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Introduction: Environmental phenols are endocrine disrupting chemicals hypothesized to affect early life development. Previous research examining the effects of phenols on fetal growth has focused primarily on associations with measures of size at delivery. Few have included ultrasound measures to examine growth across pregnancy. Objective: Investigate associations between prenatal exposure to phenols and ultrasound and delivery measures of fetal growth. Methods: Using the LIFECODES Fetal Growth Study (n = 900), a case-cohort including 248 small-for-gestational-age, 240 large-for-gestational age, and 412 appropriate-for-gestational-age births, we estimated prenatal exposure to 12 phenols using three urine samples collected during pregnancy (median 10, 24, and 35 weeks gestation). We abstracted ultrasound and delivery measures of fetal growth from medical records. We estimated associations between pregnancy-average phenol biomarker concentrations and repeated ultrasound measures of fetal growth using linear mixed effects models and associations with birthweight using linear regression models. We also used logistic regression models to estimate associations with having a small- or large-for-gestational birth. Results: We observed positive associations between 2,4-dichlorophenol, benzophenone-3, and triclosan (TCS) and multiple ultrasound measures of fetal growth. For example, TCS was associated with a 0.09 (95 % CI: 0.01, 0.18) higher estimated fetal weight z-score longitudinally across pregnancy. This effect size corresponds to a 21 g increase in estimated fetal weight at 30 weeks gestation. Associations with delivery measures of growth were attenuated, but TCS remained positively associated with birthweight z-scores (mean difference: 0.13, 95 % CI: 0.02, 0.25). Conversely, methylparaben was associated with higher odds of a small-for-gestational age birth (odds ratio: 1.45, 95 % CI: 1.06, 1.98). Discussion: We observed associations between some biomarkers of phenol exposure and ultrasound measures of fetal growth, though associations at the time of delivery were attenuated. These findings are consistent with hypotheses that phenols have the potential to affect growth during the prenatal period.

Background: There is inconclusive evidence for an association between per- and polyfluoroalkyl substances (PFAS) and fetal growth. Objectives: We conducted a nation-wide register-based cohort study to assess the associations of the estimated maternal exposure to the sum (PFAS4) of perfluorooctane sulfonic acid (PFOS), perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA) and perfluorohexane sulfonic acid (PFHxS) with birthweight as well as risk of small- (SGA) and large-for-gestational-age (LGA). Materials and methods: We included all births in Sweden during 2012–2018 of mothers residing ≥ four years prior to partus in localities served by municipal drinking water where PFAS were measured in raw and drinking water. Using a one-compartment toxicokinetic model we estimated cumulative maternal blood levels of PFAS4 during pregnancy by linking residential history, municipal PFAS water concentration and year-specific background serum PFAS concentrations in Sweden. Individual birth outcomes and covariates were obtained via register linkage. Mean values and 95 % confidence intervals (CI) of β coefficients and odds ratios (OR) were estimated by linear and logistic regressions, respectively. Quantile g-computation regression was conducted to assess the impact of PFAS4 mixture. Results: Among the 248,804 singleton newborns included, no overall association was observed for PFAS4 and birthweight or SGA. However, an association was seen for LGA, multivariable-adjusted OR 1.08 (95% CI: 1.01–1.16) when comparing the highest PFAS4 quartile to the lowest. These associations remained for mixture effect approach where all PFAS, except for PFOA, contributed with a positive weight. Discussions: We observed an association of the sum of PFAS4 – especially PFOS – with increased risk of LGA, but not with SGA or birthweight. The limitations linked to the exposure assessment still require caution in the interpretation.

Background: Most previous studies investigating the associations between prenatal exposure to phthalates and fetal growth relied on measurements of phthalate metabolites at a single time point. They also focused on weight at birth without assessing growth over pregnancy, preventing the identification of potential periods of fetal vulnerability. We examined the associations between pregnancy urinary phthalate metabolites and fetal growth outcomes measured twice during pregnancy and at birth. Methods: For 484 pregnant women, we assessed 13 phthalate and two 1,2-cyclohexane dicarboxylic acid, diisononyl ester (DINCH) metabolite concentrations from two within-subject weekly pools of up to 21 urine samples (median of 18 and 34 gestational weeks, respectively). Fetal biparietal diameter, femur length, head and abdominal circumferences were measured during two routine pregnancy follow-up ultrasonographies (median 22 and 32 gestational weeks, respectively) and estimated fetal weight (EFW) was calculated. Newborn weight, length, and head circumference were measured at birth. Associations between phthalate/DINCH metabolite and growth parameters were investigated using adjusted linear regression and Bayesian kernel machine regression models. Results: Detection rates were above 99 % for all phthalate/DINCH metabolites. While no association was observed with birth measurements, mono-iso-butyl phthalate (MiBP) and mono-n-butyl phthalate (MnBP) were positively associated with most fetal growth parameters measured at the second trimester. Specifically, MiBP was positively associated with biparietal diameter, head and abdominal circumferences, while MnBP was positively associated with EFW, head and abdominal circumferences, with stronger associations among males. Pregnancy MnBP was positively associated with biparietal diameter and femur length at third trimester. Mixture of phthalate/DINCH metabolites was positively associated with EFW at second trimester. Conclusions: In this pregnancy cohort using repeated urine samples to assess exposure, MiBP and MnBP were associated with increased fetal growth parameters. Further investigation on the effects of phthalates on child health would be relevant for expanding current knowledge on their long-term effects.

Background: Bisphenols and phthalates are high production volume chemicals used as additives in a variety of plastic consumer products leading to near ubiquitous human exposure. These chemicals have established endocrine disrupting properties and have been linked to a range of adverse reproductive and developmental outcomes. Here, we investigated exposure in relation to fetal growth. Methods: Participants included 855 mother-fetal pairs enrolled in the population-based New York University Children’s Health and Environment Study (NYU CHES). Bisphenols and phthalates were measured in maternal urine collected repeatedly during pregnancy. Analyses included 15 phthalate metabolites and 2 bisphenols that were detected in 50 % of participants or more. Fetal biometry data were extracted from electronic ultrasonography records and estimated fetal weight (EFW) was predicted for all fetuses at 20, 30, and 36 weeks gestation. We used quantile regression adjusted for covariates to model exposure-outcome relations across percentiles of fetal weight at each gestational timepoint. We examined sex differences using stratified models. Results: Few statistically significant associations were observed across chemicals, gestational time periods, percentiles, and sexes. However, within gestational timepoints, we found that among females, the molar sums of the phthalates DiNP and DnOP were generally associated with decreases in EFW among smaller babies and increases in EFW among larger babies. Among males, the opposite trend was observed. However, confidence intervals were generally wide at the tails of the distribution. Conclusion: In this sample, exposure to bisphenols and phthalates was associated with small sex-specific shifts in fetal growth; however, few associations were observed at the median of fetal weight and confidence intervals in the tails were wide. Findings were strongest for DiNP and DnOP, which are increasingly used as replacements for DEHP, supporting the need for future research on these contaminants.

Environmental phenols are endocrine disrupting chemicals hypothesized to affect early life development. Previous research examining the effects of phenols on fetal growth has focused primarily on associations with measures of size at delivery. Few have included ultrasound measures to examine growth across pregnancy. Investigate associations between prenatal exposure to phenols and ultrasound and delivery measures of fetal growth. Using the LIFECODES Fetal Growth Study (n = 900), a case-cohort including 248 small-for-gestational-age, 240 large-for-gestational age, and 412 appropriate-for-gestational-age births, we estimated prenatal exposure to 12 phenols using three urine samples collected during pregnancy (median 10, 24, and 35 weeks gestation). We abstracted ultrasound and delivery measures of fetal growth from medical records. We estimated associations between pregnancy-average phenol biomarker concentrations and repeated ultrasound measures of fetal growth using linear mixed effects models and associations with birthweight using linear regression models. We also used logistic regression models to estimate associations with having a small- or large-for-gestational birth. We observed positive associations between 2,4-dichlorophenol, benzophenone-3, and triclosan (TCS) and multiple ultrasound measures of fetal growth. For example, TCS was associated with a 0.09 (95 % CI: 0.01, 0.18) higher estimated fetal weight z-score longitudinally across pregnancy. This effect size corresponds to a 21 g increase in estimated fetal weight at 30 weeks gestation. Associations with delivery measures of growth were attenuated, but TCS remained positively associated with birthweight z-scores (mean difference: 0.13, 95 % CI: 0.02, 0.25). Conversely, methylparaben was associated with higher odds of a small-for-gestational age birth (odds ratio: 1.45, 95 % CI: 1.06, 1.98). We observed associations between some biomarkers of phenol exposure and ultrasound measures of fetal growth, though associations at the time of delivery were attenuated. These findings are consistent with hypotheses that phenols have the potential to affect growth during the prenatal period. [ABSTRACT FROM AUTHOR]

