Hyagriv N Simhan

University of Pennsylvania, Filadelfia, Pennsylvania, United States

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Publications (242)

  • Rosemary Froehlich · Hyagriv N Simhan · Jacob C Larkin
    [Show abstract] [Hide abstract] ABSTRACT: Objective This study aims to determine the risk of adverse outcomes associated with the current diagnostic criteria for fetal macrosomia. Study Design We evaluated three techniques for characterizing birth weight as a predictor of shoulder dystocia or third- or fourth-degree laceration in 79,879 vaginal deliveries. First, we compared deliveries with birth weights above or below 4,500 g. We then performed logistic regression using birth weight as a continuous predictor, both with and without fractional polynomial transformation. Finally, we calculated the number of cesarean sections required to prevent one incident of the interrogated outcomes (number needed to treat [NNT]). Results Rates of adverse intrapartum outcomes increase incrementally with increasing birth weight and are predicted most accurately with logistic regression following fractional polynomial transformation. The NNT for third- or fourth-degree laceration dropped from 14.3 (95% confidence interval [CI], 13.9-14.7) at a birth weight of 3,500 g to 6.4 (95% CI, 6.1-6.8) at 4,500 g and, for shoulder dystocia, from 54.9 (95% CI, 51.5-58.6) at 3,500 g to 5.6 (95% CI, 5.2-6.0) at 4,500 g. Conclusion The conventional distinction between "normal" and "macrosomic" does not reflect the incremental effect of increasing birth weight on the risk of obstetric morbidity. Outcomes analysis can inform fetal growth standards to better reflect relevant thresholds of risk.
    Article · Oct 2015 · American Journal of Perinatology
  • Lisa M Bodnar · W Tony Parks · Kiran Perkins · [...] · Hyagriv N Simhan
    [Show abstract] [Hide abstract] ABSTRACT: In high-income countries, maternal obesity is one of the most important modifiable causes of stillbirth, yet the pathways underpinning this association remain unclear. We estimated the association between maternal prepregnancy body mass index (BMI) and the risk of stillbirth defined by pathophysiologic contributors or causes. Using a case-cohort design, we randomly sampled 1829 singleton deliveries from a cohort of 68,437 eligible deliveries at Magee-Womens Hospital in Pittsburgh, Pennsylvania (2003-2010), and augmented it with all remaining cases of stillbirth for a total of 658 cases. Stillbirths were classified based on probable cause(s) of death (maternal medical conditions, obstetric complications, fetal abnormalities, placental diseases, and infection). A panel of clinical experts reviewed medical records, placental tissue slides and pathology reports, and fetal postmortem reports of all stillbirths. Causes of fetal death were assigned by using the Stillbirth Collaborative Research Network Initial Causes of Fetal Death protocol from the Eunice Kennedy Shriver National Institute of Child Health and Human Development. Proportional hazards models were used to estimate the BMI-stillbirth association after adjustment for confounders. The rate of stillbirth among lean, overweight, obese, and severely obese women was 7.7, 10.6, 13.9, and 17.3 per 1000 live-born and stillborn infants, respectively. Adjusted stillbirth HRs (95% CIs) were 1.4 (1.1, 1.8) for overweight, 1.8 (1.3, 2.4) for obese, and 2.0 (1.5, 2.8) for severely obese women, respectively, compared with lean women; associations strengthened when limited to antepartum stillbirths. Obesity and severe obesity were associated with stillbirth resulting from placental diseases, hypertension, fetal anomalies, and umbilical cord abnormalities. BMI was not related to stillbirth caused by placental abruption, obstetric conditions, or infection. Multiple mechanisms appear to link obesity to stillbirth. Interventions to reduce stillbirth among obese mothers should consider targeting stillbirth due to hypertension and placental diseases-the most common causes of fetal death in this at-risk group. © 2015 American Society for Nutrition.
