Gestational PBDE concentrations, persistent externalizing, and emerging internalizing behaviors in adolescents: The HOME study.

BACKGROUND: Polybrominated diphenyl ethers (PBDEs) are ubiquitous environmental chemicals used as flame retardants in commercial and consumer products. Gestational PBDE concentrations are associated with adverse behaviors in children; however, the persistence of these associations into adolescence remains understudied. OBJECTIVE: We estimated the association of gestational PBDE serum concentrations with early adolescent self- and caregiver-reported behaviors at age 12 years and determined the consistency with previously observed associations in childhood with caregiver-reported behaviors in a prospective pregnancy and birth cohort. METHODS: We measured maternal serum concentrations of five individual PBDE congeners and created a summary exposure variable (∑5BDE: 28, -47, -99, -100 and -153) during pregnancy. At age 12 years, we assessed behaviors for 237 adolescents using self- and caregiver-reports with the Behavioral Assessment System for Children-3 (BASC3). We used multivariable linear regression models to estimate covariate-adjusted associations of lipid standardized, log10-transformed gestational PBDE concentrations with BASC3 scores. We obtained estimates and 95% confidence intervals through a bootstrapping approach. We evaluated potential effect measure modification (EMM) of adolescent sex by examining sex-stratified regression models and estimating the EMM p-values. RESULTS: Gestational PBDE concentrations were positively associated with adolescent-reported BASC3 composite indices for inattention & hyperactivity (BDE-28, -47, -99, -100, ∑5BDE), internalizing problems (BDE-28, -47, -99), functional impairment (BDE-28, ∑5BDE), and emotional symptoms (BDE-28). Gestational PBDE concentrations were positively associated with caregiver-reported BASC3 composite indices for externalizing problems (BDE-28, -47, -99, -100, -153, ∑5BDE) and behavioral symptoms (BDE-99). For caregiver reported behaviors, we observed stronger associations with gestational BDE concentrations among males, especially for executive functioning (BDE-28, -47, -99, -100, ∑5BDE). DISCUSSION: Gestational PBDE serum concentrations were associated with self-reported internalizing and externalizing behavior problems in early adolescence. Caregiver-reported externalizing behaviors recognized during childhood remain associated with gestational PBDE concentrations and persist into early adolescence. Internalizing behaviors were less recognized by caregivers.

Maternal and newborn metabolomic changes associated with urinary polycyclic aromatic hydrocarbon metabolite concentrations at delivery: an untargeted approach.

INTRODUCTION: Prenatal exposure to polycyclic aromatic hydrocarbons (PAHs) has been associated with adverse human health outcomes. To explore the plausible associations between maternal PAH exposure and maternal/newborn metabolomic outcomes, we conducted a cross-sectional study among 75 pregnant people from Cincinnati, Ohio. METHOD: We quantified 8 monohydroxylated PAH metabolites in maternal urine samples collected at delivery. We then used an untargeted high-resolution mass spectrometry approach to examine alterations in the maternal (n = 72) and newborn (n = 63) serum metabolome associated with PAH metabolites. Associations between individual maternal urinary PAH metabolites and maternal/newborn metabolome were assessed using linear regression adjusted for maternal and newborn factors while accounting for multiple testing with the Benjamini-Hochberg method. We then conducted functional analysis to identify potential biological pathways. RESULTS: Our results from the metabolome-wide associations (MWAS) indicated that an average of 1% newborn metabolome features and 2% maternal metabolome features were associated with maternal urinary PAH metabolites. Individual PAH metabolite concentrations in maternal urine were associated with maternal/newborn metabolome related to metabolism of vitamins, amino acids, fatty acids, lipids, carbohydrates, nucleotides, energy, xenobiotics, glycan, and organic compounds. CONCLUSION: In this cross-sectional study, we identified associations between urinary PAH concentrations during late pregnancy and metabolic features associated with several metabolic pathways among pregnant women and newborns. Further studies are needed to explore the mediating role of the metabolome in the relationship between PAHs and adverse pregnancy outcomes.

Maternal urinary OPE metabolite concentrations and blood pressure during pregnancy: The HOME study.

