Publications by authors named "Melissa M Smarr"

29 Publications

  • Page 1 of 1

Prenatal exposure to mixtures of persistent endocrine disrupting chemicals and postnatal body size in British girls.

Early Hum Dev 2021 Aug 14;161:105450. Epub 2021 Aug 14.

Department of Epidemiology, Rollins School of Public Health, Emory University, 1518 Clifton Rd NE, Atlanta, GA 30322, United States; Division of Environmental Health Science and Practice, National Center for Environmental Health, Centers for Disease Control and Prevention, 4770 Buford Hwy, Atlanta, GA 30341, United States.

Background: Endocrine disrupting chemical (EDC) exposure is ubiquitous. EDC exposure during critical windows of development may interfere with the body's endocrine system, affecting growth. Previous human studies have examined one EDC at a time in relation to infant growth. By studying mixtures, the human experience can be better approximated.

Aims: We investigated the association of prenatal exposure to persistent EDCs (per- and polyfluoroalkyl substances (PFAS), polychlorinated biphenyls (PCBs), and organochlorine pesticides (OCPs)) as mixtures with postnatal body size among female offspring.

Subjects: We used a sub-sample of the Avon Longitudinal Study of Parents and Children (N = 425), based in the United Kingdom.

Study Design: We quantified 52 EDCs in maternal serum collected during pregnancy. We used Bayesian kernel machine regression with a random intercept to examine the association of prenatal concentrations of EDC mixtures with longitudinal postnatal body size measures for each EDC class separately (PFAS, PCBs, and OCPs) and for all three classes combined.

Outcome Measures: Weight and height measures at 0, 2, 9, and 19 months were obtained by health professionals as part of routine child health surveillance.

Results: The mixture representing all three classes combined (31 chemicals) (n = 301) was inversely associated with postnatal body size. Holding all EDCs in the 31-chemical mixture at the 75th percentile compared to the 50th percentile was associated with 0.15 lower weight-for-age z-score (95% credible interval -0.26, -0.03). Weak inverse associations were also seen for height-for-age and body mass index-for-age scores.

Conclusions: These results suggest that prenatal exposure to mixtures of persistent EDCs may affect postnatal body size.
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http://dx.doi.org/10.1016/j.earlhumdev.2021.105450DOI 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

Associations of single and multiple per- and polyfluoroalkyl substance (PFAS) exposure with vitamin D biomarkers in African American women during pregnancy.

Environ Res 2021 Jul 18;202:111713. Epub 2021 Jul 18.

Gangarosa Department of Environmental Health, Rollins School of Public Health, Emory University, Atlanta, GA, USA. Electronic address:

Vitamin D has been linked to various physiological functions in pregnant women and their fetuses. Previous studies have suggested that some per- and polyfluoroalkyl substances (PFAS) may alter serum vitamin D concentrations. However, no study has investigated the relationship between PFAS and vitamin D in pregnant women. This study aims to evaluate the associations of serum PFAS with serum total and free 25-hydroxyvitamin D (25(OH)D) during pregnancy in a cohort of African American women in Atlanta, GA. Blood samples from 442 participants were collected in early pregnancy (8-14 weeks of gestation) for PFAS and 25(OH)D measurements, and additional samples were collected in late pregnancy (24-30 weeks) for the second 25(OH)D measurements. We fit multivariable linear regressions and weighted quantile sum (WQS) regressions to estimate the associations of individual PFAS and their mixtures with 25(OH)D concentrations. We found mostly positive associations of total 25(OH)D with PFHxS (perfluorohexane sulfonic acid), PFOS (perfluorooctane sulfonic acid), PFDA (perfluorodecanoic acid), and NMeFOSAA (N-methyl perfluorooctane sulfonamido acetic acid), and negative associations with PFPeA (perfluoropentanoic acid). For free 25(OH)D, positive associations were observed with PFHxS, PFOS, PFOA (perfluorooctanoic acid), and PFDA, and a negative association with PFPeA among the women with male fetuses in the models using 25(OH)D measured in late pregnancy. In mixture models, a quartile increase in WQS index was associated with 2.88 ng/mL (95%CI 1.14-4.59) and 5.68 ng/mL (95%CI 3.31-8.04) increases in total 25(OH)D measured in the early and late pregnancy, respectively. NMeFOSAA, PFDA, and PFOS contributed the most to the overall effects among the eight PFAS. No association was found between free 25(OH)D and the PFAS mixture. These results suggest that PFAS may affect vitamin D biomarker concentrations in pregnant African American women, and some of the associations were modified by fetal sex.
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http://dx.doi.org/10.1016/j.envres.2021.111713DOI Listing
July 2021

Prenatal Exposure to Mixtures of Persistent Endocrine-disrupting Chemicals and Birth Size in a Population-based Cohort of British Girls.

