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Introduction: Twin gestations have greater nutritional demands than singleton gestations, yet dietary intakes of women with twin gestations have not been well described., Methods: In a prospective, multi-site US study of 148 women with dichorionic twin gestations (2012-2013), we examined longitudinal changes in diet across pregnancy. Women completed a food frequency questionnaire during each trimester of pregnancy. We examined changes in means of total energy and energy-adjusted dietary components using linear mixed effects models., Results: Mean energy intake (95% CI) across the three trimesters was 2010 kcal/day (1846, 2175), 2177 kcal/day (2005, 2349), 2253 kcal/day (2056, 2450), respectively (P = 0.01), whereas the Healthy Eating Index-2010 was 63.9 (62.1, 65.6), 64.5 (62.6, 66.3), 63.2 (61.1, 65.3), respectively (P = 0.53)., Discussion: Women with twin gestations moderately increased total energy as pregnancy progressed, though dietary composition and quality remained unchanged. These findings highlight aspects of nutritional intake that may need to be improved among women carrying twins., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Background: Fibroids (hormonally responsive benign tumors) often undergo volume changes in pregnancy. Because per- and polyfluoroalkyl substances (PFAS) disrupt hormonal signaling, they might affect fibroid growth. We assessed associations between PFAS and fibroid changes in pregnancy., Methods: We analyzed seven PFAS, including perfluorohexanesulfonic acid (PFHxS), perfluorooctanesulfonic acid (PFOS), perfluorodecanoic acid (PFDA), and perfluoroundecanoic acid (PFUnDA), in plasma collected at 10-13 wk gestation from 2,621 women in the NICHD Fetal Growth Studies - Singletons cohort (2009-2013). Sonographers recorded fibroid number and volume of the three largest fibroids during up to six timed ultrasounds. Generalized linear models assessed associations of baseline log 2 - transformed PFAS and fibroid number, volume, and presence, and weighted quantile sum regression evaluated the PFAS mixture. Generalized linear mixed models with random intercepts assessed associations of PFAS and longitudinal fibroid number and total volume. Volume analyses were stratified by total volume at first visualization [equivalent to a fibroid < 1 cm (small), 1  to < 3 cm (medium), or ≥ 3 cm (large) in diameter]., Results: Fibroid prevalence was 9.4% ( n = 245 women). PFAS were not associated with changes in fibroid number, but were associated with volume trajectory, depending on baseline volume. Among women with small volume, PFAS were associated with fibroid growth: Each doubling in PFHxS and PFOS concentrations was associated with 3.6% [95% confidence interval (CI): 0.2, 7.0 and 5.2% (95% CI: - 0.4 , 11.1)] greater weekly fibroid growth, respectively. Among women with medium volume, PFAS were associated with shrinking: Doublings in PFOS, PFDA, and PFUnDA concentrations were associated with 1.9% (95% CI: 0.4, 3.3), 1.2% (95% CI: 0.1, 2.4), and 1.6% (95% CI: 0.4, 2.8) greater weekly fibroid volume reduction, respectively., Discussion: Certain PFAS were associated with fibroid growth among women with small fibroids and decreases among women with medium fibroids. PFAS were not associated with fibroid prevalence or number; therefore, PFAS may influence prevalent fibroids rather than initiating fibroid development. https://doi.org/10.1289/EHP11606.

Purpose: To investigate the relationship of fibroids in pregnancy, preterm birth, and neonatal anthropometry., Methods: Pregnant women (n = 2578) in the National Institute of Child Health and Human Development Fetal Growth Studies-Singletons cohort had up to six ultrasounds across pregnancy. Sonographers recorded fibroid number and volume of the three largest fibroids. Trained personnel measured neonatal anthropometry. Linear and logistic regression compared neonatal anthropometry and pregnancy outcomes among pregnancies with versus without fibroids. Causal mediation analysis evaluated preterm birth as a mediator., Results: Average birthweight did not differ by fibroid status. However, compared with pregnancies without fibroids, neonates from pregnancies with single fibroids had 0.3- (95% confidence interval [CI], 0.0, 0.5) cm larger head circumferences; those with multiple fibroids had 0.3- (95% CI, 0.0, 0.6) cm larger arm circumferences; and those with small fibroid volume had 0.7- (95% CI, 0.3, 1.2) cm larger head, 0.4- (95% CI, 0.0, 0.8) cm larger arm, and 0.7- (95% CI, 0.1, 1.3) cm larger thigh circumferences. Presence versus absence of fibroids was associated with 1.73-2.65 times higher odds of preterm birth. Differences in preterm birth did not explain fibroid-anthropometry results., Conclusions: We found no evidence that fibroids negatively impacted fetal growth; instead, fibroids were associated with increased head, arm, and thigh circumferences., Clinical Trial Registration: ClinicalTrials.gov, NCT00912132., (Published by Elsevier Inc.)