BACKGROUND: Few studies have examined the association between maternal exposure to organophosphate esters (OPEs) and systolic/diastolic blood pressure (SBP/DBP) during pregnancy. METHODS: We analyzed data from 346 women with a singleton live birth in the HOME Study, a prospective birth cohort in Cincinnati, Ohio, USA. We quantified four OPE metabolites in maternal spot urine samples collected at 16 and 26 weeks pregnancy, standardized by specific gravity. We calculated intraclass correlation coefficients (ICCs). We extracted the first two recorded BP measurements (<20 weeks), the two highest recorded BP measurements (≥20 weeks), and diagnoses of hypertensive disorders of pregnancy (HDP) via chart review. Women with two BP measurements ≥140/90 mmHg or HDP noted in the chart at ≥20 weeks pregnancy were defined as HDP cases. We used linear mixed models and modified Poisson regression with covariate adjustment to estimate associations between OPE concentrations as continuous variables or in tertiles with maternal BP and HDP. RESULTS: ICCs of OPEs were 0.17-0.45. Diphenyl phosphate (DPHP) had the highest geometric mean concentration among OPE metabolites. Increasing the average bis(2-chloroethyl) phosphate (BCEP) concentrations were positively associated with two highest recorded DBP ≥20 weeks pregnancy. Compared with women in the 1st DPHP tertile, women in the 3rd tertile at 16 weeks pregnancy had 1.72 mmHg (95% CI: -0.01, 3.46) higher DBP <20 weeks pregnancy, and women in the 3rd tertile of the average DPHP concentrations had 2.25 mmHg (95% CI: 0.25, 4.25) higher DBP ≥20 weeks pregnancy. 33 women (9.5%) were identified with HDP. Di-n-butyl phosphate (DNBP) concentrations at 16 weeks were positively associated with HDP, with borderline significance (RR = 2.98, 95% CI 0.97-9.15). Other OPE metabolites were not significantly associated with HDP. CONCLUSION: Maternal urinary BCEP and DPHP concentrations were associated with increased BP during pregnancy. Maternal urinary DNBP concentrations were associated with HDP, with borderline significance.

Childhood urinary organophosphate esters and cognitive abilities in a longitudinal cohort study.

The use of organophosphate esters (OPEs) as flame retardants, which has increased over the past two decades, raises concerns that OPEs may be harmful to humans, especially children. Animal studies and some human studies have reported that OPEs may adversely impact brain development, but few human studies evaluated OPE exposure during early childhood and neurodevelopmental outcomes. We aimed to fill this knowledge gap with the present study on urinary OPE metabolite concentrations at ages 1-5 years and cognitive abilities at 8 years. We used data of 223 children from the Health Outcomes and Measures of the Environment (HOME) Study, a prospective pregnancy and birth cohort in Cincinnati, Ohio. The point estimates for bis-2-chloroethyl-phosphate (BCEP) and bis(1,3-dichloro-2-propyl)-phosphate (BDCIPP) in association with IQ tended to be small and positive, while the point estimates for diphenyl-phosphate (DPHP) were small and negative, with 95% CIs including the null. However, we did find that socioeconomic status (SES) variables modified associations between OPEs and child IQ, with adverse OPE-IQ associations being stronger in socioeconomically disadvantaged children than in others. We identified an additional 1- to 2-point decrease in Full Scale IQ for every log-unit increase in BDCIPP, BCEP, and DPHP among those with lower maternal education, non-white race, lower income, or living in more deprived neighborhoods. We observed similar results for the Perceptual Reasoning, Verbal Comprehension, and Working Memory Index Scores. We suspect that there is residual confounding related to socioeconomic disadvantage, which was not captured with the available SES variables typically used in epidemiologic studies.

Plasma Fluorescent Oxidation Products and Bone Mineral Density Among Male Veterans: A Cross-Sectional Study.

In vitro and vivo studies indicate that oxidative stress contributes to bone loss. Fluorescent oxidation products (FlOPs) are novel biomarkers of oxidative stress; they reflect global oxidative damage of lipids, proteins, carbohydrates, and DNA. However, whether FlOPs are associated with bone mineral density (BMD) is still unclear. In the present study, we examined the association between FlOPs and BMD among male veterans. This cross-sectional study was conducted among participants recruited from the Department of Medical Examination, The Second Hospital of Jilin University in Jilin, China. We identified male veterans who were at least 50 y old between June and October of 2019. Plasma FlOPs were measured with a fluorescent microplate reader (excitation/emission wavelength: 320/420 nm). BMD were measured by dual-energy X-ray absorptiometry (DXA). The association between FlOPs and BMD was tested by multivariable linear regression models. A total of 164 male veterans were enrolled in the study, the average age was 56.6 y. After adjusting for covariates, veterans who had FlOP levels in the highest tertile had a statistically significant lower femoral neck (ß = -0.044; p = 0.007) and total hip BMD (ß = -0.045; p = 0.020) as compared to those with FlOP levels in the lowest tertile. Similar results were found when FlOPs were treated as a continuous variable (per 1-SD increase, ß = -0.014 and p = 0.033 for femoral neck BMD; ß = -0.016 and p = 0.047 for total hip BMD). Higher FlOP levels were associated with lower BMD among male veterans.