Epidemiology 2021 07;32(4):573-582

From the Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA.

Background: Previous studies of endocrine-disrupting chemicals have examined one of these chemicals at a time in association with an outcome; studying mixtures better approximates human experience. We investigated the association of prenatal exposure to mixtures of persistent endocrine disruptors (perfluoroalkyl and polyfluoroalkyl substances [PFAS], polychlorinated biphenyls [PCBs], and organochlorine pesticides) with birth size among female offspring in the Avon Longitudinal Study of Parents and Children (ALSPAC), based in the United Kingdom in 1991-1992.

Methods: We quantified concentrations of 52 endocrine-disrupting chemicals in maternal serum collected during pregnancy at median 15-week gestation. Birth weight, crown-to-heel length, and head circumference were measured at birth; ponderal index and small for gestational age were calculated from these. We used repeated holdout Weighted Quantile Sum (WQS) regression and Bayesian kernel machine regression to examine mixtures in 313 mothers.

Results: Using WQS regression, all mixtures (each chemical class separately and all three together) were inversely associated with birth weight. A one-unit increase in WQS index (a one-decile increase in chemical concentrations) for all three classes combined was associated with 55 g (β = -55 g, 95% confidence interval [CI] = -89, -22 g) lower birth weight. Associations were weaker but still inverse using Bayesian kernel machine regression. Under both methods, PFAS were the most important contributors to the association with birth weight. We also observed inverse associations for crown-to-heel length.

Conclusions: These results are consistent with the hypothesis that prenatal exposure to mixtures of persistent endocrine-disrupting chemicals affects birth size.
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http://dx.doi.org/10.1097/EDE.0000000000001351DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8159871PMC
July 2021

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

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

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

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

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

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

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

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

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

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

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

Prenatal exposure to mixtures of persistent endocrine disrupting chemicals and early menarche in a population-based cohort of British girls.

Environ Pollut 2021 May 9;276:116705. Epub 2021 Feb 9.

Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA, United States; National Center for Environmental Health, Centers for Disease Control and Prevention, Atlanta, GA, United States.

Exposure to endocrine disrupting chemicals (EDCs) is ubiquitous. EDC exposure, especially during critical periods of development like the prenatal window, may interfere with the body's endocrine system, which can affect growth and developmental outcomes such as puberty. Most studies have examined one EDC at a time in relation to disease; however, humans are exposed to many EDCs. By studying mixtures, the human experience can be more closely replicated. We investigated the association of prenatal exposure to persistent EDCs (poly- and perfluoroalkyl substances (PFAS), polychlorinated biphenyls (PCBs), and organochlorine pesticides (OCPs)) as mixtures with early menarche among female offspring in a nested case-control study within the Avon Longitudinal Study of Parents and Children (ALSPAC) recruited in the United Kingdom in 1991-1992. Concentrations of 52 EDCs were quantified in maternal serum samples collected during pregnancy. Daughter's age at menarche was ascertained through mailed questionnaires sent annually. We used repeated holdout weighted quantile sum (WQS) regression and Bayesian kernel machine regression (BKMR) to examine the association between prenatal exposure to multiple EDCs and early menarche (<11.5 (n = 218) vs. ≥11.5 years (n = 230)) for each chemical class separately (PFAS, PCBs, and OCPs) and for all three classes combined. Models adjusted for maternal age at menarche, maternal education, parity, pre-pregnancy body mass index, maternal age, prenatal smoking, and gestational week at sample collection. Mixture models showed null associations between prenatal exposure to EDC mixtures and early menarche. Using WQS regression, the odds ratio for early menarche for a one-decile increase in chemical concentrations for all three classes combined was 0.89 (95% CI: 0.76, 1.05); using BKMR, the odds ratio when all exposures were at the 60th percentile compared to the median was 0.98 (95% CI: 0.91, 1.05). Results suggest the overall effect of prenatal exposure to persistent EDC mixtures is not associated with early menarche.
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http://dx.doi.org/10.1016/j.envpol.2021.116705DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8111784PMC
May 2021

Serum per- and polyfluoroalkyl substance (PFAS) concentrations and predictors of exposure among pregnant African American women in the Atlanta area, Georgia.