Objective: To describe the natural history of fibroids in pregnancy in a racially diverse cohort and explore whether fibroid changes were associated with participant characteristics., Design: Prospective cohort study., Setting: Twelve clinical sites., Patient(s): Pregnant women (n = 2774; 27% non-Hispanic White, 28% non-Hispanic Black, 29% Hispanic, 17% Asian/Pacific Islander) who had up to 6 obstetric ultrasounds in gestational weeks 10-41., Intervention(s): Sonographers recorded fibroid number and volume of the 3 largest fibroids at each visit. Generalized linear mixed models estimated the trajectories of fibroid number and total volume (overall and stratified by total volume at first visualization: equivalent to a fibroid of <1 cm [small], 1 to <3 cm [medium], or ≥3 cm [large] in diameter). We tested the interactions between the trajectories and race/ethnicity, age (<26, 26-30, 31-34, and ≥35 years), body mass index (<25, 25-29.9, and ≥30 kg/m 2 ), previous miscarriage, parity, and fetal sex, adjusted for total volume at first visualization., Main Outcome Measure(s): Average change in total fibroid volume during pregnancy., Result(s): Overall, 9.6% (266/2,774) of women had a visualized fibroid at any time during pregnancy, including 9% (67/745) of non-Hispanic White women, 14% (106/770) of non-Hispanic Black women, 6% (47/794) of Hispanic women, and 10% (46/465) of Asian or Pacific Islander women. The mean total fibroid volume decreased by 1.0% (95% confidence interval [CI], -1.9%, -0.2%) per week, with a variation in starting total volume. On average, the total volume increased by 2.0% (95% CI, -0.3%, 4.5%) per week among women with small volume; decreased by 0.5% (95% CI, -2.0%, 1.0%) per week among women with medium volume; and decreased by 2.2% (95% CI, -3.4%, -1.0%) per week among women with large volume at first visualization. The volume change also varied by race or ethnicity, parity, age, and miscarriage history. For example, non-Hispanic Black women's total fibroid volume decreased more than those of non-Hispanic White, Hispanic and Asian/Pacific Islander women (-2.6%, 0.1%, 0.5%, and 0.9% average change per week, respectively). The visualized fibroid number declined on an average by 1.2% per week (95% CI, -1.9%, -0.5%) without significant variation by demographic characteristics., Conclusion(s): The total fibroid volume declined on average throughout pregnancy. However, summarizing across all fibroids disguises substantial heterogeneity by starting total fibroid volume and maternal characteristics. The findings may be a useful reference for clinicians to anticipate how fibroids may change in obstetric patients., Clinical Trial Registration Number: NCT00912132., (Copyright © 2022 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Introduction: Exercise in pregnancy is associated with many perinatal benefits, but patterns of home, work, and commuting activity are not well described. We investigated longitudinal activity in singleton and twin pregnancy by activity domain and maternal characteristics., Methods: In the National Institute of Child Health and Human Development Fetal Growth Studies cohorts, 2778 women with singleton and 169 women with twin gestations reported activity using the Pregnancy Physical Activity Questionnaire at up to six or seven study visits, respectively. Metabolic equivalent of task-hours per week (MET-h·wk -1 ) was calculated from reported activity. Baseline measurements (obtained between 10 and 13 wk) reflected past year activity. Linear mixed models estimated MET-h·wk -1 by domain (household/childcare, occupational, inactive, transportation, sports/exercise), self-reported race/ethnicity (non-Hispanic White, non-Hispanic Black, Hispanic, Asian/Pacific Islander), prepregnancy body mass index (<25, 25 to < 30, ≥30 kg·m -2 ), parity (0, ≥1), baseline activity (quartiles), and plurality (singleton, twin)., Results: Household/caregiving activity made up the largest fraction of reported MET-h·wk -1 at baseline (42%), followed by occupational activity (28%). Median summed activity declined 47%, from 297 to 157 MET-h·wk -1 , between 10 and 40 wk, largely driven by changes in household/caregiving (44% decline), and occupational activity (63% decline). Sports/exercise activity declined 55% but constituted only 5% of reported MET-h·wk -1 at baseline. At baseline, non-Hispanic Black women reported significantly higher activity than non-Hispanic White or Hispanic women, but differences did not persist across pregnancy. Across gestation nulliparous women reported significantly lower activity than parous women. Women with singleton gestations reported significantly more activity than women with twins from weeks 26 to 38. Baseline activity level was strongly associated with later activity levels., Conclusions: Measuring domains of activity beyond exercise, and collecting longitudinal measurements, is necessary to fully describe activity in diverse populations of pregnant women., (Copyright © 2022 by the American College of Sports Medicine.)

