Publications by authors named "Germaine M Buck Louis"

189 Publications

A multi-pollutant assessment of preconception persistent endocrine disrupting chemicals and incident pregnancy loss.

Environ Int 2021 Jul 28;157:106788. Epub 2021 Jul 28.

Biostatistics and Bioinformatics Branch, Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA. Electronic address:

Background: A few endocrine disrupting chemicals (EDCs) have been associated with pregnancy loss often as reported by women, though there has been no study of EDC mixtures and pregnancy loss in keeping with the nature of human exposure.

Objectives: To investigate preconception exposure to a mixture of EDCs to identify important drivers and inform multi-pollutant models of EDCs in relation to incident human gonadrophin chorionic (hCG) pregnancy loss.

Methods: A cohort of 501 couples were recruited from the general population and prospectively followed until a hCG-confirmed pregnancy or 12 months of trying to become pregnant. Pregnant (n = 344; 69%) women were followed daily through seven weeks post-conception then monthly until delivery. Loss was defined as conversion to negative pregnancy test or a clinical diagnosis. Preconception exposure assessment of EDCs included sixty-three serum chemicals and three blood metals. EDCs were measured using isotope dilution gas chromatography-high resolution mass spectrometry or high-performance liquid chromatography-tandem mass spectrometry, and inductively coupled plasma-mass spectrometry, respectively. Using elastic net variable selection to identify important factors from the exposure mixture, EDC levels and covariates were then included in Cox proportional hazard models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of time-to-pregnancy loss in multi-pollutant models.

Results: Incidence of hCG pregnancy loss was 28%. Nine EDCs of the sixty-six chemical mixture were associated with pregnancy loss; HRs were elevated for polychlorinated biphenyl 194, 2-(N-methyl-perfluorooctane sulfonamido) acetate, polybrominated diphenyl ether 28, and cadmium, even in sensitivity models adjusting for male partners' EDC concentrations. In final multivariable multi-pollutant Cox proportional hazard models, female partners'polybrominated diphenyl ether 28 (aHR = 1.16, 95% CI: 1.02, 1.31) and cadmium (aHR = 1.23, 95% CI: 1.07, 1.40) remained associated with hCG pregnancy loss. Female partners' preconception serum polychlorinated biphenyl 194 and 2-(N-methyl-perfluorooctane sulfonamido) acetate concentrations were consistently inversely associated with loss [(aHR = 0.72, 95% CI: 0.56, 0.92) and (aHR = 0.79, 95% CI: 0.65, 0.95), respectively].

Conclusion: Assessing exposure to a mixture of 66 persistent EDCs, females' preconception concentrations of polybrominated diphenyl ether 28 and cadmium were positively associated with incident hCG pregnancy loss in a cohort of couples from the general population trying for pregnancy.
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http://dx.doi.org/10.1016/j.envint.2021.106788DOI Listing
July 2021

Association Between Maternal Caffeine Consumption and Metabolism and Neonatal Anthropometry: A Secondary Analysis of the NICHD Fetal Growth Studies-Singletons.

JAMA Netw Open 2021 03 1;4(3):e213238. Epub 2021 Mar 1.

Epidemiology Branch, Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland.

Importance: Higher caffeine consumption during pregnancy has been associated with lower birth weight. However, associations of caffeine consumption, based on both plasma concentrations of caffeine and its metabolites, and self-reported caffeinated beverage intake, with multiple measures of neonatal anthropometry, have yet to be examined.

Objective: To evaluate the association between maternal caffeine intake and neonatal anthropometry, testing effect modification by fast or slow caffeine metabolism genotype.

Design, Setting, And Participants: A longitudinal cohort study, the National Institute of Child Health and Human Development Fetal Growth Studies-Singletons, enrolled 2055 nonsmoking women at low risk for fetal growth abnormalities with complete information on caffeine consumption from 12 US clinical sites between 2009 and 2013. Secondary analysis was completed in 2020.

Exposures: Caffeine was evaluated by both plasma concentrations of caffeine and paraxanthine and self-reported caffeinated beverage consumption measured/reported at 10-13 weeks gestation. Caffeine metabolism defined as fast or slow using genotype information from the single nucleotide variant rs762551 (CYP1A2*1F).

Main Outcomes And Measures: Neonatal anthropometric measures, including birth weight, length, and head, abdominal, arm, and thigh circumferences, skin fold and fat mass measures. The β coefficients represent the change in neonatal anthropometric measure per SD change in exposure.

Results: A total of 2055 participants had a mean (SD) age of 28.3 (5.5) years, mean (SD) body mass index of 23.6 (3.0), and 580 (28.2%) were Hispanic, 562 (27.4%) were White, 518 (25.2%) were Black, and 395 (19.2%) were Asian/Pacific Islander. Delivery occurred at a mean (SD) of 39.2 (1.7) gestational weeks. Compared with the first quartile of plasma caffeine level (≤28 ng/mL), neonates of women in the fourth quartile (>659 ng/mL) had lower birth weight (β = -84.3 g; 95% CI, -145.9 to -22.6 g; P = .04 for trend), length (β = -0.44 cm; 95% CI, -0.78 to -0.12 cm; P = .04 for trend), and head (β = -0.28 cm; 95% CI, -0.47 to -0.09 cm; P < .001 for trend), arm (β = -0.25 cm; 95% CI, -0.41 to -0.09 cm: P = .02 for trend), and thigh (β = -0.29 cm; 95% CI, -0.58 to -0.04 cm; P = .07 for trend) circumference. Similar reductions were observed for paraxanthine quartiles, and for continuous measures of caffeine and paraxanthine concentrations. Compared with women who reported drinking no caffeinated beverages, women who consumed approximately 50 mg per day (~ 1/2 cup of coffee) had neonates with lower birth weight (β = -66 g; 95% CI, -121 to -10 g), smaller arm (β = -0.17 cm; 95% CI, -0.31 to -0.02 cm) and thigh (β = -0.32 cm; 95% CI, -0.55 to -0.09 cm) circumference, and smaller anterior flank skin fold (β = -0.24 mm; 95% CI, -0.47 to -0.01 mm). Results did not differ by fast or slow caffeine metabolism genotype.

Conclusions And Relevance: In this cohort study, small reductions in neonatal anthropometric measurements with increasing caffeine consumption were observed. Findings suggest that caffeine consumption during pregnancy, even at levels much lower than the recommended 200 mg per day of caffeine, are associated with decreased fetal growth.
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http://dx.doi.org/10.1001/jamanetworkopen.2021.3238DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7994948PMC
March 2021

FutureTox IV Workshop Summary: Predictive Toxicology for Healthy Children.

Toxicol Sci 2021 04;180(2):198-211

U.S. Environmental Protection Agency, ORD, Research Triangle Park, North Carolina, USA.

FutureTox IV, a Society of Toxicology Contemporary Concepts in Toxicology workshop, was held in November 2018. Building upon FutureTox I, II, and III, this conference focused on the latest science and technology for in vitro profiling and in silico modeling as it relates to predictive developmental and reproductive toxicity (DART). Publicly available high-throughput screening data sets are now available for broad in vitro profiling of bioactivities across large inventories of chemicals. Coupling this vast amount of mechanistic data with a deeper understanding of molecular embryology and post-natal development lays the groundwork for using new approach methodologies (NAMs) to evaluate chemical toxicity, drug efficacy, and safety assessment for embryo-fetal development. NAM is a term recently adopted in reference to any technology, methodology, approach, or combination thereof that can be used to provide information on chemical hazard and risk assessment to avoid the use of intact animals (U.S. Environmental Protection Agency [EPA], Strategic plan to promote the development and implementation of alternative test methods within the tsca program, 2018, https://www.epa.gov/sites/production/files/2018-06/documents/epa_alt_strat_plan_6-20-18_clean_final.pdf). There are challenges to implementing NAMs to evaluate chemicals for developmental toxicity compared with adult toxicity. This forum article reviews the 2018 workshop activities, highlighting challenges and opportunities for applying NAMs for adverse pregnancy outcomes (eg, preterm labor, malformations, low birth weight) as well as disorders manifesting postnatally (eg, neurodevelopmental impairment, breast cancer, cardiovascular disease, fertility). DART is an important concern for different regulatory statutes and test guidelines. Leveraging advancements in such approaches and the accompanying efficiencies to detecting potential hazards to human development are the unifying concepts toward implementing NAMs in DART testing. Although use of NAMs for higher level regulatory decision making is still on the horizon, the conference highlighted novel testing platforms and computational models that cover multiple levels of biological organization, with the unique temporal dynamics of embryonic development, and novel approaches for estimating toxicokinetic parameters essential in supporting in vitro to in vivo extrapolation.
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http://dx.doi.org/10.1093/toxsci/kfab013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8041457PMC
April 2021

Nutrition during Pregnancy: Findings from the National Institute of Child Health and Human Development (NICHD) Fetal Growth Studies-Singleton Cohort.

