Urinary polycyclic aromatic hydrocarbon (PAH) metabolite concentrations in three pregnancy cohorts from 7 U.S. study sites.

OBJECTIVE: Prenatal exposure to polycyclic aromatic hydrocarbons (PAHs) is associated with adverse birth and developmental outcomes in children. We aimed to describe prenatal PAH exposures in a large, multisite U.S. consortium. METHODS: We measured 12 mono-hydroxylated metabolites (OH-PAHs) of 7 PAHs (naphthalene, fluorene, phenanthrene, pyrene, benzo(c)phenanthrene, chrysene, benz(a)anthracene) in mid-pregnancy urine of 1,892 pregnant individuals from the ECHO PATHWAYS consortium cohorts: CANDLE (n = 988; Memphis), TIDES (n = 664; Minneapolis, Rochester, San Francisco, Seattle) and GAPPS (n = 240; Seattle and Yakima, WA). We described concentrations of 8 OH-PAHs of non-smoking participants (n = 1,695) by site, socioeconomic characteristics, and pregnancy stage (we report intraclass correlation coefficients (ICC) for n = 677 TIDES participants). RESULTS: Exposure to the selected PAHs was ubiquitous at all sites. 2-hydroxynaphthalene had the highest average concentrations at all sites. CANDLE had the highest average concentrations of most metabolites. Among non-smoking participants, we observed some patterns by income, education, and race but these were not consistent and varied by site and metabolite. ICCs of repeated OH-PAH measures from TIDES participants were ≤ 0.51. CONCLUSION: In this geographically-diverse descriptive analysis of U.S. pregnancies, we observed ubiquitous exposure to low molecular weight PAHs, highlighting the importance of better understanding PAH sources and their pediatric health outcomes attributed to early life PAH exposure.

Prenatal exposure to polycyclic aromatic hydrocarbons and executive functions at school age: Results from a combined cohort study.

BACKGROUND: Executive functions develop rapidly in childhood, enabling problem-solving, focused attention, and planning. Exposures to environmental toxicants in pregnancy may impair healthy executive function development in children. There is increasing concern regarding polycyclic aromatic hydrocarbons (PAHs) given their ability to transfer across the placenta and the fetal blood-brain barrier, yet evidence from epidemiological studies is limited. METHODS: We examined associations between prenatal PAH exposure and executive functions in 814 children of non-smoking mothers from two U.S. cohorts in the ECHO-PATHWAYS Consortium. Seven mono-hydroxylated PAH metabolites were measured in mid-pregnancy urine and analyzed individually and as mixtures. Three executive function domains were measured at age 8-9: cognitive flexibility, working memory, and inhibitory control. A composite score quantifying overall performance was further calculated. We fitted linear regressions adjusted for socio-demographics, maternal health behaviors, and psychological measures, and examined modification by child sex and stressful life events in pregnancy. Bayesian kernel machine regression was performed to estimate the interactive and overall effects of the PAH mixture. RESULTS: The results from primary analysis of linear regressions were generally null, and no modification by child sex or maternal stress was indicated. Mixture analyses suggested several pairwise interactions between individual PAH metabolites in varied directions on working memory, particularly interactions between 2/3/9-FLUO and other PAH metabolites, but no overall or individual effects were evident. CONCLUSION: We conducted a novel exploration of PAH-executive functions association in a large, combined sample from two cohorts. Although findings were predominantly null, the study carries important implications for future research and contributes to evolving science regarding developmental origins of diseases.

Associations of prenatal ambient air pollution exposures with asthma in middle childhood.

We examined associations between prenatal fine particulate matter (PM2.5), nitrogen dioxide (NO2), and ozone (O3) exposures and child respiratory outcomes through age 8-9 years in 1279 ECHO-PATHWAYS Consortium mother-child dyads. We averaged spatiotemporally modeled air pollutant exposures during four fetal lung development phases: pseudoglandular (5-16 weeks), canalicular (16-24 weeks), saccular (24-36 weeks), and alveolar (36+ weeks). We estimated adjusted relative risks (RR) for current asthma at age 8-9 and asthma with recent exacerbation or atopic disease, and odds ratios (OR) for wheezing trajectories using modified Poisson and multinomial logistic regression, respectively. Effect modification by child sex, maternal asthma, and prenatal environmental tobacco smoke was explored. Across all outcomes, 95% confidence intervals (CI) included the null for all estimates of associations between prenatal air pollution exposures and respiratory outcomes. Pseudoglandular PM2.5 exposure modestly increased risk of current asthma (RRadj = 1.15, 95% CI: 0.88-1.51); canalicular PM2.5 exposure modestly increased risk of asthma with recent exacerbation (RRadj = 1.26, 95% CI: 0.86-1.86) and persistent wheezing (ORadj = 1.28, 95% CI: 0.86-1.89). Similar findings were observed for O3, but not NO2, and associations were strengthened among mothers without asthma. While not statistically distinguishable from the null, trends in effect estimates suggest some adverse associations of early pregnancy air pollution exposures with child respiratory conditions, warranting confirmation in larger samples.