Study Question: Is sperm epigenetic aging (SEA) associated with probability of pregnancy among couples in the general population?, Summary Answer: We observed a 17% lower cumulative probability at 12 months for couples with male partners in the older compared to the younger SEA categories., What Is Known Already: The strong relation between chronological age and DNA methylation profiles has enabled the estimation of biological age as epigenetic 'clock' metrics in most somatic tissue. Such clocks in male germ cells are less developed and lack clinical relevance in terms of their utility to predict reproductive outcomes., Study Design, Size, Duration: This was a population-based prospective cohort study of couples discontinuing contraception to become pregnant recruited from 16 US counties from 2005 to 2009 and followed for up to 12 months., Participants/materials, Setting, Methods: Sperm DNA methylation from 379 semen samples was assessed via a beadchip array. A state-of-the-art ensemble machine learning algorithm was employed to predict age from the sperm DNA methylation data. SEA was estimated from clocks derived from individual CpGs (SEACpG) and differentially methylated regions (SEADMR). Probability of pregnancy within 1 year was compared by SEA, 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: Our SEACpG clock had the highest predictive performance with correlation between chronological and predicted age (r = 0.91). In adjusted discrete Cox models, SEACpG was negatively associated with TTP (fecundability odds ratios (FORs)=0.83; 95% CI: 0.76, 0.90; P = 1.2×10-5), indicating a longer TTP with advanced SEACpG. For subsequent birth outcomes, advanced SEACpG was associated with shorter gestational age (n = 192; -2.13 days; 95% CI: -3.67, -0.59; P = 0.007). Current smokers also displayed advanced SEACpG (P < 0.05). Finally, SEACpG showed a strong performance in an independent IVF cohort (n = 173; r = 0.83). SEADMR performance was comparable to SEACpG but with attenuated effect sizes., Limitations, Reasons for Caution: This prospective cohort study consisted primarily of Caucasian men and women, and thus analysis of large diverse cohorts is necessary to confirm the associations between SEA and couple pregnancy success in other races/ethnicities., Wider Implications of the Findings: These data suggest that our sperm epigenetic clocks may have utility as a novel biomarker to predict TTP among couples in the general population and underscore the importance of the male partner for reproductive success., Study Funding/competing Interest(s): This work was funded in part by grants the National Institute of Environmental Health Sciences, National Institutes of Health (R01 ES028298; PI: J.R.P. and P30 ES020957); Robert J. Sokol, MD Endowed Chair of Molecular Obstetrics and Gynecology (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). S.L.M. was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health. The authors declare no competing interests., Trial Registration Number: N/A., (© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

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., (Copyright © 2021. Published by Elsevier Ltd.)

Understanding implications of passive smoke exposure during pregnancy is an important public health issue under the Developmental Origins of Health and Disease paradigm. In a prospective cohort of low-risk non-smoking pregnant women (NICHD Fetal Growth Studies-Singletons, 2009-2013, N = 2055), the association between first trimester passive smoke exposure and neonatal size was assessed by race/ethnicity. Plasma biomarker concentrations (cotinine, nicotine) assessed passive smoke exposure. Neonatal anthropometric measures included weight, 8 non-skeletal, and 2 skeletal measures. Linear regression evaluated associations between continuous biomarker concentrations and neonatal anthropometric measures by race/ethnicity. Cotinine concentrations were low and the percent above limit of quantification varied by maternal race/ethnicity (10% Whites; 14% Asians; 15% Hispanics; 49% Blacks). The association between cotinine concentration and infant weight differed by race/ethnicity (Pinteraction = 0.034); compared to women of the same race/ethnicity, per 1 log-unit increase in cotinine, weight increased 48g (95%CI -44, 139) in White and 51g (95%CI -81, 183) in Hispanic women, but decreased -90g (95%CI -490, 309) in Asian and -93g (95%CI -151, -35) in Black women. Consistent racial/ethnic differences and patterns were found for associations between biomarker concentrations and multiple non-skeletal measures for White and Black women (Pinteraction<0.1). Among Black women, an inverse association between cotinine concentration and head circumference was observed (-0.20g; 95%CI -0.38, -0.02). Associations between plasma cotinine concentration and neonatal size differed by maternal race/ethnicity, with increasing concentrations associated with decreasing infant size among Black women, who had the greatest biomarker concentrations. Public health campaigns should advocate for reducing pregnancy exposure, particularly for vulnerable populations., Competing Interests: NG and DH are employed by a commercial company: The Prospective Group. This does not alter our adherence to PLOS ONE policies on sharing data and materials. The authors have declared that no additional competing interests exist.

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&#95;alt&#95;strat&#95;plan&#95;6-20-18&#95;clean&#95;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., (Published by Oxford University Press on behalf of the Society of Toxicology 2021.)

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 2 ), 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., (Copyright © 2021 Elsevier Inc. All rights reserved.)

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.

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., (© The Author(s) 2020. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

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 -21 to 2.11 × 10 -7 ). 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.

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., Competing Interests: Declaration of competing interest None., (Copyright © 2019 Elsevier GmbH. All rights reserved.)

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., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

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.

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 larger - weight smaller ]/weight larger )*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., (Published by Elsevier Inc.)

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., (Published by Oxford University Press on behalf of the Endocrine Society 2019.)

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 t -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 p,p '-DDT is negatively associated with the day-specific probability of pregnancy.

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.

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.

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.

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.

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., (Copyright © 2019 Endocrine Society.)