Background: Maternal exposure to ozone (O3) may cause systemic inflammation and oxidative stress and contribute to fetal growth restriction. We sought to estimate the association between maternal exposure to O3 and term birth weight and term small for gestational age (SGA) in the United States (US). Methods: We conducted a nationwide study including 2,179,040 live term singleton births that occurred across 453 populous counties in the contiguous US in 2002. Daily county-level concentrations of O3 data were estimated using a Bayesian fusion model. We used linear regression to estimate the association between O3 exposure and term birth weight and logistic regression to estimate the association between O3 exposure and term SGA during each trimester of the pregnancy and the entire pregnancy after adjusting for maternal characteristics, infant sex, season of conception, ambient temperature, county poverty rate, and census region. We additionally used distributed lag models to identify the critical exposure windows by estimating the monthly and weekly associations. Results: A 10 parts per billion (ppb) increase in O3 over the entire pregnancy was associated with a lower term birth weight (-7.6 g; 95 % CI: −8.8 g, −6.4 g) and increased risk of SGA (odds ratio = 1.030; 95 % CI: 1.020, 1.040). The identified critical exposure windows were the 13th- 25th and 32nd −37th gestational weeks for term birth weight and 13th- 25th for term SGA.We found the association was more pronounced among mothers who were non-Hispanic Black, unmarried, or had lower education level. Conclusions: Among US singleton term births, maternal exposure to O3 was associated with lower rates of fetal growth, and the 13th- 25th gestational weeks were the identified critical exposure windows.

There is inconclusive evidence for an association between per- and polyfluoroalkyl substances (PFAS) and fetal growth. We conducted a nation-wide register-based cohort study to assess the associations of the estimated maternal exposure to the sum (PFAS4) of perfluorooctane sulfonic acid (PFOS), perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA) and perfluorohexane sulfonic acid (PFHxS) with birthweight as well as risk of small- (SGA) and large-for-gestational-age (LGA). We included all births in Sweden during 2012–2018 of mothers residing ≥ four years prior to partus in localities served by municipal drinking water where PFAS were measured in raw and drinking water. Using a one-compartment toxicokinetic model we estimated cumulative maternal blood levels of PFAS4 during pregnancy by linking residential history, municipal PFAS water concentration and year-specific background serum PFAS concentrations in Sweden. Individual birth outcomes and covariates were obtained via register linkage. Mean values and 95 % confidence intervals (CI) of β coefficients and odds ratios (OR) were estimated by linear and logistic regressions, respectively. Quantile g-computation regression was conducted to assess the impact of PFAS4 mixture. Among the 248,804 singleton newborns included, no overall association was observed for PFAS4 and birthweight or SGA. However, an association was seen for LGA, multivariable-adjusted OR 1.08 (95% CI: 1.01–1.16) when comparing the highest PFAS4 quartile to the lowest. These associations remained for mixture effect approach where all PFAS, except for PFOA, contributed with a positive weight. We observed an association of the sum of PFAS4 – especially PFOS – with increased risk of LGA, but not with SGA or birthweight. The limitations linked to the exposure assessment still require caution in the interpretation. [ABSTRACT FROM AUTHOR]

• MiBP and MnBP were positively associated with most second trimester growth parameters. • At second trimester, MiBP was associated with head and abdominal circumferences. • MnBP was associated with all fetal measurements at either second or third trimester. • MnBP associations with fetal growth parameters were stronger among males. • Metabolites mixture was positively associated with fetal weight at second trimester. Most previous studies investigating the associations between prenatal exposure to phthalates and fetal growth relied on measurements of phthalate metabolites at a single time point. They also focused on weight at birth without assessing growth over pregnancy, preventing the identification of potential periods of fetal vulnerability. We examined the associations between pregnancy urinary phthalate metabolites and fetal growth outcomes measured twice during pregnancy and at birth. For 484 pregnant women, we assessed 13 phthalate and two 1,2-cyclohexane dicarboxylic acid, diisononyl ester (DINCH) metabolite concentrations from two within-subject weekly pools of up to 21 urine samples (median of 18 and 34 gestational weeks, respectively). Fetal biparietal diameter, femur length, head and abdominal circumferences were measured during two routine pregnancy follow-up ultrasonographies (median 22 and 32 gestational weeks, respectively) and estimated fetal weight (EFW) was calculated. Newborn weight, length, and head circumference were measured at birth. Associations between phthalate/DINCH metabolite and growth parameters were investigated using adjusted linear regression and Bayesian kernel machine regression models. Detection rates were above 99 % for all phthalate/DINCH metabolites. While no association was observed with birth measurements, mono- iso -butyl phthalate (MiBP) and mono-n-butyl phthalate (MnBP) were positively associated with most fetal growth parameters measured at the second trimester. Specifically, MiBP was positively associated with biparietal diameter, head and abdominal circumferences, while MnBP was positively associated with EFW, head and abdominal circumferences, with stronger associations among males. Pregnancy MnBP was positively associated with biparietal diameter and femur length at third trimester. Mixture of phthalate/DINCH metabolites was positively associated with EFW at second trimester. In this pregnancy cohort using repeated urine samples to assess exposure, MiBP and MnBP were associated with increased fetal growth parameters. Further investigation on the effects of phthalates on child health would be relevant for expanding current knowledge on their long-term effects. [ABSTRACT FROM AUTHOR]

Background: A growing number of studies have identified both toxic and essential metals which influence fetal growth. However, most studies have conducted single-cohort analyses, which are often limited by narrow exposure ranges, and evaluated metals individually. The objective of the current study was to conduct an environmental mixture analysis of metal impacts on fetal growth, pooling data from three geographically and demographically diverse cohorts in the United States participating in the Environmental Influences on Child Health Outcomes program. Methods: The pooled sample (N = 1,002) included participants from the MADRES, NHBCS, and PROTECT cohorts. Associations between seven metals (antimony, cadmium, cobalt, mercury, molybdenum, nickel, tin) measured in maternal urine samples collected during pregnancy (median: 16.0 weeks gestation) and birth weight for gestational age z-scores (BW for GA) were investigated using Bayesian Kernel Machine Regression (BKMR). Models were also stratified by cohort and infant sex to investigate possible heterogeneity. Chromium and uranium concentrations fell below the limits of detection for most participants and were evaluated separately as binary variables using pooled linear regression models. Results: In the pooled BKMR analysis, antimony, mercury, and tin were inversely and linearly associated with BW for GA, while a positive linear association was identified for nickel. The inverse association between antimony and BW for GA was observed in both males and females and for all three cohorts but was strongest for MADRES, a predominantly low-income Hispanic cohort in Los Angeles. A reverse j-shaped association was identified between cobalt and BW for GA, which was driven by female infants. Pooled associations were null for cadmium, chromium, molybdenum, and uranium, and BKMR did not identify potential interactions between metal pairs. Conclusions: Findings suggest that antimony, an understudied metalloid, may adversely impact fetal growth. Cohort- and/or sex-dependent associations were identified for many of the metals, which merit additional investigation.

Background: Prenatal exposures to per- and polyfluoroalkyl substances (PFAS) have been linked to reduced fetal growth. However, the detailed molecular mechanisms remain largely unknown. This study aims to investigate biological pathways and intermediate biomarkers underlying the association between serum PFAS and fetal growth using high-resolution metabolomics in a cohort of pregnant African American women in the Atlanta area, Georgia. Methods: Serum perfluorohexane sulfonic acid (PFHxS), perfluorooctane sulfonic acid (PFOS), perfluorooctanoic acid (PFOA), and perfluorononanoic acid (PFNA) measurements and untargeted serum metabolomics profiling were conducted in 313 pregnant African American women at 8–14 weeks gestation. Multiple linear regression models were applied to assess the associations of PFAS with birth weight and small-for-gestational age (SGA) birth. A high-resolution metabolomics workflow including metabolome-wide association study, pathway enrichment analysis, and chemical annotation and confirmation with a meet-in-the-middle approach was performed to characterize the biological pathways and intermediate biomarkers of the PFAS-fetal growth relationship. Results: Each log2-unit increase in serum PFNA concentration was significantly associated with higher odds of SGA birth (OR = 1.32, 95% CI 1.07, 1.63); similar but borderline significant associations were found in PFOA (OR = 1.20, 95% CI 0.94, 1.49) with SGA. Among 25,516 metabolic features extracted from the serum samples, we successfully annotated and confirmed 10 overlapping metabolites associated with both PFAS and fetal growth endpoints, including glycine, taurine, uric acid, ferulic acid, 2-hexyl-3-phenyl-2-propenal, unsaturated fatty acid C18:1, androgenic hormone conjugate, parent bile acid, and bile acid-glycine conjugate. Also, we identified 21 overlapping metabolic pathways from pathway enrichment analyses. These overlapping metabolites and pathways were closely related to amino acid, lipid and fatty acid, bile acid, and androgenic hormone metabolism perturbations. Conclusion: In this cohort of pregnant African American women, higher serum concentrations of PFOA and PFNA were associated with reduced fetal growth. Perturbations of biological pathways involved in amino acid, lipid and fatty acid, bile acid, and androgenic hormone metabolism were associated with PFAS exposures and reduced fetal growth, and uric acid was shown to be a potential intermediate biomarker. Our results provide opportunities for future studies to develop early detection and intervention for PFAS-induced fetal growth restriction.