Ultra-processed and fast food consumption, exposure to phthalates during pregnancy, and socioeconomic disparities in phthalate exposures.

BACKGROUND: Consuming ultra-processed foods may increase exposure to phthalates, a group of endocrine disruptors prevalent in food contact materials. OBJECTIVES: Investigate associations between ultra-processed food intake and urinary phthalates during pregnancy, and evaluate whether ultra-processed foods mediate socioeconomic disparities in phthalate exposures. METHODS: In a socioeconomically diverse sample of 1031 pregnant women from the Conditions Affecting Neurocognitive Development and Learning in Early Childhood (CANDLE) Study in the urban South, the Block Food Frequency Questionnaire was administered and urinary phthalate metabolites were measured in the second trimester. Linear regressions modeled associations between phthalates and overall ultra-processed food consumption, individual ultra-processed foods, and exploratory factor analysis dietary patterns. Causal mediation analyses examined whether ultra-processed food intake mediates relationships between socioeconomic disparities and phthalate exposures. RESULTS: Ultra-processed foods constituted 9.8-59.0 % (mean = 38.6 %) of participants' diets. 10 % higher dietary proportion of ultra-processed foods was associated with 13.1 % (95 %CI: 3.4 %-22.9 %) higher molar sum concentrations of di(2-ethylhexyl) phthalate metabolites (ΣDEHP). 10 % higher consumption of minimally-processed foods was associated with lower ΣDEHP (10.8 %: 3.4 %-22.9 %). Ultra- and minimally-processed food consumption were not associated with non-DEHP metabolites. Standard deviation higher consumptions of hamburger/cheeseburger, French fries, soda, and cake were associated with 10.5 % (4.2 %-17.1 %), 9.2 % (2.6 %-16.2 %), 7.4 % (1.4 %-13.6 %), and 6.0 % (0.0 %-12.4 %), respectively, higher ΣDEHP. Exploratory factor analysis corroborated positive associations of processed food with ΣDEHP, and uncovered a healthy dietary pattern associated with lower urinary ΣDEHP, mono(2-ethyl-5-hydroxyhexyl) (MEHHP), mono(2-ethyl-5-carboxypentyl) (MECPP), mono(2-carboxymethylhexyl) (MCMHP), and mono-isononyl (MINP) phthalates. Significant indirect effects indicated that lower income and education levels were associated with 1.9 % (0.2 %-4.2 %) and 1.4 % (0.1 %-3.3 %) higher ΣDEHP, respectively, mediated via increased ultra-processed food consumption. CONCLUSIONS: Consumption of ultra-processed foods may increase exposure to phthalates. Policies to reduce dietary phthalate exposures from food packaging and processing are needed, as socioeconomic barriers can preclude dietary recommendations as a sole means to reduce phthalate exposures.

Early prenatal sex steroids and sex-typed play behavior at 4 years of age.

During pregnancy, estrogens and testosterone influence brain development, resulting in sex-typical behavioral phenotypes. Prenatal testosterone exposure is associated with more male-typical behaviors in rodents, monkeys, and humans; however, few studies have examined the relationship between maternal sex hormones within the normal range and sex-dimorphic behaviors. In this study, we examined associations between prenatal estrogens and testosterone and sex-typical play in The Infant Development and the Environment Study (TIDES), a multicenter pregnancy cohort. We collected prenatal serum during the first trimester (mean=11.1 ± 2.6 weeks) and assessed child play behavior using the maternally completed Pre-School Activities Inventory (PSAI) at a mean age of 4.5 ± 0.3 years. This analysis includes mother-child pairs with complete data on hormones, play behavior, and covariates (n = 192 boys and 207 girls). No associations were seen between testosterone and PSAI scores in boys or girls or between estrogens and PSAI scores in boys. In girls, we observed an inverse relationship between feminine PSAI scores and both estradiol (E2) and estriol (E3) in multivariable linear regression analyses (E2: -0.11 [95% CI -0.20, -0.02]; E3: -0.44 [95% CI -0.83,-0.04]). Because the relationship between sex hormones and PSAI scores appeared nonlinear, we fit piecewise regression models to better fit the data and identify inflection points (point at which there is a significant change in slope). Piecewise regression analyses yielded inverse associations between masculine PSAI scores and estrone (E1) at values of E1 > 1340 pg/mL and E2 at values of E2 > 2870 pg/mL in girls. Further studies are needed to better understand the role of prenatal sex steroids on sexually dimorphic behavior.