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 larger twin  - Size smaller twin ]/Size larger twin  × 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 2 ]; underweight [<18.5]; normal weight [18.5-24.9]; overweight [25.0-29.9]; obese [≥30.0]; P interaction  = .022); and conception method (in vitro fertilisation [IVF], intrauterine insemination, ovulation induction medication, donor egg/embryo, none; P interaction  = .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 interaction  = .026) and AC % by pre-pregnancy BMI (P interaction  = .071); changes in HC % differed by parity (nulliparous, multiparous; P interaction  = .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., (© 2019 John Wiley & Sons Ltd.)

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.

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., (Copyright © 2019 Elsevier Inc. All rights reserved.)

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., (Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.)

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., (Copyright © 2019. Published by Elsevier Ltd.)

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.

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., (Published 2018. This article is a U.S. Government work and is in the public domain in the USA.)

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., (© 2018 John Wiley & Sons, Ltd.)

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., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Experimental studies suggest that prenatal exposure to endocrine disrupting chemicals interferes with developmental processes in the fetal brain. Yet, epidemiological evidence is inconclusive. In a birth cohort (2008-2010, upstate New York), we quantified concentrations of perfluorooctane sulfonic acid (PFOS), perfluorooctanoic acid (PFOA), and bisphenol A (BPA) in stored newborn dried blood spots using liquid chromatography/tandem mass spectrometry. Mothers reported on children's behavior using the Strengths and Difficulties Questionnaire at age 7 (650 singletons and 138 twins). Difficulties in total behavior (i.e., emotional, conduct, hyperactivity, and peer problems) and prosocial behavior were classified using validated cut-offs. We used logistic regression with generalized estimating equations to estimate the odds of having difficulties per exposure category. In total, 111 children (12.1%) had total behavioral difficulties and 60 (6.5%) had difficulties in prosocial behavior. The median (interquartile range) of PFOS, PFOA, and BPA were 1.74 ng/ml (1.33), 1.12 ng/ml (0.96), and 7.93 ng/ml (10.79), respectively. Higher PFOS levels were associated with increased odds of having behavioral difficulties (OR per SD of log PFOS = 1.30, 95%CI: 1.03-1.65). We observed associations between PFOS in the highest relative to the lowest quartile and behavioral difficulties (OR for PFOS 1.14-1.74  = 1.65, 95%CI: 0.84-3.34; PFOS 1.75-2.47  = 1.73, 95%CI: 0.87-3.43; and PFOS >2.47  = 2.47, 95%CI: 1.29-4.72 compared to PFOS <1.41 ). The associations between higher concentrations of PFOS and behavioral difficulties at age 7 years were driven by problems in conduct and emotional symptoms. Higher PFOA levels were associated with difficulties in prosocial behavior (OR = 1.35, 95%CI: 1.03-1.75). There was an inverse association between BPA concentrations and difficulties in prosocial behavior but only in the 2nd and 4th quartiles. We found no interactions between sex and chemical concentrations. Increasing prenatal exposure to PFOS and PFOA, as reflected in neonatal concentrations, may pose risk for child behavioral difficulties., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Novel methodologies to quantify infant exposures to endocrine disrupting chemicals (EDCs) for population-based studies are needed., Objectives: We used newborn dried blood spots to quantify three EDCs and their associations with infant outcomes in the Upstate KIDS Cohort., Methods: We measured bisphenol A (BPA), perfluorooctanesulfonic acid (PFOS) and perfluorooctanoic acid (PFOA) in 2071 singleton and 1040 twin infants born to mothers in New York State. We log transformed concentrations after rescaling by their standard deviations and modeled each in relation to gestational age, birthweight, length, head circumference and Ponderal Index (PI) using linear regression techniques. All models were adjusted for maternal age, body mass index, education, infertility treatment and parity. Generalized estimating equations with robust standard errors were used to assess the associations for twins., Results: Chemicals were largely quantified above the limits of detection (>99% for PFOS and PFOA; 90% for BPA). Overall, we observed no significant associations between PFASs and birth size irrespective of plurality of birth. However, among twins, BPA was associated with decreases in gestational age (adjusted β = -0.09 weeks; 95% Confidence Interval (CI): -0.16, -0.02) and birthweight (adjusted β = -32.52 g; 95% CI: -60.99, -4.05), head circumference (adjusted β = -0.18 cm; 95% CI: -0.38, -0.02) and increased PI in singletons (adjusted β = 0.02 cm; 95% CI: 0.004, 0.04)., Conclusion: We observed negative associations between BPA and birth size in twins. Our findings demonstrate the feasibility of newborn dried blood spots for quantifying neonatal exposure at the population level., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Some non-persistent endocrine disruptors (EDCs) are adversely associated with semen quality and few studies have measured those EDCs in seminal plasma., Objective: To find an association between EDCs in seminal plasma and semen quality parameters., Methods: Five chemical classes of non-persistent EDCs were quantified in seminal plasma from 339 male partners who participated in a prospective pregnancy study. Bisphenols, benzophenone UV-filters, antimicrobials and phthalate diesters and their monoester metabolites were measured using high performance liquid chromatography-tandem mass spectrometry and gas chromatography-mass spectrometry. Semen samples underwent next day analysis using a standardized protocol for the quantification of 35 endpoints. Linear mixed-effects models of EDCs that were log transformed and rescaled by their standard deviations or dichotomized at the 75th percentile for each exposure and outcomes with covariate adjustment were performed. EDCs in seminal plasma were also assessed relative to clinical reference values of semen quality endpoints using logistic regression or generalized estimating equations., Results: The most consistent findings supporting adverse associations between seminal EDCs and semen quality were observed for some phthalate metabolites. For example, seminal plasma mono-ethyl, mono-n-butyl, mono-2-isobutyl