Curr Dev Nutr 2021 Jan 24;5(1):nzaa182. Epub 2020 Dec 24.

Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, MD, USA.

Background: Accumulating evidence indicates that maternal diets are important for optimizing maternal and offspring health. Existing research lacks comprehensive profiles of maternal diets throughout pregnancy, especially in a racially/ethnically diverse obstetrical population.

Objective: The aim was to characterize diets in a longitudinal US pregnancy cohort by trimester, race/ethnicity, and prepregnancy BMI.

Methods: Data were obtained from pregnant women in the National Institute of Child Health and Human Development (NICHD) Fetal Growth Studies-Singleton cohort (2009-2013). A food-frequency questionnaire (FFQ) at 8-13 wk of gestation assessed periconception and first-trimester diet (= 1615). Automated, self-administered, 24-h dietary recalls targeted at 16-22, 24-29, 30-33, and 34-37 wk of gestation assessed second- and third-trimester diets (= 1817 women/6791 recalls). The Healthy Eating Index-2010 (HEI-2010) assessed diet quality (i.e., adherence to US Dietary Guidelines). Variations in weighted energy-adjusted means for foods and nutrients were examined by trimester, self-identified race/ethnicity, and self-reported prepregnancy BMI.

Results: Mean (95% CI) HEI-2010 was 65.9 (64.9, 67.0) during periconception to the first trimester assessed with an FFQ and 51.6 (50.8, 52.4) and 51.5 (50.7, 52.3) during the second trimester and third trimester, respectively, assessed using 24-h recalls. No significant differences were observed between the second and third trimester in macronutrients, micronutrients, foods, or HEI-2010 components (≥ 0.05). Periconception to first-trimester HEI-2010 was highest among Asian/Pacific Islander [67.2 (65.9, 68.6)] and lowest among non-Hispanic Black [58.7 (57.5, 60.0)] women and highest among women with normal weight [67.2 (66.1, 68.4)] and lowest among women with obesity [63.5 (62.1, 64.9)]. Similar rankings were observed in the second/third trimesters.

Conclusions: Most pregnant women in this cohort reported dietary intakes that, on average, did not meet US Dietary Guidelines for nonpregnant individuals. Also, diet differed across race/ethnic groups and by prepregnancy BMI, with the lowest overall dietary quality in all trimesters among non-Hispanic Black women and women with obesity. No meaningful changes in dietary intake were observed between the second and third trimesters.
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http://dx.doi.org/10.1093/cdn/nzaa182DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7846139PMC
January 2021

Adipose to serum ratio and mixtures of persistent organic pollutants in relation to endometriosis: Findings from the ENDO Study.

Environ Res 2021 04 21;195:110732. Epub 2021 Jan 21.

College of Health and Human Services George Mason University, Fairfax, VA, 22030, USA.

Background: Endometriosis is an estrogen-dependent disease. Endocrine disrupting chemicals (EDCs) and their mixtures may play an etiologic role.

Objectives: We evaluated an adipose-to-serum ratio (ASR) of lipophilic EDCs and their mixtures associated with incident endometriosis.

Methods: We quantified 13 polychlorinated biphenyl (PCB) congeners, 6 polybrominated diphenyl ether (PBDE) congeners, and 11 organochlorine pesticides (OCPs) in serum and omental fat among women from the ENDO Study (2007-2009) aged 18-44 years diagnosed with (n=190) or without (n=283) surgically-visualized incident endometriosis. Odds ratios (OR) and 95% confidence intervals (CI) between ASR and endometriosis were estimated using logistic regression models adjusted for age (years), body mass index (kg/m), serum cotinine (ng/ml), and breastfeeding conditional on parity. Bayesian hierarchical models (BHM) compared estimated associations for adipose and ASR to serum. Bayesian kernel machine regression (BKMR) estimated change in latent health and 95% posterior intervals (PI) between chemical mixtures and endometriosis.

Results: Select ASR for estrogenic PCBs and OCPs were associated with an increased odds of an endometriosis diagnosis, but not for anti-estrogenic PCBs or PBDEs. Across all chemicals, BHMs generated ORs that were on average 14% (95% PI: 6%, 22%) higher for adipose and 20% (95% PI: 12%, 29%) higher for ASR in comparison to serum. ORs from BHMs were greater for estrogenic PCBs and OCPs, with no differences for PBDEs. BKMR models comparing the 75th to 25th percentile were moderately associated with endometriosis for estrogenic PCBs [adipose 0.27 (95% PI: 0.18, 0.72) and ASR 0.37 (95% PI: 0.06, 0.80)] and OCPs [adipose 0.17 (95% PI: 0.21, 0.56) and ASR 0.26 (95% PI: 0.05, 0.57)], but not for antiestrogenic PCBs and PBDEs.

Discussion: ASR added little insight beyond adipose for lipophilic chemicals. BKMR results supported associations between ASR and adipose estrogenic PCB and OCP mixtures and incident endometriosis. These findings underscore the importance of choice of biospecimen and considering mixtures when assessing exposure-disease relationships.
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http://dx.doi.org/10.1016/j.envres.2021.110732DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8432300PMC
April 2021

A Model-Based Approach to Detection Limits in Studying Environmental Exposures and Human Fecundity.

Stat Biosci 2019 Dec 7;11(3):524-547. Epub 2019 Jun 7.

College of Health and Human Services, George Mason University, Fairfax, VA 22030, USA.

Human exposure to persistent environmental pollutants often results in concentrations with a range of values below the laboratory detection limits. Growing evidence suggests that inadequate handling of concentrations below the limit of detection (LOD) may bias assessment of health effects in relation to environmental exposures. We seek to quantify such bias in models focusing on the day-specific probability of pregnancy during the fertile window and propose a model-based approach to reduce such bias. A multivariate skewed generalized -distribution constrained by the LOD is assumed for the chemical concentrations, which realistically represents the underlying distribution. A latent variable-based framework is used to model fecundibility, which nonlinearly relates conception probability to chemical concentrations, daily intercourses, and other important covariates. The advantages of the proposed approach include the use of multiple chemical concentrations to aid the estimation of left censored chemical exposures, as well as the model-based feedback mechanism for fecundibility outcome to inform the estimations, and an adequate handling of model uncertainty through a joint modeling framework. A Markov chain Monte Carlo sampling algorithm is developed for implementing the Bayesian computations and the logarithm of pseudo-marginal likelihood measure is used for model choices. We conduct simulation studies to demonstrate the performance of the proposed approach and apply the framework to the Longitudinal Investigation of Fertility and the Environment study which evaluates the effects of exposures to environmental pollutants on the probability of pregnancy. We found that '-DDT is negatively associated with the day-specific probability of pregnancy.
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http://dx.doi.org/10.1007/s12561-019-09243-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7561047PMC
December 2019

Sperm mitochondrial DNA biomarkers and couple fecundity.

Hum Reprod 2020 11;35(11):2619-2625

Department of Environmental Health Sciences, School of Public Health and Health Sciences, University of Massachusetts Amherst, Amherst, MA, USA.

Study Question: Do sperm mitochondrial DNA measures predict probability of pregnancy among couples in the general population?

Summary Answer: Those with high sperm mitochondrial DNA copy number (mtDNAcn) had as much as 50% lower odds of cycle-specific pregnancy, and 18% lower probability of pregnancy within 12 months.

What Is Known Already: Semen parameters have been found to poorly predict reproductive success yet are the most prevalent diagnostic tool for male infertility. Increased sperm mtDNAcn and mitochondrial DNA deletions (mtDNAdel) have been associated with decreased semen quality and lower odds of fertilization in men seeking fertility treatment.

Study Design, Size, Duration: A population-based prospective cohort study of couples discontinuing contraception to become pregnant recruited from 16 US counties from 2005 to 2009 followed for up to 16 months.

Participants/materials, Setting, Methods: Sperm mtDNAcn and mtDNAdel from 384 semen samples were assessed via triplex probe-based quantitative PCR. Probability of pregnancy within 1 year was compared by mitochondrial DNA, and discrete-time proportional hazards models were used to evaluate the relations with time-to-pregnancy (TTP) with adjustment for covariates.