Association between maternal eating and young child feeding in a community sample.

BACKGROUND: Early childhood is a pivotal period for the development of healthy eating practices. One way to promote child health is to identify early modifiable factors that affect child eating and weight. Given the intergenerational transmission of eating behaviors, this study examined how mothers' eating behaviors were associated with child feeding practices, and whether child weight-for-length (z-WFL) moderated this relation, in a community sample. METHODS: Participants were 72 mother-child dyads. Maternal eating behaviors-emotional, external and restrained-were assessed 9-months postpartum, using the Dutch Eating Behavior Questionnaire. Child feeding-restrictive, pressure, and concern about overeating/overweight or undereating/underweight-was measured using the Infant Feeding Questionnaire, and child z-WFL were assessed 18-months postpartum. Linear regressions were used to test the main effect of maternal eating and the interaction effect of maternal eating and child z-WFL, on child feeding practices. RESULTS: Maternal restrained eating was associated with child pressure feeding, and contrarily with concerns about overeating/overweight. However, a significant interaction between child z-WFL and both maternal emotional and external eating were found with regard to concern about child undereating/underweight. Paradoxically, among children who weighed more, greater maternal emotional and greater external eating were associated with greater concern about child undereating/underweight. CONCLUSIONS: In this community sample, mothers were more likely to report contradictory feeding practices and concerns, suggesting complicated relations among a mother's own eating behavior, her child's weight, and her perceptions of child eating and weight. This may indicate a need for better communication and support of infant feeding practices. TRIAL REGISTRATION: Data was collected as part of two grants (MAMAS Grant ID: HL097973-01; SEED Grant ID: HL116511-02) conducted at the University of California, San Francisco (UCSF). All subjects gave their informed consent for inclusion before they participated in the study. The study was conducted in accordance with the Declaration of Helsinki, and the protocol was approved by institutional review board at UCSF.

Linking specific biological signatures to different childhood adversities: findings from the HERO project.

BACKGROUND: Although investigations have begun to differentiate biological and neurobiological responses to a variety of adversities, studies considering both endocrine and immune function in the same datasets are limited. METHODS: Associations between proximal (family functioning, caregiver depression, and anxiety) and distal (SES-D; socioeconomic disadvantage) early-life adversities with salivary inflammatory biomarkers (IL-1ß, IL-6, IL-8, and TNF-α) and hair HPA markers (cortisol, cortisone, and dehydroepiandrosterone) were examined in two samples of young U.S. children (N = 142; N = 145). RESULTS: Children exposed to higher SES-D had higher levels of TNF-α (B = 0.13, p = 0.011), IL-1ß (B = 0.10, p = 0.033), and DHEA (B = 0.16, p = 0.011). Higher family dysfunction was associated with higher cortisol (B = 0.08, p = 0.033) and cortisone (B = 0.05, p = 0.003). An interaction between SES-D and family dysfunction was observed for cortisol levels (p = 0.020) whereby children exposed to lower/average levels of SES-D exhibited a positive association between family dysfunction and cortisol levels, whereas children exposed to high levels of SES-D did not. These findings were partially replicated in the second sample. CONCLUSIONS: Our results indicate that these biological response systems may react differently to different forms of early-life adversity. IMPACT: Different forms of early-life adversity have varied stress signatures, and investigations of early-life adversities with inflammation and HPA markers are lacking. Children with higher socioeconomic disadvantage had higher TNF-α, IL-1ß, and DHEA. Higher family dysfunction was associated with higher hair cortisol and cortisone levels, and the association between family dysfunction and cortisol was moderated by socioeconomic disadvantage. Biological response systems (immune and endocrine) were differentially associated with distinct forms of early-life adversities.

A study on the association of placental and maternal urinary phthalate metabolites.