Environ Res 2021 07 10;198:110445. Epub 2020 Nov 10.

Gangarosa Department of Environmental Health, Rollins School of Public Health, Emory University, Atlanta, GA, USA. Electronic address:

Exposure to per- and polyfluoroalkyl substances (PFAS) has been associated with adverse health outcomes, especially when exposure occurs within sensitive time windows such as the pre- and post-natal periods and early childhood. However, few studies have focused on PFAS exposure distribution and predictors in pregnant women, especially among African American women. We quantified serum concentrations of the four most common PFAS collected in all 453 participants and an additional 10 PFAS in 356 participants who were pregnant African American women enrolled from 2014 to 2018 in Atlanta, Georgia, and investigated the sociodemographic predictors of exposure. Additional home environment and behavior predictors were also examined in 130 participants. Perfluorohexane sulfonic acid (PFHxS), perfluorooctane sulfonic acid (PFOS), perfluorooctanoic acid (PFOA), and perfluorononanoic acid (PFNA) were detected in >95% of the samples with PFOS having the highest concentrations (geometric mean (GM) 2.03 ng/mL). N-Methyl perfluorooctane sulfonamido acetic acid (NMeFOSAA), perfluoropentanoic acid (PFPeA), perfluorodecanoic acid (PFDA), and perfluoroundecanoic acid (PFUnDA) were found in 40-50% of the samples, whereas the detection frequencies for the other six PFAS were below 15%. When compared to National Health and Nutrition Examination Survey (NHANES) participants matching sex, race, and age with this study, our results showed similar concentrations of most PFAS, but higher concentrations of PFHxS (GM 0.99 ng/mL in this study; 0.63 and 0.4 ng/mL in NHANES, 2014-2015 and 2016-2017 cycles). A decline in concentrations over the study period was found for most PFAS but not PFPeA. In adjusted models, education, sampling year, parity, BMI, tobacco and marijuana use, age of house, drinking water source, and cosmetic use were significantly associated with serum PFAS concentrations. Our study reports the first PFAS exposure data among pregnant African American women in the Atlanta area, Georgia. The identified predictors will facilitate the setting of research priorities and enable development of exposure mitigation strategies.
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http://dx.doi.org/10.1016/j.envres.2020.110445DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8107192PMC
July 2021

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

Comparison of fetal growth by maternal prenatal acetaminophen use.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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 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

Preconception seminal plasma concentrations of endocrine disrupting chemicals in relation to semen quality parameters among male partners planning for pregnancy.

Environ Res 2018 11 4;167:78-86. Epub 2018 Jul 4.

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

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.
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http://dx.doi.org/10.1016/j.envres.2018.07.004DOI Listing
November 2018

Male urinary biomarkers of antimicrobial exposure and bi-directional associations with semen quality parameters.

Reprod Toxicol 2018 04 21;77:103-108. Epub 2018 Feb 21.

Office of the Director, 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 20829, USA; Dean's Office, College of Health and Human Services, George Mason University, 4400 University Ave., Fairfax, VA 22030, USA. Electronic address:

Antimicrobials including parabens, triclosan, and triclocarban have endocrine disrupting properties. Among 501 male partners of couples planning to become pregnant, preconception urinary biomarkers of parabens, triclosan and triclocarban exposure were quantified in spot urine samples. Men also provided two fresh semen samples collected approximately one month to undergo 24-h semen quality analysis. Linear mixed-effects models, adjusted for creatinine, race, age and body mass index, were utilized to assess the relationship between log transformed chemical concentrations rescaled by their standard deviations and semen parameters. Methyl, ethyl and butyl parabens, were associated with diminished sperm count and several sperm motility parameters. Hydroxylated paraben metabolites and triclosan were significantly positively associated with select semen quality parameters. Overall, our findings suggest that specific urinary parabens found in consumer goods (methyl, ethyl and butyl parabens) may adversely impact sperm quality parameters among reproductive-age male partners of couples trying for pregnancy.
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http://dx.doi.org/10.1016/j.reprotox.2018.02.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5878147PMC
April 2018

Endocrine disrupting chemicals in seminal plasma and couple fecundity.

Environ Res 2018 05 22;163:64-70. Epub 2018 Feb 22.