Main Results And The Role Of Chance: Higher sperm mtDNAcn was associated with lower pregnancy probability within 12 months and longer TTP. In unadjusted comparisons by quartile (Q), those in Q4 had a pregnancy probability of 63.5% (95% CI: 53.1% to 73.1%) compared to 82.3% (95% CI: 73.2% to 89.9%) for Q1 (P = 0.002). Similar results were observed in survival analyses adjusting for covariates to estimate fecundability odds ratios (FORs) comparing mtDNAcn in quartiles. Relative to those in Q1 of mtDNAcn, FORs (95% CI) were for Q2 of 0.78 (0.52 to 1.16), Q3 of 0.65 (0.44 to 0.96) and Q4 of 0.55 (0.37 to 0.81), and this trend of decreasing fecundability with increasing mtDNAcn quartile was statistically significant (FOR per log mtDNAcn = 0.37; P < 0.001). Sperm mtDNAdel was not associated with TTP.

Limitations, Reasons For Caution: This prospective cohort study consisted primarily of Caucasian men and women and thus large diverse cohorts are necessary to confirm the associations between sperm mtDNAcn and couple pregnancy success in other races/ethnicities.

Wider Implications Of The Findings: Our results demonstrate that sperm mtDNAcn has utility as a biomarker of male reproductive health and probability of pregnancy success in the general population.

Study Funding/competing Interest(s): This work was funded in part by the National Institute of Environmental Health Sciences, National Institutes of Health (R01-ES028298; PI: J.R.P.) and the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland (Contracts N01-HD-3-3355, N01-HD-3-3356 and N01-HD-3-3358). The authors declare no competing interests.

Trial Registration Number: N/A.
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http://dx.doi.org/10.1093/humrep/deaa191DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7603861PMC
November 2020

Concentrations of persistent organic pollutants in maternal plasma and epigenome-wide placental DNA methylation.

Clin Epigenetics 2020 07 11;12(1):103. Epub 2020 Jul 11.

Epidemiology Branch, Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, 6710B Rockledge Drive, Bethesda, MD, 20892-7004, USA.

Background: Prenatal maternal plasma persistent organic pollutant (POP) concentrations have been associated with neonatal outcomes. However, the underlying mechanisms remain unknown. Placental epigenetic mechanisms may be involved, but no prior epigenome-wide studies have investigated the impact of maternal POPs on placental DNA methylation. We studied the association between maternal plasma POP concentration in early pregnancy and epigenome-wide placental DNA methylation among 260 pregnant women from the NICHD Fetal Growth Studies.

Results: Our analysis focused on POPs with more than 80% plasma concentrations above the limit of quantification, including 3 organochlorine pesticides (hexachlorobenzene, trans-nonachlor, p,p'-dichlorodiphenyldichloroethylene), 1 polybrominated diphenyl ether (PBDE 47), 3 polychlorinated biphenyls (138/158, 153, 180), and 6 poly- and perfluorinated alkyl substances (PFASs) (perfluorodecanoic acid, perfluorohexanesulfonic acid, perfluorononanoic acid, perfluorooctanesulfonic acid, perfluoroundecanoic acid (PFUnDA)). Using 5% false discovery rate, POPs were associated with a total of 214 differentially methylated CpG sites (nominal p values ranging from 2.61 × 10 to 2.11 × 10). Out of the 214 CpG sites, 24 (11%) were significantly correlated with placental expression of 21 genes. Notably, higher PFUnDA was associated with increased methylation at 3 CpG sites (cg13996963, cg12089439, cg18145877) annotated to TUSC3, and increased methylation at those 3 CpG sites was correlated with decreased expression of TUSC3 in the placenta. Increased methylation at cg18145877 (TUSC3) and decreased expression of TUSC3 were correlated with shorter birth length. Out of the 214 CpG sites, methylation at 44 CpG sites was correlated (p value < 0.10) with at least one neonatal anthropometry measure (i.e., birth weight, birth length, and head circumference). Seven CpG sites mediated (p value < 0.05) the association between PBDE 47 and neonatal anthropometry measures. Genes annotating the top differentially methylated CpG sites were enriched in pathways related to differentiation of embryonic cells (PBDE 47) and in pathways related to brain size and brain morphology (PFASs).

Conclusions: DNA methylation changes in the placenta were significantly associated with maternal plasma POPs concentration. The findings suggest that placental DNA methylation and gene expression mechanism may be involved in the prenatal toxicity of POPs and their association with neonatal anthropometry measures.
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http://dx.doi.org/10.1186/s13148-020-00894-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7371466PMC
July 2020

Glycaemic status during pregnancy and longitudinal measures of fetal growth in a multi-racial US population: a prospective cohort study.

Lancet Diabetes Endocrinol 2020 04 2;8(4):292-300. Epub 2020 Mar 2.

Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA. Electronic address:

Background: The timepoint at which fetal growth begins to differ by maternal glycaemic status is not well understood. To address this lack of data, we examined gestational diabetes, impaired glucose tolerance, and early pregnancy glucose concentrations in relation to fetal growth trajectories.

Methods: This cohort study included 2458 pregnant women from the NICHD Fetal Growth Studies-Singletons study, which took place between 2009 and 2013. Women were recruited from 12 clinical centres in the USA. Women aged 18-40 years without major chronic conditions when entering pregnancy were included and those with records of neither glucose screening test or glucose tolerance test were excluded from the study. Women were enrolled at gestational weeks 8-13 and randomly assigned to four ultrasonogram schedules (Group A; weeks 16, 24, 30, 34; Group B: weeks 18, 26, 31, 35, 39; Group C: weeks 20, 28, 32, 36; Group D: weeks 22, 29, 33, 37, 41) to capture weekly fetal growth. Gestational diabetes, impaired glucose tolerance, and normal glucose tolerance were defined by medical record review. Glucose was measured in a subsample of women at weeks 10-14. We modelled fetal growth trajectories using linear mixed models with cubic splines. This study is registered with ClinicalTrials.gov, NCT00912132.

Findings: Of the 2458 women included in this study, 107 (4·4%) had gestational diabetes, 118 (4·8%) had impaired glucose tolerance, and 2020 (82·2%) had NGT. 213 women were excluded from the main analysis. The cohort with gestational diabetes was associated with a larger estimated fetal weight that started at week 20 and was significant at week 28-40 (at week 37: 3061 g [95% CI 2967-3164] for women with gestational diabetes vs 2943 g [2924-2962] for women with normal glucose tolerance, adjusted p=0·02). In addition, glucose levels at weeks 10-14 were positively associated with estimated fetal weight starting at week 23 and the association became significant at week 27 (at week 37: 3073 g [2983-3167] in the highest tertile vs 2853 g [2755-2955] in the lowest tertile, adjusted p=0·0009.

Interpretation: Gestational diabetes was associated with a larger fetal size that started at week 20 and became significant at gestational week 28. Efforts to mitigate gestational diabetes-related fetal overgrowth should start before 24-28 gestational weeks, when gestational diabetes is typically screened for in the USA.

Funding: National Institutes of Health.
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http://dx.doi.org/10.1016/S2213-8587(20)30024-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7676113PMC
April 2020

Urinary Phytoestrogens and Relationship to Menstrual Cycle Length and Variability Among Healthy, Eumenorrheic Women.

J Endocr Soc 2020 Feb 5;4(2):bvz003. Epub 2019 Dec 5.

Epidemiology Branch, Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute for Child Health and Human Development, National Institutes of Health, Bethesda, Maryland.

Context: Phytoestrogens may influence fecundability, although biological mechanisms remain elusive. Since it is hypothesized that phytoestrogens may act through influencing hormone levels, we investigated associations between phytoestrogens and menstrual cycle length, a proxy for the hormonal milieu, in healthy women attempting pregnancy.

Design: A population-based prospective cohort of 326 women ages 18 to 40 with self-reported cycles of 21 to 42 days were followed until pregnancy or for 12 months of attempting pregnancy.

Methods: Urinary genistein, daidzein, O-desmethylangolensin, equol, enterodiol, and enterolactone were measured upon enrollment. Cycle length was determined from fertility monitors and daily journals. Linear mixed models assessed associations with continuous cycle length and were weighted by the inverse number of observed cycles. Logistic regression models assessed menstrual regularity (standard deviation > 75th vs ≤ 75th percentile). Models were adjusted for age, body mass index, race, creatinine, exercise, supplements, lipids, lead, cadmium, cotinine, parity, alcohol, and other phytoestrogens.

