Publications by authors named "Rajeshwari Sundaram"

133 Publications

Predictors of Age at Juice Introduction and Associations with Subsequent Beverage Intake in Early and Middle Childhood.

J Nutr 2021 Sep 6. Epub 2021 Sep 6.

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

Background: The American Academy of Pediatrics recommends that if parents choose to introduce juice, they wait until ≥12 months, citing concerns of obesity and dental caries.

Objectives: We sought to identify correlates of early juice introduction (<6 months) and determine whether early introduction establishes a pattern of sugary beverage intake in childhood.

Methods: Upstate KIDS is a prospective birth cohort study with follow-up through 7 years (n = 4989). The age of juice introduction was assessed from responses on periodic questionnaires from 4-18 months and categorized as <6,  6 to <12, and ≥12 months. Sociodemographic information was reported using vital records or maternal questionnaires. At 24, 30, and 36 months and 7 years, mothers reported their child's regular juice, soda, water, and milk intakes. The analysis was restricted to singletons and 1 randomly selected twin from each pair with information on juice introduction (n = 4067). We assessed associations of sociodemographic correlates with juice introduction using Cox proportional hazard models. The relations of juice introduction with beverage intake were evaluated using Poisson or logistic regression for adjusted risk ratios (aRR) or ORs, adjusting for sociodemographic covariates and total beverage intake.

Results: Of the mothers, 25% and 74% introduced juice prior to 6 and 12 months, respectively. Younger maternal age; black or Hispanic race/ethnicity; lower educational attainment; Special Supplemental Nutrition Program for Women, Infants, and Children participation (yes); smoking during pregnancy; a higher pre-pregnancy BMI; a lower household income; and living in a townhouse/condominium or mobile home were associated with earlier juice introduction. Earlier juice introduction was related to a higher childhood juice intake, any soda intake, and lower water intake, holding total beverage intake constant [aRR, 1.5 (95% CI: 1.3-1.7; P-trend < 0.0001); adjusted OR 1.6 (95% CI: 1.0-2.4; P-trend = 0.01); aRR 0.9 (95% CI: 0.8-0.9; P-trend < 0.0001), respectively].

Conclusions: Markers of lower socioeconomic status are strongly associated with earlier juice introduction, which, in turn, relates to sugary beverage intake in childhood, potentially replacing water.
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http://dx.doi.org/10.1093/jn/nxab260DOI Listing
September 2021

Developmental outcomes in small for gestational age twins using a singleton versus twin birthweight reference in Upstate KIDS.

Am J Obstet Gynecol MFM 2021 Aug 17:100465. Epub 2021 Aug 17.

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

Background: Little is known about potential developmental delays in appropriately-grown twins, though they may be at higher risk for developmental delay than singletons. Small-for-gestational age (SGA) is a risk factor for developmental delay and typically based on singleton birthweight references, which may misclassify SGA in a subset of appropriately-grown twins.

Objective: To evaluate risk of developmental delay in twins classified as small-for-gestational age (SGA) according to twin and singleton birthweight references (<10 percentile).

Study Design: In a birth cohort (2008-2010) of twins (n=1790) and singletons (n=3829) with parent-completed Ages and Stages Questionnaires (ASQ) for child development between 4-36 months, we used a U.S. population-based birthweight reference to categorize singletons and twins as SGA. "Uncertain SGA" twins were defined as SGA by a singleton (<10 percentile) but not twin reference, and "twin-reference SGA" twins were SGA by a twin reference. Adjusted generalized linear mixed-effects models estimated odds of failure on any ASQ domain and each of five domains (Fine motor, Gross motor, Communication, Personal-Social, and Problem-Solving); random intercepts accounted for repeated measures and twin clustering.

Results: When compared to non-SGA twins (>10 percentile), uncertain SGA twins did not have higher odds of ASQ failure (aOR: 1.28; 95% CI: 0.91, 1.80). When compared to non-SGA singletons, both twin-reference and uncertain SGA twins had higher odds of ASQ failure, with the highest risk conferred to twin-reference SGA twins (twin-reference aOR: 3.14; 95% CI: 1.94, 5.10; uncertain aOR: 2.35; 95% CI: 1.69, 3.26; p-value for trend <0.01). Results remained consistent when limiting analyses to term births (≥37 weeks).

Conclusions: Although a singleton reference may overestimate SGA in twins, these findings indicate that a singleton birthweight reference may be appropriate for twins because it identifies more twins at-risk of developmental delay than a twin reference.
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http://dx.doi.org/10.1016/j.ajogmf.2021.100465DOI Listing
August 2021

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

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

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

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

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

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

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

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

Acute ambient air pollution exposure and placental Doppler results in the NICHD fetal growth studies - Singleton cohort.

Environ Res 2021 Jul 21;202:111728. Epub 2021 Jul 21.

Epidemiology Branch, Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD, USA; Department of Epidemiology and Environmental Health, School of Public Health and Health Professions, University at Buffalo, Buffalo, NY, USA. Electronic address:

Background: Increased placental vascular resistance is a proposed mechanism by which air pollution exposure during pregnancy lowers birth weight and increases pregnancy-induced hypertensive disorders.

Objective: To examine the impact of acute air pollution exposure during pregnancy on uterine and umbilical artery Doppler indicators of placental vascular resistance.