Wadsworth Center, New York State Department of Health, Department of Environmental Health Sciences, School of Public Health, State University of New York at Albany, Albany, New York 12201, United States. Electronic address:

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.
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http://dx.doi.org/10.1016/j.envres.2018.01.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5878734PMC
May 2018

Characterization of Thermal and Mechanical Indices from Serial Ultrasound Exams and Associations with Neonatal Anthropometry: The NICHD Fetal Growth Studies.

Am J Perinatol 2018 06 30;35(7):632-642. Epub 2017 Nov 30.

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

Objective: This article aims to determine if the number of maternal ultrasound scans where the highest thermal (TI) or mechanical (MI) indices recorded during obstetrical ultrasound exceed 1.0 were associated with neonatal anthropometric measurements.

Study Design: A prospective cohort of 2,334 nonobese low-risk pregnant women from 12 U.S. clinical sites underwent a total of six ultrasound scans, for which the highest TI and MI values were recorded. Neonatal anthropometric measurements were obtained within 12 to 24 hours of delivery. Multiple linear regression models adjusted for maternal race/ethnicity, body mass index, weight gain, and gestational age were used to examine associations between the number of maternal ultrasounds during gestation with a TI or MI exceeding 1.0 and the mean change in neonatal anthropometry.

Results: Ultrasounds with TI or MI >1.0 were not associated with birth weight, neonatal length, nor head, chest, and abdominal circumferences. TI >1.0 was negatively associated with neonatal mid-upper arm and mid-upper thigh circumferences. MI >1.0 was negatively associated with neonatal skinfold measurements of the anterior thigh and triceps, and neonatal circumferences of the mid-upper thigh and umbilicus.

Conclusion: Prenatal ultrasound examinations in which TI or MI intermittently exceeded 1.0 did not identify a pattern of alterations of birth size.
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http://dx.doi.org/10.1055/s-0037-1608926DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6177281PMC
June 2018

The Exposome Research Paradigm: an Opportunity to Understand the Environmental Basis for Human Health and Disease.

Curr Environ Health Rep 2017 03;4(1):89-98

Department of Biomedical Informatics, Harvard Medical School, 10 Shattuck St., Boston, MA, 02115, USA.

Purpose Of Review: This paper presents an overview of the exposome research paradigm with particular application to understanding human reproduction and development and its implications for health across a lifespan.

Recent Findings: The exposome research paradigm has generated considerable discussion about its feasibility and utility for delineating the impact of environmental exposures on human health. Early initiatives are underway, including smaller proof-of-principle studies and larger concerted efforts. Despite the notable challenges underlying the exposome paradigm, analytic techniques are being developed to handle its untargeted approach and correlated and multi-level or hierarchical data structures such initiatives generate, while considering multiple comparisons. The relatively short intervals for critical and sensitive windows of human reproduction and development seem well suited for exposome research and may revolutionize our understanding of later onset diseases. Early initiatives suggest that the exposome paradigm is feasible, but its utility remains to be established with applications to population human health research.
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http://dx.doi.org/10.1007/s40572-017-0126-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5363405PMC
March 2017

Low-level environmental metals and metalloids and incident pregnancy loss.

Reprod Toxicol 2017 04 2;69:68-74. Epub 2017 Feb 2.

Laboratory of Inorganic and Nuclear Chemistry, Wadsworth Center, New York State Department of Health, Albany, NY 12201-0509 USA; Department of Environmental Health Sciences, School of Public Health, The University at Albany, State University of New York, Albany, NY 12201-0509 USA. Electronic address:

Environmental exposure to metals and metalloids is associated with pregnancy loss in some but not all studies. We assessed arsenic, cadmium, mercury, and lead concentrations in 501 couples upon trying for pregnancy and followed them throughout pregnancy to estimate the risk of incident pregnancy loss. Using Cox proportional hazard models, we estimated hazard ratios (HR) and 95% confidence intervals (CIs) for pregnancy loss after covariate adjustment for each partner modeled individually then we jointly modeled both partners' concentrations. Incidence of pregnancy loss was 28%. In individual partner models, the highest adjusted HRs were observed for female and male blood cadmium (HR=1.08; CI 0.81, 1.44; HR=1.09; 95% CI 0.84, 1.41, respectively). In couple based models, neither partner's blood cadmium concentrations were associated with loss (HR=1.01; 95% CI 0.75, 1.37; HR=0.92; CI 0.68, 1.25, respectively). We observed no evidence of a significant relation between metal(loids) at these environmentally relevant concentrations and pregnancy loss.
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http://dx.doi.org/10.1016/j.reprotox.2017.01.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5406243PMC
April 2017

Is human fecundity changing? A discussion of research and data gaps precluding us from having an answer.