Introduction: Four epidemiological studies have shown a negative association between prenatal acrylamide exposure and birth size. In order to shed light on the possible underlying mechanism(s), we analysed associations between acrylamide biomarkers and biomarkers related to fetal growth. Methods: In newborns of the ENVIRONAGE birth cohort (n ranges from 215 to 434), we investigated the association between prenatal acrylamide exposure (acrylamide and glycidamide hemoglobin adduct levels in cord blood) and thyroid hormones (TSH, T3, T4 and the ratio of T4 to T3 in cord plasma), insulin-related factors (cord plasma insulin and IGF1, and placental IGF2), neurotrophins (cord plasma BDNF, and placental NGF, NT3 and NT4), and cord plasma homocysteine and progesterone, using multiple linear regression analysis. In addition, we investigated whether the biomarkers mediated the associations between prenatal acrylamide exposure and birth outcomes. Results: We observed lower cord plasma TSH (−10.2% [95% CI: −15.0, −4.3]) and higher placental NGF levels (10.0% [95% CI 3.7, 17.4]) for a twofold increase of acrylamide adducts, a decrease in the ratio of cord plasma free T4 and free T3 with higher acrylamide and glycidamide adducts of −2.9% (95% CI: −5.7, −0.1) and −3.9% (95% CI: −6.2, −1.6) for a twofold increase in acrylamide and glycidamide adduct levels, respectively, and higher cord plasma free T3 with increases in both acrylamide and glycidamide adducts of 2.8% (95% CI: 0.2, 5.6) and 3.6% (95% CI: 0.8, 6.6) for a twofold increase in acrylamide and glycidamide adduct levels, respectively. Additionally, a twofold increase in glycidamide adducts was associated with lower cord plasma insulin levels, particularly among newborns of non-smoking mothers (−11.2% [95% CI: −19.5, −0.1]).Cord plasma insulin seemed to mediate the association between glycidamide adducts and birth weight. Conclusions: A decrease in cord plasma insulin levels may be (a marker of) a mechanism by which gestational acrylamide exposure is associated with decreased fetal growth. The possible health consequences of the associations between gestational acrylamide exposure and thyroid hormones and neurotrophins warrant future study.

Importance: Exposure to phthalates may affect fetal growth, but previous studies are inconsistent and have not explored the trimester-specific effects of phthalates on repeated measures of fetal growth. Objective: To assess the associations of maternal phthalate metabolites urine concentrations with fetal growth measures and birth outcomes and identify potential windows of vulnerability to exposure. Design: Population-based prospective cohort study, the Generation R Study (2002–2006). Data analysis was performed from November 2019 to June 2020. Setting: Rotterdam, the Netherlands. Participants: 1379 pregnant women. Exposures: Maternal phthalate metabolites urine concentrations in first, second and third trimester. Main outcomes and measures: Fetal head circumference, length and weight measured in the second and third trimester by ultrasound and at birth and preterm birth and small size for gestational age at birth. Results: Higher pregnancy-averaged phthalic acid, low molecular weight phthalate (LMWP), high molecular weight phthalate (HMWP) and di-2-ethylhexylphthalate (DEHP) concentrations tended to be associated with lower fetal weight SDS across gestation. The associations of phthalic acid and LMWP with fetal weight became stronger as pregnancy progressed (differences −0.08 (95% CI −0.14 to −0.02) SDS and −0.09 (95% CI −0.16 to −0.02) SDS at 40 weeks per interquartile range increase in phthalic acid and LMWP, respectively). Higher concentrations of specific LMWP, HMWP and DEHP metabolites were also associated with smaller head circumference and lower length SDS at birth and an increased risk of preterm birth and small size for gestational age at birth (p-values

Objective: Exposure to airborne pollutants during pregnancy appears to be associated with uterine growth restriction and adverse neonatal outcome. Proprotein convertase subtilisin/kexin type (PCSK9), the key modulator of low-density lipoprotein (LDL) metabolism, increases following particulate matter (PM10) exposure. Because maternal cholesterol is required for fetal growth, PCSK9 levels could be used to evaluate the potential impact of airborne pollutants on fetal growth. Design: A cohort of 134 healthy women during early pregnancy (11–12 weeks of gestational age) was studied. Results: A significant association between circulating PCSK9 levels and three tested air pollutants (PM10, PM2.5, nitric oxide (NO2)) was found. Of importance, gestational age at birth was reduced by approximately 1 week for each 100 ng/mL rise in circulating PCSK9 levels, an effect that became more significant at the highest quartile of PM2.5 (with a 1.8 week advance in delivery date for every 100 ng/mL rise in circulating PCSK9; p for interaction = 0.026). This finding was supported by an elevation of the odds ratio for urgent cesarean delivery for each 100 ng/mL rise in PCSK9 (2.99, 95% CI, 1.22–6.57), similar trends being obtained for PM10 and NO2. Conclusions: The association between exposure to air pollutants during pregnancy and elevation in PCSK9 advances our understanding of the unforeseen influences of environmental exposure in terms of pregnancy associated disorders.

This study was designed to examine the impact of prenatal fine particulate matter (PM2.5) exposure on fetal growth and the underlying placental epigenetic mechanism in a cohort of Chinese women. Within the prospective Shanghai Mother-Child Pairs cohort (Shanghai MCPC), 329 women carrying singleton pregnancy with a due date in 2018 were recruited between 2017 and 2018. Maternal PM2.5 exposure levels were estimated using gestational exposure prediction model combining satellite-driven ambient concentrations and personal air sampling. Fetal growth characteristics were evaluated by prenatal ultrasound examinations and anthropometric measurements at birth. In a discovery phase, whole-genome DNA methylation analysis was performed using the Infinium 850 K array. In a validation phase, placental DNA methylation was measured using bisulfite pyrosequencing for five candidate genes that showed the most significant alterations and function relevance in our methylation array screen, including BID (BH3 interacting domain death agonist), FOXN3 (Forkhead box N3), FOXP1 (Forkhead box P1), IGF2 (Insulin-like growth factor 2) and HSD11B2 (Hydroxysteroid 11-beta dehydrogenase 2). Multivariate linear regression models were applied to examine the associations among PM2.5 exposure, fetal growth characteristics and DNA methylation on placental candidate genes. Sobel tests were used to evaluate the mediating role of DNA methylation in multivariable models. After excluding women who withdrew or failed to provide placenta, a total of 287 pregnant women with an average age of 30 entered the final analysis. Increased PM2.5 exposure was significantly associated with reduced biparietal diameter (BPD) (β: −0.136 mm, 95% CI: −0.228 to −0.043), head circumference (HC) (β: −0.462 mm, 95% CI: −0.782 to −0.142), femur length (FL) (β: −0.113 mm, 95% CI: −0.185 to −0.041) and abdominal circumference (AC) (β: −0.371 mm, 95% CI: −0.672 to −0.071) in the second trimester and birth length (β: −0.013 cm, 95% CI: −0.025 to −0.001). Prenatal PM2.5 exposure could lead to aberrant changes in DNA methylation profile of placenta genome, which were mainly enriched in reproductive development, energy metabolism and immune response. DNA methylation of IGF2 and BID showed significant associations with PM2.5 exposures during all exposure windows. In addition, BID methylation was negatively correlated with HC (β: −1.396 mm, 95% CI: −2.582 to −0.209) and BPD (β: −0.330 mm, 95% CI: −0.635 to −0.026) in the second trimester. Further mediation analysis indicated that BID methylation mediated about 30% of the effects of PM2.5 exposure on HC. These findings collectively suggested that prenatal PM2.5 exposure may cause adverse effects on fetal growth by modifying placental DNA methylation.

Background: Prenatal exposure to metals may play an important role in fetal growth. However, the epidemiologic evidence for certain metals is sparse, and most of the existing research has focused on evaluating single metals in highly exposed target populations. Objectives: We evaluated associations of cadmium, lead, manganese, selenium, and total mercury exposures during pregnancy with fetal growth using data from mother-infant pairs participating in the National Children's Study. Methods: Prenatal metal exposures were measured using maternal blood collected from 6 to 32 weeks of gestation. Birth outcomes, including gestational age, birthweight, birth length, head circumference, and ponderal index, were ascertained through physical measurement at birth or abstraction from medical records. Regression coefficients and their 95% confidence intervals were estimated from multivariable linear regression models in the overall study population as well as among male and female infants. We further evaluated pairwise metal–metal interactions. Results: Sex-specific associations were observed for lead, with inverse associations for birthweight, birth length, head circumference, and gestational age observed only among female infants. Sex-specific associations were also observed for selenium, with a positive association for birthweight observed among male infants; selenium was also positively associated with ponderal index and inversely associated with birth length among female infants. Overall, total mercury was inversely associated with birthweight and ponderal index, and the association with birthweight was stronger among female infants. No significant associations were observed with cadmium and manganese. In the metal–metal interaction analyses, we found evidence of a synergistic interaction between lead and total mercury and antagonistic interaction between selenium and total mercury with selected birth outcomes. Conclusions: Our findings suggest that prenatal exposure to metals may be related to birth outcomes, and infant sex may modify these associations.