Methods: After a first ultrasound to confirm gestational age, 2562 pregnant women recruited in 12 clinics throughout the United States underwent up to five standardized ultrasounds with Doppler measurements. Exposures to 11 air pollutants were estimated for the hour of ultrasound and each of the 2 h prior to ultrasound at the clinics using the National Air Quality Forecast Capability reanalysis products. We used mixed logistic regression to study the longitudinal odds ratio (OR) of any, uni- or bi-lateral systolic and diastolic uterine artery notching compared to no notching and the longitudinal OR of abnormal end diastolic flow of the umbilical artery compared to forward flow. Uterine and umbilical artery resistance indexes were studied using linear mixed models.

Results: Each inter-quartile range (IQR) increase of particulate matter < 2.5 μm, nitrate, ammonium, primary organic matter (POM) and nitrogen dioxide during the hour of ultrasound was associated with a decreased risk of unilateral systolic notch and with increased resistance index of the left uterine artery. For the umbilical artery, each IQR increase in ozone was associated with decreased resistance index (b: -0.26, 95 % CI: -0.52, -0.01) and with a decreased risk of abnormal end diastolic flow (OR: 0.36, 95 % CI: 0.14, 0.94); while each IQR increase of elemental carbon and POM was associated with increased risk of abnormal end diastolic flow (OR: 1.47, 95 % CI: 1.02, 2.13 and OR: 1.67, 95 % CI: 1.17, 2.39, respectively).

Discussion: Our results suggest acute air pollution exposure may influence placental vascular resistance.
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http://dx.doi.org/10.1016/j.envres.2021.111728DOI Listing
July 2021

Gestational age at term delivery and children's neurocognitive development.

Int J Epidemiol 2021 Jul 15. Epub 2021 Jul 15.

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

Background: Preterm birth is associated with lower neurocognitive performance. However, whether children's neurodevelopment improves with longer gestations within the full-term range (37-41 weeks) is unclear. Given the high rate of obstetric intervention in the USA, it is critical to determine whether long-term outcomes differ for children delivered at each week of term.

Methods: This secondary analysis included 39 199 live-born singleton children of women who were admitted to the hospital in spontaneous labour from the US Collaborative Perinatal Project (1959-76). At each week of term gestation, we evaluated development at 8 months using the Bayley Scales of Infant Development, 4 years using the Stanford-Binet IQ (SBIQ) domains and 7 years using the Wechsler Intelligence Scales for Children (WISC) and Wide-Range Achievement Tests (WRAT).

Results: Children's neurocognitive performance improved with each week of gestation from 37 weeks, peaking at 40 or 41 weeks. Relative to those delivered at 40 weeks, children had lower neurocognitive scores at 37 and 38 weeks for all assessments except SBIQ and WISC Performance IQ. Children delivered at 39 weeks had lower Bayley Mental (β = -1.18; confidence interval -1.77, -0.58) and Psychomotor (β = -1.18; confidence interval -1.90, -0.46) scores. Results were similar for within-family analyses comparing siblings, with the addition of lower WRAT scores at 39 weeks.

Conclusions: The improvement in development scores across assessment periods indicates that each week up to 40 or 41 weeks of gestation is important for short- and long-term cognitive development, suggesting 40-41 weeks may be the ideal delivery window for optimal neurodevelopmental outcomes.
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http://dx.doi.org/10.1093/ije/dyab134DOI Listing
July 2021

Conception by fertility treatment and offspring deoxyribonucleic acid methylation.

Fertil Steril 2021 08 3;116(2):493-504. Epub 2021 Apr 3.

Department of Epidemiology and Biostatistics, University at Albany School of Public Health, Albany, New York.

Objective: To investigate whether deoxyribonucleic acid (DNA) methylation at birth and in childhood differ by conception using assisted reproductive technologies (ART) or ovulation induction compared with those in children conceived without fertility treatment.

Design: Upstate KIDS is a matched exposure cohort which oversampled on newborns conceived by treatment.

Setting: New York State (excluding New York City).

Patient(s): This analysis included 855 newborns and 152 children at approximately 9 years of age.

Intervention(s): None.

Main Outcome Measure(s): DNA methylation levels were measured using the Illumina EPIC platform. Single CpG and regional analyses at imprinting genes were conducted.

Result(s): Compared to no fertility treatment, ART was associated with lower mean DNA methylation levels at birth in 11 CpGs (located in/near SYCE1, SPRN, KIAA2013, MYO1D, GET1/WRB-SH4BGR, IGF1R, SORD, NECAB3/ACTL10, and GET1) and higher mean methylation level in 1 CpG (KLK4; all false discovery rate P<.05). The strongest association (cg17676129) was located at SYCE1, which codes for a synaptonemal complex that plays a role in meiosis and therefore infertility. This CpG remained associated with newborn hypomethylation when the analysis was limited to those conceived with ICSI, but this may be because of underlying male infertility. In addition, nine regions in maternally imprinted genes (IGF1R, PPIEL, SVOPL GNAS, L3MBTL, BLCAP, HYMAI/PLAGL1, SNU13, and MEST) were observed to have decreased mean DNA methylation levels among newborns conceived by ART. In childhood, hypomethylation of the maternally imprinted gene, GNAS, persisted. No CpGs or regions were associated with ovulation induction.

Conclusion(s): ART but not ovulation induction was associated with hypomethylation at birth, but only one difference at an imprinting region appeared to persist in childhood.
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http://dx.doi.org/10.1016/j.fertnstert.2021.03.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8349775PMC
August 2021

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

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

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

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

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

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

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

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

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

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

Prenatal medication use in a prospective pregnancy cohort by pre-pregnancy obesity status.