    Article · Aug 2015 · American Journal of Clinical Nutrition
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    [Show abstract] [Hide abstract] ABSTRACT: Several lines of evidence suggest that male embryos may have greater vulnerability than female embryos to disordered inflammation; therefore, antiinflammatory drugs, such as low-dose aspirin (LDA), may alter the sex ratio. Here, we assessed the effect of LDA on male live birth and male offspring, incorporating pregnancy losses (n = 56) via genetic assessment, as part of a parallel-design, block-randomized, placebo-controlled trial of preconception LDA. Participants (615 treated with LDA, 613 treated with placebo) ranged in age from 18 to 40 years of age, with 1 to 2 prior pregnancy losses. We estimated the intention-to-treat (ITT) risk ratio (RR) and 95% CI and assessed interaction with baseline high-sensitivity C-reactive protein (hsCRP) serum concentration - a marker of systemic inflammation. Among the 1,078 women who completed follow-up (535 treated with LDA, 543 treated with placebo), the male live birth ITT RR equaled 1.31 (95% CI: 1.07-1.59). With increasing tertile of hsCRP, the proportion of males at birth decreased in the placebo group, and the effect of LDA on male live birth increased (first tertile: 48% male in LDA vs. 52% in placebo, ITT RR = 0.97, 95% CI: 0.70-1.35; second tertile: 57% male in LDA vs. 43% in placebo, ITT RR = 1.36, 95% CI: 0.98-1.90; third tertile: 53% male in LDA vs. 35% in placebo, ITT RR = 1.70, 95% CI: 1.13-2.57; P interaction = 0.03). Analysis of pregnancy with male offspring yielded similar results. Initiation of LDA prior to conception restored numbers of male live births and pregnancy with male offspring among women with 1 to 2 prior pregnancy losses. Moreover, our data suggest that LDA modulates inflammation that would otherwise reduce the conception or survival of male embryos. ClinicalTrials.gov NCT00467363. Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health.
    Full-text available · Article · Aug 2015 · The Journal of clinical investigation
  • [Show abstract] [Hide abstract] ABSTRACT: To compare the pharmacokinetics of 2g and 3g doses of cefazolin when used for peri-operative prophylaxis in obese gravidae undergoing cesarean delivery. We performed a double-blinded randomized controlled trial from August 2013 to April 2014. Twenty-six obese women were randomized to receive either 2g or 3g IV cefazolin within 30min of skin incision. Serial maternal plasma samples were obtained at specific time points up to 8hrs after drug administration. Umbilical cord blood was obtained after placental delivery. Maternal adipose samples were obtained prior to fascial entry, after closure of the hysterotomy and subsequent to fascial closure. Pharmacokinetic parameters were determined via non-compartmental analysis. The median area under the plasma concentration vs. time curve was significantly greater in the 3g group than in the 2g group (27204 μg/mL/min vs. 14058 μg/mL/min: p=0.001). Maternal plasma concentrations were impacted by body mass index. For every 1 kg/m(2) increase in body mass index at time of cesarean delivery, there was an associated 13.77μg/mL lower plasma concentration of cefazolin across all time points (p=0.01). By the completion of cesarean delivery, cefazolin concentrations in maternal adipose were consistently above the minimal inhibitory concentration for both gram-positive and gram-negative bacteria with both the 2g and 3g doses. The median umbilical cord blood concentrations were significantly higher in the 3g vs. the 2g group (34.5 μg/mL and 21.4 μg/mL: p=.003). Cefazolin concentrations in maternal adipose both at time of hysterotomy closure and fascial closure were above the minimal inhibitory concentration for both gram-positive and gram-negative bacteria when either 2g or 3g cefazolin was administered as perioperative surgical prophylaxis. Maternal cefazolin concentrations in plasma and maternal adipose tissue are related to both dose and body mass index. Copyright © 2015 Elsevier Inc. All rights reserved.
