live birth (LB) rate and clinical miscarriage (CM) rate were similar.The standard of care for management of patients with RPL is EM. Due to the prevalence of aneuploidy in CM, PGS has been proposed as an alternate strategy for reducing CM rates and improving LB rates.Retrospective cohort study of 300 RPL patients treated between 2009 and 2014.Among two academic fertility centers, 112 RPL patients desired PGS and 188 patients chose EM. Main outcomes measured were pregnancy rate and LB per attempt and CM rate per pregnancy. One attempt was defined as an IVF cycle followed by a fresh embryo transfer or a frozen embryo transfer (PGS group) and 6 months trying to conceive (EM group).In the IVF group, 168 retrievals were performed and 38 cycles canceled their planned PGS. Cycles in which PGS was intended but cancelled had a significantly lower LB rate (15 versus 36%, P = 0.01) and higher CM rate (50 versus 14%, P < 0.01) compared with cycles that completed PGS despite similar maternal ages. Of the 130 completed PGS cycles, 74% (n = 96) yielded at least one euploid embryo. Clinical pregnancy rate per euploid embryo transfer was 72% and LB rate per euploid embryo transfer was 57%. Among all attempts at PGS or EM, clinical outcomes were similar. Median time to pregnancy was 6.5 months in the PGS group and 3.0 months in the EM group.The largest limitation is the retrospective study design, in which patients who elected for IVF/PGS may have had different clinical prognoses than patients who elected for expectant management. In addition, the definition of one attempt at conception for PGS and EM groups was different between the groups and can introduce potential confounders. For example, it was not confirmed that patients in the EM group were trying to conceive for each month of the 6-month period.Success rates with PGS are limited by the high incidence of cycles that intend but cancel PGS or cycles that do not reach transfer. Counseling RPL patients on their treatment options should include not only success rates with PGS per euploid embryo transferred, but also LB rate per initiated PGS cycle. Furthermore, patients who express an urgency to conceive should be counseled that PGS may not accelerate time to conception.None.N/A.N/A.N/A.

    View details for DOI 10.1093/humrep/dew135

    View details for PubMedID 27278003

  • AGE-STRATIFIED OUTCOMES ARE SIMILAR BETWEEN PGS AND EXPECTANT MANAGEMENT IN RPL PATIENTS Murugappan, G., Shahine, L., Hickok, L., Lathi, R. B. ELSEVIER SCIENCE INC. 2016: E32
  • Cost-effectiveness analysis of preimplantation genetic screening and in vitro fertilization versus expectant management in patients with unexplained recurrent pregnancy loss FERTILITY AND STERILITY Murugappan, G., Ohno, M. S., Lathi, R. B. 2015; 103 (5): 1215-1220

    Abstract

    To determine whether in vitro fertilization with preimplantation genetic screening (IVF/PGS) is cost effective compared with expectant management in achieving live birth for patients with unexplained recurrent pregnancy loss (RPL).Decision analytic model comparing costs and clinical outcomes.Academic recurrent pregnancy loss programs.Women with unexplained RPL.IVF/PGS with 24-chromosome screening and expectant management.Cost per live birth.The IVF/PGS strategy had a live-birth rate of 53% and a clinical miscarriage rate of 7%. Expectant management had a live-birth rate of 67% and clinical miscarriage rate of 24%. The IVF/PGS strategy was 100-fold more expensive, costing $45,300 per live birth compared with $418 per live birth with expectant management.In this model, IVF/PGS was not a cost-effective strategy for increasing live birth. Furthermore, the live-birth rate with IVF/PGS needs to be 91% to be cost effective compared with expectant management.

    View details for DOI 10.1016/j.fertnstert.2015.02.012

    View details for Web of Science ID 000353843700024

    View details for PubMedID 25772770

  • Time to next pregnancy in spontaneous pregnancies versus treatment cycles in fertile patients with recurrent pregnancy loss. Fertility research and practice Perfetto, C. O., Murugappan, G., Lathi, R. B. 2015; 1: 5

    Abstract

    BACKGROUND: The current standard of care for management of patients with recurrent pregnancy loss is expectant management. However, the emotional impact of pregnancy losses and the urgency to conceive often leads couples to consider a variety of fertility treatments. The objective of this study is to report the time to next pregnancy and subsequent live birth and miscarriage rates in fertile patients with recurrent pregnancy loss (RPL) who choose to attempt spontaneous conception compared to those that opt to pursue fertility treatment.METHODS: Retrospective cohort study of one hundred and fifty-eight fertile RPL patients treated at a university-based fertility center. Patients were followed for a minimum of 6months. Patients were encouraged to attempt spontaneous conception, but allowed to initiate fertility treatments (ovarian stimulation, insemination, IVF or PGS) according to their preferences. Main outcome measures were time to next pregnancy and pregnancy outcome.RESULTS: For those patients who achieved a spontaneous conception, 88% conceived within 6months, with a median time of 2months and range of 1-10 months. Patients using IUI, IVF and PGS conceived in a median of 3, 4 and 5months, respectively. The live birth rate and clinical miscarriage rate was not improved with any fertility treatment.CONCLUSIONS: In the fertile RPL patient population, there does not appear to be a benefit to proceeding directly with fertility treatment. Patients should be encouraged to attempt spontaneous conception for at least 6months.

    View details for PubMedID 28620510

  • Separation of miscarriage tissue from maternal decidua for chromosome analysis FERTILITY AND STERILITY Murugappan, G., Gustin, S., Lathi, R. B. 2014; 102 (4): E9-E10

    Abstract

    To demonstrate a technique for separation of miscarriage tissue from maternal decidua to reduce maternal cell contamination for chromosome analysis.Retrospective.University-based infertility center.Not applicable.Retrospective collection of de-identified images and video from manual vacuum aspiration (MVA) performed after first-trimester pregnancy losses. This project was exempt from institutional review board approval as no patient-identifying data were used.Reduction of maternal cell contamination and improvement of the accuracy of chromosome analysis.Video demonstration of separation of miscarriage tissue from maternal decidua after MVA.Chromosome analysis of a miscarriage is performed to assess the etiology of miscarriage and recurrent pregnancy loss. However, maternal cell contamination can limit the accuracy. This video demonstrates a technique for separating miscarriage tissue from maternal decidua after MVA to reduce maternal cell contamination prior to sending tissue for analysis. The same technique has been used in our clinic with first-trimester dilation and curettage using mechanical suction.

    View details for DOI 10.1016/j.fertnstert.2014.07.006

    View details for Web of Science ID 000343108200001

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