Background: Although studies have examined the association between residential greenness and birth weight, there is no evidence regarding the association between residential greenness and fetal growth in utero. We aimed to investigate the associations of residential greenness with both fetal growth in utero and birth weight. Methods: A birth cohort (2014–2017) with 18,665 singleton pregnancies was established in Tongzhou Maternal and Child hospital of Beijing, China. Residential greenness was matched with maternal residential address and estimated from remote satellite data using normalized difference vegetation index with 200 m and 500 m buffers (NDVI-200 and NDVI-500). Fetal parameters including estimated fetal weight (EFW), abdominal circumference (AC), head circumference (HC) and femur length (FL) were assessed by ultrasound measurements during pregnancy. Fetal parameters were standardized as gestational-age- and gender-adjusted Z-score and undergrowth was defined as Z-score

Abstract Background Prenatal exposure to chromium may be associated with reduced birth weight; however, critical windows of such exposure for fetal growth are unclear. Objective Our study was aimed to assess trimester-specific associations of chromium exposure with fetal growth parameters measured repeatedly by ultrasound and birth size, and to see whether these associations were modified by fetal sex. Methods We conducted a prospective cohort of 3041 women in Wuhan, China, from 2013 to 2016. Chromium concentrations were measured in maternal urine samples collected in the 1st, 2nd, and 3rd trimesters using an inductively coupled plasma mass spectrometry. We calculated standard deviation scores for ultrasound measured head circumference, abdominal circumference (AC), femur length, and estimated fetal weight (EFW) at 16, 24, and 31 weeks of gestation. Linear regressions with generalized estimating equations were used to estimate the associations of specific gravity-adjusted urinary chromium concentrations in each trimester with fetal growth parameters and birth weight, birth length, and ponderal index. Results Inverse associations of chromium exposure in the 1st trimester with fetal growth parameters at 31 weeks of gestation were observed, resulting in significant reductions in AC of −5.4% (95% confidence interval [CI]: −9.6%, −1.2%) and EFW of −5.6% (95% CI: −9.8%, −1.4%) per unit increase in natural logarithm transformed urinary chromium concentration. Urinary chromium concentration in the 2nd trimester was also associated with reductions in AC of −7.0% (95% CI: −12.5%, −1.4%) and in EFW of −5.0% (95% CI: −10.6%, 0.6%) at 31 weeks, and these inverse associations were evident in boys (reduction in AC of −13.9% [95% CI: −21.1%, −6.7%]; EFW of −9.5% [95% CI: −16.9%, −2.0%]) but not in girls (increase in AC of 2.9% [95% CI: −5.7%, 11.5%]; EFW of 1.5% [95% CI: −6.8%, 9.8%]) (both p ineraction < 0.05). Moreover, one-unit increase in urinary chromium concentrations in the 1st and 2nd trimesters were both associated with significant reductions in ponderal index of −0.11 kg/m3 (95% CI: −0.19, −0.03 kg/m3) and −0.15 kg/m3 (95% CI: −0.27, −0.03 kg/m3), respectively. Conclusion Our findings suggest that chromium may be a toxic metal for fetal growth. Early and mid-pregnancy seem to be the most vulnerable period for fetal exposure to chromium, but these results need further confirmation. Highlights • Trimester-specific associations of chromium with fetal growth were assessed. • Higher chromium levels were associated with reduced fetal growth. • Early and mid-pregnancy may be critical windows of chromium exposure for fetal growth. [ABSTRACT FROM AUTHOR]

Abstract Background Fine particulate matter (PM 2.5) exposure may impair fetal growth. Aims/objectives Our aim was to assess the effect of portable high efficiency particulate air (HEPA) filter air cleaner use during pregnancy on fetal growth. Methods The Ulaanbaatar Gestation and Air Pollution Research (UGAAR) study is a single-blind randomized controlled trial conducted in Ulaanbaatar, Mongolia. Non-smoking pregnant women recruited at ≤18 weeks gestation were randomized to an intervention (1–2 air cleaners in homes from early pregnancy until childbirth) or control (no air cleaners) group. Participants were not blinded to their intervention status. Demographic, health, and birth outcome data were obtained via questionnaires and clinic records. We used unadjusted linear and logistic regression and time-to-event analysis to evaluate the intervention. Our primary outcome was birth weight. Secondary outcomes were gestational age-adjusted birth weight, birth length, head circumference, gestational age at birth, and small for gestational age. The study is registered at ClinicalTrials.gov (NCT01741051). Results We recruited 540 participants (272 control and 268 intervention) from January 9, 2014 to May 1, 2015. There were 465 live births and 28 losses to follow up. We previously reported a 29% (95% CI: 21, 37%) reduction in indoor PM 2.5 concentrations with portable HEPA filter air cleaner use. The median (25th, 75th percentile) birth weights for control and intervention participants were 3450 g (3150, 3800 g) and 3550 g (3200, 3800 g), respectively (p = 0.34). The intervention was not associated with birth weight (18 g; 95% CI: −84, 120 g), but in a pre-specified subgroup analysis of 429 term births the intervention was associated with an 85 g (95% CI: 3, 167 g) increase in mean birth weight. Conclusions HEPA filter air cleaner use in a high pollution setting was associated with greater birth weight only among babies born at term. Highlights • Few randomized studies of air pollution and fetal growth haven been conducted. • We evaluated the effect of portable HEPA air cleaner use during pregnancy on fetal growth. • Air cleaners were not associated with fetal growth outcomes among all births. • Among term births, air cleaners were associated with greater birth weight. • Reducing air pollution may improve fetal growth. [ABSTRACT FROM AUTHOR]

Abstract Background Triclosan (TCS) is known to possess endocrine disrupting properties and metabolize rapidly in the human body. Human data concerning repeated measurements of TCS throughout pregnancy in relation to fetal and childhood growth are sparse. Objectives We investigated the associations between multiple measurements of maternal urinary concentrations of TCS during pregnancy and fetal and early-childhood growth. Methods The study population included 850 mother-infant pairs who participated in a prenatal cohort established between 2014 and 2015 in Wuhan. Prenatal TCS exposure was measured in a complete series of urine samples collected at the first, second and third trimesters. General linear models and generalized estimating equation models were applied to evaluate the associations of the averaged maternal urinary concentrations of TCS over trimesters and trimester-specific urinary TCS with the z -scores of estimated fetal weight, head circumference, abdominal circumference, and femur length at 16, 24, and 31 gestational weeks, weight and length at birth, and weight and height at 0.5, 1, and 2 years of age. Results In overall infants, we did not observe any significant association of the averaged maternal urinary concentrations of TCS over trimesters with ultrasound parameters and size at birth. However, a positive association of borderline statistical significance was found between averaged prenatal TCS exposure and the third-trimester estimated fetal weight z -score in girls in sex-stratified analyses (β = 0.054, 95% CI: −0.005, 0.113, p = 0.07). Moreover, averaged prenatal TCS exposure was positively associated with 2 year-old weight z -score among total infants (β = 0.046, 95% CI: 0.005, 0.087). After stratifying by sex, the same association was observed in girls with more prominent estimation (β = 0.062, 95% CI: 0.000, 0.124), whereas the association weakened and became not significant in boys (β = 0.033, 95% CI: −0.024, 0.089). TCS exposure at 1st and 2nd-trimester were positively associated with weight z -score at 2 years, in both overall and female infants. Conclusions Prenatal exposure to triclosan was associated with elevated third-trimester estimated fetal weight and 2 year-old weight z -score in girls, and the early and middle stage of pregnancy may be the windows of vulnerability. Apart from these findings, we did not find strong evidence for prenatal triclosan exposure in relation to fetal and early-childhood growth. Highlights • We assessed prenatal triclosan exposure in urine samples collected at three trimesters. • We included multiple growth measures start from intra-uterine to 2 years as outcomes. • Prenatal TCS was associated with higher 3rd-trimester estimated fetal weight in girls. • Prenatal TCS was positively associated with weight z -score of 2-year-old infants. • Early and middle stage of pregnancy may be the windows of vulnerability for TCS exposure. [ABSTRACT FROM AUTHOR]

Abstract 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/m2, 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. Highlights • 76 endocrine disruptor chemicals (EDCs) were measured in cohort of pregnant women. • Newborns underwent standardized neonatal assessments at ≈1–2 days after birth. • EDC were not associated with gestation, birth weight or head circumference. • Reductions in umbilical circumference, birth length, arm and thigh length were found. • Poly-and-perfluorinated alkyl substances were most often associated with reductions. [ABSTRACT FROM AUTHOR]