BACKGROUND: Phthalate exposure in pregnancy is typically estimated using maternal urinary phthalate metabolite levels. Our aim was to evaluate the association of urinary and placental tissue phthalates, and to explore the role of maternal and pregnancy characteristics that may bias estimates. METHODS: Fifty pregnancies were selected from the CANDLE Study, recruited from 2006 to 2011 in Tennessee. Linear models were used to estimate associations of urinary phthalates (2nd, 3rd trimesters) and placental tissue phthalates (birth). Potential confounders and modifiers were evaluated in categories: temporality (time between urine and placenta sample), fetal sex, demographics, social advantage, reproductive history, medication use, nutrition and adiposity. Molar and quantile normalized phthalates were calculated to facilitate comparison of placental and urinary levels. RESULTS: Metabolites detectable in >80% of both urine and placental samples were MEP, MnBP, MBzP, MECPP, MEOHP, MEHHP, and MEHP. MEP was most abundant in urine (geometric mean [GM] 7.00 ×102 nmol/l) and in placental tissue (GM 2.56 ×104 nmol/l). MEHP was the least abundant in urine (GM 5.32 ×101 nmol/l) and second most abundant in placental tissue (2.04 ×104 nmol/l). In aggregate, MEHP differed the most between urine and placenta (2.21 log units), and MEHHP differed the least (0.07 log units). MECPP was positively associated between urine and placenta (regression coefficient: 0.31 95% CI 0.09, 0.53). Other urine-placenta metabolite associations were modified by measures of social advantage, reproductive history, medication use, and adiposity. CONCLUSION: Phthalates were ubiquitous in 50 full-term placental samples, as has already been shown in maternal urine. MEP and MEHP were the most abundant. Measurement and comparison of urinary and placental phthalates can advance knowledge on phthalate toxicity in pregnancy and provide insight into the validity and accuracy of relying on maternal urinary concentrations to estimate placental exposures. IMPACT STATEMENT: This is the first report of correlations/associations of urinary and placental tissue phthalates in human pregnancy. Epidemiologists have relied exclusively on maternal urinary phthalate metabolite concentrations to assess exposures in pregnant women and risk to their fetuses. Even though it has not yet been confirmed empirically, it is widely assumed that urinary concentrations are strongly and positively correlated with placental and fetal levels. Our data suggest that may not be the case, and these associations may vary by phthalate metabolite and associations may be modified by measures of social advantage, reproductive history, medication use, and adiposity.

Associations between social, biologic, and behavioral factors and biomarkers of oxidative stress during pregnancy: Findings from four ECHO cohorts.

BACKGROUND: Lower socioeconomic status (SES) and elevated psychosocial stress are known contributors to adverse pregnancy outcomes; however, biological mechanisms linking these factors to adverse pregnancy outcomes are not well-characterized. Oxidative stress may be an important, yet understudied mechanistic pathway. We used a pooled study design to examine biological, behavioral, and social factors as predictors of prenatal oxidative stress biomarkers. METHODS: Leveraging four pregnancy cohorts from the Environmental influences on Child Health Outcomes (ECHO) Program spanning multiple geographic regions across the United States (U.S.) (N = 2082), we measured biomarkers of oxidative stress in urine samples at up to three time points during pregnancy, including 8-isoprostane-prostaglandin F2α (8-isoPGF2α), its major metabolite, 2,3-dinor-5,6-dihydro-15-F2t-isoprostane, and prostaglandin F2α (PGF2α). Maternal age, pre-pregnancy body mass index, marital/partnered status, parity, and smoking status were included as biological and behavioral factors while race/ethnicity, maternal education, and stressful life events were considered social factors. We examined associations between each individual biological, behavioral, and social factor with oxidative stress biomarkers using multivariable-adjusted linear mixed models. RESULTS: Numerous biological, behavioral, and social factors were associated with elevated levels of 8-isoPGF2α, its major metabolite, and PGF2α. Pregnant people who were current smokers relative to non-smokers or had less than a high school education relative to a college degree had 11.04% (95% confidence interval [CI] = -1.97%, 25.77%) and 9.13% (95% CI = -1.02%, 20.32%) higher levels of 8-isoPGF2α, respectively. CONCLUSIONS: Oxidative stress biomarkers are elevated among pregnant people with higher socioeconomic disadvantage and may represent one pathway linking biological, behavioral, and social factors to adverse pregnancy and child health outcomes, which should be explored in future work.

Prenatal exposure to polycyclic aromatic hydrocarbons and gestational age at birth.