Hum Reprod 2017 03;32(3):499-504

Office of the Director, Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, 6710B Rockledge Dr. Room 3131A, Bethesda, MD 20829, USA.

Fecundity, the biologic capacity to reproduce, is essential for the health of individuals and is, therefore, fundamental for understanding human health at the population level. Given the absence of a population (bio)marker, fecundity is assessed indirectly by various individual-based (e.g. semen quality, ovulation) or couple-based (e.g. time-to-pregnancy) endpoints. Population monitoring of fecundity is challenging, and often defaults to relying on rates of births (fertility) or adverse outcomes such as genitourinary malformations and reproductive site cancers. In light of reported declines in semen quality and fertility rates in some global regions among other changes, the question as to whether human fecundity is changing needs investigation. We review existing data and novel methodological approaches aimed at answering this question from a transdisciplinary perspective. The existing literature is insufficient for answering this question; we provide an overview of currently available resources and novel methods suitable for delineating temporal patterns in human fecundity in future research.
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http://dx.doi.org/10.1093/humrep/dew361DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5850610PMC
March 2017

Proximity to major roadways and prospectively-measured time-to-pregnancy and infertility.

Sci Total Environ 2017 Jan 23;576:172-177. Epub 2016 Oct 23.

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

We aimed to study the potential impact of proximity to major roadways on time-to-pregnancy and infertility in couples attempting pregnancy in the Longitudinal Investigation of Fertility and Environment (LIFE) study (2005-2009), a population-based, prospective cohort study. Couples attempting pregnancy (n=500) were enrolled and followed prospectively until pregnancy or 12months of trying and 393 couples (78%) had complete data and full follow-up. Time-to-pregnancy was based on a standard protocol using fertility monitors, tracking estrone-3-glucuonide and luteinizing hormone, and pregnancy test kits to detect human chorionic gonadotropin (hCG). The fecundability odds ratio (FOR) and 95% confidence interval (CI) were estimated using proportional odds models. Infertility was defined as 12months of trying to conceive without an hCG pregnancy and the relative risk (RR) and 95% CI were estimated with log-binomial regression. Final models were adjusted for age, parity, study site, and salivary alpha-amylase, a stress marker. Infertile couples (53/393; 14%) tended to live closer to major roadways on average than fertile couples (689m vs. 843m, respectively) but the difference was not statistically significant. The likelihood of pregnancy was increased 3% for every 200m further away the couples residence was from a major roadway (FOR=1.03; CI=1.01-1.06). Infertility also appeared elevated at moderate distances compared to 1000m or greater, but estimates lacked precision. Our findings suggest that proximity to major roadways may be related to reductions in fecundity. Prospective data from larger populations is warranted to corroborate these findings.
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http://dx.doi.org/10.1016/j.scitotenv.2016.10.038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5164942PMC
January 2017

Endocrine disrupting chemicals and endometriosis.

Fertil Steril 2016 09 15;106(4):959-66. Epub 2016 Jul 15.

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

Endometriosis is an estrogen dependent gynecologic disease with lasting implications for many women's fertility, somatic health, and overall quality of life. Growing evidence suggests that endocrine disrupting chemicals (EDCs) may be etiologically involved in the development and severity of disease. We weigh the available human evidence focusing on EDCs and endometriosis, restricting to research that has individually quantified chemical concentrations for women, included a comparison group of unaffected women, and used multivariable analytic techniques. Evidence supporting an environmental etiology for endometriosis includes metals/trace elements, dioxins, and other persistent organic pollutants, as well as nonpersistent chemicals, such as benzophenones and phthalates. To address the equivocal findings for various EDCs, future research directions for filling data gaps include [1] use of integrated clinical and population sampling frameworks allowing for incorporation of new diagnostic modalities; [2] the collection of various biologic media, including target tissues for quantifying exposures; [3] study designs that offer various comparison groups to assess potentially shared etiologies with other gynecologic disorders; and [4] novel laboratory and statistical approaches that fully explore all measured EDCs for the assessment of mixtures and low dose effects and the use of directed acyclic graphs and supporting causal analysis for empirically delineating relationships between EDCs and endometriosis.
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http://dx.doi.org/10.1016/j.fertnstert.2016.06.034DOI Listing
September 2016

Urinary paracetamol and time-to-pregnancy.