Maternal Urinary Organophosphate Esters and Alterations in Maternal and Neonatal Thyroid Hormones.

Production of organophosphate esters (OPEs), which represent a major flame-retardant class present in consumer goods, has increased over the past 2 decades. Experimental studies suggest that OPEs may be associated with thyroid hormone disruption, but few human studies have examined this association. We quantified OPE metabolites in the urine of 298 pregnant women from Cincinnati, Ohio, in the Health Outcomes and Measures of the Environment Study (enrolled 2003-2006) at 3 time points (16 and 26 weeks' gestation, and at delivery), and thyroid hormones in 16-week maternal and newborn cord sera. Urinary bis(1,3-dichloro-2-propyl)-phosphate concentrations were generally associated with decreased triiodothyronine and thyroxine levels and increased thyroid-stimulating hormone levels in maternal and newborn thyroid hormones in quartile dose-response analyses and multiple informant models. There was weaker evidence for thyroid hormone alterations in association with diphenyl-phosphate and di-n-butyl-phosphate. Bis-2-chloroethyl-phosphate was not associated with alterations in thyroid hormones in any analyses. We did not observe any evidence of effect modification by infant sex. These results suggest that gestational exposure to some OPEs may influence maternal and neonatal thyroid function, although replication in other cohorts is needed.

Prenatal exposure to per- and polyfluoroalkyl substances (PFAS) and neurobehavior in US children through 8 years of age: The HOME study.

BACKGROUND: Studies of prenatal per- and polyfluoroalkyl substances (PFAS) and attention deficit hyperactivity disorder (ADHD)-related behaviors in children are inconsistent. OBJECTIVES: To examine associations between maternal serum PFAS concentrations and child behavior in 241 mother-child dyads within the Health Outcomes and Measures of the Environment (HOME) Study. METHODS: We quantified perfluorooctanoate (PFOA), perfluorooctane sulfonate (PFOS), perfluorohexane sulfonate (PFHxS), and perfluorononanoate (PFNA) in maternal serum collected during pregnancy or at delivery. We evaluated a total of 17 outcomes of child behavior using the Behavioral Assessment System for Children-2 (BASC-2) at 5 and 8 years (n = 240) and ADHD diagnostic symptoms and criteria with the Diagnostic Interview Schedule for Children-Young Child (DISC-YC) at 5 years (n = 190). We used linear mixed models and logistic regression with generalized estimating equations to assess associations between PFAS and continuous or dichotomous "at risk" BASC-2 scores; negative binomial regression to calculate incident rate ratios for counts of ADHD symptoms; and Poisson regression with robust standard errors to calculate relative risks of meeting ADHD diagnostic criteria. RESULTS: Each ln-unit increase in PFOS, PFHxS, and PFNA was associated with higher BASC-2 scores and increased odds of "at-risk" scores for externalizing behaviors, including hyperactivity (PFOS: odds ratio [OR] 2.7, 95% confidence interval [CI] 1.2, 5.9; PFHxS: OR 2.5, 95% CI 1.5, 4.3; PFNA: OR 3.2, 95% CI 1.3, 8.0). PFHxS was also associated with internalizing problems (OR 2.0, 95% CI 1.1, 3.4) and somatization (OR 2.2, 95% CI 1.2, 4.0). PFOS and PFNA were significantly associated with 50-80% more DISC-YC symptoms and diagnostic criteria related to hyperactive-impulsive type ADHD. Prenatal PFNA was associated with increased risk of any-type ADHD. CONCLUSIONS: Prenatal PFOS and PFNA were consistently associated with measures related to hyperactive-impulsive type ADHD across two validated assessment instruments. PFHxS was associated with increased problems with both externalizing and internalizing behaviors. No associations were noted between PFOA and child neurobehavior.