Results: Individual phytoestrogens were not associated with cycle length, although total phytoestrogens were associated with shorter cycles (-0.042 days; 95% confidence interval [CI], -0.080 to -0.003, per 10% increase). Each 1 nmol/L increase in enterolactone (odds ratio [OR] 0.88; 95% CI, 0.79-0.97) and total lignans (OR 0.85; 95% CI, 0.76-0.95) was associated with reduced irregularity, and each 1 nmol/L increase in genistein with irregularity (OR 1.19; 95% CI, 1.02-1.38).

Conclusion: Phytoestrogens were not meaningfully associated with cycle length but may be associated with menstrual regularity, among women with self-reported regular cycles. These results highlight differences between isoflavones and lignans and are reassuring for women attempting pregnancy.
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http://dx.doi.org/10.1210/jendso/bvz003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7003981PMC
February 2020

Evaluating associations between early pregnancy trace elements mixture and 2nd trimester gestational glucose levels: A comparison of three statistical approaches.

Int J Hyg Environ Health 2020 03 28;224:113446. Epub 2019 Dec 28.

Departments of Environmental Health, USA; Departments of Epidemiology, USA.

Objective: Studies have shown that individual trace element levels might be associated with abnormal glycemic status, with implications for diabetes. Few studies have considered these trace elements as a mixture and their impact on gestational glucose levels. Comparing three statistical approaches, we assessed the associations between essential trace elements mixture and gestational glucose levels.

Methods: We used data from 1720 women enrolled in the Eunice Kennedy Shriver National Institute of Child Health and Human Development's Fetal Growth Study, for whom trace element concentrations (zinc, selenium, copper, molybdenum) were measured by inductively coupled plasma mass spectrometry (ICP-MS) using plasma collected during the 1st trimester. Non-fasting glucose levels were measured during the gestational diabetes mellitus (GDM) screening test in the 2nd trimester. We applied (1) Bayesian Kernel Machine Regression (BKMR); (2) adaptive Least Absolute Shrinkage and Selection Operator (LASSO) in a mutually adjusted linear regression model; and (3) generalized additive models (GAMs) to evaluate the joint associations between trace elements mixture and glucose levels adjusting for potential confounders.

Results: Using BKMR, we observed a mean 2.7 mg/dL higher glucose level for each interquartile increase of plasma copper (95% credible interval: 0.9, 4.5). The positive association between plasma copper and glucose levels was more pronounced at higher quartiles of zinc. Similar associations were detected using adaptive LASSO and GAM. In addition, results from adaptive LASSO and GAM suggested a super-additive interaction between molybdenum and selenium (both p-values = 0.04).

Conclusion: Employing different statistical methods, we found consistent evidence of higher gestational glucose levels associated with higher copper and potential synergism between zinc and copper on glucose levels.
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http://dx.doi.org/10.1016/j.ijheh.2019.113446DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7609138PMC
March 2020

Adiposity and Endometriosis Severity and Typology.

J Minim Invasive Gynecol 2020 Nov - Dec;27(7):1516-1523. Epub 2020 Jan 9.

Department of Family and Preventive Medicine, Division of Public Health (Ms. Byun and Drs. Stanford, Allen-Brady, and Schliep). Electronic address:

Study Objective: Prior research has collectively shown that endometriosis is inversely related to women's adiposity. The aim of this study was to assess whether this inverse relationship holds true by disease severity and typology.

Design: Cross-sectional study among women with no prior diagnosis of endometriosis.

Setting: Fourteen clinical centers in Salt Lake City, UT, and San Francisco, CA.

Patients: A total of 495 women (of which 473 were analyzed), aged 18-44 years, were enrolled in the operative cohort of the Endometriosis, Natural History, Diagnosis, and Outcomes (ENDO) Study.

Interventions: Gynecologic laparoscopy/laparotomy regardless of clinical indication.

Measurements And Main Results: Participants underwent anthropometric assessments, body composition measurements, and evaluations of body fat distribution ratios before surgery. Surgeons completed a standardized operative report immediately after surgery to capture revised American Society for Reproductive Medicine staging (I-IV) and typology of disease (superficial endometriosis [SE], ovarian endometrioma [OE], and deep infiltrating endometriosis [DIE]). Linear mixed models, taking into account within-clinical-center correlation, were used to generate least square means (95% confidence intervals) to assess differences in adiposity measures by endometriosis stage (no endometriosis, I-IV) and typology (no endometriosis, SE, DIE, OE, OE + DIE) adjusting for age, race/ethnicity, and parity. Although most confidence intervals were wide and overlapping, 3 general impressions emerged: (1) women with incident endometriosis had the lowest anthropometric/body composition indicators compared with those without incident endometriosis, (2) women with stage I or IV endometriosis had lower indicators compared with women with stage II or III, and (3) women with OE and/or DIE tended to have the lowest indicators, whereas women with SE had the highest indicators.

Conclusion: Our research highlights that the relationship between women's adiposity and endometriosis severity and typology may be more complicated than prior research indicates.
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http://dx.doi.org/10.1016/j.jmig.2020.01.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7343585PMC
February 2021

Association of urinary metabolites of organophosphate and pyrethroid insecticides, and phenoxy herbicides with endometriosis.

Environ Int 2020 03 7;136:105456. Epub 2020 Jan 7.

Wadsworth Center, New York State Department of Health, and Department of Environmental Health Sciences, School of Public Health, State University of New York at Albany, Empire State Plaza, P.O. Box 509, Albany, NY 12201-0509, United States; Biochemistry Department, Faculty of Science and Experimental Biochemistry Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia. Electronic address:

Endometriosis is a hormone-responsive gynecologic disease, signifying its connotations across a woman's life span. Previous studies suggested that endocrine disrupting chemicals were risk factors for endometriosis. Nevertheless, little is known on exposure to organophosphate, pyrethroid and phenoxy acid pesticides on endometriosis diagnosis. In this study, we determined the concentrations of 11 pesticides, metabolites of organophosphate and pyrethroid insecticides, and phenoxy herbicides, in urine collected from 619 reproductive-age women in Utah and California, using liquid chromatography-tandem mass spectrometry. The association of urinary concentrations of pesticides with an increase in the odds of endometriosis diagnosis was examined in 594 women who underwent laparoscopy/laparotomy (operative cohort: n = 471) or pelvic magnetic resonance imaging (population cohort: n = 123), during 2007-2009. 2-Isopropyl-4-methyl-6-hydroxypyrimidine (IMPY), malathion dicarboxylic acid (MDA), para-nitrophenol (PNP), 3,5,6-trichloro-2-pyridinol (TCPY), 3-phenoxybenzoic acid (3-PBA), and 2,4-dichlorophenoxyacetic acid (2,4-D) were detected in ≥95% of the urine samples analyzed. Urinary concentrations of IMPY, MDA, PNP, 3-PBA and 2,4-D tended to be higher in younger, non-Hispanic black, nulliparous and less affluent women. IMPY was the most dominant compound in urine followed by PNP and TCPY. When women in the 4th quartile of IMPY and the 2nd quartile of TCPY concentrations (μg/g creatinine) were compared with women in the 1st quartile, the odds ratios (ORs) for diagnosis of endometriosis increased significantly in unadjusted models (IMPY OR = 1.89, 95% confidence interval (Cl) = 1.12-3.20; TCPY OR = 1.65, 95% Cl = 1.02-2.69) for the operative (n = 471) and entire data set (n = 594), respectively. Our results suggest that exposure to elevated concentrations of diazinon (the parent compound of IMPY) and chlorpyrifos and chlorpyrifos-methyl (parent compounds of TCPY) may be associated with endometriosis.
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http://dx.doi.org/10.1016/j.envint.2019.105456DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7023990PMC
March 2020

Association of Maternal Exposure to Persistent Organic Pollutants in Early Pregnancy With Fetal Growth.

JAMA Pediatr 2020 02;174(2):149-161

Epidemiology Branch, Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health, Bethesda, Maryland.

Importance: Prenatal exposure to persistent organic pollutants (POPs) has been associated with birth size, but data on fetal growth and among racially/ethnically diverse pregnant women remain scarce.

Objectives: To assess the association between maternal plasma POPs in early pregnancy and fetal growth and by infant sex and maternal race/ethnicity.

Design, Setting, And Participants: This cohort study used the National Institute of Child Health and Human Development Fetal Growth Studies-Singleton cohort, which recruited nonobese, low-risk pregnant women before 14 weeks' gestation between July 1, 2009, and January 31, 2013, in 12 community-based clinics throughout the United States. Participants self-identified their race/ethnicity, self-reported their behavioral risk factors, and were followed up throughout their pregnancy. Data were analyzed from July 31, 2018, to June 3, 2019.

