Thyroid hormones are crucial in normal brain development. Transient and mild thyroid hormone insufficiency in pregnancy is also associated with impaired neurodevelopment in the offspring (e.g., 3-4 ...IQ score loss in association with maternal free thyroxine in the lowest fifth percentile). While inadequate iodine intake remains the most common underlying cause of mild thyroid hormone insufficiency in vulnerable populations including pregnant women, other factors such as exposure to environmental contaminants have recently attracted increasing attention, in particular in interaction with iodine deficiency. Endocrine-disrupting chemicals (EDCs) are natural and synthetic substances with ubiquitous exposure in children and adults including pregnant women. EDCs interfere, temporarily or permanently, with hormonal signaling pathways in the endocrine system by binding to hormone receptors and modifying gene expression. Other mechanisms involve alterations in production, metabolism, and transfer of hormones. Experimental studies have shown that exposures to EDCs affect various brain processes such as neurogenesis, neural differentiation and migration, as well as neural connectivity. Neuroimaging studies confirm brain morphological abnormalities (e.g., cortical thinning) consistent with neurodevelopmental impairments as a result of EDC exposures at standard use levels. In this review, we provide an overview of present findings from toxicological and human studies on the anti-thyroid effect of EDCs with a specific attention to fetal and early childhood exposure. This brief overview highlights the need for additional multidisciplinary studies with a focus on thyroid disruption as an underlying mechanism for developmental neurotoxicity of EDC, which can provide insight into modifiable risk factors of developmental delays in children.
To identify homogenous depressive symptom trajectories over the postpartum period and the demographic and perinatal factors linked to different trajectories.
Mothers (
= 4866) were recruited for ...Upstate KIDS, a population-based birth cohort study, and provided assessments of depressive symptoms at 4, 12, 24, and 36 months postpartum. Maternal demographic and perinatal conditions were obtained from vital records and/or maternal report.
Four depression trajectories were identified: low-stable (74.7%), characterized by low symptoms at all waves; low-increasing (8.2%), characterized by initially low but increasing symptoms; medium-decreasing (12.6%), characterized by initially moderate but remitting symptoms; and high-persistent (4.5%), characterized by high symptoms at all waves. Compared with the high-persistent group, older mothers (maximum odds ratio OR of the 3 comparisons: 1.10; 95% confidence interval CI: 1.05 to 1.15) or those with college education (maximum OR: 2.52; 95% CI: 1.36 to 4.68) were more likely to be in all other symptom groups, and mothers who had a history of mood disorder (minimum OR: 0.07; 95% CI: 0.04 to 0.10) or gestational diabetes mellitus diagnosis (minimum OR: 0.23; 95% CI: 0.08 to 0.68) were less likely to be in other symptom groups. Infertility treatment, multiple births, prepregnancy BMI, gestational hypertension, and infant sex were not differentially associated with depressive symptom trajectories.
One-quarter of mothers in a population-based birth cohort had elevated depressive symptoms in 3 years postpartum. Screening for maternal depression beyond the postpartum period may be warranted, particularly after mood and diabetic disorders.