and mono-benzyl phthalate concentrations were associated with decreased odds of having semen volume above clinical reference values (mEP: aOR=0.46; 95%CI= 0.32, 0.66; mBP: aOR=0.40; 95%CI= 0.28, 0.57; miBP: aOR=0.39; 95%CI= 0.27, 0.56), and mBzP: aOR= 0.34; 95%CI= 0.24, 0.49)., Conclusions: Environmentally relevant concentrations of specific phthalates in seminal plasma were associated with diminished semen volume, sperm motility, viability, and morphological alterations in sperm heads such that semen volume and sperm viability fall below reference values., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Intrauterine exposure to endocrine disrupting chemicals (EDCs) has been equivocally associated with birth weight, length and head circumference with limited attention to anthropometric endpoints such as umbilical circumference and limb lengths., Objective: To explore 76 prenatal maternal plasma EDC concentrations in a healthy obstetric cohort and 7 neonatal anthropometric endpoints by maternal race/ethnicity., Methods: The study cohort comprised 2106 (564 White, 549 Black, 590 Hispanic, 403 Asian) healthy pregnant women recruited from 12 U.S. clinical sites between 2009 and 2012 who were followed through delivery. Neonates underwent standardized anthropometric assessment (weight, length, head and umbilical circumference, and mid- upper arm and thigh length). Plasma EDC concentrations were quantified using high resolution gas chromatography-high resolution mass spectrometry and liquid chromatography-tandem mass spectrometry. EDCs were log-transformed and rescaled by their deviations (SD) when modeled relative to neonatal endpoints using linear regression adjusting for age, education, pre-pregnancy body mass index (BMI), serum cotinine, serum lipids for lipophilic chemicals, and a race/ethnicity interaction term; p-values had false discovery rate correction (<0.05)., Results: The cohort comprised women aged 28 (SD = 5) years with normal BMIs (23.6 kg/m 2 , SD = 3). Maternal EDC concentrations varied by self-identified race/ethnicity and neonatal outcomes, though no specific EDC was consistently associated with neonatal anthropometric outcomes across racial/ethnic groups. For the overall cohort, perfluorooctanoic acid was negatively associated with birth length per SD increase in concentration (β = -0.23 cm; 95% CI -0.35, -0.10), while perfluorohexanesulfonic acid was negatively associated with umbilical circumference (β = -0.26 cm; 95% CI -0.40, -0.13), perfluorodecanoic acid with arm length (-0.09 cm; 95% CI -0.14, -0.04), and PCBs congeners 118/106 (-0.12 cm; 95% CI -0.20, -0.04) and 146/161 (-0.14 cm; 95% CI -0.23, -0.05) with thigh length, as were 7 other poly-and-perfluorinated alkyl substances (PFASs)., Conclusions: Among healthy pregnant women with low risk antenatal profiles and relatively low EDC concentrations, reductions in umbilical circumference and bone lengths may be a sensitive marker of intrauterine EDC exposure, particularly for PFAS., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Accurately identifying pregnancies with accelerated or diminished fetal growth is challenging and generally based on cross-sectional percentile estimates of fetal weight. Longitudinal growth velocity might improve identification of abnormally grown fetuses., Objective: We sought to complement fetal size standards with fetal growth velocity, develop a model to compute fetal growth velocity percentiles for any given set of gestational week intervals, and determine association between fetal growth velocity and birthweight., Study Design: This was a prospective cohort study with data collected at 12 US sites (2009 through 2013) from 1733 nonobese, low-risk pregnancies included in the singleton standard. Following a standardized sonogram at 10w0d-13w6d, each woman was randomized to 1 of 4 follow-up visit schedules with 5 additional study sonograms (targeted ranges: 16-22, 24-29, 30-33, 34-37, and 38-41 weeks). Study visits could occur ± 1 week from the targeted GA. Ultrasound biometric measurements included biparietal diameter, head circumference, abdominal circumference, and femur length, and estimated fetal weight was calculated. We used linear mixed models with cubic splines for the fixed effects and random effects to flexibly model ultrasound trajectories. We computed velocity percentiles in 2 ways: (1) difference between 2 consecutive weekly measurements (ie, weekly velocity), and (2) difference between any 2 ultrasounds at a clinically reasonable difference between 2 gestational ages (ie, velocity calculator). We compared correlation between fetal growth velocity percentiles and estimated fetal weight percentiles at 4-week intervals, with 32 (±1) weeks' gestation for illustration. Growth velocity was computed as estimated fetal growth rate (g/wk) between ultrasound at that gestational age and from prior visit [ie, for 28-32 weeks' gestational age: velocity = (estimated fetal weight 32-28)/(gestational age 32-28)]. We examined differences in birthweight by whether or not estimated fetal weight and estimated fetal weight velocity were <5th or ≥5th percentiles using χ 2 ., Results: Fetal growth velocity was nonmonotonic, with acceleration early in pregnancy, peaking at 13, 14, 15, and 16 weeks for biparietal diameter, head circumference, femur length, and abdominal circumference, respectively. Biparietal diameter, head circumference, and abdominal circumference had a second acceleration at 19-22, 19-21, and 27-31 weeks, respectively. Estimated fetal weight velocity peaked around 35 weeks. Fetal growth velocity varied slightly by race/ethnicity although comparisons reflected differences for parameters at various gestational ages. Estimated fetal weight velocity percentiles were not highly correlated with fetal size percentiles (Pearson r = 0.40-0.41, P < .001), suggesting that these measurements reflect different aspects of fetal growth and velocity may add additional information to a single measure of estimated fetal weight. At 32 (SD ± 1) weeks, if both estimated fetal weight velocity and size were <5th percentile, mean birthweight was 2550 g; however, even when size remained <5th percentile but velocity was ≥5th percentile, birthweight increased to 2867 g, reflecting the important contribution of higher growth velocities. For estimated fetal weight ≥5th percentile, but growth velocity <5th, birthweight was smaller (3208 vs 3357 g, respectively, P < .001)., Conclusion: We provide fetal growth velocity data to complement our previous work on fetal growth size standards, and have developed a calculator to compute fetal growth velocity. Preliminary findings suggest that growth velocity adds additional information over knowing fetal size alone., (Published by Elsevier Inc.)