Exposures: Levels of 76 POPs in early gestation plasma were measured: 11 perfluoroalkyl and polyfluoroalkyl substances, 1 polybrominated biphenyl, 9 polybrominated diphenyl ethers (PBDEs), 44 polychlorinated biphenyls (PCBs), and 11 organochlorine pesticides (OCPs). The bayesian kernel machine regression method was used to examine chemical class mixtures, and generalized additive mixed model was used to analyze individual chemicals.

Main Outcomes And Measures: Fourteen fetal biometrics were measured, including head circumference, abdominal circumference, and femur length, within 5 ultrasonography appointments.

Results: A total of 2284 low-risk pregnant women were included: 606 women (26.5%) self-identified as white with a mean (SD) age of 30.3 (4.4) years, 589 (25.8%) as black with a mean (SD) age of 25.5 (5.5) years, 635 (27.8%) as Hispanic with a mean (SD) age of 27.1 (5.5) years, and 454 (19.9%) as Asian with a mean (SD) age of 30.5 (4.5) years. A comparison between the 75th and 25th percentile of exposure revealed that the OCP mixture was negatively associated with most fetal growth measures, with a reduction of 4.7 mm (95% CI, -6.7 to -2.8 mm) in head circumference, 3.5 mm (95% CI, -4.7 to -2.2 mm) in abdominal circumference, and 0.6 mm (95% CI, -1.1 to -0.2 mm) in femur length. Higher exposure to the PBDE mixture was associated with reduced abdominal circumference (-2.4 mm; 95% CI, -4.0 to -0.5 mm) and femur length (-0.5 mm; 95% CI, -1.0 to -0.1 mm), and the dioxin-like PCB mixture was associated with reduced head circumference (-6.4 mm; 95% CI, -8.4 to -4.3 mm) and abdominal circumference (-2.4 mm; 95% CI, -3.9 to -0.8 mm). Associations with individual chemicals were less consistent. There were some interactions by fetal sex, although most of the results did not vary by maternal race/ethnicity. For example, oxychlordane (-0.98 mm; 95% CI, -1.60 to -0.36 mm; P for interaction <.001), trans-nonachlor (-0.31 mm; 95% CI, -0.54 to -0.08 mm; P for interaction = .005), and p,p'-dichlorodiphenyldichloroethylene (-0.19 mm; 95% CI, -0.22 to -0.09 mm; P for interaction = .006) were associated with shorter femur length among boys only.

Conclusions And Relevance: This study found that, among pregnant women with low POP levels, a mixture of OCPs was negatively associated with most fetal growth measures and that mixtures of PBDEs and dioxin-like PCBs were associated with reduced abdominal circumference. These findings suggested that, although exposures may be low, associations with fetal growth are apparent.
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http://dx.doi.org/10.1001/jamapediatrics.2019.5104DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6990715PMC
February 2020

Exposure to Persistent Organic Pollutants and Birth Characteristics: The Upstate KIDS Study.

Epidemiology 2019 11;30 Suppl 2:S94-S100

From the Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD.

Background: Prenatal exposure to persistent organic pollutants (POPs) may be associated with obesogenic effects in offspring. Our study is the first to investigate associations between concentrations of POPs from newborn dried blood spots (DBS) and birth characteristics.

Methods: Concentrations of 10 polychlorinated biphenyl congeners (PCBs), polybrominated diphenyl ether-47 (PBDE-47), and p,p'-dichlorodiphenyldichloroethylene (p,p'-DDE) were measured from DBSs collected at birth from 2,065 singleton infants. DBS samples were pooled in groups of five and assayed together to reach limits of detection. Differences in risk of large for gestational age (LGA, defined as >90th percentile of birth weight for sex and gestational age), small for gestational age (SGA, <10th), and preterm birth (gestational age <37 weeks) were estimated using logistic regression per unit (ng/ml) increase in concentration of each chemical, adjusting for individual-level covariates, including maternal age, race/ethnicity, prepregnancy BMI, education, parity, smoking, and infant sex while assuming a gamma distribution and using multiple imputation to account for pools.

Results: There were 215 (11.3%) singletons born LGA, 158 (7.5%) born SGA, and 157 (7.6%) born preterm. Higher concentrations of POPs were positively associated with slightly higher risk of LGA and higher birth weight.

Conclusions: Relationships between POPs measured in newborn DBS and birth size were mixed. Pooled analysis methods using DBS could address challenges in limits of detection and costs for population-based research.
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http://dx.doi.org/10.1097/EDE.0000000000001095DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7047652PMC
November 2019

Patterns and Variability of Endocrine-disrupting Chemicals During Pregnancy: Implications for Understanding the Exposome of Normal Pregnancy.

Epidemiology 2019 11;30 Suppl 2:S65-S75

Biostatistics and Bioinformatics Branch, Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD.

Background: The exposome is a novel research paradigm offering promise for understanding the complexity of human exposures, including endocrine-disrupting chemicals (EDCs) and pregnancy outcomes. The physiologically active state of pregnancy requires understanding temporal changes in EDCs to better inform the application of the exposome research paradigm and serve as the impetus for study.

Methods: We randomly selected 50 healthy pregnant women with uncomplicated pregnancies from a pregnancy cohort who had available serum/urine samples in each trimester for measuring 144 persistent and 48 nonpersistent EDCs. We used unsupervised machine-learning techniques capable of handling hierarchical clustering of exposures to identify EDC patterns across pregnancy, and linear mixed-effects modeling with false-discovery rate correction to identify those that change over pregnancy trimesters. We estimated the percent variation in chemical concentrations accounted for by time (pregnancy trimester) using Akaike Information Criterion-based R methods.

Results: Four chemical clusters comprising 80 compounds, of which six consistently increased, 63 consistently decreased, and 11 reflected inconsistent patterns over pregnancy. Overall, concentrations tended to decrease over pregnancy for persistent EDCs; a reverse pattern was seen for many nonpersistent chemicals. Explained variance was highest for five persistent chemicals: polybrominated diphenyl ethers #191 (51%) and #126 (47%), hexachlorobenzene (46%), p,p'-dichloro-diphenyl-dichloroethylene (46%), and o,p'-dichloro-diphenyl-dichloroethane (36%).

Conclusions: Concentrations of many EDCs are not stable across pregnancy and reflect varying patterns depending on their persistency underscoring the importance of timed biospecimen collection. Analytic techniques are available for assessing temporal patterns of EDCs during pregnancy apart from physiologic changes.
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http://dx.doi.org/10.1097/EDE.0000000000001082DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6777854PMC
November 2019

Advancing the Health of Populations Across the Life Course: 50 Years of Discoveries in the Division of Intramural Population Health Research.

Epidemiology 2019 11;30 Suppl 2:S47-S54

Epidemiology Branch, Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD.

In 2017, the Division of Intramural Population Health Research (DIPHR), within the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), reached a significant milestone: 50 years in existence. DIPHR celebrated this anniversary with a scientific program that reviewed past accomplishments and reflected on future directions in support of promoting the health of populations across the life course. Extending from the scientific program, the impetus of this article is to contribute to archiving and consolidating the legacy of intramural population health research at NICHD over the past 50 years. We present a brief history of the origin and evolution of intramural population health research at NICHD. Next, we conduct an empirical assessment of the scientific impact and evolving scope of this research over the past five decades and present specific key discoveries emerging from topics spanning the life course: (1) reproductive health, (2) the health of pregnant women and fetuses, (3) the health of children, and (4) associated methodologies. We also explore the Division's service to the profession in the form of mentorship of the next generation of scientists in population health research. Finally, we conclude with thoughts about future directions of population health research and reaffirm the DIPHR's commitment to promoting the health and well-being of the many populations we serve, both locally and globally.
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http://dx.doi.org/10.1097/EDE.0000000000001067DOI Listing
November 2019

The Relation of Birth Weight and Adiposity Across the Life Course to Semen Quality in Middle Age.

Epidemiology 2019 11;30 Suppl 2:S17-S27

Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY.

Background: Studies of body mass index and semen quality have reported mixed results, but almost all were cross-sectional and many were conducted in selected populations. Longitudinal studies in population-based cohorts are necessary to identify how timing and duration of excess adiposity may affect semen quality.

Methods: In 193 members of the Child Health and Development Studies birth cohort, we examined associations of birth weight and adiposity at six time points spanning early childhood and adulthood with sperm concentration, motility, and morphology at mean age 44 years, as well as with corresponding 2010 World Health Organization (WHO) subfertility reference levels.