Maternal cadmium exposure and neurobehavior in children: The HOME study.

BACKGROUND: It is unclear whether cadmium (Cd) exposure during fetal brain development is associated with child neurobehavior. OBJECTIVE: To examine the potential associations between Cd exposure during pregnancy and neurobehavior among children. METHODS: We used data from 276 children in the Health Outcomes and Measures of the Environment (HOME) Study, a well-established prospective pregnancy and birth cohort. We measured maternal urinary Cd concentrations at 26 weeks of gestation. For cognitive function, we assessed Mental Development Index (MDI) and Full-Scale Intelligence Quotient (FSIQ) using the Bayley Scales of Infant Development-II, the Wechsler Preschool and Primary Scales of Intelligence-III, or the Wechsler Intelligence Scales for Children-IV at ages 1, 2, 3, 5, and 8 years. We assessed child behaviors using the Behavior Assessment System for Children-2 at ages 2, 3, 4, 5, and 8 years, yielding four composite measures: Externalizing Problems, Internalizing Problems, Behavioral Symptoms Index, and Adaptive Skills. We used linear mixed models with covariate adjustment to estimate the associations between maternal urinary Cd concentrations and child neurobehavior. RESULTS: We categorized study participants into three groups based on maternal urinary Cd concentrations (Group 1: < limit of detection (LOD), Group 2: 0.06-0.22 µg/g creatinine, Group 3: ＞0.22 µg/g creatinine). In linear mixed models adjusting for maternal and child characteristics, maternal urinary Cd levels were not significantly associated with cognitive function at ages 1, 2, 3, 5, and 8 years or with behavioral composite measures at 2, 3, 4, 5, and 8 years. CONCLUSIONS: No significant associations were observed between maternal urinary Cd and cognitive or behavioral measures in children at 1-8 years of age in this study.

Organophosphate esters in a cohort of pregnant women: Variability and predictors of exposure.

Organophosphate esters (OPEs) are a group of chemicals used as flame retardants and plasticizers that replaced polybrominated diphenyl ethers in consumer products such as furniture and electronics. To characterize exposure to OPEs during fetal development, we measured urinary OPE metabolite concentrations in women twice during pregnancy (16 and 26 weeks' gestation) and at delivery (n = 357). We also previously quantified house dust OPE parent compound concentrations at 20 weeks' gestation (n = 317). Diphenyl phosphate (DPHP) had the highest geometric mean urinary concentrations (1.5-2.3 µg/g creatinine), followed by bis(1,3-dichloro-2-propyl) phosphate (BDCIPP; 0.75-0.99 µg/g creatinine), and bis(2-chloroethyl) phosphate (BCEP; 0.72-0.97 µg/g creatinine), while dibutyl phosphate (DNBP) had the lowest concentrations (0.25-0.28 µg/g creatinine). Urinary OPE metabolites were moderately correlated with each other at 26 weeks (rs: 0.23-0.38, p < 0.001) while the correlations at 16 weeks and delivery were slightly weaker. Intra-class correlations for urinary metabolites measured at three time points were poor (0.16-0.34), indicating high variability within individuals. Dust concentrations of OPE parent compounds were associated with BCEP, BDCIPP, and DPHP concentrations in urine at some but not all time points. In linear mixed models of urinary OPE metabolite concentrations, household size was inversely associated with BCEP concentrations, and being non-white was associated with lower BDCIPP and DPHP concentrations. Urine samples collected in the summer had the highest OPE metabolite concentrations. This study highlights the need to collect multiple urine samples during pregnancy to define exposure patterns and investigate potential periods of susceptibility.

Effects of ß-carotene intake on the risk of fracture: a Bayesian meta-analysis.