Context: Marine long-chain omega-3 fatty acids have been positively related to markers of fecundity in both men and women. However, seafood, their primary food source, can also be a source of toxicants, which could counteract the reproductive benefits., Objective: To examine the relationship of male and female seafood intake with time to pregnancy (TTP)., Design: Our prospective cohort study included 501 couples planning pregnancy, who participated in the Longitudinal Investigation of Fertility and the Environment study (2005 to 2009) and were followed up for ≤1 year or until pregnancy was detected. Seafood intake was collected daily during follow-up in journals., Setting: Couples residing in Michigan and Texas were recruited using population-based sampling frameworks., Main Outcome Measures: The primary outcome was the TTP, determined using an in-home pregnancy test. A secondary outcome was sexual intercourse frequency (SIF) as recorded in the daily journals., Results: Couples with male and female partners who consumed eight or more seafood servings per cycle had 47% (95% CI, 7% to 103%) and 60% (95% CI, 15% to 122%) greater fecundity (shorter TTP) than couples with male and female partners who consumed one or fewer seafood servings per cycle. Couples with both partners consuming eight or more seafood servings per cycle had 61% (95% CI, 17% to 122%) greater fecundity than couples consuming less. Male and female partners with the highest seafood intake (eight or more servings per cycle) also had 22% greater SIF., Conclusions: Greater male and female seafood intake was associated with a higher SIF and fecundity among a large prospective cohort of couples attempting pregnancy.

Background: Ambient air pollution is associated with systemic increases in oxidative stress, to which sperm are particularly sensitive. Although decrements in semen quality represent a key mechanism for impaired fecundability, prior research has not established a clear association between air pollution and semen quality. To address this, we evaluated the association between ambient air pollution and semen quality among men with moderate air pollution exposure., Methods: Of 501 couples in the LIFE study, 467 male partners provided one or more semen samples. Average residential exposure to criteria air pollutants and fine particle constituents in the 72 days before ejaculation was estimated using modified Community Multiscale Air Quality models. Generalized estimating equation models estimated the association between air pollutants and semen quality parameters (volume, count, percent hypo-osmotic swollen, motility, sperm head, morphology and sperm chromatin parameters). Models adjusted for age, body mass index, smoking and season., Results: Most associations between air pollutants and semen parameters were small. However, associations were observed for an interquartile increase in fine particulates ≤2.5 µm and decreased sperm head size, including -0.22 (95% CI -0.34, -0.11) µm 2 for area, -0.06 (95% CI -0.09, -0.03) µm for length and -0.09 (95% CI -0.19, -0.06) µm for perimeter. Fine particulates were also associated with 1.03 (95% CI 0.40, 1.66) greater percent sperm head with acrosome., Conclusions: Air pollution exposure was not associated with semen quality, except for sperm head parameters. Moderate levels of ambient air pollution may not be a major contributor to semen quality., (Published by Elsevier Inc.)