Abstract Prenatal exposure to persistent organic pollutants (POPs) has been linked to numerous adverse birth outcomes among newborn infants in many epidemiological studies. Although epigenetic modifications have been suggested as possible explanations for those associations, studies have rarely reported a relationship between POP exposure during pregnancy and DNA methylation in the placenta. In the present study, we investigated the association between prenatal exposure to several POPs, including organochlorine pesticides (OCPs), polybrominated diphenyl ethers (PBDEs), and polychlorinated biphenyls (PCBs), and methylation levels of long interspersed element 1 (LINE-1), as well as imprinted genes in placental DNAs among Korean mother-child pairs (N = 109). We assessed the association of DNA methylation not only with each target POP (single-POP models) but also with multiple POPs applying principal component analysis (multiple-POP models). Potential associations between placental DNA methylation and birth outcomes of newborn infants were also estimated. In single-POP models, significant associations were detected between OCP measurements and placental DNA methylation. Elevated concentrations of β-hexachlorhexane (β-HCH) in maternal serum collected during delivery were significantly associated with a decrease in methylation of LINE-1 in the placenta. Higher levels of p , p ′-dichlorodiphenyltrichloroethane (p , p ′-DDT) in maternal serum were associated with hypermethylation of insulin-like growth factor 2 (IGF2). In multiple-POP models, a significant and positive association between DDTs and IGF2 methylation was also observed. Placental LINE-1 methylation was inversely associated with birth length. Our observations indicate that prenatal exposure to several POPs including DDTs is associated with the changes in methylation of genes, including major imprinted genes in the placenta. The consequences of these epigenetic alterations in placenta during development deserve further investigation. Highlights • Associations between POP exposure and placental DNA methylation were evaluated. • A multi-pollutant exposure was added in the models with principal component analysis. • Exposure to DDTs, including p , p ′-DDT, was related to methylation of IGF2 in the placenta. • Several POPs might affect epigenetic regulation of key placental DNAs. [ABSTRACT FROM AUTHOR]

Environmental phenols are used commonly in personal care products and exposure is widespread in pregnant women. In this study, we sought to assess the association between maternal urinary phenol concentrations in pregnancy and fetal growth. The study population included 476 mothers who participated in the prospective LIFECODES birth cohort between 2006 and 2008 at Brigham and Women's Hospital in Boston, Massachusetts, USA. Dichlorophenols (DCPs), benzophenone-3, parabens, triclosan, triclocarban, and bisphenol-S were measured in urine from three time points during pregnancy and averaged. Outcome measures were all standardized to create gestational-age specific z-scores and included: 1) birth weight; 2) ultrasound parameters measured at up to two time points in pregnancy (head and abdominal circumference and femur length); and 3) ultrasound estimates of fetal weight from two time points in combination with birth weight. Models were stratified to investigate sex differences. Inverse associations were observed between average 2,4- and 2,5-DCP concentrations and birth weight z-scores in males. For example, an interquartile range difference in 2,4-DCP was associated with a 0.18 standard deviation decrease in birth weight z-score (95% confidence interval [CI] = − 0.33, − 0.02). These associations were observed in models that included repeated ultrasound estimates of fetal weight during gestation as well. Also in males, we noted inverse associations between average triclosan exposure over pregnancy and estimated fetal weight combined with birth weight in repeated measures models. For females, associations were generally null. However, mothers with a detectable concentration of bisphenol-S at any of the study visits had lower weight females. In conclusion, we observed inverse associations between indicators of maternal phenol exposure during pregnancy and fetal growth, with several differences observed by sex. [ABSTRACT FROM AUTHOR]

Parental exposure to polybrominated diphenyl ethers (PBDEs) is associated with adverse birth outcomes. This study aims to examine differentially-expressed protein profiles in umbilical cord tissue, derived from mothers exposed to PBDEs, and investigate candidate biomarkers to reveal the underlying molecular mechanisms. Umbilical cord samples were obtained from women residing in an electronic waste (e-waste) recycling area (Guiyu) and reference area (Haojiang) in China. The concentration of PBDEs in umbilical cord tissue was determined by gas chromatography and mass spectrometry (GC/MS). Isobaric tagging for relative and absolute quantification (iTRAQ)-based proteomic technology was conducted to analyze differentially-expressed protein profiles. The total PBDE concentration was approximately five-fold higher in umbilical cords from Guiyu than from Haojiang (median 71.92 ng/g vs. 15.52 ng/g lipid, P < 0.01). Neonatal head circumference, body-mass index (BMI) and Apgar1 score were lower in Guiyu and negatively correlated with PBDE concentration ( P < 0.01). Proteomic analysis showed 697 proteins were differentially expressed in the e-waste-exposed group compared with the reference group. The differentially-expressed proteins were principally involved in antioxidant defense, apoptosis, cell structure and metabolism. Among them, catalase and glutathione S-transferase omega-1, were down-regulated, and cytochrome c was found to be up-regulated, changes which were further verified by enzyme-linked immunosorbent assays. These results suggest that an antioxidant imbalance and cell apoptosis in the umbilical cord following PBDE exposure is associated with neonatal birth outcomes. [ABSTRACT FROM AUTHOR]

Background Prenatal perfluorooctanoate (PFOA) exposure has been associated with reduced birth weight but maternal glomerular filtration rate (GFR) may attenuate this association. Further, this association remains unclear for other perfluoroalkyl substances (PFAS), such as perfluorooctane sulfonate (PFOS), perfluorohexane sulfonate (PFHxS), and perfluorononanoate (PFNA). We estimated associations between prenatal PFAS exposure and birth outcomes, and the influence of GFR, in a Spanish birth cohort. Methods We measured PFHxS, PFOS, PFOA, and PFNA in 1st-trimester maternal plasma (years: 2003–2008) in 1202 mother-child pairs. Continuous birth outcomes included standardized weight, length, head circumference, and gestational age. Binary outcomes included low birth weight (LBW), small-for-gestational-age, and preterm birth. We calculated maternal GFR from plasma-creatinine measurements in the 1st-trimester of pregnancy ( n = 765) using the Cockcroft-Gault formula. We used mixed-effects linear and logistic models with region of residence as random effect and adjustment for maternal age, parity, pre-pregnancy BMI, and fish intake during pregnancy. Results Newborns in this study weighted on average 3263 g and had a median gestational age of 39.8 weeks. The most abundant PFAS were PFOS and PFOA (median: 6.05 and 2.35 ng/mL, respectively). Overall, PFAS concentrations were not significantly associated to birth outcomes. PFOA, PFHxS, and PFNA showed weak, non-statistically significant associations with reduced birth weights ranging from 8.6 g to 10.3 g per doubling of exposure. Higher PFOS exposure was associated with an OR of 1.90 (95% CI: 0.98, 3.68) for LBW (similar in births-at-term) in boys. Maternal GFR did not confound the associations. Conclusions In this study, PFAS showed little association with birth outcomes. Higher PFHxS, PFOA, and PFNA concentrations were non-significantly associated with reduced birth weight. The association between PFOS and LBW seemed to be sex-specific. Finally, maternal GFR measured early during pregnancy had little influence on the estimated associations. [ABSTRACT FROM AUTHOR]

Background Maternal ambient air pollution exposure is associated with reduced birthweight. Few studies have examined the effect on growth in utero and none have examined the effect of exposure to particulates less than 2.5 µm (PM 2.5 ) and possible effect modification by smoking status. Objectives Examine the effect of maternal exposure to ambient concentrations of PM 10 , PM 2.5 and nitrogen dioxide (NO 2 ) for in utero fetal growth, size at birth and effect modification by smoking status. Methods Administratively acquired second and third trimester fetal measurements (bi-parietal diameter, femur length and abdominal circumference), birth outcomes (weight, crown heel length and occipito-frontal circumference) and maternal details were obtained from routine fetal ultrasound scans and maternity records (period 1994–2009). These were modelled against residential annual pollution concentrations (calendar year mean) adjusting for covariates and stratifying by smoking status. Results In the whole sample ( n = 13,775 pregnancies), exposure to PM 10 , PM 2.5 and NO 2 was associated with reductions in measurements at birth and biparietal diameter from late second trimester onwards. Among mothers who did not smoke at all during pregnancy ( n = 11,075), associations between biparietal diameter and pollution exposure remained significant but were insignificant among those who did smoke ( n = 2700). Femur length and abdominal circumference were not significantly associated with pollution exposure. Conclusions Fetal growth is strongly associated with particulates exposure from later in second trimester onwards but the effect appears to be subsumed by smoking. Typical ambient exposures in this study were relatively low compared to other studies and given these results, it may be necessary to consider reducing recommended “safe” ambient air exposures. [ABSTRACT FROM AUTHOR]