BACKGROUND: Epidemiological studies examining the association between ß-carotene intake and risk of fracture have reported inconsistent findings. We conducted a meta-analysis to investigate the association between ß-carotene intake and risk of fracture. METHODS: We systematically searched PubMed, EMBASE and Cochrane library databases for relevant articles that were published until December 2019. We also identified studies from reference lists of articles identified from the clinical databases. The frequentist and Bayesian random-effects model was used to synthesize data. RESULTS: Nine studies with a total of 190,545 men and women, with an average age of 59.8 years, were included in this meta-analysis. For ß-carotene intake (1.76-14.30 mg/day), the pooled risk ratio (RR) of any fracture was 0.67 (95% Credible Interval (CrI): 0.51-0.82; heterogeneity: P = 0.66, I2 = 0.00%) and 0.63 (95%CrI: 0.44-0. 82) for hip fracture. By study design, the pooled RRs were 0.55 (95% CrI: 0.14-0.96) for case-control studies and 0.82 (95% CrI: 0.58-0.99) for cohort studies. By geographic region, the pooled RRs were 0.58 (95% CrI: 0.28-0.89), 0.86 (95% CrI: 0.35-0.1.37), and 0.91(95% CrI: 0.75-1.00) for studies conducted in China, the United States, and Europe, respectively. By sex, the pooled RRs were 0.88 (95% CrI: 0.73-0.99) for males and 0.76 (95% CrI, 0.44-1.07) for females. There was a 95% probability that ß-carotene intake reduces risk of hip fracture and any type of fracture by more than 20%. CONCLUSIONS: The present meta-analysis suggests that ß-carotene intake was inversely associated with fracture risk, which was consistently observed for case-control and cohort studies. Randomized controlled trials are warranted to confirm this relationship.

Prenatal and childhood exposure to poly- and perfluoroalkyl substances (PFAS) and cognitive development in children at age 8 years.

BACKGROUND: Toxicological studies indicate that poly- and perfluoroalkyl substances (PFAS) may be neurotoxic, but human studies have yet to provide compelling evidence for PFAS' impact on cognitive abilities. OBJECTIVE: To test whether prenatal and childhood PFAS are associated with cognitive abilities at 8 years and whether sex modifies these associations. METHODS: We included 221 mother-child pairs from the Health Outcomes and Measures of the Environment (HOME) Study, a birth cohort in Cincinnati, OH (USA). We quantified PFAS in maternal serum at 16 ±â€¯3 weeks gestation and in child serum at 3 and 8 years. We used the Wechsler Intelligence Scale for Children-Fourth Edition (WISC-IV) at age 8 years, assessing Full Scale IQ (FSIQ), verbal comprehension, perceptual reasoning, working memory, and processing speed. We used multiple informant models to estimate covariate-adjusted differences in WISC-IV scores by repeated ln-transformed PFAS. RESULTS: Prenatal and childhood perfluorooctane sulfonate (PFOS) and perfluorohexane sulfonate (PFHxS) were not associated with WISC-IV measures. We observed an increase of 4.1-points (95% CI 0.3, 8.0) and 5.7-points (95% CI 1.2, 10.2) in working memory with 1-ln unit increase in prenatal perfluorooctanoate (PFOA) and perfluorononanoate (PFNA), respectively. In addition, PFNA at 3 years was associated with better FSIQ and perceptual reasoning. Child sex modified the relationship between prenatal PFOA and FSIQ; the association was positive in females only. Sex also modified the association between concurrent PFOS and FSIQ, with males having higher scores. CONCLUSION: We did not observe adverse associations between prenatal and childhood PFAS and cognitive function at age 8 years.

Exposure to polybrominated diphenyl ethers (PBDEs) and child behavior: Current findings and future directions.

Polybrominated diphenyl ethers (PBDEs) are recognized neurotoxicants, but the extent to which PBDEs influence various domains of behavior in children is not fully understood. As such, we reviewed epidemiologic studies published to date to provide an overview of the current state of knowledge on PBDEs' potential role in behavioral development. We identified 19 epidemiologic studies reporting on associations of prenatal and childhood concentrations of PBDEs with behaviors assessed in children from 1 to 12years, including executive function, attention, externalizing and internalizing behaviors, adaptive skills, and social behaviors/Autism Spectrum Disorder (ASD). While the mechanisms of PBDE neurotoxicity in humans are still not clearly elucidated, findings from this review indicate that PBDE exposure during fetal development is associated with impairments in executive function and poorer attentional control in children. Results from large prospective cohorts demonstrate that prenatal and postnatal PBDE exposure adversely impacts externalizing behavior (e.g., hyperactivity and conduct problems). Additional studies are needed to determine whether PBDEs are associated with internalizing problems, adaptive skills, and social behaviors/ASD in children. Future studies will help better understand the potential neurotoxic effects of PBDE exposures during adolescence, possible sex-dependent effects, and the impact of exposure to BDE-209 and alternative flame retardants. Future studies should also examine chemical mixtures to capture real-world exposures when examining PBDEs and their impact on various behavioral domains in the context of multiple chemical exposures.