Hum Reprod 2016 09 13;31(9):2119-27. Epub 2016 Jul 13.

Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, 6100 Executive Blvd., Room 7B05, Rockville, MD 20852, USA.

Study Question: Is preconception urinary paracetamol (acetaminophen) associated with time-to-pregnancy (TTP)?

Summary Answer: Higher urinary paracetamol concentrations among male partners were associated with a longer TTP.

What Is Known Already: Paracetamol is a commonly used analgesic among women and men of all ages. As metabolites of select chemicals used in the manufacturing of polyurethane foam, dyes and various industrial products, as well as a common medicinal product, paracetamol and its primary metabolite p-aminophenol, are ubiquitous in the environment. Studies investigating the relationship between adult urinary concentrations of paracetamol and TTP are lacking.

Study Design, Size, Duration: This prospective cohort included 501 couples discontinuing contraception for the purposes of attempting conception during the years 2005-2009 and residing in Michigan or Texas, USA.

Participants/materials, Setting, Methods: Total urinary paracetamol, its metabolite para-aminophenol (p-aminophenol), and a summary measure of both urinary biomarkers were quantified by ultra-performance liquid chromatography coupled with an electrospray triple quadrupole mass spectrometry (UPLC-ESI-MS/MS). Female partners used the Clearblue® digital home test to confirm pregnancy. Cox's proportional odds models for discrete survival time were used to estimate fecundability odds ratios (FORs) and 95% confidence intervals (CIs), adjusting for age, body mass index (BMI), urinary creatinine, preconception smoking status, race/ethnicity and household income. Models were further adjusted for hypothyroidism and hypertension as an attempt to account for possible indications of paracetamol medication use. FOR estimates <1.0 denote a longer TTP (diminished fecundity). Models were performed to examine urinary concentrations of paracetamol as a continuous and variable or categorized into quartiles. In light of TTP being a couple-dependent outcome, models were first performed for females and males, modeled separately, and then modeled for couples with each partner's concentrations being adjusted for the other.

Main Results And The Role Of Chance: Among the 501 enrolled couples, 347 (69%) had an human chorionic gonadotrophin confirmed pregnancy. Urinary concentrations of paracetamol were lowest among females and males who achieved pregnancy and p-aminophenol concentrations were lowest among those not achieving pregnancy. Urinary paracetamol concentrations were higher among female than male partners (Median = 26.6 and 13.2 ng/ml, respectively; P < 0.0001). After adjustment for age, BMI, urinary creatinine, preconception smoking status, race/ethnicity and household income, the highest quartile of male urinary paracetamol was associated with a longer TTP [FOR = 0.67; 95% CI = (0.47, 0.95)]. This association remained after adjustment for chronic health conditions, hypothyroidism and hypertension and female partner's urinary paracetamol concentration [FOR = 0.65; 95% CI = (0.45, 0.94)]. No associations were observed between female or male partners' urinary concentrations of paracetamol or of its metabolite p-aminophenol when urinary concentrations were modeled continuously.

Limitations, Reasons For Caution: Only a single spot urine was available for analysis despite the short-lived nature of paracetamol. Additionally, participants were not asked to provide information on indication of use for paracetamol medications; any underlying conditions for the paracetamol use would have been potential confounders.

Wider Implications Of The Findings: If corroborated with more robust studies, findings from our exploratory analysis may have both clinical and public health relevance among reproductive aged individuals, including those trying for pregnancy, given the prevalent use of paracetamol/acetaminophen medications and the ubiquitous nature of paracetamol in the environment.

Study Funding/competing Interests: This research was supported by the National Institutes of Health, Intramural Research Program, and Eunice Kennedy Shriver National Institute of Child Health and Human Development (contracts N01-HD-3-3355; N01-HD-3-3356; NOH-HD-3-3358; HHSN27500001/HHSN27500001). None of the authors have any conflicts to declare.
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http://dx.doi.org/10.1093/humrep/dew172DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4991660PMC
September 2016

Urinary Concentrations of Parabens and Other Antimicrobial Chemicals and Their Association with Couples' Fecundity.

Environ Health Perspect 2017 04 10;125(4):730-736. Epub 2016 Jun 10.

Office of the Director, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services, Rockville, Maryland, USA.