Results: Birth weight for gestational age percentile was positively associated with square-root sperm concentration (regression coefficient B [95% confidence interval] = 0.02 × 103 sperm/ml [0.004, 0.04]). Overweight/obesity in men's 20s was associated with lower percent progressive motility (B =-5.2 [-9.9, -0.63]), higher odds of low motility (odds ratio (OR) = 2.4 [1.3, 4.4]), and higher odds of poor morphology (OR = 1.9 [0.94, 3.8]). Those who were overweight/obese in their 20s were also more likely to meet two or three WHO subfertility criteria (OR = 3.9 [1.6, 9.4]) compared with normal-weight men. Each additional adult decade in which a participant was overweight/obese was associated with higher odds of low motility (OR = 1.3 [0.96, 1.6]) and higher odds of meeting two or three WHO subfertility criteria (OR = 1.5 [1.0, 2.2]).

Conclusions: In our data, associations among adiposity and sperm concentration, motility, and morphology varied according to timing and duration of exposure, potentially reflecting different biological mechanisms that influence these semen parameters.
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http://dx.doi.org/10.1097/EDE.0000000000001070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7055633PMC
November 2019

Associations between estimated foetal weight discordance and clinical characteristics within dichorionic twins: The NICHD Fetal Growth Studies.

Paediatr Perinat Epidemiol 2019 09 3;33(5):332-342. Epub 2019 Sep 3.

Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland.

Background: Birthweight discordance is well studied, with less known about longitudinal inter-twin differences in foetal growth.

Objective: To examine inter-twin per cent differences in EFW (EFW ), head (HC ) and abdominal circumference (AC ), and femur length (FL ) across gestation in dichorionic twin gestations and explore associated characteristics.

Methods: Foetal biometrics were assessed by ultrasound and EFW calculated at ≤6 study visits among women with dichorionic twin pregnancies enrolled in the NICHD Fetal Growth Studies cohort (US, 2012-2013). Inter-twin per cent difference was defined: ([Size  - Size ]/Size  × 100). Linear mixed models evaluated per cent differences in foetal biometrics at 15 weeks and their change per week overall and by maternal/neonatal characteristics in unadjusted and adjusted models.

Results: In 140 pregnancies, inter-twin per cent differences increased across gestation for EFW (0.18%/week, 95% confidence interval [CI] 0.10, 0.27), HC (0.03%/week, 95% CI 0.00, 0.06), and AC (0.03%/week, 95%CI -0.01, 0.08) but decreased for FL (-0.03%/week, 95% CI -0.09, 0.02). After adjustment, change in EFW difference across gestation differed by pre-pregnancy body mass index (BMI [kg/m ]; underweight [<18.5]; normal weight [18.5-24.9]; overweight [25.0-29.9]; obese [≥30.0]; P  = .022); and conception method (in vitro fertilisation [IVF], intrauterine insemination, ovulation induction medication, donor egg/embryo, none; P  = .060). While EFW difference increased with normal pre-pregnancy BMI (0.24%/week, 95% CI 0.12, 0.37), little change was noted with pre-pregnancy obesity (0.01%/week, 95% CI -0.15, 0.17). EFW difference increased in conceptions without fertility treatments (0.23%/week, 95% CI 0.11, 0.34) but not IVF conceptions (-0.00%/week, 95% CI -0.16, 0.16). Similar patterns of differences across gestation were noted for HC by conception method (P  = .026) and AC by pre-pregnancy BMI (P  = .071); changes in HC differed by parity (nulliparous, multiparous; P  = .004).

Conclusions: EFW difference increased across gestation in dichorionic twins, but remained stable with pre-pregnancy obesity or IVF conception, patterns mirrored for HC and AC. Research is needed to understand pathologic versus physiologic differential twin growth trajectories.
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http://dx.doi.org/10.1111/ppe.12570DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7593826PMC
September 2019

Intrauterine growth discordance across gestation and birthweight discordance in dichorionic twins.

Am J Obstet Gynecol 2020 02 24;222(2):174.e1-174.e10. Epub 2019 Aug 24.

Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD. Electronic address:

Background: Although intertwin size difference is an important measure of fetal growth, the appropriate cut point to define discordance is unclear. Few studies have assessed intertwin differences in estimated fetal weight longitudinally or in relation to size differences at birth.

Objectives: The objectives of the study were to estimate the magnitude of percentage differences in estimated fetal weight across gestation in dichorionic twins in relation to a fixed discordance cut point and compare classification of aberrant fetal growth by different measures (estimated fetal weight differences, birthweight discordance, small for gestational age).

Study Design: Women aged 18-45 years from 8 US centers with dichorionic twin pregnancies at 8 weeks 0 days to 13 weeks 6 days gestation planning to deliver in participating hospitals were recruited into the Eunice Kennedy Shriver National Institute of Child Health and Human Development Fetal Growth Studies-Dichorionic Twins study and followed through delivery (n = 140; 2012-2013). Ultrasounds were conducted at 6 targeted study visits to obtain fetal biometrics and calculate estimated fetal weight. Percent estimated fetal weight and birthweight differences were calculated: ([weight - weight]/weight)*100; discordance was defined as ≥18% for illustration. Birth sizes for gestational age (both, 1, or neither small for gestational age) were determined; twins were categorized into combined birthweight plus small for gestational age groups: birthweight discordance ≥18% (yes, no) with both, 1, or neither small for gestational age. Linear mixed-models estimated percentiles of estimated fetal weight percent differences across gestation and compared estimated fetal weight differences between combined birthweight discordance and small for gestational age groups. A Fisher exact test compared birthweight discordance and small for gestational age classifications.

Results: Median estimated fetal weight percentage difference increased across gestation (5.9% at 15.0, 8.4% at 38.0 weeks), with greater disparities at higher percentiles (eg, 90th percentile: 15.6% at 15.0, 26.3% at 38.0 weeks). As gestation advanced, an increasing percentage of pregnancies were classified as discordant using a fixed cut point: 10% at 27.0, 15% at 34.0, and 20% at 38.0 weeks. Birthweight discordance and small for gestational age classifications differed (P = .002); for birthweight discordance ≥18% vs <18%: 44% vs 71% had neither small for gestational age; 56% vs 18% had 1 small for gestational age; no cases (0%) vs 11% had both small for gestational age, respectively. Estimated fetal weight percent difference varied across gestation by birthweight discordance plus small for gestational age classification (P = .040). Estimated fetal weight percentage difference increased with birthweight discordance ≥18% (neither small for gestational age: 0.46%/week [95% confidence interval, 0.08-0.84]; 1 small for gestational age: 0.57%/week [95% confidence interval, 0.25-0.90]) but less so without birthweight discordance (neither small for gestational age: 0.17%/week [95% confidence interval, 0.06-0.28]; 1 small for gestational age: 0.03%/week [95% confidence interval, -0.17 to 0.24]); both small for gestational age: 0.10%/week [95% confidence interval, -0.15 to 0.36]).

Conclusion: The percentage of dichorionic pregnancies exceeding a fixed discordance cut point increased over gestation. A fixed cut point for defining twin discordance would identify an increasing percentage of twins as discordant as gestation advances. Small for gestational age and percentage weight differences assess distinct aspects of dichorionic twin growth. A percentile cut point may be more clinically useful for defining discordance, although further study is required to assess whether any specific percentile cut point correlates to adverse outcomes.
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http://dx.doi.org/10.1016/j.ajog.2019.08.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7535857PMC
February 2020

Sex differences in the associations of placental epigenetic aging with fetal growth.

Aging (Albany NY) 2019 08 8;11(15):5412-5432. Epub 2019 Aug 8.

Dean's Office, College of Health and Human Services, George Mason University, Fairfax, VA 22030, USA.

Identifying factors that influence fetal growth in a sex-specific manner can help unravel mechanisms that explain sex differences in adverse neonatal outcomes and origins of cardiovascular disease disparities. Premature aging of the placenta, a tissue that supports fetal growth and exhibits sex-specific epigenetic changes, is associated with pregnancy complications. Using DNA methylation-based age estimator, we investigated the sex-specific relationship of placental epigenetic aging with fetal growth across 13-40 weeks gestation, neonatal size, and risk of low birth weight. Placental epigenetic age acceleration (PAA), the difference between DNA methylation age and gestational age, was associated with reduced fetal weight among males but with increased fetal weight among females. PAA was inversely associated with fetal weight, abdominal circumference, and biparietal diameter at 32-40 weeks among males but was positively associated with all growth measures among females across 13-40 weeks. A 1-week increase in PAA was associated with 2-fold (95% CI 1.2, 3.2) increased odds for low birth weight and 1.5-fold (95% CI 1.1, 2.0) increased odds for small-for-gestational age among males. In all, fetal growth was significantly reduced in males but not females exposed to a rapidly aging placenta. Epigenetic aging of the placenta may underlie sex differences in neonatal outcomes.
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http://dx.doi.org/10.18632/aging.102124DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6710059PMC
August 2019

A Prospective Study of Early Pregnancy Essential Metal(loid)s and Glucose Levels Late in the Second Trimester.