Childhood polybrominated diphenyl ether (PBDE) exposure and neurobehavior in children at 8 years.

BACKGROUND: Prenatal polybrominated diphenyl ether (PBDE) exposure has been associated with decrements in IQ and increased attention deficit/hyperactivity disorder related behaviors in children; however, data are limited for the role of postnatal exposures. OBJECTIVES: We investigated the association between a series of childhood PBDE concentrations and Full-Scale Intelligence Quotient (FSIQ) and externalizing problems at 8 years. METHODS: We used data from 208 children in the Health Outcomes and Measures of the Environment (HOME) Study, a prospective pregnancy and birth cohort. Child serum PBDEs were measured at 1, 2, 3, 5, and 8 years; missing serum PBDE concentrations were estimated via multiple imputation. The Wechsler Intelligence Scales for Children-IV and the Behavior Assessment System for Children-2 was used to assess intelligence and externalizing behavior, respectively, in children at 8 years. We used multiple informant models to estimate associations between repeated lipid-adjusted PBDEs and child neurobehavior and to test for windows of susceptibility. RESULTS: Postnatal exposure to PBDE congeners (- 28, - 47, - 99, - 100, and - 153) at multiple ages was inversely associated with FSIQ at 8 years. For instance, a 10-fold increase in BDE-153 concentrations at 2, 3, 5, and 8 years were all related to lower FSIQ at age 8 (ß for 3 years: - 7.7-points, 95% CI - 12.5, - 2.9; ß for 8 years: - 5.6-points, 95% CI - 10.8, - 0.4). Multiple PBDE congeners at 8 years were associated with increased hyperactivity and aggressive behaviors at 8 years. CONCLUSIONS: Postnatal PBDE exposure was associated with decrements in FSIQ and increases in hyperactivity and aggressive behaviors.

Prenatal and postnatal polybrominated diphenyl ether exposure and visual spatial abilities in children.

Polybrominated diphenyl ethers (PBDEs) are associated with impaired visual spatial abilities in toxicological studies, but no epidemiologic study has investigated PBDEs and visual spatial abilities in children. The Health Outcomes and Measures of the Environment Study, a prospective birth cohort (2003-2006, Cincinnati, OH), was used to examine prenatal and childhood PBDEs and visual spatial abilities in 199 children. PBDEs were measured at 16±3 weeks gestation and at 1, 2, 3, 5, and 8 years using gas chromatography/isotope dilution high-resolution mass spectrometry. We used the Virtual Morris Water Maze to measure visual spatial abilities at 8 years. In covariate-adjusted models, 10-fold increases in BDE-47, -99, and -100 at 5 years were associated with shorter completion times by 5.2s (95% Confidence Interval [CI] -9.3, -1.1), 4.5s (95% CI -8.1, -0.9), and 4.7s (95% CI -9.0, -0.3), respectively. However, children with higher BDE-153 at 3 years had longer completion times (ß=5.4s, 95% CI -0.3, 11.1). Prenatal PBDEs were associated with improved visual spatial memory retention, with children spending a higher percentage of their search path in the correct quadrant. Child sex modified some associations between PBDEs and visual spatial learning. Longer path lengths were observed among males with increased BDE-47 at 2 and 3 years, while females had shorter paths. In conclusion, prenatal and postnatal BDE-28, -47, -99, and -100 at 5 and 8 years were associated with improved visual spatial abilities, whereas a pattern of impairments in visual spatial learning was noted with early childhood BDE-153 concentrations.

Prenatal Exposure to Nitrosatable Drugs, Dietary Intake of Nitrites, and Preterm Birth.

Prenatal exposure to nitrosatable drugs, including secondary or tertiary amines, has been associated with preterm birth. Associations may be accentuated by higher intakes of dietary nitrites because of the increased formation of N-nitroso compounds. Using data from mothers of babies without major birth defects (controls) from the National Birth Defects Prevention Study, we examined the relationship between nitrosatable drug exposure in conjunction with dietary nitrite intake and preterm birth among 496 mothers of preterm infants and 5,398 mothers with full-term deliveries in 1997-2005. A protective association was observed with a high intake of plant nitrites (adjusted hazard ratio (AHR) = 0.72, 95% confidence interval (CI): 0.53, 0.97). Secondary amines in conjunction with high nitrite intake were associated with preterm birth during the first (AHR = 1.84, 95% CI: 1.14, 2.98), second (AHR = 1.89, 95% CI: 1.17, 3.07), and third (AHR = 2.00, 95% CI: 1.22, 3.29) trimesters. The adjusted hazard ratios for tertiary amine use in the third trimester by increasing tertiles of nitrite intake were 0.67 (95% CI: 0.35, 1.31), 1.25 (95% CI: 0.71, 2.19), and 2.02 (95% CI: 1.17, 3.49). Prenatal exposure to nitrosatable drugs, particularly secondary and tertiary amines, in conjunction with higher levels of dietary nitrite intake may increase the risk of preterm birth.