IMPORTANCE: Maternal thyroid hormone insufficiency during pregnancy can affect children’s cognitive development. Nevertheless, the behavioral outcomes of children exposed prenatally to mild thyroid ...hormone insufficiency are understudied. OBJECTIVE: To examine whether exposure to maternal mild thyroid hormone insufficiency in early pregnancy was related to symptoms of attention-deficit/hyperactivity disorder (ADHD) in children at 8 years of age. DESIGN, SETTING, AND PARTICIPANTS: The study was embedded within the Generation R, a population-based birth cohort in the Netherlands. Children in the Generation R Study are followed up from birth (April 1, 2002, through January 31, 2006) until young adulthood. Of the 4997 eligible mother-child pairs with data on maternal thyroid levels (excluding twins), 3873 pairs of children and caregivers (77.5%) visited the Generation R research center for in-depth assessments and were included in the main analyses. Data collection in Generation R started December 1, 2001 (enrollment of pregnant women), and is ongoing. For this study, we used the data that were collected until January 1, 2014. Data analyses started on January 31 and finished June 30, 2014. MAIN OUTCOMES AND MEASURES: Maternal hypothyroxinemia, characterized by low levels of free thyroxine coexisting with reference thyrotropin levels, and children’s symptoms of ADHD. Maternal thyroid hormone levels (thyrotropin, free thyroxine, thyroid peroxidase antibodies) were measured at a mean (SD) of 13.6 (1.9) weeks of gestation. Children’s ADHD symptoms were assessed at 8 years of age using the Conners’ Parent Rating Scale–Revised Short Form; higher scores indicate more ADHD symptoms (possible range, 0-36). RESULTS: Maternal hypothyroxinemia (n = 127) in early pregnancy was associated with higher scores for ADHD symptoms in children at 8 years of age after adjustments for child and maternal factors (ie, sex, ethnicity, maternal age, maternal educational level, and income) (increase in ADHD scores, 7% 95% CI, 0.3%-15%). The results remained essentially unchanged when women with elevated levels of thyroid peroxidase antibodies were excluded from the analyses (increase in ADHD scores, 8% 95% CI, 1%-16%). Additional adjustment for children’s IQ or comorbid autistic symptoms attenuated the association (increase in ADHD scores adjusted for autistic symptoms, 7% 95% CI, 1%-15%; increase in ADHD scores adjusted for IQ, 6% 95% CI, 1%-14%). CONCLUSIONS AND RELEVANCE: Children exposed to maternal hypothyroxinemia in early pregnancy had more ADHD symptoms, independent of confounders. This finding suggests that intrauterine exposure to insufficient thyroid hormone levels influences neurodevelopment in offspring.
•Higher exposure to BPS attenuated the association of maternal FT4 with TSH.•Higher late-pregnancy maternal BPA is associated with offspring thyroid function.•The association of BPA with offspring ...thyroid function is sex-specific.
Most pregnant women are exposed to bisphenols, a group of chemicals that can interfere with various components of the thyroid system.
To investigate the association of maternal urinary bisphenol concentrations during pregnancy with maternal, newborn and early childhood thyroid function.
This study was embedded in Generation R, a prospective, population-based birth cohort (Rotterdam, the Netherlands). Maternal urine samples were analyzed for eight bisphenols at early (<18), mid (18–25) and late (>25 weeks) pregnancy. Maternal serum thyroid stimulating hormone (TSH), free thyroxine (FT4) and total thyroxine (TT4) were measured in early pregnancy and child TSH and FT4 were measured in cord blood and childhood.
The final study population comprised 1,267 mothers, 853 newborns and 882 children. Of the eight bisphenols measured, only bisphenol A (BPA) was detected in >50% of samples at all three time-points and bisphenol S (BPS) at the first time-point. There was no association of BPA or the bisphenol molar sum with maternal thyroid function. Higher BPS concentrations were associated with a higher maternal TT4 (β 95% CI per 1 (natural-log) unit increase: 0.97 0.03 to 1.91) but there was no association with TSH or FT4. Furthermore, higher BPS was associated with an attenuation of the association between maternal FT4 and TSH (Pinteraction = 0.001). There was no association of early or mid-pregnancy BPA or early pregnancy BPS with cord blood or childhood TSH and FT4. A higher late pregnancy maternal BPA exposure was associated with a higher TSH in female newborns (Pinteraction = 0.06) and a higher FT4 during childhood in males (Pinteraction = 0.08).
Our findings show that exposure to bisphenols may interfere with the thyroid system during pregnancy. Furthermore, the potential developmental toxicity of exposure to bisphenols during pregnancy could affect the thyroid system in the offspring in a sex-specific manner.