BACKGROUND: Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous chemicals with mechanisms of toxicity that include endocrine disruption. We examined associations of prenatal urinary PAH with spontaneous preterm birth (PTB) and gestational age (GA) at birth. We also assessed whether infant sex modifies the association of PAH exposure with spontaneous PTB and GA at birth. METHODS: Participants included 1,677 non-smoking women from three cohorts (CANDLE, TIDES, and GAPPS) in the ECHO PATHWAYS Consortium. Twelve monohydroxylated-PAHs were measured in second trimester maternal urine. Seven metabolites with >60% overall detection were included in analyses: 1-hydroxynaphthalene [1-OH-NAP], 2-hydroxynaphthalene [2-OH-NAP], 2-hydroxyphenanthrene [2-OH-PHEN], 3-hydroxyphenanthrene [3-OH-PHEN], 1/9-hydroxyphenanthrene [1/9-OH-PHEN], 2/3/9-hydroxyfluorene [2/3/9-OH-FLUO], and 1-hydroxypyrene [1-OH-PYR]. Logistic and linear regression models were fit for spontaneous PTB and GA among births ≥34 weeks, respectively, with log10-transformed OH-PAH concentrations as the exposure, adjusted for specific gravity and suspected confounders. Effect modification by infant sex was assessed using interaction terms and marginal estimates. RESULTS: Percent detection was highest for 2-OH-NAP (99.8%) and lowest for 1-OH-PYR (65.2%). Prevalence of spontaneous PTB was 5.5% (N = 92). Ten-fold higher 2-OH-NAP exposure was associated with 1.60-day (95% CI: -2.92, -0.28) earlier GA at birth. Remaining associations in the pooled population were null. Among females, we observed significant inverse associations between 1-OH-PYR and PTB (OR: 2.65 [95% CI: 1.39, 5.05]); and 2-OH-NAP with GA: -2.46 days [95% CI: -4.15, -0.77]). Among males, we observed an inverse association between 2/3/9-OH-FLUO and PTB (OR = 0.40 [95% CI: 0.17,0.98]). ORs for PTB were higher among females than males for 2-OH-PHEN (p = 0.02) and 1-OH-PYR (p = 0.02). DISCUSSION: We observed inverse associations of 2-OH-NAP exposure with GA and null associations of remaining OH-PAHs with GA and PTB. Females may be more susceptible to spontaneous PTB or shorter GA following prenatal exposure to some OH-PAHs. This study is the first to assess sex-specific OH-PAH toxicity in relation to spontaneous PTB and GA.

Adversity in early life and pregnancy are immunologically distinct from total life adversity: macrophage-associated phenotypes in women exposed to interpersonal violence.

Early childhood and pregnancy are two sensitive periods of heightened immune plasticity, when exposure to adversity may disproportionately increase health risks. However, we need deeper phenotyping to disentangle the impact of adversity during sensitive periods from that across the total lifespan. This study examined whether retrospective reports of adversity during childhood or pregnancy were associated with inflammatory imbalance, in an ethnically diverse cohort of 53 low-income women seeking family-based trauma treatment following exposure to interpersonal violence. Structured interviews assessed early life adversity (trauma exposure ≤ age 5), pregnancy adversity, and total lifetime adversity. Blood serum was assayed for pro-inflammatory (TNF-a, IL-1ß, IL-6, and CRP) and anti-inflammatory (IL-1RA, IL-4, and IL-10) cytokines. CD14+ monocytes were isolated in a subsample (n = 42) and gene expression assayed by RNA sequencing (Illumina HiSeq 4000; TruSeq cDNA library). The primary outcome was a macrophage-associated M1/M2 gene expression phenotype. To evaluate sensitivity and specificity, we contrasted M1/M2 gene expression with a second, clinically-validated macrophage-associated immunosuppressive phenotype (endotoxin tolerance) and with pro-inflammatory and anti-inflammatory cytokine levels. Adjusting for demographics, socioeconomic status, and psychopathology, higher adversity in early life (ß = .337, p = 0.029) and pregnancy (ß = .332, p = 0.032) were each associated with higher M1/M2 gene expression, whereas higher lifetime adversity (ß = -.341, p = 0.031) was associated with lower immunosuppressive gene expression. Adversity during sensitive periods was uniquely associated with M1/M2 imbalance, among low-income women with interpersonal violence exposure. Given that M1/M2 imbalance is found in sepsis, severe COVID-19 and myriad chronic diseases, these findings implicate novel immune mechanisms underlying the impact of adversity on health.

Exposure to prenatal phthalate mixtures and neurodevelopment in the Conditions Affecting Neurocognitive Development and Learning in Early childhood (CANDLE) study.