Prenatal polybrominated diphenyl ether and perfluoroalkyl substance exposures and executive function in school-age children.

Executive function is a critical behavioral trait rarely studied in relation to potential neurotoxicants. Prenatal exposure to polybrominated diphenyl ethers (PBDEs) and perfluoroalkyl substances (PFASs) has been associated with adverse neurodevelopment, but there is limited research on executive function. Data from 256 mother-child pairs in the Health Outcomes and Measures of the Environment Study, a prospective birth cohort (2003-2006, Cincinnati, OH), was used to examine maternal serum PBDEs and PFASs and executive function in children ages 5 and 8 years. Maternal serum PBDEs and PFASs were measured at 16±3 weeks gestation. Executive function was assessed with the parent-rated Behavior Rating Inventory of Executive Function (BRIEF), which yields composite measures: behavioral regulation index, metacognition index, and global executive composite. Higher BRIEF scores indicate executive function impairments. Linear mixed models and generalized estimating equations were used to estimate covariate-adjusted associations between PBDEs and PFASs and executive function. A 10-fold increase in BDE-153 was associated with poorer behavior regulation (ß=3.23, 95% CI 0.60, 5.86). Higher odds of having a score ≥60 in behavior regulation (OR=3.92, 95% CI 1.76, 8.73) or global executive functioning (OR=2.34, 95% CI 1.05, 5.23) was observed with increased BDE-153. Each ln-unit increase in perfluorooctane sulfonate (PFOS) was associated with poorer behavior regulation (ß=3.14, 95% CI 0.68, 5.61), metacognition (ß=3.10, 95% CI 0.62, 5.58), and global executive functioning (ß=3.38, 95% CI 0.86, 5.90). However, no association was observed between perfluorooctanoate (PFOA) and executive function. Prenatal exposures to BDE-153 and PFOS may be associated with executive function deficits in school-age children.

Gestational Weight Gain Trend and Population Attributable Risks of Adverse Fetal Growth Outcomes in Ohio.

BACKGROUND: The trend of gestational weight gain (GWG) in relation to the Institute of Medicine (IOM) guidelines and the population attributable risks (PARs) of GWG on fetal growth outcomes remain unclear. METHODS: We analysed Ohio birth certificates from 2006 to 2012 to examine GWG trend by prepregnancy body mass index, to calculate the risk of small- and large-for-gestational age (SGA and LGA), and macrosomia (birthweight >4000 g or >4500 g) infants, and to estimate the PARs of GWG below or above the guidelines. RESULTS: Of 869,531 women who delivered singleton live births at 22-44 weeks of gestation, 4.5% were underweight, 48.9% were normal weight, 23.9% were overweight, and 22.7% were obese before pregnancy. About 36.5% of underweight, 52.6% of normal weight, 72.5% of overweight, and 62.4% of obese women gained weight above the guidelines, with only slight changes from 2006 to 2012. Also, 34.9% of underweight, 20.1% of normal weight, 16.3% of overweight, and 27.0% of obese women gained weight below the guidelines. The PAR of GWG below or above the guidelines was -13% for SGA, 32.6% for LGA, 28.1% for macrosomia >4000 g, and 48.3% for macrosomia >4500 g, mostly driven by currently GWG above the guidelines in normal weight, overweight, and obese women. CONCLUSIONS: A high percentage of pregnant women gained weight outside of the current IOM GWG guidelines; however, changes from 2006 to 2012 were small. GWG above the IOM guidelines significantly contributed to a large proportion of LGA and macrosomic infants in the general population.

Nitrosatable Drug Exposure during Pregnancy and Preterm and Small-for-Gestational-Age Births.