    Article · Jun 2015 · American journal of obstetrics and gynecology
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    [Show abstract] [Hide abstract] ABSTRACT: Background. Chronic poor oral health has a high prevalence in Appalachia, a large region in the eastern USA. The Center for Oral Health Research in Appalachia (COHRA) has been enrolling pregnant women and their babies since 2011 in the COHRA2 study of genetic, microbial, and environmental factors involved in oral health in Northern Appalachia. Methods. The COHRA2 protocol is presented in detail, including inclusion criteria (healthy, adult, pregnant, US Caucasian, English speaking, and nonimmunocompromised women), recruiting (two sites: Pittsburgh, Pennsylvania, and West Virginia, USA), assessments (demographic, medical, dental, psychosocial/behavioral, and oral microbial samples and DNA), timelines (longitudinal from pregnancy to young childhood), quality control, and retention rates. Results. Preliminary oral health and demographic data are presented in 727 pregnant women, half from the greater Pittsburgh region and half from West Virginia. Despite similar tooth brushing and flossing habits, COHRA2 women in West Virginia have significantly worse oral health than the Pittsburgh sample. Women from Pittsburgh are older and more educated and have less unemployment than the West Virginia sample. Conclusions. We observed different prevalence of oral health and demographic variables between pregnant women from West Virginia (primarily rural) and Pittsburgh (primarily urban). These observations suggest site-specific differences within Northern Appalachia that warrant future studies.
    Full-text available · Article · Jun 2015 · International Journal of Dentistry
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    [Show abstract] [Hide abstract] ABSTRACT: Telomere biology plays a fundamental role in genomic integrity and cell physiology. The newborn setting of telomere length (TL) likely has important implications for telomere dynamics over the lifespan; however, its determinants are poorly understood. Folate is essential for DNA integrity. The maternal compartment is the only source of folate for the developing fetus. We, therefore, tested the hypothesis that variation in maternal folate during pregnancy is associated with newborn TL. A prospective, longitudinal study was conducted in 119 mother-newborn dyads. Eligible mothers were enrolled at 9.5 (SD ±2.1) weeks gestation and followed through birth. Concentrations of maternal serum folate were measured in the first trimester of pregnancy. Newborn telomere length was measured in cord blood mononuclear cells (CBMC). After accounting for the effects of other established determinants of newborn TL, each 10 ng/ml increase in maternal total folate was associated with a 5.8% increase in median TL (p = 0.03). The median TL in newborns of mother in the lowest quartile of total folate levels was approximately 10% shorter than that of newborns of mothers in the highest folate quartile. Our findings suggest that fetal TL exhibits developmental plasticity, and provide evidence that maternal nutrition may exert a 'programming' effect on this system. © 2015 S. Karger AG, Basel.
    Full-text available · Article · Jun 2015 · Annals of Nutrition and Metabolism
  • [Show abstract] [Hide abstract] ABSTRACT: The objective of the Sleep Disordered Breathing substudy of the Nulliparous Pregnancy Outcomes Study Monitoring Mothers-to-be (nuMoM2b) is to determine whether sleep disordered breathing during pregnancy is a risk factor for adverse pregnancy outcomes. NuMoM2b is a prospective cohort study of 10,037 nulliparous women with singleton gestations that was conducted across 8 sites with a central Data Coordinating and Analysis Center. The Sleep Disordered Breathing substudy recruited 3702 women from the cohort to undergo objective, overnight in-home assessments of sleep disordered breathing. A standardized level 3 home sleep test was performed between 6(0)-15(0) weeks' gestation (visit 1) and again between 22(0)-31(0) weeks' gestation (visit 3). Scoring of tests was conducted by a central Sleep Reading Center. Participants and their health care providers were notified if test results met "urgent referral" criteria that were based on threshold levels of apnea hypopnea indices, oxygen saturation levels, or electrocardiogram abnormalities but were not notified of test results otherwise. The primary pregnancy outcomes to be analyzed in relation to maternal sleep disordered breathing are preeclampsia, gestational hypertension, gestational diabetes mellitus, fetal growth restriction, and preterm birth. Objective data were obtained at visit 1 on 3261 women, which was 88.1% of the studies that were attempted and at visit 3 on 2511 women, which was 87.6% of the studies that were attempted. Basic characteristics of the substudy cohort are reported in this methods article. The substudy was designed to address important questions regarding the relationship of sleep-disordered breathing on the risk of preeclampsia and other outcomes of relevance to maternal and child health. Copyright © 2015 Elsevier Inc. All rights reserved.