Growing evidence supports the importance of men's exposure to non-persistent endocrine disruptors (EDCs) and couple fecundability, as measured by time-to-pregnancy (TTP). This evolving literature contrasts with the largely equivocal findings reported for women's exposures and fecundity. While most evidence relies upon urinary concentrations, quantification of EDCs in seminal plasma may be more informative about potential toxicity arising within the testes. We analyzed 5 chemical classes of non-persistent EDCs in seminal plasma for 339 male partners of couples who were recruited prior to conception and who were followed daily until pregnant or after one year of trying. Benzophenones, bisphenols, parabens, and phthalate metabolites and phthalate diesters were measured using high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) except for phthalate diesters, which were analyzed using gas chromatography-mass spectrometry. Cox regression with discrete-time was used to estimate fecundability odds ratios (FORs) and 95% confidence intervals (CIs) for each chemical to estimate the probability of pregnancy. While most EDCs were detected in seminal plasma, concentrations were lower than urinary concentrations previously analyzed for the cohort. None of the EDCs were significantly associated with fecundability even after covariate adjustment, though benzophenones consistently yielded FORs <1.0 (ranging from 0.72 to 0.91) in couple-adjusted models suggestive of diminished fecundity (longer TTP). The findings underscore that a range of EDCs can be quantified in seminal plasma, but the lower concentrations may require a large cohort for assessing couple fecundability, as well as the need to consider other fecundity outcomes such as semen quality., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Study Question: Are biomarkers of preconception stress associated with pregnancy loss?, Summary Answer: Preconception stress, as measured by basal salivary cortisol and alpha-amylase concentrations, is not associated with pregnancy loss., What Is Known Already: Many studies, most of which have been retrospective, have identified an association between stressful life events and perceived stress and miscarriage., Study Design, Size, Duration: A prospective pregnancy study with preconception enrollment was conducted between 2005 and 2009. Among the 344 women who became pregnant during the Longitudinal Investigation of Fertility and the Environment (LIFE) study, 337 (98%) had salivary biomarker data for analysis., Participants/materials, Setting, Methods: Couples planning pregnancy were followed for up to 12 months as they tried to become pregnant and through pregnancy if it occurred. Participating women collected a basal saliva sample on the morning following enrollment and a second on the morning following their next menses to measure cortisol and alpha-amylase, biomarkers of stress. Women used home pregnancy tests on the day of expected menses. A pregnancy loss was defined as a negative pregnancy test following a positive pregnancy test, the onset of menses, or for pregnancies that survived to clinical recognition, recognition of the loss by a healthcare provider., Main Results and the Role of Chance: Among the 337 couples, the median age of female and male partners was 29 and 31 years, respectively. Most of the women were non-Hispanic white (83%) and highly educated. There were 97 pregnancy losses reported among the 337 pregnancies. The median gestational age at loss was 6 weeks 5 days with only two losses occurring in the second trimester. Using Cox proportional hazards models, we found no clear pattern of association between two preconceptional biomarkers of stress (salivary cortisol and alpha-amylase concentrations) modeled both continuously or in tertiles and incident pregnancy loss after adjustment for confounders., Limitations Reasons for Caution: Our prior work suggests that women enrolled in the LIFE Study had lower stress levels than women in the general population. Owing to concerns regarding participant burden, we were unable to collect serial saliva measurements, which would have allowed us to examine the association between stress in early pregnancy and pregnancy loss. Further, with regard to the measurement of perceived stress, the Cohen's Perceived Stress Scale was only administered at baseline. While every attempt was made to ensure diversity in the cohort, non-Hispanic white women were over-represented, therefore it is possible that the results might not be generalizable to all women., Wider Implications of the Findings: In one of the largest studies in the USA to prospectively capture data on the incidence of early pregnancy loss, we found no clear association between two biomarkers of preconception stress (measured in saliva) and pregnancy loss., Study Funding/competing Interest(s): This study was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (contracts #N01-HD-3-3355, N01-HD-3-3356, N01-HD-3358). There are no conflicts of interest to declare., Trial Registration Number: Not applicable.