J Matern Fetal Neonatal Med 2021 Mar 11:1-8. Epub 2021 Mar 11.

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

Background: The association between obesity (body mass index (BMI) ≥ 30 kg/m) and pattern of medication use during pregnancy in the United States is not well-studied. Higher pre-pregnancy BMI may be associated with increases or decreases in medication use across pregnancy as symptoms (e.g. reflux) or comorbidities (e.g. gestational diabetes) requiring treatment that may be associated with higher BMI could also change with advancing gestation.

Objectives: To determine whether prenatal medication use, by the number and types of medications, varies by pre-pregnancy obesity status.

Methods: In a secondary data analysis of a racially/ethnically diverse prospective cohort of pregnant women with low risk for fetal abnormalities enrolled in the first trimester of pregnancy and followed to delivery (singleton, 12 United States clinical sites), free text medication data were obtained at enrollment and up to five follow-up visits and abstracted from medical records at delivery.

Results: In 436 women with obesity and 1750 women without obesity (pre-pregnancy BMI, 19-29.9 kg/m), more than 70% of pregnant women (77% of women with and 73% of women without obesity) reported taking at least one medication during pregnancy, respectively (adjusted risk ratio (aRR)=1.10, 95% confidence interval (CI)=1.01, 1.20), with 81% reporting two and 69% reporting three or more. A total of 17 classes of medications were identified. Among medication classes consumed by at least 5% of all women, the only class that differed between women with and without obesity was hormones and synthetic substitutes (including steroids, progesterone, diabetes, and thyroid medications) in which women with obesity took more medications (11 vs. 5%, aRR = 1.9, 95% CI = 1.38, 2.61) compared to women without obesity. Within this class, a higher percentage of women with obesity took diabetes medications (2.3 vs. 0.7%) and progesterone (3.4 vs. 1.3%) than their non-obese counterparts. Similar percentages of women with and without obesity reported consuming medications in the remaining medication classes including central nervous system agents (50 and 46%), gastrointestinal drugs (43 and 40%), anti-infective agents (23 and 21%), antihistamines (20 and 17%), autonomic drugs (10 and 9%), and respiratory tract agents (7 and 6%), respectively ( > 0.05 for all adjusted comparisons). There were no differences in medication use by obesity status across gestation. Since the study exclusion criteria limited the non-obese group to women without thyroid disease, in a sensitivity analysis we excluded all women who reported thyroid medication intake and still a higher proportion of women with obesity took the hormones and synthetic substitutes class compared to women without obesity.

Conclusion: Our findings suggest that pre-pregnancy obesity in otherwise healthy women is associated with a higher use of only selected medications (such as diabetes medications and progesterone) during pregnancy, while the intake of other more common medication types such as analgesics, antibiotics, and antacids does not vary by pre-pregnancy obesity status. As medication safety information for prenatal consumption is insufficient for many medications, these findings highlight the need for a more in-depth examination of factors associated with prenatal medication use.
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http://dx.doi.org/10.1080/14767058.2021.1893296DOI Listing
March 2021

Perfluorooctanoic acid (PFOA) or perfluorooctane sulfonate (PFOS) and DNA methylation in newborn dried blood spots in the Upstate KIDS cohort.

Environ Res 2021 03 30;194:110668. Epub 2020 Dec 30.

Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, 6710B Rockledge Drive, Bethesda, MD, 20892, United States. Electronic address:

Perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) are persistent organic pollutants which may alter prenatal development, potentially through epigenetic modifications. Prior studies examining PFOS/PFOA and DNA methylation have relatively few subjects (n < 200) and inconsistent results. We examined relations of PFOA/PFOS with DNA methylation among 597 neonates in the Upstate KIDS cohort study. PFOA/PFOS were quantified in newborn dried blood spots (DBS) using high-performance liquid chromatography/tandem mass spectrometry. DNA methylation was measured using the Infinium MethylationEPIC BeadChip with DNA extracted from DBS. Robust linear regression was used to examine the associations of PFOA/PFOS with DNA methylation at individual CpG sites. Covariates included sample plate, estimated cell type, epigenetically derived ancestry, infant sex and plurality, indicators of maternal socioeconomic status, and prior pregnancy loss. In supplemental analysis, we restricted the analysis to 2242 CpG sites previously identified as Correlated Regions of Systemic Interindividual Variation (CoRSIVs) which include metastable epialleles. At FDR<0.05, PFOA concentration >90th percentile was related to DNA methylation at cg15557840, near SCRT2, SRXN1; PFOS>90th percentile was related to 2 CpG sites in a sex-specific manner (cg19039925 in GVIN1 in boys and cg05754408 in ZNF26 in girls). When analysis was restricted to CoRSIVs, log-scaled, continuous PFOS concentration was related to DNA methylation at cg03278866 within PTBP1. In conclusion, there was limited evidence of an association between high concentrations of PFOA/PFOS and DNA methylation in newborn DBS in the Upstate KIDS cohort. These findings merit replication in populations with a higher median concentration of PFOA/PFOS.
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http://dx.doi.org/10.1016/j.envres.2020.110668DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7946760PMC
March 2021

Trajectories of Maternal Postpartum Depressive Symptoms.

Pediatrics 2020 11;146(5)

Epidemiology Branch.

Objectives: To identify homogenous depressive symptom trajectories over the postpartum period and the demographic and perinatal factors linked to different trajectories.