    Article · Mar 2015 · American Journal of Obstetrics and Gynecology
  • [Show abstract] [Hide abstract] ABSTRACT: Objective Reference charts for classifying and monitoring pregnancy weight gain in severely obese women do not exist. The goal was to construct pregnancy weight-gain-for-gestational-age z-score charts for overweight and obese mothers, stratified by severity of obesity.Methods Serial weight gain measurements were abstracted from 1047, 1202, 1267, and 730 overweight, class I, II, and III obese women, respectively, delivering uncomplicated term pregnancies at Magee-Womens Hospital in Pittsburgh, PA. Multi-level linear regression models were used to express serial weight gain measurements as a function of gestational age.ResultsThere were a median [interquartile range] of 11 [9-12] and 11 [9-13] serial weight measurements for overweight and obese (class I, II, and III) women, respectively. The rate of weight gain was minimal until 15-20 weeks and then increased in a slow, linear manner until term. The slope of weight gain flattened as pre-pregnancy BMI increased. Charts were created describing the mean, standard deviation, and select percentiles of weight gain in class I, II, and III obese and overweight pregnancies.Conclusions These charts are an innovative tool for studying the association between gestational weight gain and adverse pregnancy outcomes.
    Article · Mar 2015 · Obesity
  • [Show abstract] [Hide abstract] ABSTRACT: Microbial invasion of the amniotic cavity (MIAC) is common in early preterm labor and is associated with maternal and neonatal infectious morbidity. MIAC is usually occult and is reliably detected only with amniocentesis. We sought to develop a noninvasive test to predict MIAC based on protein biomarkers in cervicovaginal fluid (CVF) in a cohort of women with preterm labor (Phase 1) and to validate the test in an independent cohort (Phase 2). Prospective study of women with preterm labor who had amniocentesis to screen for MIAC. MIAC was defined by positive culture and/or 16S-rDNA results. Nine candidate CVF proteins were analyzed by ELISA. Logistic regression was used to identify combinations of up to 3 proteins that could accurately classify the Phase 1 cohort (N=108) into those with or without MIAC. The best models, selected by area under the receiver operating characteristic curve (AUC) in Phase 1, included various combinations of interleukin-6 (IL-6), GRO-alpha (CXCL1), alpha fetoprotein (AFP), and insulin-like growth factor binding protein 1 (IGFBP-1). Model performance was then tested in the Phase 2 cohort (N=306). MIAC was present in 15% of cases in Phase 1 and 9% in Phase 2. A three-marker CVF model using IL-6+CXCL1+IGFBP-1 had AUC 0.87 in Phase 1 and 0.78 in Phase 2. Two-marker models using IL-6+CXCL1 or AFP+CXCL1 performed similarly in Phase 2 (AUC 0.78, 0.75 respectively), but were not superior to CVF IL-6 alone (AUC 0.80). A cut-off value of CVF IL-6 ≥463 pg/mL (which had 81% sensitivity in Phase 1) predicted MIAC in Phase 2 with sensitivity 79%, specificity 78%, positive predictive value 38%, and negative predictive value 97%. High levels of interleukin-6 in cervicovaginal fluid are strongly associated with MIAC. If developed into a bedside test or rapid lab assay, cervicovaginal IL-6 might be useful in selecting patients in whom the probability of MIAC is high enough to warrant amniocentesis or transfer to a higher level of care. Such a test might also guide selection of potential subjects for treatment trials. Copyright © 2015 Elsevier Inc. All rights reserved.