Background: Little is known about the predictors of sexual intercourse frequency (SIF) among couples trying to conceive despite the well-established link between SIF and fecundity., Aim: To evaluate men's and women's demographic, occupational, and lifestyle predictors of SIF among couples., Methods: 469 Couples without a history of infertility participating in the Longitudinal Investigation of Fertility and the Environment Study (2005-2009) were followed up for ≤1 year while trying to conceive. At enrollment, both partners were interviewed about demographic, occupational, lifestyle, and psychological characteristics using standardized questionnaires. Multivariable generalized linear mixed models with Poisson distribution were used to estimate the adjusted percent difference in SIF across exposure categories., Outcomes: SIF was recorded in daily journals and summarized as average SIF/mo., Results: The median (interquartile range) SIF during follow-up was 6 (4-9) acts/mo. For every year increase in age for women and men, SIF decreased by -0.8% (95% CI -2.5 to 1.0%) and -1.7% (95% CI -3.1 to -0.3%). Women with high school education or less and those of non-white race had 34.4% and 16.0% higher SIF, respectively. A similar trend was seen for men's education and race. Only couples where both partners (but not just 1 partner) worked rotating shifts had -39.1% (95% CI -61.0 to -5.0%) lower SIF compared to couples where neither partner worked rotating shifts. Men's (but not women's) exercise was associated with 13.2% (95% CI 1.7-26.0%) higher SIF. Diagnosis of a mood or anxiety disorder in men (but not women) was associated with a 26.0% (95% CI -42.7 to -4.4%) lower SIF. Household income, smoking status, body mass index, night work, alcohol intake, and psychosocial stress were not associated with SIF., Clinical Translation: Even among couples trying to conceive, there was substantial variation in SIF. Both partners' age, education, race, and rotating shift work as well as men's exercise and mental health play an important role in determining SIF., Conclusions: As this was a secondary analysis of an existing study, we lacked information on many pertinent psychological and relationship quality variables and the hormonal status of participants, which could have affected SIF. The unique population-based couple design, however, captured both partners' demographics, occupational characteristics, and lifestyle behaviors in advance of their daily, prospective reporting of SIF, which was a major strength. Important predictors of SIF among couples attempting to conceive include men's exercise and mental health and both partners' age, education, race, and rotating shift work. Gaskins AJ, Sundaram R, Buck Louis GM, et al. Predictors of Sexual Intercourse Frequency Among Couples Trying to Conceive. J Sex Med 2018;15:519-528., (Copyright © 2018 International Society for Sexual Medicine. All rights reserved.)

Study Question: Is iodine deficiency associated with decreased fecundability?, Summary Answer: Moderate to severe iodine deficiency is associated with a 46% decrease in fecundability., What Is Known Already: Iodine deficiency is common in women of childbearing age but its effect on fecundability has not been investigated., Study Design, Size, Duration: The LIFE Study, a population-based prospective cohort study, enrolled 501 women who had discontinued contraception within 2 months to become pregnant between 2005 and 2009., Participants/materials, Setting, Methods: Women reported on risk factors for infertility by interview then kept daily journals of relevant information. Women used fertility monitors to time intercourse relative to ovulation then used home digital pregnancy tests to identify pregnancies on the day of expected menstruation. Urine samples for iodine analysis were collected on enrollment., Main Results and the Role of Chance: Samples were in the deficiency range in 44.3% of participants. The group whose iodine-creatinine ratios were below 50 μg/g (moderate to severe deficiency) had a 46% reduction in fecundity (P = 0.028) compared with the group whose iodine-creatinine ratios were in the adequate range: adjusted fecundability odds ratio of becoming pregnant per cycle, 0.54 (95% confidence interval 0.31-0.94)., Limitations, Reasons for Caution: Iodine concentrations vary within individuals over time, so the data must be interpreted by group as we have done; residual confounding is possible., Wider Implications of the Findings: Significant delays in becoming pregnant occur at iodine concentrations that are common in women in the USA and parts of Europe. Replicating these findings will be important to determine whether improving iodine status could be beneficial in improving fecundability., Study Funding/competing Interest(s): This study was funded by the Intramural Research Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, USA. Contracts N01-HD-3-3355; N01-HD-3-3356; N01-HD-3-3358 and HHSN275201100001l/HHSN27500007. None of the authors has any conflict of interest to declare.

Recent declines in the secondary sex ratio (SSR), defined as the ratio of males to females at birth, in some industrialized countries may be attributed to exposure to environmental toxicants such as persistent organic pollutants (POPs). This study aimed to evaluate the association of couples' preconception exposure to POPs with the SSR. The study cohort comprised 235 couples who were enrolled in the Longitudinal Investigation of Fertility and the Environment (LIFE) Study between 2005 and 2009 prior to conception and prospectively followed through delivery of a singleton birth. Upon enrollment, couples' serum concentrations (ng/g) were measured for 9 organochlorine pesticides, 1 polybrominated biphenyl, 10 polybrominated diphenyl ethers, and 36 polychlorinated biphenyls (PCBs). Birth outcome data including infant sex were collected upon delivery. Modified Poisson regression models were used to estimate the relative risks (RRs) and 95% confidence intervals (CIs) of a male birth for each chemical. Of the 56 POPs examined, maternal PCB 128 and paternal hexachlorobenzene were significantly associated with a female excess (RRs, 0.75 [95% CI, 0.60-0.94] and 0.81 [95% CI, 0.68-0.97] per 1SD increase in log-transformed serum chemical concentrations, respectively), whereas maternal mirex and paternal PCB 128 and p,p'-dichlorodiphenyldichloroethylene were significantly associated with a male excess (RR range, 1.10-1.22 per 1SD increase in log-transformed serum chemical concentrations). After adjusting for multiple comparisons, only maternal mirex remained significantly associated with the SSR. This exploratory study on multiple classes of POPs demonstrated no conclusive evidence on the association between parental preconception exposure to POPs and the SSR., (Copyright © 2017 Elsevier Inc. All rights reserved.)