Methods: Mothers ( = 4866) were recruited for Upstate KIDS, a population-based birth cohort study, and provided assessments of depressive symptoms at 4, 12, 24, and 36 months postpartum. Maternal demographic and perinatal conditions were obtained from vital records and/or maternal report.

Results: Four depression trajectories were identified: low-stable (74.7%), characterized by low symptoms at all waves; low-increasing (8.2%), characterized by initially low but increasing symptoms; medium-decreasing (12.6%), characterized by initially moderate but remitting symptoms; and high-persistent (4.5%), characterized by high symptoms at all waves. Compared with the high-persistent group, older mothers (maximum odds ratio [OR] of the 3 comparisons: 1.10; 95% confidence interval [CI]: 1.05 to 1.15) or those with college education (maximum OR: 2.52; 95% CI: 1.36 to 4.68) were more likely to be in all other symptom groups, and mothers who had a history of mood disorder (minimum OR: 0.07; 95% CI: 0.04 to 0.10) or gestational diabetes mellitus diagnosis (minimum OR: 0.23; 95% CI: 0.08 to 0.68) were less likely to be in other symptom groups. Infertility treatment, multiple births, prepregnancy BMI, gestational hypertension, and infant sex were not differentially associated with depressive symptom trajectories.

Conclusions: One-quarter of mothers in a population-based birth cohort had elevated depressive symptoms in 3 years postpartum. Screening for maternal depression beyond the postpartum period may be warranted, particularly after mood and diabetic disorders.
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http://dx.doi.org/10.1542/peds.2020-0857DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7772818PMC
November 2020

Racial/Ethnic Differences in Prenatal Supplement and Medication Use in Low-Risk Pregnant Women.

Am J Perinatol 2020 Oct 8. Epub 2020 Oct 8.

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

Objective:  This study aimed to describe the overall quantity and type of supplements and medications used during pregnancy in a low-risk cohort and to examine any racial/ethnic differences in intake.

Study Design:  We used data from 2,164 racially/ethnically diverse, nonobese, and low-risk pregnant women participating without pre-pregnancy chronic conditions in a prospective cohort study at 12 sites across the United States. Medication data were self-reported as free text in enrollment, follow-up visit questionnaires, and abstracted from medical records at delivery. Supplements and medications data were mapped to their active ingredients and categorized into corresponding classes using the Slone Drug Dictionary. The total number and classes of supplements and medications consumed during pregnancy were calculated. Modified Poisson regression models were used to estimate the racial/ethnic differences in supplements and medications intake. All models were adjusted for maternal sociodemographic factors and study site.

Results:  98% of women took at least one supplement during pregnancy, with prenatal vitamins/multivitamins being most common. While only 31% reported taking no medications during pregnancy, 23% took one, 18% took two, and 28% took three or more. The percentage of women taking at least one medication during pregnancy was highest among non-Hispanic white women and lowest among Asians (84 vs. 55%,  < 0.001). All racial/ethnic groups reported taking the same top four medication classes including central nervous system agents, gastrointestinal drugs, anti-infective agents, and antihistamines. Compared with non-Hispanic white women, Hispanic (adjusted relative risk [aRR]: 0.84, 95% confidence interval [CI]: 0.71-0.98), and Asian women (aRR: 0.83, 95% CI: 0.70-0.98) were less likely to take central nervous system agents, as well as gastrointestinal drugs (Hispanics aRR: 0.79, 95% CI: 0.66-0.94; Asians aRR = 0.75, 95% CI: 0.63-0.90), and antihistamines (Hispanics aRR: 0.65, 95% CI: 0.47-0.92).

Conclusion:  Supplement intake was nearly universal. Medication use was also common among this low-risk pregnancy cohort and differed by race/ethnicity. CLINICALTRIALS.

Gov Identifier:  NCT00912132.

Key Points: · In women without chronic conditions, medication use is common.. · Racial/ethnic differences exist in prenatal medications use.. · Almost all women use supplements during pregnancy..
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http://dx.doi.org/10.1055/s-0040-1717097DOI Listing
October 2020

Predicting the risk of cardiac myxoma in Carney complex.

Genet Med 2021 01 7;23(1):80-85. Epub 2020 Sep 7.

Section on Genetics and Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health, 10 Center Drive, Building 10, NIH-Clinical Research Center, Bethesda, MD, USA.

Purpose: Carney complex (CNC), is an autosomal dominant multiple neoplasia and lentiginosis syndrome. We aimed to identify risk factors associated with the occurrence and recurrence of cardiac myxomas, the predominant cause of death in CNC patients.

Methods: Patients with CNC were monitored prospectively between 1995 and 2020 for the development of cardiac myxomas.

Results: Of the 319 patients studied, 136 (42.6%) developed myxomas. The mean age at diagnosis was 28.7 ± 16.6 years in females and 25.0 ± 16.4 years in males. By age 30, 35% of females and 45% of males had at least one myxoma. The CNC-related lesions, lentigines, cutaneous, mucosal, or breast myxomas, thyroid nodules, pituitary adenoma, and schwannoma were significantly more frequent (all p < 0.05) among patients with myxomas. Forty-four percent of patients had recurrences; nearly all within the first 8 and 16 years for males and females, respectively. Recurrences were more common in females.

Conclusion: This is the largest study to date and provides the first-time risk estimates by age and gender for cardiac myxomas in CNC patients. Cardiac myxomas are common by age 30 and often recur, especially in women, but the risk drops in 10 to 20 years. These findings may guide patient counseling, screening intervals, and surgical approaches.