J Clin Endocrinol Metab 2019 10;104(10):4295-4303

Department of Environmental Health, Harvard T. H. Chan School of Public Health, Boston, Massachusetts.

Context: Studies suggest many essential trace metal(loid)s are involved in glucose metabolism, but the associations among pregnant women are unclear.

Objective: To assess associations between early pregnancy plasma zinc, selenium, copper, and molybdenum levels and blood glucose levels later in the second trimester.

Design: The Eunice Kennedy Shriver National Institute of Child Health and Human Development Fetal Growth Studies‒Singleton Cohort is a prospective cohort study conducted between July 2009 and January 2013.

Setting: Twelve academic research hospitals in the United States.

Patients: A total of 1857 multiracial, nonobese, healthy women.

Main Outcome Measure: Blood glucose levels from 1-hour 50-g gestational load test (GLT) at 24 to 28 weeks of gestation.

Results: Higher concentrations of first-trimester copper were associated with higher glucose levels from the GLT (i.e., every 50% increase in copper concentration was related to 4.9 mg/dL higher glucose level; 95% CI: 2.2, 7.5 mg/dL) adjusted for maternal sociodemographic characteristics and reproductive history. In contrast, every 50% increase in molybdenum concentration was associated with 1.2 mg/dL lower mean glucose level (95% CI: -2.3, -0.1 mg/dL). The magnitude of these associations was greater at the upper tails of glucose level distribution based on quantile regressions of the 10th, 50th, and 90th percentiles.

Conclusions: Higher copper and lower molybdenum concentrations could increase the risk of glucose dysregulation during pregnancy, with women at higher risk of gestational diabetes mellitus potentially affected to a greater extent. Further work is needed to understand the mechanisms involved with early pregnancy essential metal(loid)s to inform clinical diagnosis and prevention of glucose intolerance during pregnancy.
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http://dx.doi.org/10.1210/jc.2019-00109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6736048PMC
October 2019

Comparison of fetal growth by maternal prenatal acetaminophen use.

Pediatr Res 2019 08 25;86(2):261-268. Epub 2019 Mar 25.

Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD, USA.

Background: Equivocal findings exist regarding prenatal acetaminophen use and various adverse neonatal and childhood health outcomes, though with no data on fetal growth. We evaluated whether fetal growth differed by maternal acetaminophen use.

Methods: Racially diverse, healthy women with low-risk antenatal profiles from 12 US clinical centers were enrolled in a prospective cohort study and followed until delivery. Ultrasound measurements of fetal parameters and self-reported prenatal acetaminophen use were collected at enrollment and up to five follow-up visits. Prenatal acetaminophen use was dichotomized as none or any.

Results: Among 2291 women, 932 (41%) reported the use of acetaminophen medications during the current pregnancy. Estimated growth curves of fetal parameters did not differ between women reporting use of any medication containing acetaminophen and women with no reported use of the same.

Conclusion: Among healthy mothers with low-risk pregnancies, maternal acetaminophen use was not associated with alterations in fetal growth.
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http://dx.doi.org/10.1038/s41390-019-0379-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6658344PMC
August 2019

Pregnancy Loss and Iodine Status: The LIFE Prospective Cohort Study.

Nutrients 2019 03 1;11(3). Epub 2019 Mar 1.

Biostatistics and Bioinformatics Branch, Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA.

Iodine deficiency in pregnancy is a common problem in the United States and parts of Europe, but whether iodine deficiency is associated with increased pregnancy loss has not been well studied. The LIFE study provided an excellent opportunity to examine the relationship between iodine status and pregnancy loss because women were monitored prospectively to ensure excellent ascertainment of conceptions. The LIFE study, a population-based prospective cohort study, monitored 501 women who had discontinued contraception within two months to become pregnant; 329 became pregnant, had urinary iodine concentrations measured on samples collected at enrollment, and were followed up to determine pregnancy outcomes. Of the 329, 196 had live births (59.5%), 92 (28.0%) had losses, and 41 (12.5%) withdrew or were lost to follow up. Urinary iodine concentrations were in the deficiency range in 59.6% of the participants. The risk of loss, however, was not elevated in the mildly deficient group (hazard ratio 0.69, 95% confidence interval 0.34, 1.38), the moderately deficient group (hazard ratio 0.81, 95% confidence interval 0.43, 1.51), or the severely deficient group (hazard ratio 0.69, 95% confidence interval 0.32, 1.50). Iodine deficiency, even when moderate to severe, was not associated with increased rates of pregnancy loss. This study provides some reassurance that iodine deficiency at levels seen in many developed countries does not increase the risk of pregnancy loss.
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http://dx.doi.org/10.3390/nu11030534DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6471412PMC
March 2019

A contemporary amniotic fluid volume chart for the United States: The NICHD Fetal Growth Studies-Singletons.

Am J Obstet Gynecol 2019 07 18;221(1):67.e1-67.e12. Epub 2019 Feb 18.

Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD.

Background: Amniotic fluid is essential to normal fetal development and is estimated clinically with ultrasound scanning to identify pregnancies that are at risk for poor perinatal outcome.

Objective: Our goal was to develop a United States standard for amniotic fluid volume that is estimated by the amniotic fluid index and single deepest pocket.

Study Design: We performed a planned secondary analysis of a multicenter observational study of 2334 low-risk women with normal singleton gestations from 1 of 4 self-reported racial/ethnic groups. Eligible women had confirmed first-trimester dating criteria with health status, lifestyles, and medical and obstetric histories that were associated with normal fetal growth. Consenting women underwent serial (up to 5) sonographic evaluations of amniotic fluid between 15 and 40 weeks of gestation after being assigned randomly to 1 of 4 gestational age observation schedules. Twelve United States perinatal centers participated, and all sonograms were performed by credentialed sonographers who used identical, high-resolution equipment; caregivers were unaware of results but were notified for oligohydramnios. Women (n=597) who were subsequently found to have clinically significant antepartum complications were excluded. Racial/ethnic-specific nomograms for amniotic fluid index and single deepest pocket across gestation were developed with the use of linear mixed models with cubic splines; racial/ethnic differences were evaluated both with global and between-group tests. Median, 3rd, 5th, 10th, 90th, 95th and 97th percentile values were also estimated. We further considered the possible confounding effects of selected maternal characteristics and the estimated fetal weight at each sonogram.

Results: A total of 1719 pregnant women met inclusion criteria and had available data. These included 480 non-Hispanic white women, 418 non-Hispanic black women, 485 Hispanic women, and 336 Asian women. Both the amniotic fluid index and the single deepest pocket varied across gestation with maximal values at 26 and 33 weeks of gestation, respectively. Statistically significant differences were observed by maternal race/ethnicity. The between-group differences that were observed at 17-22 and 35-40 weeks of gestation remained statistically significant after adjustment for maternal characteristics and estimated fetal weight. These between-group racial/ethnic differences were most prominent after 35 weeks of gestation and at the extremes of dispersion (3rd and 97th percentiles). All 3rd and 97th percentile amniotic fluid index values were within the range of commonly used cutoffs to define oligohydramnios (≤5 cm) and polyhydramnios (≥25 cm). However, the 3rd percentile values ranged between 5.9 cm at 40 weeks of gestation and 10.1 cm at 25-27 weeks of gestation; the 97th percentile values ranged between 24.8 cm at 38 weeks of gestation and 15.7 cm at 15 weeks of gestation.

Conclusion: Sonographic amniotic fluid volume estimates vary by racial/ethnic group, but the absolute differences appear to be small and may not be clinically significant. Selected maternal characteristics and estimated fetal weight did not affect the racial/ethnic differences. Between-group differences are maximal after 35 weeks of gestation and at the extremes of the upper and lower dispersion estimates. Given the observed variability in extreme (3rd and 97th percentile) dispersion values over the gestation, use of single cutoffs to define out-of-range measurements may not be appropriate clinically. These data might form a contemporary United States standard for amniotic fluid estimation that uses the amniotic fluid index and the single deepest pocket.
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http://dx.doi.org/10.1016/j.ajog.2019.02.030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6592729PMC
July 2019

Persistent organic pollutants and gestational diabetes: A multi-center prospective cohort study of healthy US women.

Environ Int 2019 03 16;124:249-258. Epub 2019 Jan 16.