BACKGROUND: Nitrosatable drugs react with nitrite in the stomach to form N-nitroso compounds, observed in animal models to result in adverse pregnancy outcomes, such as birth defects and reduced fetal weight. Previous studies examining prenatal exposure to medications classified as nitrosatable have reported an increased risk of preterm births (PTBs) and small-for-gestational-age (SGA) infants. METHODS: Using data from mothers (controls) of babies without major birth defects from the National Birth Defects Prevention Study, prenatal nitrosatable drug usage by trimester and month of gestation was examined in relation to PTBs and SGA infants. RESULTS: Positive associations were observed with nitrosatable drug use and PTBs, with the strongest relationship with second trimester exposure (adjusted hazard ratio [aHR] 1.37, [95% confidence interval (CI) 1.10, 1.70]). Of the nitrosatable functional groups, secondary amines were the most notable, with a higher association among women with second (aHR 1.37, [95% CI 1.05, 1.79]) and third (aHR 1.34, [95% CI 1.02, 1.76]) trimester exposure compared with women with no prenatal nitrosatable drug use. Among SGA infants, a borderline association was noted with amide exposure during the third trimester (adjusted odds ratio 1.43 [95% confidence interval [CI] 1.00, 2.05]). CONCLUSIONS: Prenatal exposure to nitrosatable drugs during the second and third trimester of pregnancy, particularly secondary amines, might increase the risk of PTBs. However, prenatal exposure to nitrosatable drugs was not associated with SGA infants, with the exception of amide drugs.

Gestational urinary bisphenol A and maternal and newborn thyroid hormone concentrations: the HOME Study.

Bisphenol A (BPA), an endocrine disruptor used in consumer products, may perturb thyroid function. Prenatal BPA exposure may have sex-specific effects on thyroid hormones (THs). Our objectives were to investigate whether maternal urinary BPA concentrations during pregnancy were associated with THs in maternal or cord serum, and whether these associations differed by newborn sex or maternal iodine status. We measured urinary BPA concentrations at 16 and 26 weeks gestation among pregnant women in the HOME Study (2003-2006, Cincinnati, Ohio). Thyroid stimulating hormone (TSH) and free and total thyroxine (T4) and triiodothyronine (T3) were measured in maternal serum at 16 weeks (n=181) and cord serum at delivery (n=249). Associations between BPA concentrations and maternal or cord serum TH levels were estimated by multivariable linear regression. Mean maternal urinary BPA was not associated with cord THs in all newborns, but a 10-fold increase in mean BPA was associated with lower cord TSH in girls (percent change=-36.0%; 95% confidence interval (CI): -58.4, -1.7%), but not boys (7.8%; 95% CI: -28.5, 62.7%; p-for-effect modification=0.09). We observed no significant associations between 16-week BPA and THs in maternal or cord serum, but 26-week maternal BPA was inversely associated with TSH in girls (-42.9%; 95% CI: -59.9, -18.5%), but not boys (7.6%; 95% CI: -17.3, 40.2%; p-for-effect modification=0.005) at birth. The inverse BPA-TSH relation among girls was stronger, but less precise, among iodine deficient versus sufficient mothers. Prenatal BPA exposure may reduce TSH among newborn girls, particularly when exposure occurs later in gestation.

Assessing bottled water nitrate concentrations to evaluate total drinking water nitrate exposure and risk of birth defects.

Previous epidemiologic studies of maternal exposure to drinking water nitrate did not account for bottled water consumption. The objective of this National Birth Defects Prevention Study (NBDPS) (USA) analysis was to assess the impact of bottled water use on the relation between maternal exposure to drinking water nitrate and selected birth defects in infants born during 1997-2005. Prenatal residences of 1,410 mothers reporting exclusive bottled water use were geocoded and mapped; 326 bottled water samples were collected and analyzed using Environmental Protection Agency Method 300.0. Median bottled water nitrate concentrations were assigned by community; mothers' overall intake of nitrate in mg/day from drinking water was calculated. Odds ratios for neural tube defects, limb deficiencies, oral cleft defects, and heart defects were estimated using mixed-effects models for logistic regression. Odds ratios (95% CIs) for the highest exposure group in offspring of mothers reporting exclusive use of bottled water were: neural tube defects [1.42 (0.51, 3.99)], limb deficiencies [1.86 (0.51, 6.80)], oral clefts [1.43 (0.61, 3.31)], and heart defects [2.13, (0.87, 5.17)]. Bottled water nitrate had no appreciable impact on risk for birth defects in the NBDPS.