Clinical Trial Registration: Clinical Trial Registration: Defining the Genetic Basis for the Development of Primary Pigmented Nodular Adrenocortical Disease and the Carney complex, Registration number: NCT00001452 URL: https://clinicaltrials.gov/ct2/show/NCT00001452.
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http://dx.doi.org/10.1038/s41436-020-00956-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7796922PMC
January 2021

Newborn Iodine Status Is Not Related to Congenital Hypothyroidism.

J Nutr 2020 09;150(9):2429-2434

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

Background: Severe iodine deficiency or excess during pregnancy can cause congenital hypothyroidism (CH). Iodine deficiency is common in pregnant women in the United States.

Objectives: We conducted a nested case-control study in a cohort of ∼2.5 million births in California to determine whether iodine status is related to CH in a US population.

Methods: Dried blood spots from 907 newborns with CH identified by newborn screening and 909 unaffected controls matched by month of birth were obtained from the California Newborn Screening Program to measure whole-blood iodine concentration. Iodine status was compared between cases and controls, and logistic regression was used to assess the association between CH status and blood iodine concentrations. Iodine status was also compared between cases and controls among infants treated in a neonatal intensive care unit (NICU) because CH has been reported in infants exposed to high levels of iodine in the NICU.

Results: Blood iodine concentrations did not differ significantly between cases (median: 20.0 ng/mL; IQR: 12.1-29.8 ng/mL) and controls (median: 20.3 ng/mL; IQR: 12.5-30.9 ng/mL; P = 0.59). Neither extremely high nor extremely low blood iodine concentrations (1st, 5th, 95th, and 99th percentiles of the distribution) were more common in cases. Among infants treated in NICUs, however, cases had significantly (P = 0.01) higher iodine (median: 22.7 ng/mL; IQR: 16.4-32.1 ng/mL) compared with controls (median: 17.3 ng/mL; IQR: 8.3-26.6 ng/mL).

Conclusions: CH cases did not have significantly higher or lower iodine in this population, which is reassuring given that maternal iodine deficiency is common in the United States. Among newborns in the NICU, CH cases had higher blood iodine concentrations compared with controls, suggesting that excess iodine exposure in the NICU could be causing CH. It may be beneficial to monitor iodine exposure from surgical procedures, imaging, and iodine-containing disinfectants and to consider non-iodine alternatives.
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http://dx.doi.org/10.1093/jn/nxaa178DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7540063PMC
September 2020

Gestational Age at Birth and Risk of Developmental Delay: The Upstate KIDS Study.

Am J Perinatol 2021 08 6;38(10):1088-1095. Epub 2020 Mar 6.

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

Objective: The aim of this study is to model the association between gestational age at birth and early child development through 3 years of age.

Study Design: Development of 5,868 children in Upstate KIDS (New York State; 2008-2014) was assessed at 7 time points using the Ages and Stages Questionnaire (ASQ). The ASQ was implemented using gestational age corrected dates of birth at 4, 8, 12, 18, 24, 30, and 36 months. Whether children were eligible for developmental services from the Early Intervention Program was determined through linkage. Gestational age was based on vital records. Statistical models adjusted for covariates including sociodemographic factors, maternal smoking, and plurality.

Results: Compared with gestational age of 39 weeks, adjusted odds ratios (aOR) and 95% confidence intervals of failing the ASQ for children delivered at <32, 32-34, 35-36, 37, 38, and 40 weeks of gestational age were 5.32 (3.42-8.28), 2.43 (1.60-3.69), 1.38 (1.00-1.90), 1.37 (0.98-1.90), 1.29 (0.99-1.67), 0.73 (0.55-0.96), and 0.51 (0.32-0.82). Similar risks of being eligible for Early Intervention Program services were observed (aOR: 4.19, 2.10, 1.29, 1.20, 1.01, 1.00 [ref], 0.92, and 0.78 respectively for <32, 32-34, 37, 38, 39 [ref], 40, and 41 weeks).

Conclusion: Gestational age was inversely associated with developmental delays for all gestational ages. Evidence from our study is potentially informative for low-risk deliveries at 39 weeks, but it is notable that deliveries at 40 weeks exhibited further lower risk.
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http://dx.doi.org/10.1055/s-0040-1702937DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7507972PMC
August 2021

The associations of maternal polycystic ovary syndrome and hirsutism with behavioral problems in offspring.

Fertil Steril 2020 02;113(2):435-443

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

Objective: To study the associations between maternal polycystic ovary syndrome (PCOS) and hirsutism with offspring attention-deficit/hyperactivity disorder (ADHD), anxiety, conduct disorder, and behavioral problems.

Design: Prospective birth cohort study.

Setting: Not applicable.

Patient(s): A total of 1,915 mother-child dyads.

Intervention(s): None.

Main Outcome Measure(s): Maternal report of offspring ADHD, anxiety, or conduct disorder diagnosis at 7 to 8 years; emotional symptoms, behavioral problems (including peer relationship, conduct, hyperactivity/inattention), and prosocial problems measured with the Strengths and Difficulties Questionnaire (SDQ) at 7 years.