Objective
Transient gestational hypothyroxinemia in rodents induces cortical neuronal migration brain lesions resembling those of autism. We investigated the association between maternal ...hypothyroxinemia (gestational weeks 6–18) and autistic symptoms in children.
Methods
The mother‐and‐child cohort of the Generation R Study (Rotterdam, the Netherlands) began prenatal enrollment between 2002 and 2006. At a mean gestational age of 13.4 weeks (standard deviation = 1.9, range = 5.9–17.9), maternal thyroid function tests (serum thyrotropin TSH, free thyroxine fT4, and thyroid peroxidase TPO antibodies) were assessed in 5,100 women. We defined severe maternal hypothyroxinemia as fT4 < 5th percentile with normal TSH. Six years later, parents reported behavioral and emotional symptoms in 4,039 children (79%) using the Pervasive Developmental Problems (PDP) subscale of the Child Behavior Checklist and/or the Social Responsiveness Scale (SRS). We defined a probable autistic child by a PDP score > 98th percentile and SRS score in the top 5% of the sample (n = 81, 2.0%).
Results
Severe maternal hypothyroxinemia (n = 136) was associated with an almost 4‐fold increase in the odds of having a probable autistic child (adjusted odds ratio = 3.89, 95% confidence interval CI = 1.83–8.20, p < 0.001). Using PDP scores, children of mothers with severe hypothyroxinemia had higher scores of autistic symptoms by age 6 years (adjusted B = 0.23, 95% CI = 0.03–0.37); SRS results were similar. No risk was found for children of TPO‐antibody–positive mothers (n = 308).
Interpretation
We found a consistent association between severe, early gestation maternal hypothyroxinemia and autistic symptoms in offspring. Findings are concordant with epidemiological, biological, and experimental data on autism. Although these findings cannot establish causality, they open the possibility of preventive interventions. Ann Neurol 2013;74:733–742
Environmental health research aims to assess the impact of environmental exposures, making it crucial to understand their effects due to their broad impacts on the general population. However, a ...common issue with measuring exposures using bio-samples in laboratory is that values below the limit of detection (LOD) are either left unreported or inaccurately read by machines, which subsequently influences the analysis and assessment of exposure effects on health outcomes. We address the challenge of handling exposure variables subject to LOD when they are treated as either covariates or an outcome. We evaluate the performance of commonly-used methods including complete-case analysis and fill-in method, and advanced techniques such as multiple imputation, missing-indicator model, two-part model, Tobit model, and several others. We compare these methods through simulations and a dataset from NHANES 2013–2014. Our numerical studies show that the missing-indicator model generally yields reasonable estimates when considering exposure variables as covariates under various settings, while other methods tend to be sensitive to the LOD-missing proportions and/or distributional skewness of exposures. When modeling an exposure variable as the outcome, Tobit model performs well under Gaussian distribution and quantile regression generally provides robust estimates across various shapes of the outcome’s distribution. In the presence of missing data due to LOD, different statistical models should be considered for being aligned with scientific questions, model assumptions, requirements of data distributions, as well as their interpretations. Sensitivity analysis to handle LOD-missing exposures can improve the robustness of model conclusions.
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•Bisphenols and phthalates are ubiquitous endocrine disrupting chemicals.•Fetal exposure to bisphenols is associated with higher weight between 0 and 4 years.•Fetal exposure to ...phthalates is associated with adiposity at 3 and 4 years.
Exposure to endocrine-disrupting chemicals such as bisphenols and phthalates during pregnancy may disrupt fetal developmental programming and influence early-life growth. We hypothesized that prenatal bisphenol and phthalate exposure was associated with alterations in adiposity through 4 years. This associations might change over time.
Among 1091 mother–child pairs in a New York City birth cohort study, we measured maternal urinary concentrations of bisphenols and phthalates at three time points in pregnancy and child weight, height, and triceps and subscapular skinfold thickness at ages 1, 2, 3, and 4 years. We used linear mixed models to assess associations of prenatal individual and grouped bisphenols and phthalates with overall and time-point-specific adiposity outcomes from birth to 4 years.