• Bisphenols and phthalate metabolites may be associated with altered fetal growth. • Associations were greatest among small and large fetuses and varied by sex. • Associations were strongest for replacement DEHP phthalates (DiNP and DnOP). • Effects of exposure on fetal growth may occur by the second trimester. Bisphenols and phthalates are high production volume chemicals used as additives in a variety of plastic consumer products leading to near ubiquitous human exposure. These chemicals have established endocrine disrupting properties and have been linked to a range of adverse reproductive and developmental outcomes. Here, we investigated exposure in relation to fetal growth. Participants included 855 mother-fetal pairs enrolled in the population-based New York University Children's Health and Environment Study (NYU CHES). Bisphenols and phthalates were measured in maternal urine collected repeatedly during pregnancy. Analyses included 15 phthalate metabolites and 2 bisphenols that were detected in 50 % of participants or more. Fetal biometry data were extracted from electronic ultrasonography records and estimated fetal weight (EFW) was predicted for all fetuses at 20, 30, and 36 weeks gestation. We used quantile regression adjusted for covariates to model exposure-outcome relations across percentiles of fetal weight at each gestational timepoint. We examined sex differences using stratified models. Few statistically significant associations were observed across chemicals, gestational time periods, percentiles, and sexes. However, within gestational timepoints, we found that among females, the molar sums of the phthalates DiNP and DnOP were generally associated with decreases in EFW among smaller babies and increases in EFW among larger babies. Among males, the opposite trend was observed. However, confidence intervals were generally wide at the tails of the distribution. In this sample, exposure to bisphenols and phthalates was associated with small sex-specific shifts in fetal growth; however, few associations were observed at the median of fetal weight and confidence intervals in the tails were wide. Findings were strongest for DiNP and DnOP, which are increasingly used as replacements for DEHP, supporting the need for future research on these contaminants. [ABSTRACT FROM AUTHOR]

Background As population lead levels decrease, the toxic effects of lead may be distributed to more sensitive populations, such as infants with poor fetal growth. Objectives To determine the association of prenatal lead exposure and fetal growth; and to evaluate whether infants with poor fetal growth are more susceptible to lead toxicity than those with normal fetal growth. Methods We examined the association of second trimester maternal blood lead levels (BLL) with birthweight-for-gestational age (BWGA) z-score in 944 mother-infant participants of the PROGRESS cohort. We determined the association between maternal BLL and BWGA z-score by using both linear and quantile regression. We estimated odds ratios for small-for-gestational age (SGA) infants between maternal BLL quartiles using logistic regression. Maternal age, body mass index, socioeconomic status, parity, household smoking exposure, hemoglobin levels, and infant sex were included as confounders. Results While linear regression showed a negative association between maternal BLL and BWGA z-score ( β = − 0.06 z-score units per log 2 BLL increase; 95% CI: − 0.13, 0.003; P = 0.06), quantile regression revealed larger magnitudes of this association in the < 30th percentiles of BWGA z-score ( β range [− 0.08, − 0.13] z-score units per log 2 BLL increase; all P values < 0.05). Mothers in the highest BLL quartile had an odds ratio of 1.62 (95% CI: 0.99–2.65) for having a SGA infant compared to the lowest BLL quartile. Conclusions While both linear and quantile regression showed a negative association between prenatal lead exposure and birthweight, quantile regression revealed that smaller infants may represent a more susceptible subpopulation. [ABSTRACT FROM AUTHOR]

Background In utero polybrominated diphenyl ethers (PBDEs) exposure has been associated with adverse fetal growth. Alterations in placental DNA methylation might mediate those adverse effects. Objectives To examine the associations between in utero PBDEs exposure and DNA methylation in human placenta. Methods Eighty apparently healthy mother-newborn pairs delivering at the Second Affiliated Hospital of Wenzhou Medical College were enrolled in this study. Placental DNA methylation of LINE1 , NR3C1 and IGF2 was measured by quantitative polymerase chain reaction-pyrosequencing. In utero PBDEs exposure was assessed by measuring umbilical cord blood PBDEs concentrations. Results For LINE-1 , higher levels of BDE-66 exposure were associated with decreased DNA methylation (β = − 0.9, 95% CI, − 1.8 to − 0.1); For NR3C1 , BDE-153 concentrations was significantly inversely associated with DNA methylation (β = − 2.0, 95% CI, − 3.7 to − 0.2); For IGF2 , elevated concentrations of both BDE-153 (β = − 1.7; 95% CI, − 3.0 to − 0.4) and BDE-209 (β = − 1.0; 95% CI, − 1. 9 to − 0.1) were significantly associated with decreased DNA methylation. Conclusions We found that placental DNA methylation is associated with in utero PBDEs exposure. Changes in placental DNA methylation might be part of the underlying biological pathway between in utero PBDEs exposure and adverse fetal growth. [ABSTRACT FROM AUTHOR]

Background Maternal exposure to air pollution and traffic noise has been suggested to impair fetal growth, but studies have reported inconsistent findings. Objective To investigate associations between residential air pollution and traffic noise during pregnancy and newborn's size at birth. Methods From a national birth cohort we identified 75,166 live-born singletons born at term with information on the children's size at birth. Residential address history from conception until birth was collected and air pollution (NO 2 and NO x ) and road traffic noise was modeled at all addresses. Associations between exposures and indicators of newborn's size at birth: birth weight, placental weight and head and abdominal circumference were analyzed by linear and logistic regression, and adjusted for potential confounders. Results In mutually adjusted models we found a 10 μg/m 3 higher time-weighted mean exposure to NO 2 during pregnancy to be associated with a 0.35 mm smaller head circumference (95% confidence interval (CI): 95% CI: − 0.57; − 0.12); a 0.50 mm smaller abdominal circumference (95% CI: − 0.80; − 0.20) and a 5.02 g higher placental weight (95% CI: 2.93; 7.11). No associations were found between air pollution and birth weight. Exposure to residential road traffic noise was weakly associated with reduced head circumference, whereas none of the other newborn's size indicators were associated with noise, neither before nor after adjustment for air pollution. Conclusions This study indicates that air pollution may result in a small reduction in offspring's birth head and abdominal circumference, but not birth weight, whereas traffic noise seems not to affect newborn's size at birth. [ABSTRACT FROM AUTHOR]

[Display omitted] • We estimated the association of O 3 exposure with fetal growth across 453 US counties. • Maternal exposure to O 3 was associated with reduced birth weight. • Maternal exposure to O 3 was associated with a higher risk of SGA. • The 13th-25th gestational weeks were the identified critical exposure windows. Maternal exposure to ozone (O 3) may cause systemic inflammation and oxidative stress and contribute to fetal growth restriction. We sought to estimate the association between maternal exposure to O 3 and term birth weight and term small for gestational age (SGA) in the United States (US). We conducted a nationwide study including 2,179,040 live term singleton births that occurred across 453 populous counties in the contiguous US in 2002. Daily county-level concentrations of O 3 data were estimated using a Bayesian fusion model. We used linear regression to estimate the association between O 3 exposure and term birth weight and logistic regression to estimate the association between O 3 exposure and term SGA during each trimester of the pregnancy and the entire pregnancy after adjusting for maternal characteristics, infant sex, season of conception, ambient temperature, county poverty rate, and census region. We additionally used distributed lag models to identify the critical exposure windows by estimating the monthly and weekly associations. A 10 parts per billion (ppb) increase in O 3 over the entire pregnancy was associated with a lower term birth weight (-7.6 g; 95 % CI: −8.8 g, −6.4 g) and increased risk of SGA (odds ratio = 1.030; 95 % CI: 1.020, 1.040). The identified critical exposure windows were the 13th- 25th and 32nd −37th gestational weeks for term birth weight and 13th- 25th for term SGA. We found the association was more pronounced among mothers who were non-Hispanic Black, unmarried, or had lower education level. Among US singleton term births, maternal exposure to O 3 was associated with lower rates of fetal growth, and the 13th- 25th gestational weeks were the identified critical exposure windows. [ABSTRACT FROM AUTHOR]

Growth of the fetus is highly sensitive to environmental perturbations, and disruption can lead to problems in pregnancy as well as later in life. This study investigates the relationship between maternal exposure to common plasticizers in pregnancy and fetal growth. Participants from a longitudinal birth cohort in Boston were recruited early in gestation and followed until delivery. Urine samples were collected at up to four time points and analyzed for concentrations of phthalate metabolites and bisphenol A (BPA). Ultrasound scans were performed at four time points during pregnancy for estimation of growth parameters, and birthweight was recorded at delivery. Growth measures were standardized to a larger population. For the present analysis we examined cross-sectional and repeated measures associations between exposure biomarkers and growth estimates in 482 non-anomalous singleton pregnancies. Cross-sectional associations between urinary phthalate metabolites or BPA and growth indices were imprecise. However, in repeated measures models, we observed significant inverse associations between di-2-ethylhexyl phthalate (DEHP) metabolites and estimated or actual fetal weight. An interquartile range increase in summed DEHP metabolites was associated with a 0.13 standard deviation decrease in estimated or actual fetal weight (95% confidence interval = − 0.23, − 0.03). Associations were consistent across different growth parameters (e.g., head circumference, femur length), and by fetal sex. No consistent associations were observed for other phthalate metabolites or BPA. Maternal exposure to DEHP during pregnancy was associated with decreased fetal growth, which could have repercussive effects. [ABSTRACT FROM AUTHOR]