Result(s): Prevalence of PCOS and hirsutism were 12.0% and 3.9%; 84% of women with hirsutism had PCOS. After adjustment for sociodemographic covariates, prepregnancy body mass index, and parental history of affective disorders, children born to mothers with PCOS had higher risk of anxiety (adjusted risk ratio [aRR] 1.62; 95% confidence interval [CI], 1.02-2.57) and borderline emotional symptoms (aRR 1.66; 95% CI, 1.18-2.33) compared with children born to mothers without PCOS. The associations between maternal PCOS and offspring ADHD were positive but imprecise. Maternal hirsutism was related to a higher risk of children's ADHD (aRR 2.33; 95% CI, 1.28-4.24), conduct disorder (aRR 2.54; 95% CI 1.18-5.47), borderline emotional symptoms, peer relationship problems, and conduct problems (aRRs 2.61; 95% CI, 1.69-4.05; 1.92; 95% CI, 1.16-3.17; and 2.22; 95% CI, 1.30-3.79, respectively).

Conclusion(s): Maternal PCOS was associated with offspring anxiety, and hirsutism was related to other offspring behavioral problems. These findings should be interpreted with caution as replication is needed in prospective cohort studies that assess PCOS and hirsutism diagnoses using medical records.
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http://dx.doi.org/10.1016/j.fertnstert.2019.09.034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7185046PMC
February 2020

Parental Weight Status and Offspring Behavioral Problems and Psychiatric Symptoms.

J Pediatr 2020 05 14;220:227-236.e1. Epub 2020 Feb 14.

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

Objectives: To assess relations of prepregnancy maternal and paternal obesity with offspring behavioral problems and psychiatric symptoms at 7-8 years in the Upstate KIDS study, a prospective cohort study.

Study Design: Maternal body mass index (BMI) was calculated from prepregnancy height and weight provided in vital records or self-report at 4 months postpartum. Mothers reported paternal height and weight. At 7-8 years, mothers indicated if their children had been diagnosed with ADHD or anxiety (n = 1915). Additionally, children's behavior was measured with the Strengths and Difficulties Questionnaire at 7 years of age (n = 1386) and the Vanderbilt ADHD Diagnostic Parent Rating Scale at 8 years of age (n = 1484). Based on Strengths and Difficulties Questionnaire scores, we identified children with borderline behavioral problems. Adjusted risk ratios (aRR) and 95% CIs were estimated with robust multivariable Poisson regression.

Results: Compared with children of mothers with a BMI of <25, children whose mothers had BMI 25-30, 30-35, and ≥35 kg/m had higher risks of reported ADHD (aRR, 1.14, 95% CI, 0.78-1.69; aRR, 1.96, 95% CI, 1.29-2.98; and aRR, 1.82, 95% CI,1.21-2.74, respectively). Risks of hyperactivity problems identified by the Strengths and Difficulties Questionnaire and a positive screen for inattentive or hyperactive/impulsive behavior with the Vanderbilt ADHD Diagnostic Parent Rating Scale were also higher with increasing maternal prepregnancy BMI. Paternal BMI was not associated with child outcomes.

Conclusions: Our findings suggest that maternal, rather than paternal, obesity is associated with maternal report of child ADHD diagnosis and inattentive or hyperactivity problems. Further research is needed to understand how maternal obesity might influence these behavioral changes during or after pregnancy.
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http://dx.doi.org/10.1016/j.jpeds.2020.01.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7186145PMC
May 2020

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Association of Trajectory and Covariates of Children's Screen Media Time.

JAMA Pediatr 2020 01;174(1):71-78

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

Importance: Many children begin interacting with screen media as early as infancy. Although screen time is associated with negative developmental consequences, few longitudinal studies in the United States have examined covariates of screen time among children under 3 years of age.

Objectives: To identify trajectories of screen time among children aged 1 to 3 years, to examine their association with screen use at 8 years of age, and to assess potential determinants of screen time.

Design, Setting, And Participants: This prospective birth cohort study included 3895 children (3083 singletons and 812 unrelated multiples) in New York State who had screen time data available for at least 1 time point from 1 to 3 years of age; 1156 children had data at 8 years. The study spanned September 4, 2007, through June 12, 2014, in the first phase, and August 29, 2014, through November 15, 2019, in the second phase. Data analysis for the present study was conducted from September 28, 2018, to July 15, 2019.

Main Outcomes And Measures: Maternal reports of children's television, movie, and computer game times were summed for total daily screen time at 12, 18, 24, 30, and 36 months of age. Two screen time trajectories (low and increasing use) were classified by cluster analysis, and logistic regression was used to model risk factors for the increasing trajectory. Children exhibiting the highest 10th percentile of screen use at each point were examined, and linear mixed models were used to identify risk factors of this high exposure category.

Results: Among the 3895 children included in the analysis (2031 boys [52.1%] and 1864 girls [47.9%]), median daily screen time increased from 30 (interquartile range, 0-60) minutes at 12 months of age to 120 (interquartile range, 75-200) minutes at 36 months of age. Of 1045 children with complete data at all 5 time points, 279 (26.7%) had an increasing screen time trajectory. Female child sex (adjusted odds ratio [aOR], 0.90; 95% CI, 0.81-0.99) and graduate school levels of paternal (aOR, 0.73; 95% CI, 0.56-0.95) and maternal (aOR, 0.60; 95% CI, 0.47-0.77) education, compared with having completed college, were associated with lower risk of increasing trajectory. Maternal nulliparity was associated with higher risk of increasing trajectory (aOR, 1.14; 95% CI, 1.00-1.30). Children with an increasing trajectory from 1 to 3 years of age had an additional 22 (95% CI, 11-33) minutes per day of screen time at 8 years of age. Covariates associated with the highest 10th percentile of screen exposure included paterman graduate school education compared with college (aOR, 0.63; 95% CI, 0.39-0.99), maternal graduate school education compared with college (aOR, 0.55; 95% CI, 0.37-0.82), maternal nulliparity (aOR, 1.98; 95% CI, 1.50-2.61), twins compared with singletons (aOR, 1.41; 95% CI, 1.05-1.91), non-Hispanic black compared with non-Hispanic white race/ethnicity (aOR, 4.77; 95% CI, 2.25-10.10), and type of care (home-based care aOR, 2.17 [95% CI, 1.38-3.41]; parental care aOR, 2.11 [95% CI, 1.41-3.15]) compared with center-based care.