We observed associations of higher maternal urinary second trimester total bisphenol and bisphenol A concentrations in pregnancy and overall child weight between birth and 4 years only (Beta 0.10 (95 % confidence interval 0.04, 0.16) and 0.07 (0.02, 0.12) standard deviation score (SDS) change in weight per natural log increase in exposure), We reported an interaction of the exposures with time, and analysis showed associations of higher pregnancy-averaged mono-(2-carboxymethyl) phthalate with higher child weight at 3 years (0.14 (0.06, 0.22)), and of higher high-molecular-weight phthalate, di-2-ethylhexyl phthalate, mono-(2-ethyl-5-carboxypentyl) phthalate, mono-(2-carboxymethyl) phthalate, and mono-(2-ethylhexyl) phthalate with higher child weight at 4 years (0.16 (0.04, 0.28), 0.15 (0.03, 0.27), 0.19 (0.07, 0.31), 0.16 (0.07, 0.24), 0.11 (0.03, 0.19)). Higher pregnancy-averaged high-molecular-weight phthalate, di-2-ethylhexyl phthalate, mono-(2-ethyl-5-carboxypentyl) phthalate, mono-(2-ethyl-5-hydroxyhexyl) phthalate, and mono-2(ethyl-5-oxohexyl) phthalate concentrations were associated with higher child BMI at 4 years (0.20 (0.05, 0.35), 0.20 (0.05, 0.35), 0.22 (0.06, 0.37), 0.20 (0.05, 0.34), 0.20 (0.05, 0.34)). For skinfold thicknesses, we observed no associations.
This study contributes to the evidence suggesting associations of prenatal exposure to bisphenols and high-molecular-weight phthalates on childhood weight and BMI.
•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.
Animal models and epidemiological studies suggest that mild maternal thyroid hormone deficiency in early gestation has adverse consequences on the cognitive abilities of the children. However, ...methodological problems, lack of a consistent definition for mild thyroid hormone deficiency, and short follow-up of the children reduce the confidence in the conclusion of existing studies. In this review, we summarize the main findings of a series of studies performed in Generation R, a population-based birth cohort in Rotterdam, the Netherlands. In this iodine sufficient region, we aimed to investigate the relation between mild maternal thyroid hormone deficiency in early gestation and children's verbal and nonverbal cognitive function and executive function. We discuss the main findings of these studies, present recommendations for clinicians and formulate suggestions for future research.
Early infant growth trajectories have been linked to obesity risk. The aim of this study was to examine early infant feeding practices in association with anthropometric measures and risk of ...overweight/obesity in childhood. A total of 2492 children from Upstate KIDS, a population-based longitudinal cohort, were included for the analysis. Parents reported breastfeeding and complementary food introduction from 4 to 12 months on questionnaires. Weight and height were reported at 2-3 years of age and during later follow-up at 7-9 years of age. Age and sex z-scores were calculated. Linear mixed models were conducted, adjusting for maternal and child sociodemographic factors. Approximately 54% of infants were formula-fed at <5 months of age. Compared to those formula-fed, BMI- (adjusted B, -0.23; 95% CI: -0.42, -0.05) and weight-for-age z-scores (adjusted B, -0.16; -0.28, -0.03) were lower for those exclusively breastfed. Infants breastfed for ≥12 months had a lower risk of being overweight (aRR, 0.33; 0.18, 0.59) at 2-3 years, relative to formula-fed infants. Compared to introduction at <5 months, the introduction of fruits and vegetables between 5 and 8 months was associated with lower risk of obesity at 7-9 years (aRR, 0.45; 0.22, 0.93). The type and duration of breastfeeding and delayed introduction of certain complementary foods was associated with lower childhood BMI.
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