BACKGROUND: Findings from epidemiological studies of prenatal phthalate exposure and child cognitive development are inconsistent. Methods for evaluating mixtures of phthalates, such as weighted quantile sum (WQS) regression, have rarely been applied. We developed a new extension of the WQS method to improve specificity of full-sample analyses and applied it to estimate associations between prenatal phthalate mixtures and cognitive and language outcomes in a diverse pregnancy cohort. METHODS: We measured 22 phthalate metabolites in third trimester urine from mother-child dyads who completed early childhood visits in the Conditions Affecting Neurodevelopment and Learning in Early childhood (CANDLE) study. Language and cognitive ability were assessed using the Bayley Scales of Infant Development (age 3) and the Stanford Binet-5 (age 4-6), respectively. We used multivariable WQS regression to identify phthalate mixtures that were negatively and positively associated with language score and full-scale IQ, in separate models, adjusted for maternal IQ, race, marital status, smoking, BMI, socioeconomic status (SES), child age, sex, and breastfeeding. We evaluated effect modification by sex and SES. If full sample 95% WQS confidence intervals (which are known to be anti-conservative) excluded the null, we calculated a p-value using a permutation test (ppermutation). The performance of this new approach to WQS regression was evaluated in simulated data. We compared the power and type I error rate of WQS regression conducted within datasets split into training and validation samples (WQSSplit) and in the full sample (WQSNosplit) to WQS regression with a permutation test (WQSpermutation). Individual metabolite associations were explored in secondary analyses. RESULTS: The analytic sample (N = 1015) was 62.1% Black/31.5% White, and the majority of mothers had a high school education or less (56.7%) at enrollment. Associations between phthalate mixtures and primary outcomes (language score and full-scale IQ) in the full sample were null. Individual metabolites were not associated with IQ, and only one metabolite (mono-benzyl phthalate, MBzP) was associated with Bayley language score (ß = -0.68, 95% CI: -1.37, 0.00). In analyses stratified by sex or SES, mixtures were positively and negatively associated with outcomes, but the precision of full-sample WQS regression results were not supported by permutation tests, with one exception. In the lowest SES category, a phthalate mixture dominated by mono-methyl phthalate (MMP) and mono-carboxy-isooctyl phthalate (MCOP) was associated with higher language scores (ßlow SES = 2.41, full-sample 95%CI: 0.58, 4.24; ppermutation = 0.04). Performance testing in simulated data showed that WQSpermutation had improved power over WQSSplit (90% versus 56%) and a lower type I error rate than WQSNosplit (7% versus 47%). CONCLUSIONS: In the largest study of these relationships to date, we observed predominantly null associations between mixtures of prenatal phthalates and both language and IQ. Our novel extension of WQS regression improved sensitivity to detect true associations by obviating the need to split the data into training and test sets and should be considered for future analyses of exposure mixtures.

Associations Between Maternal Nutrition in Pregnancy and Child Blood Pressure at 4-6 Years: A Prospective Study in a Community-Based Pregnancy Cohort.

BACKGROUND: The intrauterine environment may influence offspring blood pressure, with effects possibly extending into adulthood. The associations between prenatal nutrition and offspring blood pressure, alone or in combination with other sociodemographic or behavioral factors, are unclear. OBJECTIVES: To investigate the associations of maternal dietary patterns and plasma folate concentrations with blood pressure in children aged 4-6 years, and assess the potential effect modifications by child sex, maternal race, pre-pregnancy overweight or obesity, maternal smoking, and breastfeeding. METHODS: Participants were 846 mother-child dyads from the Conditions Affecting Neurocognitive Development and Learning in Early Childhood (CANDLE) study. Maternal nutrition was characterized by the Healthy Eating Index 2010 (HEI) scores and plasma folate concentrations in pregnancy. We calculated the systolic blood pressure (SBP) and diastolic blood pressure percentiles, incorporating sex, age, and height, and categorized children as either having high blood pressure (HBP; ≥90th percentile) or normal blood pressure. Linear regressions were performed to quantify the associations between maternal nutrition and continuous blood pressure percentiles, and Poisson regressions were used to estimate the incidence rate ratio (IRR) of binary HBP. We examined the effect modifications using interaction models. RESULTS: Mean HEI scores and folate concentrations were 60.0 (SD, 11.3) and 23.1 ng/mL (SD, 11.1), respectively. Based on measurements at 1 visit, 29.6% of the children were defined as having HBP. Maternal HEI scores and plasma folate concentrations were not associated with child blood pressure percentiles or HBP in the full cohort. Among mothers self-identified as white, there was an inverse relationship between maternal HEI score and child SBP percentile (ß, -0.40; 95%CI: -0.75 to -0.06). A maternal HEI score above 59 was associated with a reduced risk of HBP in girls (IRR, 0.53; 95% CI: 0.32-0.88). No modified associations by pre-pregnancy overweight or obesity, maternal smoking, or breastfeeding were indicated. CONCLUSIONS: We found little evidence for effects of maternal nutrition during pregnancy on childhood blood pressure, but detected sex- and race-specific associations. The study contributes to the evolving scientific inquiry regarding developmental origins of disease.