Conclusions And Relevance: These findings suggest that a range of parental and child characteristics are associated with screen time. Screen time habits appear to track from as early as infancy, emphasizing the need for earlier interventions.
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http://dx.doi.org/10.1001/jamapediatrics.2019.4488DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6902189PMC
January 2020

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

Epidemiology 2019 11;30 Suppl 2:S65-S75

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

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

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

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

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

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

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

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

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

Examining Endocrine Disruptors Measured in Newborn Dried Blood Spots and Early Childhood Growth in a Prospective Cohort.

Obesity (Silver Spring) 2019 01;27(1):145-151

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

Objective: The goal of this study was to determine whether newborn concentrations of perfluorooctane sulfonic acid (PFOS), perfluorooctanoic acid (PFOA), and bisphenol A (BPA) are associated with early childhood growth.

Methods: A total of 1,954 singletons and 966 twins from the Upstate KIDS Study (born 2008-2010) were included in this study. Newborn dried blood spot concentrations of PFOS, PFOA, and BPA were quantified by liquid chromatography tandem mass spectrometry. Children's weight and height were reported from birth through 3 years of age. Repeated measures were modeled using generalized linear mixed models.

Results: PFOS and PFOA were associated with lower BMI (-0.078 kg/m [-0.12 to -0.038] and -0.076 kg/m [-0.17 to -0.051] per 1 standard deviation increase in log PFOS and PFOA, respectively) and not with early obesity among singletons. Inconsistent associations were observed for twins. BPA levels were higher among neonates with a neonatal intensive care unit stay (P < 0.001), making associations difficult to interpret.

Conclusions: Perfluorinated alkyl substances did not exhibit obesogenic associations with early measures of childhood growth. Blood-based BPA measures are limited by the nonpersistent nature of the chemical, and unknown sources from hospital settings may present only transient exposures.
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http://dx.doi.org/10.1002/oby.22332DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6309795PMC
January 2019

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

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

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

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

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

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

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

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

Concentrations of perfluoroalkyl substances and bisphenol A in newborn dried blood spots and the association with child behavior.

Environ Pollut 2018 Dec 27;243(Pt B):1629-1636. Epub 2018 Sep 27.

Epidemiology Branch, Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, 6710B Rockledge Dr., MSC 7004, Bethesda, MD, USA. Electronic address:

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 = 1.65, 95%CI: 0.84-3.34; PFOS = 1.73, 95%CI: 0.87-3.43; and PFOS = 2.47, 95%CI: 1.29-4.72 compared to PFOS). 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.
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http://dx.doi.org/10.1016/j.envpol.2018.09.107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6221990PMC
December 2018

Concentrations of endocrine disrupting chemicals in newborn blood spots and infant outcomes in the upstate KIDS study.

Environ Int 2018 12 13;121(Pt 1):232-239. Epub 2018 Sep 13.

Dean's Office, College of Health and Human Services, George Mason University, Fairfax, VA, United States. Electronic address:

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.
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http://dx.doi.org/10.1016/j.envint.2018.09.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6376484PMC
December 2018

Endocrine disruptors and neonatal anthropometry, NICHD Fetal Growth Studies - Singletons.

Environ Int 2018 10 26;119:515-526. Epub 2018 Jul 26.

Wadsworth Center, New York State Department of Health and Department of Environmental Health Sciences, School of Public Health, State University of New York at Albany, Albany, New York 12201, USA.

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, 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.
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http://dx.doi.org/10.1016/j.envint.2018.07.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6267852PMC
October 2018

Concentrations of immune marker in newborn dried blood spots and early childhood development: Results from the Upstate KIDS Study.

Paediatr Perinat Epidemiol 2018 07 4;32(4):337-345. Epub 2018 Jul 4.

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

Background: Evidence shows cytokine dysregulation in children with developmental disabilities. The association between immune activity during the perinatal period and child development is less clear.

Methods: We examined the relationship between newborn concentrations of immune markers and child development. Within Upstate KIDS, a population-based birth cohort (2008-2010, upstate New York), we assayed immune markers, which are postulated to have neuro-modulatory effects, in newborn dried blood spots (NDBS, n = 3038). Mothers completed the Ages & Stages Questionnaire© (ASQ) for their children repeatedly through age 36 months. At 30 and 36 months, mothers also reported whether their children received any developmental services. We used generalised linear mixed models adjusted for maternal and child characteristics to test associations.

Results: Sixteen immune markers were associated with failing ASQ in unadjusted models. After full adjustment (for gestational age, mode of delivery, parity, pregnancy smoking, etc.), we observed that higher levels of 4 markers, including platelet-derived growth factor-AA (PDGF-AA, OR 0.77, 95% CI 0.67, 0.89), plasminogen activator inhibitor-1 (OR 0.80, 95% CI 0.68, 0.94), stromal cell derived factor-1 (OR 0.85, 95% CI 0.73, 0.98), and macrophage inflammatory protein-1beta (OR 0.87, 95% CI 0.77, 0.98) were associated with lower odds of ASQ failure. The associations did not exist if correction for multiple comparisons was performed, except for PDGF-AA. Analyses with developmental service use revealed similar null findings.