Dean's Office, College of Health and Human Services, George Mason University, Fairfax, VA, USA.

Background: Persistent organic pollutants (POPs) are linked with insulin resistance and type-2 diabetes (T2D) in the general population. However, their associations with gestational diabetes (GDM) are inconsistent.

Objective: We prospectively evaluated the associations of POPs measured in early pregnancy with GDM risk. We also assessed whether pre-pregnancy BMI (ppBMI) and family history of T2D modify this risk.

Methods: In NICHD Fetal Growth Study, Singletons, we measured plasma concentration of 76 POPs, including 11 organochlorine pesticides (OCPs), 9 polybrominated diphenylethers (PBDEs), 44 polychlorinated biphenyls (PCBs), and 11 per-and polyfluoroalkyl substances (PFAS) among 2334 healthy non-obese women at 8-13 weeks of gestation. GDM was diagnosed by Carpenter and Coustan criteria. We constructed chemical networks using a weighted-correlation algorithm and examined the associations of individual chemical and chemical networks with GDM using multivariate Poisson regression with robust variance.

Results: Higher concentrations of PCBs with six or more chlorine atoms were associated with increased risk of GDM in the overall cohort (risk ratios [RRs] range: 1.08-1.13 per 1-standard deviation [SD] increment) and among women with a family history of T2D (RRs range: 1.08-1.48 per 1-SD increment) or normal ppBMI (RRs range: 1.08-1.22 per 1-SD increment). Similar associations were observed for the chemical network comprised of PCBs with ≥6 chlorine atoms and the summary measure of total PCBs and non-dioxin like PCBs (138, 153, 170, 180). Furthermore, four PFAS congeners - perfluorononanoic acid (PFNA), perfluorooctanoic acid (PFOA), perfluoroheptanoic acid (PFHpA), and perfluorododecanoic acid (PFDoDA) - showed significant positive associations with GDM among women with a family history of T2D (RRs range:1.22-3.18 per 1-SD increment), whereas BDE47 and BDE153 showed significant positive associations among women without a family history of T2D.

Conclusions: Environmentally relevant levels of heavily chlorinated PCBs and some PFAS and PBDEs were positively associated with GDM with suggestive effect modifications by family history of T2D and body adiposity status.
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http://dx.doi.org/10.1016/j.envint.2019.01.027DOI Listing
March 2019

Exposome-wide association study of semen quality: Systematic discovery of endocrine disrupting chemical biomarkers in fertility require large sample sizes.

Environ Int 2019 04 22;125:505-514. Epub 2018 Dec 22.

Department of Biomedical Informatics, Harvard Medical School, Harvard University, 10 Shattuck Street, Boston, MA 02115, United States of America. Electronic address:

Objectives: Exposome-wide association studies (EWAS) are a systematic and unbiased way to investigate multiple environmental factors associated with phenotype. We applied EWAS to study semen quality and queried the sample size requirements to detect modest associations in a reproductive cohort.

Study Design And Setting: We conducted 1) a multivariate EWAS of 128 endocrine disrupting chemicals (EDCs) from 15 chemical classes measured in urine/serum relative to 7 semen quality endpoints in a prospective cohort study comprising 473 men and 2) estimated the sample size requirements for EWAS etiologic investigations.

Results: None of the EDCs were associated with semen quality endpoints after adjusting for multiple tests. However, several EDCs (e.g., polychlorinated biphenyl congeners 99, 105, 114, and 167) were associated with raw p < 0.05. In a post hoc statistical power analysis with the observed effect sizes, we determined that EWAS research in male fertility will require a mean sample size of 2696 men (1795-3625) to attain a power of 0.8. The average size of four published studies is 201 men.

Conclusion: Existing cohort studies with hundreds of participants are underpowered (<0.8) for EWAS-related investigations. Merging cohorts to ensure a sufficient sample size can facilitate the use of EWAS methods for assessing EDC mixtures that impact semen quality.
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http://dx.doi.org/10.1016/j.envint.2018.11.037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6400484PMC
April 2019

Polybrominated diphenyl ethers and incident pregnancy loss: The LIFE Study.

Environ Res 2019 01 18;168:375-381. Epub 2018 Sep 18.

Office of Director, and Bioinformatics Branch, Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA; Department of Environmental Health, Rollins School of Public Health, Emory University, Atlanta, GA, USA. Electronic address:

Background: Polybrominated diphenyl ethers (PBDEs) have not been studied in relation to incident pregnancy loss in human populations, despite their ubiquitous exposure and purported reproductive toxicity.

Objectives: To investigate the association between preconception serum PBDE concentrations and incident pregnancy loss.

Methods: A preconception cohort of 501 couples was followed while trying to become pregnant, and for whom serum concentrations of 10 PBDE congeners were measured using gas chromatography-high resolution mass spectrometry. Pregnancy was prospectively identified as a positive home pregnancy test on the day of expected menstruation. Incident pregnancy loss was defined for 344 singleton pregnancies as a conversion to a negative home pregnancy test, menses, or clinical diagnosis depending upon gestational age. Cox proportional hazards models were used to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) for individual and summed PBDEs and incident pregnancy loss, adjusting for relevant covariates and male partners' information. In sensitivity analyses, inverse probability weighting was used to account for couples not becoming pregnant and, thereby, not at risk for loss.

Results: The incidence of prospectively observed pregnancy loss was 28%, and the serum concentrations of PBDE congeners in females were consistently associated with a higher hazard of incident pregnancy loss. Specifically, statistically significant hazard ratios (HRs) for incident pregnancy loss were observed for lower brominated PBDE congeners: 17 (HR 1.23; CI: 1.07-1.42), 28 (HR 1.25; CI: 1.03-1.52), 66 (HR 1.23; CI: 1.07-1.42), and homolog triBDE (HR: 1.25; CI: 1.05-1.49). Findings were robust to various model specifications explored in sensitivity analyses.

Conclusions: Maternal preconception serum concentrations of specific PBDE congeners may increase the hazard of incident pregnancy.
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http://dx.doi.org/10.1016/j.envres.2018.09.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6294303PMC
January 2019

A Bayesian regularized mediation analysis with multiple exposures.

Stat Med 2019 02 29;38(5):828-843. Epub 2018 Oct 29.

Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland.

Mediation analysis assesses the effect of study exposures on an outcome both through and around specific mediators. While mediation analysis involving multiple mediators has been addressed in recent literature, the case of multiple exposures has received little attention. With the presence of multiple exposures, we consider regularizations that allow simultaneous effect selection and estimation while stabilizing model fit and accounting for model selection uncertainty. In the framework of linear structural-equation models, we analytically show that a two-stage approach regularizing regression coefficients does not guarantee a unimodal posterior distribution and that a product-of-coefficient approach regularizing direct and indirect effects tends to penalize excessively. We propose a regularized difference-of-coefficient approach that bypasses these limitations. Using the connection between regularizations and Bayesian hierarchical models with Laplace prior, we develop an efficient Markov chain Monte Carlo algorithm for posterior estimation and inference. Through simulations, we show that the proposed approach has better empirical performances compared to some alternatives. The methodology is illustrated using data from two epidemiological studies in human reproduction.
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http://dx.doi.org/10.1002/sim.8020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8327705PMC
February 2019

A weighted kernel machine regression approach to environmental pollutants and infertility.

Stat Med 2019 02 16;38(5):809-827. Epub 2018 Oct 16.

Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland.

In epidemiological studies of environmental pollutants in relation to human infertility, it is common that concentrations of a large number of exposures are collected in both male and female partners. Such a couple-based study poses some new challenges in statistical analysis, especially when the effect of the totality of these chemical mixtures is of interest, because these exposures may have complex nonlinear and nonadditive relationships with the infertility outcome. Kernel machine regression, as a nonparametric regression method, can be applied to model such effects, while accounting for the highly correlated structure within and across exposures. However, it does not consider the partner-specific structure in these study data, which may lead to suboptimal estimation for the effects of environmental exposures. To overcome this limitation, we developed a weighted kernel machine regression method (wKRM) to model the joint effect of partner-specific exposures, in which a linear weight procedure is used to combine the female and male partners' exposure concentrations. The proposed wKRM is not only able to reduce the number of analyzed exposures but also provide an overall importance index of female and male partners' exposures in the risk of infertility. Simulation studies demonstrate good performance of the wKRM in both estimating the joint effects of exposures and fitting the infertility outcome. Application of the proposed method to a prospective infertility study suggests that the male partner's exposure to polychlorinated biphenyls might contribute more toward infertility than the female partner's.
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http://dx.doi.org/10.1002/sim.8003DOI Listing
February 2019
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