Prenatal sex hormones and behavioral outcomes in children.

Abnormal sex hormone levels in utero have been associated with child behavioral problems, but it is unclear if normal variation in prenatal sex hormones is associated with subsequent behavior in childhood. We assessed maternal sex hormones, including serum estrone (E1), estradiol (E2), estriol (E3), free testosterone (FT), and total testosterone (TT), during early pregnancy (gestational week 6-21 (mean = 11.1)) and evaluated child behavior at ages 4-5 using the Behavioral Assessment System for Children (BASC-2) and Social Responsiveness Scale (SRS-2) in 404 mother/child pairs (211 girls, 193 boys) within The Infant Development and Environment Study, a multi-site pregnancy cohort study. Associations between hormones and composite scores were evaluated using multiple linear regressions in both sexes combined, and separate models assessed effect modification by sex with the addition of interaction terms. A 10-fold increase in maternal FT or TT was associated in both sexes with a 4.3-point (95 % CI: 0.5, 8.2) or 4.4-point (0.8, 8.0) higher BASC-2 internalizing composite T score, respectively. In addition, a 10-fold increase in FT or TT was associated with a 3.8-point (0.04, 7.5) or 4.0-point (0.5, 7.5) higher behavioral symptoms index composite score. In models evaluating effect modification by sex, a 10-fold increase in E1 was associated with a 4.3-point (1.2, 7.4) decrease in adaptive skills composite score in girls only (interaction p = 0.04). We observed associations between testosterone and internalizing behaviors and behavioral symptoms index in both sexes, as well as a female-specific association between E1 and adaptive skills. Sex hormones during pregnancy may play a key role in influencing later-life behavior, and additional studies should further examine different periods of susceptibility to hormonal signals.

The PedBE clock accurately estimates DNA methylation age in pediatric buccal cells.

The development of biological markers of aging has primarily focused on adult samples. Epigenetic clocks are a promising tool for measuring biological age that show impressive accuracy across most tissues and age ranges. In adults, deviations from the DNA methylation (DNAm) age prediction are correlated with several age-related phenotypes, such as mortality and frailty. In children, however, fewer such associations have been made, possibly because DNAm changes are more dynamic in pediatric populations as compared to adults. To address this gap, we aimed to develop a highly accurate, noninvasive, biological measure of age specific to pediatric samples using buccal epithelial cell DNAm. We gathered 1,721 genome-wide DNAm profiles from 11 different cohorts of typically developing individuals aged 0 to 20 y old. Elastic net penalized regression was used to select 94 CpG sites from a training dataset (n = 1,032), with performance assessed in a separate test dataset (n = 689). DNAm at these 94 CpG sites was highly predictive of age in the test cohort (median absolute error = 0.35 y). The Pediatric-Buccal-Epigenetic (PedBE) clock was characterized in additional cohorts, showcasing the accuracy in longitudinal data, the performance in nonbuccal tissues and adult age ranges, and the association with obstetric outcomes. The PedBE tool for measuring biological age in children might help in understanding the environmental and contextual factors that shape the DNA methylome during child development, and how it, in turn, might relate to child health and disease.

Prenatal Omega-3 and Omega-6 Polyunsaturated Fatty Acids and Childhood Atopic Dermatitis.