    Article · Feb 2015 · American Journal of Obstetrics and Gynecology
  • Jacob Larkin · Suneet Chauhan · Hyagriv Simhan
    Article · Jan 2015 · American Journal of Obstetrics and Gynecology
  • [Show abstract] [Hide abstract] ABSTRACT: The primary aim of the "Nulliparous Pregnancy Outcomes Study: monitoring mothers-to-be" is to determine maternal characteristics, which include genetic, physiologic response to pregnancy, and environmental factors that predict adverse pregnancy outcomes. Nulliparous women in the first trimester of pregnancy were recruited into an observational cohort study. Participants were seen at 3 study visits during pregnancy and again at delivery. We collected data from in-clinic interviews, take-home surveys, clinical measurements, ultrasound studies, and chart abstractions. Maternal biospecimens (serum, plasma, urine, cervicovaginal fluid) at antepartum study visits and delivery specimens (placenta, umbilical cord, cord blood) were collected, processed, and stored. The primary outcome of the study was defined as pregnancy ending at <37+0 weeks' gestation. Key study hypotheses involve adverse pregnancy outcomes of spontaneous preterm birth, preeclampsia, and fetal growth restriction. We recruited 10,037 women to the study. Basic characteristics of the cohort at screening are reported. The "Nulliparous Pregnancy Outcomes Study: monitoring mothers-to-be" cohort study methods and procedures can help investigators when they plan future projects. Copyright © 2015 Elsevier Inc. All rights reserved.
    Article · Jan 2015 · American Journal of Obstetrics and Gynecology
  • Article · Jan 2015 · American Journal of Obstetrics and Gynecology
  • Article · Jan 2015 · American Journal of Obstetrics and Gynecology
  • Ann Borders · Jennifer Culhane · Hyagriv Simhan · [...] · William Grobman
    Article · Jan 2015 · American Journal of Obstetrics and Gynecology
  • Article · Jan 2015 · American Journal of Obstetrics and Gynecology
  • Ann Borders · Jennifer Culhane · Hyagriv Simhan · [...] · William Grobman
    Article · Jan 2015 · American Journal of Obstetrics and Gynecology
  • Article · Jan 2015 · American Journal of Obstetrics and Gynecology
  • Lisa M Bodnar · Robert W Platt · Hyagriv N Simhan
    [Show abstract] [Hide abstract] ABSTRACT: To estimate the association between maternal 25-hydroxyvitamin D concentrations and risk of preterm birth subtypes. We performed a case-cohort study using data and banked samples from patients at a teaching hospital in Pittsburgh, Pennsylvania. Eligible participants were women with a prenatal aneuploidy screening serum sample at or before 20 weeks of gestation who subsequently delivered a singleton, liveborn neonate. Of the 12,861 eligible women, we selected 2,327 at random as well as all remaining preterm birth cases for a total of 1,126 cases. Serum 25-hydroxyvitamin D was measured using liquid chromatography-tandem mass spectrometry. Multivariable log-binomial regression models were used to estimate associations between maternal vitamin D status and preterm birth at 37 weeks of gestation (separately by spontaneous or indicated) and preterm birth at less than 34 weeks of gestation. The incidence of preterm birth at less than 37 weeks of gestation was 8.6% overall and 11.3%, 8.6%, and 7.3% among mothers with serum 25-hydroxyvitamin D less than 50, 50-74.9, and 75 nmol/L or greater, respectively (P<.01). After adjustment for maternal race and ethnicity, prepregnancy body mass index, season, smoking, and other confounders, the risk of preterm birth at less than 37 weeks of gestation significantly decreased as 25-hydroxyvitamin D increased to approximately 90 nmol/L and then plateaued (test of nonlinearity P<.01). Results were similar when limiting to cases that were medically indicated or occurred spontaneously and cases occurring at less than 34 weeks of gestation. Our data support a protective association maternal vitamin D sufficiency and preterm birth that combined with extant epidemiologic data may provide justification for a randomized clinical trial of maternal vitamin D replacement or supplementation to prevent preterm birth. LEVEL OF EVIDENCE:: II.