Background: Human exposure to parabens and other antimicrobial chemicals is continual and pervasive. The hormone-disrupting properties of these environmental chemicals may adversely affect human reproduction.

Objective: We aimed to prospectively assess couples' urinary concentrations of antimicrobial chemicals in the context of fecundity, measured as time to pregnancy (TTP).

Methods: In a prospective cohort of 501 couples, we examined preconception urinary chemical concentrations of parabens, triclosan and triclorcarban in relation to TTP; chemical concentrations were modeled both continuously and in quartiles. Cox's proportional odds models for discrete survival time were used to estimate fecundability odds ratios (FORs) and 95% confidence intervals (CIs) adjusting for -defined confounders. In light of TTP being a couple-dependent outcome, both partner and couple-based exposure models were analyzed. In all models, FOR estimates < 1.0 denote diminished fecundity (longer TTP).

Results: Overall, 347 (69%) couples became pregnant. The highest quartile of female urinary methyl paraben (MP) concentrations relative to the lowest reflected a 34% reduction in fecundity (aFOR = 0.66; 95% CI: 0.45, 0.97) and remained so when accounting for couples' concentrations (aFOR = 0.63; 95% CI: 0.41, 0.96). Similar associations were observed between ethyl paraben (EP) and couple fecundity for both partner and couple-based models (-trend = 0.02 and -trend = 0.05, respectively). No associations were observed with couple fecundity when chemicals were modeled continuously.

Conclusions: Higher quartiles of preconception urinary concentrations of MP and EP among female partners were associated with reduced couple fecundity in partner-specific and couple-based exposure models.
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http://dx.doi.org/10.1289/EHP189DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5381974PMC
April 2017

Obstetric and Neonatal Risks Among Obese Women Without Chronic Disease.

Obstet Gynecol 2016 07;128(1):104-112

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

Objective: To investigate whether prepregnancy obesity is associated with adverse pregnancy outcomes among women without chronic disease.

Methods: Singleton deliveries (N=112,309) among mothers without chronic diseases in the Consortium on Safe Labor, a retrospective U.S. cohort, were analyzed using Poisson regression with robust variance estimation. Relative risks and 95% confidence intervals (CIs) estimated perinatal risks in relation to prepregnancy obesity status adjusted for age, race-ethnicity, parity, insurance, smoking and alcohol use during pregnancy, and study site.

Results: Obstetric risks were variably (and mostly marginally) increased as body mass index (BMI) category and obesity class increased. In particular, the risk of gestational hypertensive disorders, gestational diabetes, cesarean delivery, and induction increased in a dose-response fashion. For example, the percentage of gestational diabetes among obese class III women was 14.6% in contrast to 2.8% among women with normal BMIs (corresponding relative risks [95% CI] 1.99 [1.86-2.13], 2.94 [2.73-3.18], 3.97 [3.61-4.36], and 5.47 [4.96-6.04] for overweight, obese class I, obese class II, and obese class III women, respectively) compared with women with normal BMIs. Similarly, neonatal risks increased in a dose-response fashion with maternal BMI status including preterm birth at less than 32 weeks of gestation, large for gestational age (LGA), transient tachypnea, sepsis, and intensive care unit admission. The percentage of LGA neonates increased from 7.9% among women with normal BMIs to 17.3% among obese class III women and relative risks increased to 1.52 (1.45-1.58), 1.74 (1.65-1.83), 1.93 (1.79-2.07), and 2.32 (2.14-2.52) as BMI category increased.

Conclusion: Prepregnancy obesity is associated with increased risks of a wide range of adverse pregnancy and neonatal outcomes among women without chronic diseases.
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http://dx.doi.org/10.1097/AOG.0000000000001465DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4917420PMC
July 2016

Persistent organic pollutants and pregnancy complications.

Sci Total Environ 2016 May 12;551-552:285-91. Epub 2016 Feb 12.