Conclusions: Immune marker concentrations in NDBS may not be associated with developmental delay in the general population. Newborn concentrations of growth factor PDGF-AA may be protective of developmental delay in childhood.
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http://dx.doi.org/10.1111/ppe.12485DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6763275PMC
July 2018

Seafood Intake, Sexual Activity, and Time to Pregnancy.

J Clin Endocrinol Metab 2018 07;103(7):2680-2688

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

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.
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http://dx.doi.org/10.1210/jc.2018-00385DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6276709PMC
July 2018

Maternal polycystic ovarian syndrome and offspring growth: the Upstate KIDS Study.

J Epidemiol Community Health 2018 09 22;72(9):852-855. Epub 2018 May 22.

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

Background: Polycystic ovarian syndrome (PCOS) is the most common cause of female infertility and is associated with higher levels of circulating androgens. Exposure to higher levels of androgens in utero may be a risk factor for obesity among children of women with PCOS.

Methods: We examined whether maternal PCOS was associated with differences in offspring growth and obesity in the Upstate KIDS study, a prospective cohort study of infants born in New York State (excluding New York City) oversampled for fertility treatments and multiple births. Measurements of offspring length/height and weight were recorded at doctor's visits through 3 years of age. PCOS diagnosis was self-reported by mothers at baseline. We used linear mixed models with robust SEs to estimate differences in growth by maternal PCOS exposure. We used logistic regression to examine whether infants experienced rapid weight gain at 4, 9 and 12 months. Growth measures were reported by 4098 mothers for 4949 children (1745 twins). Of these, 435 mothers (10.6%) had a diagnosis of PCOS.

Results: Compared with children born to mothers without PCOS, children of mothers with PCOS did not have significant differences in weight (4.81 g, 95% CI -95.1 to 104.7), length/height (0.18 cm, 95% CI -0.16 to 0.52) and body mass index (-0.14 kg/m, 95% CI -0.30 to 0.01) through 3 years of age. We also observed no association between maternal PCOS and offspring rapid weight gain.

Conclusions: Overall, we found little evidence to suggest that maternal PCOS influences early childhood growth in this large, prospective cohort study.
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http://dx.doi.org/10.1136/jech-2017-210004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6759926PMC
September 2018

Maternal polycystic ovarian syndrome and early offspring development.

Hum Reprod 2018 07;33(7):1307-1315

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

Study Question: Is maternal polycystic ovarian syndrome (PCOS) associated with developmental delays in offspring?

Summary Answer: Offspring of mothers with PCOS were at higher risk of failure on the Ages and Stages Questionnaire (ASQ).

What Is Known Already: There is growing evidence that offspring of mothers with PCOS may be at higher risk for developmental disorders due to potential exposure to hyperandrogenism and insulin resistance. Few studies exist regarding maternal PCOS and early childhood development in the USA.

Study Design, Size, Duration: The Upstate KIDS Study is a population-based prospective cohort study of infants born between 2008 and 2010 in New York State (excluding New York City), originally designed to study-and finding no impact of-infertility treatment exposure on child development. Children were followed up to 36 months of age. In all, 4453 mothers completed one or more developmental screening instruments for 5388 children (35.5% twins) up to 36 months of age.

Participants/materials, Setting, Methods: In our study, 458 mothers (10.3%) reported a healthcare provider's diagnosis of PCOS, as well as the related treatment received, on the baseline study questionnaire. Parents completed the ASQ on their child's development at 4, 8, 12, 18, 24, 30 and 36 months of age to assess fine motor, gross motor, communication, personal-social functioning and problem-solving cognitive domains. We used generalized linear mixed models to estimate odds ratios (OR) between PCOS diagnosis and failures in the ASQ adjusted for maternal age, race, BMI, education, marital status, smoking, alcohol consumption, diabetes, insurance and plurality.

Main Results And The Role Of Chance: Diagnosis of PCOS was associated with increased risk of the offspring failing the fine motor domain (adjusted odds ratio (aOR) = 1.77; 95% CI: 1.09, 2.89), largely driven by higher risk in female singletons (aOR = 2.23; 1.16, 4.29). Twins of mothers with PCOS had higher risk of failing the communication (aOR = 1.94; 1.19, 3.18) and personal-social functioning (aOR = 1.76; 1.12, 2.77) domains compared to twins born to mothers without PCOS. Compared to offspring of women without PCOS, offspring of women who reported receiving no treatment for their PCOS had a stronger association with failing the ASQ (aOR = 1.68; 0.95, 2.75) than the association among offspring of women who reported PCOS treatment (aOR = 1.16; 0.79, 1.73).

Limitations, Reasons For Caution: Further study is needed to confirm the role of maternal PCOS in early offspring development with provider-validated diagnosis of PCOS.

Wider Implications Of The Findings: If confirmed, these findings suggest that offspring of women with PCOS may be at increased risk for developmental delay.

Study Funding/competing Interest(s): Supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD; contracts HHSN275201200005C, #HHSN267200700019C). Authors have no competing interests to declare.

Trial Registration Number: Not applicable.
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http://dx.doi.org/10.1093/humrep/dey087DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6251548PMC
July 2018
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