    Article · Jan 2015 · Obstetrics and Gynecology
  • Jennifer A Hutcheon · Lisa M Bodnar · Hyagriv N Simhan
    [Show abstract] [Hide abstract] ABSTRACT: To explore whether state restrictions on Medicaid funding for pregnancy termination of anomalous fetuses could be contributing to the black-white disparity in infant death resulting from congenital anomalies. Data on deaths resulting from anomalies were obtained from U.S. vital statistics records (1983-2004) and the Nationwide Inpatient Sample (2003-2007). We conducted an ecological study using Poisson and logistic regression to explore the association between state Medicaid funding for pregnancy terminations of anomalous fetuses and infant death resulting from anomalies by calendar time, race, and individual Medicaid status. Since 1983, a gap in anomaly-related infant death has developed between states without compared with those with Medicaid funding for pregnancy termination (rate ratio in 2004 1.21, 95% confidence interval [CI] 1.18-1.24; crude risks: 146.8 compared with 121.7/100,000). Blacks were significantly more likely than whites to be on Medicaid (60.2% compared with 29.2%) and to live in a state without Medicaid funding for pregnancy termination (65.8% compared with 59.6%). The increased risk of anomaly-related death associated with lack of state Medicaid funding for pregnancy termination was most pronounced among black women on Medicaid (relative risk 1.94, 95% CI 1.52-2.36; crude risks: 245.5 compared with 129.3/100,000). States without Medicaid funding for pregnancy termination of anomalous fetuses have higher rates of infant death resulting from anomalies than those with funding, and this difference is most pronounced among black women on Medicaid. Restrictions on Medicaid funding for termination of anomalous fetuses potentially could be contributing to the black-white disparity in anomaly-related infant death. : II.
    Article · Jan 2015 · Obstetrics and Gynecology
  • Raj Shree · Hyagriv N Simhan
    [Show abstract] [Hide abstract] ABSTRACT: Objective Both history of spontaneous preterm birth (sPTB) and shorter interpregnancy intervals (IPIs) increase the risk of recurrent sPTB. Mechanisms underlying the association between IPI and recurrent sPTB are unknown. We have previously demonstrated that higher concentrations of cervical anti-inflammatory cytokines are a risk factor for sPTB and upper genital tract inflammation. Here, we examine the association between IPI and cervical anti-inflammatory cytokines among women with previous sPTB. Patients and Methods A prospective cohort of 73 women with previous sPTB and cervical interleukins (IL-4, IL-10, and IL-13) measured at < 16 weeks. Using the published principal factor analysis, the anti-inflammatory (ANTI) score was calculated. From our previous work, higher ANTI scores increase the subsequent risk of sPTB. IPI was the time from the previous birth to the conception of current pregnancy. Confounders included education level, marital status, gonorrhea, chlamydia, body mass index, race, and cigarette smoking. IPI and ANTI score were analyzed using univariable and multivariable analyses. Results There was a significant negative linear relation between IPI and ANTI score (β = -0.075, p = 0.017). This persisted after adjustment for confounders (p = 0.02). As IPI decreases by 1 month, the ANTI-score-associated risk of sPTB increases approximately by 4%. Conclusion Among women with previous sPTB, there was a significant negative linear relation between IPI and ANTI score. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.
    Article · Dec 2014 · American Journal of Perinatology

Publication Stats

4k Citations


  • 2015
    • University of Pennsylvania
      Filadelfia, Pennsylvania, United States
  • 2002-2015
    • Magee-Womens Hospital
      • Department of Obstetrics
      Pittsburgh, Pennsylvania, United States
  • 2010
    • George Washington University
      Washington, Washington, D.C., United States
  • 2008
    • University of Maryland, Baltimore
      Baltimore, Maryland, United States
  • 2007
    • Columbia University
      New York, New York, United States
  • 2003
    • University of Pittsburgh
      • Department of Obstetrics, Gynecology and Reproductive Sciences
      Pittsburgh, PA, United States
    • Society for Maternal-Fetal Medicine
      Pittsburgh, Pennsylvania, United States