Office of the Director, Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, 6100 Executive Blvd., Rockville, MD 20852, USA.. Electronic address:

We sought to investigate the relationship between maternal preconception exposures to persistent organic pollutants (POPs) and pregnancy complications, gestational diabetes (GDM) and gestational hypertension. Data from 258 (51%) women with human chorionic gonadotropin (hCG) confirmed pregnancies reaching ≥24weeks gestation, from a prospective cohort of 501 couples who discontinued contraception to attempt pregnancy, were analyzed. Preconception concentrations of 9 organochlorine pesticides (OCPs) and 10 polybrominated diphenyl ethers (PBDEs) were quantified in serum. In separate multiple logistic regression models of self-reported physician diagnosed outcomes: GDM (11%) and gestational hypertension (10%), chemicals were natural log-transformed and rescaled by their standard deviation (SD). Models were adjusted for serum lipids, and then adjusted for age, body mass index, race, and smoking. Models were additionally adjusted for the sum of the remaining POPs in each chemical class. Women's serum concentration of PBDE congener 153 (PBDE-153) was positively associated with an increased odds of GDM per SD increase in log-transformed concentration, for unadjusted (OR=1.36, 95%CI: 1.02-1.81), a priori adjusted (OR=1.38, 95% CI: 1.03-1.86) and with the sum of remaining PBDEs (OR=1.79, 95% CI: 1.18, 2.74) models. Our findings suggest that at environmentally relevant concentrations, maternal exposure to POPs prior to conception may contribute to increased chance of developing GDM.
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http://dx.doi.org/10.1016/j.scitotenv.2016.02.030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7751424PMC
May 2016

Parental urinary biomarkers of preconception exposure to bisphenol A and phthalates in relation to birth outcomes.

Environ Health 2015 Sep 11;14:73. Epub 2015 Sep 11.

Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, 6100 Executive Blvd, Rockville, MD, 20852, USA.

Background: Bisphenol A (BPA) and phthalates are ubiquitous non-persistent endocrine disrupting chemicals whose relation with infant birth size is not clearly understood.

Methods: We examined associations between maternal and paternal preconception urinary concentrations of total BPA and 14 phthalate metabolites and birth size for 233 infants. Multiple linear regression models were used to estimate parental quartiles of BPA and phthalates in relation to birth weight, length, head circumference, and ponderal index with separate models run for each parent adjusting for age, smoking, body mass index, education, alcohol, parity, and creatinine. Models also included an interaction term for each chemical and infant sex and were further adjusted to include the other partner's chemical concentrations.

Results: In maternal models adjusted for partner's exposure and covariates, reductions in birth weight (range: 178-215 g; p < 0.05) were observed for the 2nd quartile of maternal monomethyl phthalate, mono-[(2-carboxymethyl) hexyl] phthalate and mono-n-octyl phthalate when compared with the 1st quartiles. The 3rd quartile of monoethylhexyl phthalate (mEHP) was also associated with a 200.16 g (95 % CI: -386.90, -13.42) reduction. Similar reductions in birth weight were observed for the 2(nd) quartile of paternal mEHP (β = -191.93 g; 95 % CI: -381.61, -2.25). Additionally, select maternal urinary metabolites were associated with decreased head circumference, birth length and gestational age. However, paternal concentrations were generally associated with increased birth length and gestational age.

Conclusions: We observed some suggestion that preconception maternal and paternal urinary concentration of BPA and specific phthalate metabolites may be associated with smaller birth size and increased gestational age, though the findings appeared to be parent and chemical specific.
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http://dx.doi.org/10.1186/s12940-015-0060-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4567813PMC
September 2015

The use of ultrasound measurements in environmental epidemiological studies of air pollution and fetal growth.

Curr Opin Pediatr 2013 Apr;25(2):240-6

Department of Environmental Health Sciences, University of Michigan School of Public Health, Ann Arbor, Michigan 48109-2029, USA.

Purpose Of Review: Recently, several international research groups have suggested that studies about environmental contaminants and adverse pregnancy outcomes should be designed to elucidate potential underlying biological mechanisms. The purpose of this review is to examine the epidemiological studies addressing maternal exposure to air pollutants and fetal growth during gestation as assessed by ultrasound measurements.

Recent Findings: The six studies published to date found that exposure to certain ambient air pollutants during pregnancy is negatively associated with the growth rates and average attained size of fetal parameters belonging to the growth profile. Fetal parameters may respond to maternal air pollution exposures uniquely, and this response may vary by pollutant and timing of gestational exposure. Current literature suggests that mean changes in head circumference, abdominal circumference, femur length, and biparietal diameter are negatively associated with early-pregnancy exposures to ambient and vehicle-related air pollution.

Summary: The use of more longitudinal studies, employing ultrasound measures to assess fetal outcomes, may assist with the better understanding of mechanisms responsible for air pollution-related pregnancy outcomes.
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http://dx.doi.org/10.1097/MOP.0b013e32835e1e74DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4345122PMC
April 2013
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