Abstract: Studies have suggested that residential exposure to extremely low frequency (50Hz) electromagnetic fields (ELF-EMF) from high voltage cables, overhead power lines, electricity substations or towers are associated with reduced birth weight and may be associated with adverse birth outcomes or even miscarriages. We previously conducted a study of 140,356 singleton live births between 2004 and 2008 in Northwest England, which suggested that close residential proximity (≤50m) to ELF-EMF sources was associated with reduced average birth weight of 212g (95%CI: −395 to −29g) but not with statistically significant increased risks for other adverse perinatal outcomes. However, the cohort was limited by missing data for most potentially confounding variables including maternal smoking during pregnancy, which was only available for a small subgroup, while also residual confounding could not be excluded. This study, using the same cohort, was conducted to minimize the effects of these problems using multiple imputation to address missing data and propensity score matching to minimize residual confounding. Missing data were imputed using multiple imputation using chained equations to generate five datasets. For each dataset 115 exposed women (residing ≤50m from a residential ELF-EMF source) were propensity score matched to 1150 unexposed women. After doubly robust confounder adjustment, close proximity to a residential ELF-EMF source remained associated with a reduction in birth weight of −116g (95% confidence interval: −224:−7g). No effect was found for proximity ≤100m compared to women living further away. These results indicate that although the effect size was about half of the effect previously reported, close maternal residential proximity to sources of ELF-EMF remained associated with suboptimal fetal growth. [Copyright &y& Elsevier]

Abstract: Animal evidence suggests an association between exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and adverse pregnancy outcomes. Epidemiologic studies report inconsistent results, but are limited by narrow range of exposure, small sample size, and lack of a biologic measure of highest lifetime exposure. On July 10, 1976, a chemical explosion in Seveso, Italy resulted in the highest known residential exposure to TCDD. In 1996, we initiated the Seveso Women's Health Study (SWHS), a retrospective cohort of TCDD exposure and reproductive health. Individual-level TCDD was measured in serum collected soon after the explosion. After 20years of follow-up, we found no association between maternal TCDD in 1976 serum or estimated at pregnancy and spontaneous abortion (SAB), fetal growth, or gestational length. Here, we present an updated analysis of TCDD exposure and adverse pregnancy outcomes from a subsequent follow-up of the SWHS cohort in 2008–2009. SWHS women had 1211 post-explosion pregnancies through the 2008–2009 follow-up. We found no association between TCDD estimated at pregnancy and SAB, fetal growth, or gestational length. However, we found a non-significant inverse association between maternal 1976 serum TCDD and birthweight (adjusted β =−22.8, 95% CI: −80.1, 34.6). The association was stronger among first post-explosion births, but remained non-significant (adjusted β =−47.7, 95% CI: −107.3, 11.9). SWHS is the first study to be able to consider two potentially relevant measures of TCDD exposure: highest lifetime dose and in utero. Our results, although non-significant, suggest that highest dose may be more relevant in epidemiologic studies of TCDD and pregnancy outcomes. [Copyright &y& Elsevier]

[Display omitted] A growing number of studies have identified both toxic and essential metals which influence fetal growth. However, most studies have conducted single-cohort analyses, which are often limited by narrow exposure ranges, and evaluated metals individually. The objective of the current study was to conduct an environmental mixture analysis of metal impacts on fetal growth, pooling data from three geographically and demographically diverse cohorts in the United States participating in the Environmental Influences on Child Health Outcomes program. The pooled sample (N = 1,002) included participants from the MADRES, NHBCS, and PROTECT cohorts. Associations between seven metals (antimony, cadmium, cobalt, mercury, molybdenum, nickel, tin) measured in maternal urine samples collected during pregnancy (median: 16.0 weeks gestation) and birth weight for gestational age z-scores (BW for GA) were investigated using Bayesian Kernel Machine Regression (BKMR). Models were also stratified by cohort and infant sex to investigate possible heterogeneity. Chromium and uranium concentrations fell below the limits of detection for most participants and were evaluated separately as binary variables using pooled linear regression models. In the pooled BKMR analysis, antimony, mercury, and tin were inversely and linearly associated with BW for GA, while a positive linear association was identified for nickel. The inverse association between antimony and BW for GA was observed in both males and females and for all three cohorts but was strongest for MADRES, a predominantly low-income Hispanic cohort in Los Angeles. A reverse j-shaped association was identified between cobalt and BW for GA, which was driven by female infants. Pooled associations were null for cadmium, chromium, molybdenum, and uranium, and BKMR did not identify potential interactions between metal pairs. Findings suggest that antimony, an understudied metalloid, may adversely impact fetal growth. Cohort- and/or sex-dependent associations were identified for many of the metals, which merit additional investigation. [ABSTRACT FROM AUTHOR]

[Display omitted] • Serum PFNA and PFOA levels were linked to higher odds of SGA birth among African American women. • High-resolution metabolomics was used to identify biological pathways and metabolites associated with both serum PFAS and fetal growth. • Changes in amino acid, lipid and fatty acid, bile acid, and androgenic hormone metabolisms were observed. • Serum uric acid is a potential intermediate biomarker for the association between PFAS and fetal growth. Prenatal exposures to per- and polyfluoroalkyl substances (PFAS) have been linked to reduced fetal growth. However, the detailed molecular mechanisms remain largely unknown. This study aims to investigate biological pathways and intermediate biomarkers underlying the association between serum PFAS and fetal growth using high-resolution metabolomics in a cohort of pregnant African American women in the Atlanta area, Georgia. Serum perfluorohexane sulfonic acid (PFHxS), perfluorooctane sulfonic acid (PFOS), perfluorooctanoic acid (PFOA), and perfluorononanoic acid (PFNA) measurements and untargeted serum metabolomics profiling were conducted in 313 pregnant African American women at 8–14 weeks gestation. Multiple linear regression models were applied to assess the associations of PFAS with birth weight and small-for-gestational age (SGA) birth. A high-resolution metabolomics workflow including metabolome-wide association study, pathway enrichment analysis, and chemical annotation and confirmation with a meet-in-the-middle approach was performed to characterize the biological pathways and intermediate biomarkers of the PFAS-fetal growth relationship. Each log 2 -unit increase in serum PFNA concentration was significantly associated with higher odds of SGA birth (OR = 1.32, 95% CI 1.07, 1.63); similar but borderline significant associations were found in PFOA (OR = 1.20, 95% CI 0.94, 1.49) with SGA. Among 25,516 metabolic features extracted from the serum samples, we successfully annotated and confirmed 10 overlapping metabolites associated with both PFAS and fetal growth endpoints, including glycine, taurine, uric acid, ferulic acid, 2-hexyl-3-phenyl-2-propenal, unsaturated fatty acid C18:1, androgenic hormone conjugate, parent bile acid, and bile acid-glycine conjugate. Also, we identified 21 overlapping metabolic pathways from pathway enrichment analyses. These overlapping metabolites and pathways were closely related to amino acid, lipid and fatty acid, bile acid, and androgenic hormone metabolism perturbations. In this cohort of pregnant African American women, higher serum concentrations of PFOA and PFNA were associated with reduced fetal growth. Perturbations of biological pathways involved in amino acid, lipid and fatty acid, bile acid, and androgenic hormone metabolism were associated with PFAS exposures and reduced fetal growth, and uric acid was shown to be a potential intermediate biomarker. Our results provide opportunities for future studies to develop early detection and intervention for PFAS-induced fetal growth restriction. [ABSTRACT FROM AUTHOR]

Abstract: Previous research has shown that prenatal exposure to pesticides may be associated with decreased fetal growth. The specific pesticides investigated and results reported across studies have been inconsistent, and there is a mounting need for the consideration of mixtures rather than individual agents in studies of health outcomes in relation to environmental exposures. There are also many individual pesticides that have not been investigated in human health studies to date. We conducted a pilot study in rural Zhejiang province, China, measuring 20 non-persistent pesticides (10 insecticides, 6 herbicides, 3 fungicides, and 1 repellant) in umbilical cord blood of 112 full term (>37weeks) infants. The pesticides detected with the greatest frequency were diethyltoluamide (DEET) (73%), a repellant, and vinclozolin (49%), a fungicide. The samples had detectable concentrations for a mean of 4.6 pesticides (SD=1.9) with a maximum of 10. Adjusting for potential confounders, newborn birth weight was inversely associated with the number of pesticides detected in cord blood (p=0.04); birth weight decreased by a mean of 37.1g (95% CI, −72.5 to −1.8) for each detected pesticide. When assessing relationships by pesticide type, detection of fungicides was also associated with decreased birth weight (adjusted β=−116g [95% CI, −212 to −19.2]). For individual pesticides analyzed as dichotomous (detect vs. non-detect) variables, only vinclozolin (adjusted β=−174g [95% CI, −312 to −36.3]) and acetochlor (adjusted β=−165g [95% CI, −325 to −5.7]) were significantly associated with reduced birth weight. No significant associations were seen between birth weight and individual pesticides assessed as continuous or 3-level ordinal variables. Our findings from this pilot investigation suggest that exposure to fungicides may adversely impact fetal growth. Exposure to mixtures of multiple pesticides is also of concern and should be explored in addition to individual pesticides. Additional research is needed to establish causality and to understand the function and impact of fungicides and pesticide mixtures on fetal development. [Copyright &y& Elsevier]