BACKGROUND: Atopic dermatitis is a common childhood disease, potentially influenced by prenatal nutritional exposures such as polyunsaturated fatty acids (PUFAs). OBJECTIVE: In a racially diverse cohort, we hypothesized that childhood atopic dermatitis would be associated with higher prenatal omega-6 (n-6) and lower omega-3 (n-3) PUFAs. METHODS: We included mother-child dyads, births 2006 to 2011, enrolled in the University of Tennessee Health Sciences Center Conditions Affecting Neurocognitive Development in Early Childhood cohort. Primary exposures included second trimester plasma n-3 and n-6 PUFA status and the ratio of the two (n-6:n-3). We assessed child current atopic dermatitis symptoms in the previous 12 months at age approximately 4 to 6 years. We investigated the association between PUFA exposures and atopic dermatitis using multivariable logistic regression, adjusting for potential confounders. We assessed for effect modification by maternal prenatal smoking, atopic disease history, and child sex. RESULTS: Among 1131 women, 67% were African American and 42% had an atopic disease history; 17% of children had atopic dermatitis. Higher prenatal n-6 PUFAs were associated with increased relative odds of child atopic dermatitis (adjusted odds ratio: 1.25; confidence interval: 1.01-1.54 per interquartile range difference), and interaction models demonstrated that this association was seen in dyads in which the women had a history of atopic disease. Neither prenatal n-3 PUFAs nor n-6:n-3 were associated with child atopic dermatitis. CONCLUSION: In this racially diverse cohort, higher second trimester n-6 PUFAs were associated with atopic dermatitis in children of women with atopy. PUFAs may represent a modifiable risk factor for atopic dermatitis, particularly in individuals with a familial predisposition.

Childhood adversity and women's cardiometabolic health in adulthood: associations with health behaviors, psychological distress, mood symptoms, and personality.

BACKGROUND: We tested whether childhood adversity is associated with poor cardiometabolic health in adulthood among a sample of overweight or obese Dutch women of reproductive age. Health behaviors, psychological distress, mood symptoms, or personality traits were included as potential mediators. METHODS: Data came from a follow-up visit (N = 115), carried out in 2016/2017, of a randomized controlled lifestyle intervention trial in 577 obese infertile women. The associations between total adversity exposure score and cardiometabolic health were tested with regression models. Sleep, smoking and eating behavior, symptoms of depression, anxiety and stress, and personality traits were potential mediators. RESULTS: Childhood adversity scores were not associated with cardiometabolic outcomes but were associated with poorer sleep quality score (M = 7.2 (SD = 3.5) for those with ≥2 types of events versus 4.8 (2.9) for those with no events; p = 0.022), higher external eating score (26.4 (8.7) versus 21.8 (10.3); p = 0.038), higher perceived stress score (17.1 (6.8) versus 12.3 (4.5); p = 0.016), post-traumatic stress score (1.9 (1.5) versus 0.6 (1.1); p < 0.001), and lower agreeableness score (28.2 (4.2) versus 30.3 (3.1); p = 0.035). CONCLUSION: Childhood adversity was associated with poorer health behaviors including sleep and eating behavior, and more stress-related symptoms, but not with women's cardiometabolic health.

The mindful moms training: development of a mindfulness-based intervention to reduce stress and overeating during pregnancy.

BACKGROUND: Pregnancy is a time of high risk for excessive weight gain, leading to health-related consequences for mothers and offspring. Theory-based obesity interventions that target proposed mechanisms of biobehavioral change are needed, in addition to simply providing nutritional and weight gain directives. Mindfulness training is hypothesized to reduce stress and non-homeostatic eating behaviors - or eating for reasons other than hunger or caloric need. We developed a mindfulness-based intervention for high-risk, low-income overweight pregnant women over a series of iterative waves using the Obesity-Related Behavioral Intervention Trials (ORBIT) model of intervention development, and tested its effects on stress and eating behaviors. METHODS: Overweight pregnant women (n = 110) in their second trimester were enrolled in an 8-week group intervention. Feasibility, acceptability, and facilitator fidelity were assessed, as well as stress, depression and eating behaviors before and after the intervention. We also examined whether pre-to-post intervention changes in outcomes of well-being and eating behaviors were associated with changes in proposed mechanisms of mindfulness, acceptance, and emotion regulation. RESULTS: Participants attended a mean of 5.7 sessions (median = 7) out of 8 sessions total, and facilitator fidelity was very good. Of the women who completed class evaluations, at least half reported that each of the three class components (mindful breathing, mindful eating, and mindful movement) were "very useful," and that they used them on most days at least once a day or more. Women improved in reported levels of mindfulness, acceptance, and emotion regulation, and these increases were correlated with reductions in stress, depression, and overeating. CONCLUSIONS: These findings suggest that in pregnant women at high risk for excessive weight gain, it is both feasible and effective to use mindfulness strategies taught in a group format. Further, increases in certain mindfulness skills may help with better management of stress and overeating during pregnancy. TRIAL REGISTRATION: ClinicalTrials.gov NCT01307683 , March 8, 2011.