Abstract: Background: Previous studies have reported maternal exposure to airborne polycyclic aromatic hydrocarbons (PAH), as well as DNA adducts reflecting total PAH exposure, to be associated with reduced fetal growth. The role of diet, the main source of PAH exposure among non-smokers, remains uncertain. Objective: To assess associations between birth weight, length and small size for gestational age (SGA) with maternal intakes of the genotoxic PAH benzo(a)pyrene [B(a)P] during pregnancy, exploring potential effect modification by dietary intakes of vitamin C, vitamin E, alpha- and beta-carotene, as well as glutathione S-transferase P1 (GSTP1) polymorphisms, hypothesized to influence PAH metabolism. Methods: 657 women in the INMA (Environment and Childhood) Project from Sabadell (Barcelona) were recruited during the first trimester of pregnancy. Dietary B(a)P and nutrient intakes were estimated from food consumption data. Genotyping was conducted for the Ile105Val variant of GSTP1. Multivariable models were used to assess associations between size at birth and dietary B(a)P, evaluating potential interactions with candidate nutrients and GSTP1 variants. Results: There were significant interactions between elevated intakes of vitamin C (above the mean of 189.41mg/day) and dietary B(a)P during the first trimester of pregnancy in models for birth weight and length (P<0.05), but no interactions were found with other nutrients. B(a)P intakes were associated with significant reductions in birth weight and length (coefficient±SE for a 1-SD increase in B(a)P: −101.63±34.62g and −0.38±0.16cm, respectively) among women with low, but not high, vitamin C intakes. Elevated dietary B(a)P was also associated with increased risk of SGA births among women with low dietary vitamin C. Among these women, associations were strongest in those carrying the GSTP1 Val allele, associated with lower contaminant detoxification activity. Conclusion: Results suggest that dietary B(a)P exposure may impair fetal growth, particularly in genetically susceptible populations, and that increasing maternal intakes of vitamin C may help to reduce any adverse effects. [Copyright &y& Elsevier]

• Acrylamide was positively associated with placental NGF and cord blood free T3. • Glycidamide was positively associated with cord blood free T3. • Acrylamide was negatively associated with cord blood TSH and free T4/T3. • Glycidamide was negatively associated with cord blood insulin and free T4/T3. • Insulin seemed to mediate the association between glycidamide and birth weight. Four epidemiological studies have shown a negative association between prenatal acrylamide exposure and birth size. In order to shed light on the possible underlying mechanism(s), we analysed associations between acrylamide biomarkers and biomarkers related to fetal growth. In newborns of the ENVIR ON AGE birth cohort (n ranges from 215 to 434), we investigated the association between prenatal acrylamide exposure (acrylamide and glycidamide hemoglobin adduct levels in cord blood) and thyroid hormones (TSH, T3, T4 and the ratio of T4 to T3 in cord plasma), insulin-related factors (cord plasma insulin and IGF1, and placental IGF2), neurotrophins (cord plasma BDNF, and placental NGF, NT3 and NT4), and cord plasma homocysteine and progesterone, using multiple linear regression analysis. In addition, we investigated whether the biomarkers mediated the associations between prenatal acrylamide exposure and birth outcomes. We observed lower cord plasma TSH (−10.2% [95% CI: −15.0, −4.3]) and higher placental NGF levels (10.0% [95% CI 3.7, 17.4]) for a twofold increase of acrylamide adducts, a decrease in the ratio of cord plasma free T4 and free T3 with higher acrylamide and glycidamide adducts of −2.9% (95% CI: −5.7, −0.1) and −3.9% (95% CI: −6.2, −1.6) for a twofold increase in acrylamide and glycidamide adduct levels, respectively, and higher cord plasma free T3 with increases in both acrylamide and glycidamide adducts of 2.8% (95% CI: 0.2, 5.6) and 3.6% (95% CI: 0.8, 6.6) for a twofold increase in acrylamide and glycidamide adduct levels, respectively. Additionally, a twofold increase in glycidamide adducts was associated with lower cord plasma insulin levels, particularly among newborns of non-smoking mothers (−11.2% [95% CI: −19.5, −0.1]). Cord plasma insulin seemed to mediate the association between glycidamide adducts and birth weight. A decrease in cord plasma insulin levels may be (a marker of) a mechanism by which gestational acrylamide exposure is associated with decreased fetal growth. The possible health consequences of the associations between gestational acrylamide exposure and thyroid hormones and neurotrophins warrant future study. [ABSTRACT FROM AUTHOR]

• Phthalates are related with fetal growth restriction and preterm birth. • Phthalates may have trimester specific effects on fetal growth and birth outcomes. • Limiting prenatal phthalate exposure is crucial to prevent suboptimal fetal growth. Exposure to phthalates may affect fetal growth, but previous studies are inconsistent and have not explored the trimester-specific effects of phthalates on repeated measures of fetal growth. To assess the associations of maternal phthalate metabolites urine concentrations with fetal growth measures and birth outcomes and identify potential windows of vulnerability to exposure. Population-based prospective cohort study, the Generation R Study (2002–2006). Data analysis was performed from November 2019 to June 2020. Rotterdam, the Netherlands. 1379 pregnant women. Maternal phthalate metabolites urine concentrations in first, second and third trimester. Fetal head circumference, length and weight measured in the second and third trimester by ultrasound and at birth and preterm birth and small size for gestational age at birth. Higher pregnancy-averaged phthalic acid, low molecular weight phthalate (LMWP), high molecular weight phthalate (HMWP) and di-2-ethylhexylphthalate (DEHP) concentrations tended to be associated with lower fetal weight SDS across gestation. The associations of phthalic acid and LMWP with fetal weight became stronger as pregnancy progressed (differences −0.08 (95% CI −0.14 to −0.02) SDS and −0.09 (95% CI −0.16 to −0.02) SDS at 40 weeks per interquartile range increase in phthalic acid and LMWP, respectively). Higher concentrations of specific LMWP, HMWP and DEHP metabolites were also associated with smaller head circumference and lower length SDS at birth and an increased risk of preterm birth and small size for gestational age at birth (p-values < 0.05). We observed differences by timing of exposure in these associations. Higher maternal phthalate metabolites urine concentrations seem to be related with fetal growth restriction and preterm birth. Phthalates may have trimester specific effects on fetal growth and birth outcomes. Further studies are needed to explore the underlying mechanisms and long-term consequences. [ABSTRACT FROM AUTHOR]

• In healthy pregnant women, circulating PCSK9 positively correlates with air pollutants. • PCSK9 levels are associated to the outcomes of pregnancy occurring at delivery. • A rise in PCSK9 levels associates to decreased gestational age at delivery. • A rise in PCSK9 levels associates to an increased probability of urgent cesarean delivery. Exposure to airborne pollutants during pregnancy appears to be associated with uterine growth restriction and adverse neonatal outcome. Proprotein convertase subtilisin/kexin type (PCSK9), the key modulator of low-density lipoprotein (LDL) metabolism, increases following particulate matter (PM 10) exposure. Because maternal cholesterol is required for fetal growth, PCSK9 levels could be used to evaluate the potential impact of airborne pollutants on fetal growth. A cohort of 134 healthy women during early pregnancy (11–12 weeks of gestational age) was studied. A significant association between circulating PCSK9 levels and three tested air pollutants (PM 10 , PM 2.5 , nitric oxide (NO 2)) was found. Of importance, gestational age at birth was reduced by approximately 1 week for each 100 ng/mL rise in circulating PCSK9 levels, an effect that became more significant at the highest quartile of PM 2.5 (with a 1.8 week advance in delivery date for every 100 ng/mL rise in circulating PCSK9; p for interaction = 0.026). This finding was supported by an elevation of the odds ratio for urgent cesarean delivery for each 100 ng/mL rise in PCSK9 (2.99, 95% CI, 1.22–6.57), similar trends being obtained for PM 10 and NO 2. The association between exposure to air pollutants during pregnancy and elevation in PCSK9 advances our understanding of the unforeseen influences of environmental exposure in terms of pregnancy associated disorders. [ABSTRACT FROM AUTHOR]