Cross-Sectional Associations between Prenatal Per- and Poly-Fluoroalkyl Substances and Bioactive Lipids in Three Environmental Influences on Child Health Outcomes (ECHO) Cohorts.

Prenatal per- and poly-fluoroalkyl substances (PFAS) exposure may influence gestational outcomes through bioactive lipids─metabolic and inflammation pathway indicators. We estimated associations between prenatal PFAS exposure and bioactive lipids, measuring 12 serum PFAS and 50 plasma bioactive lipids in 414 pregnant women (median 17.4 weeks' gestation) from three Environmental influences on Child Health Outcomes Program cohorts. Pairwise association estimates across cohorts were obtained through linear mixed models and meta-analysis, adjusting the former for false discovery rates. Associations between the PFAS mixture and bioactive lipids were estimated using quantile g-computation. Pairwise analyses revealed bioactive lipid levels associated with PFDeA, PFNA, PFOA, and PFUdA (p < 0.05) across three enzymatic pathways (cyclooxygenase, cytochrome p450, lipoxygenase) in at least one combined cohort analysis, and PFOA and PFUdA (q < 0.2) in one linear mixed model. The strongest signature revealed doubling in PFOA corresponding with PGD2 (cyclooxygenase pathway; +24.3%, 95% CI: 7.3-43.9%) in the combined cohort. Mixture analysis revealed nine positive associations across all pathways with the PFAS mixture, the strongest signature indicating a quartile increase in the PFAS mixture associated with PGD2 (+34%, 95% CI: 8-66%), primarily driven by PFOS. Bioactive lipids emerged as prenatal PFAS exposure biomarkers, deepening insights into PFAS' influence on pregnancy outcomes.

Cross-sectional associations between prenatal maternal per- and poly-fluoroalkyl substances and bioactive lipids in three Environmental influences on Child Health Outcomes (ECHO) cohorts.

Background: Per- and poly-fluoroalkyl substances (PFAS) exposure can occur through ingestion of contaminated food and water, and inhalation of indoor air contaminated with these chemicals from consumer and industrial products. Prenatal PFAS exposures may confer risk for pregnancy-related outcomes such as hypertensive and metabolic disorders, preterm birth, and impaired fetal development through intermediate metabolic and inflammation pathways. Objective: Estimate associations between maternal pregnancy PFAS exposure (individually and as a mixture) and bioactive lipids. Methods: Our study included pregnant women in the Environmental influences on Child Health Outcomes Program: Chemicals in our Bodies cohort (CiOB, n=73), Illinois Kids Developmental Study (IKIDS, n=287), and the ECHO-PROTECT cohort (n=54). We measured twelve PFAS in serum and 50 plasma bioactive lipids (parent fatty acids and eicosanoids derived from cytochrome p450, lipoxygenase, and cyclooxygenase) during pregnancy (median 17 gestational weeks). Pairwise associations across cohorts were estimated using linear mixed models and meta-analysis. Associations between the PFAS mixture and individual bioactive lipids were estimated using quantile g-computation. Results: PFDeA, PFOA, and PFUdA were associated (p<0.05) with changes in bioactive lipid levels in all three enzymatic pathways (cyclooxygenase [n=6 signatures]; cytochrome p450 [n=5 signatures]; lipoxygenase [n=7 signatures]) in at least one combined cohort analysis. The strongest signature indicated that a doubling in PFOA corresponded with a 24.3% increase (95% CI [7.3%, 43.9%]) in PGD2 (cyclooxygenase pathway) in the combined cohort. In the mixtures analysis, we observed nine positive signals across all pathways associated with the PFAS mixture. The strongest signature indicated that a quartile increase in the PFAS mixture was associated with a 34% increase in PGD2 (95% CI [8%, 66%]), with PFOS contributing most to the increase. Conclusions: Bioactive lipids were revealed as biomarkers of PFAS exposure and could provide mechanistic insights into PFAS' influence on pregnancy outcomes, informing more precise risk estimation and prevention strategies.

Gestational Exposure to Phthalates and Phthalate Replacements in Relation to Neurodevelopmental Delays in Early Childhood.

Phthalates have been linked to changes in child neurodevelopment. However, sex-specificity has been reported inconsistently, and little is known about the impact of recent phthalate replacement chemicals. Our analysis included mother−child pairs (N = 274) from the PROTECT birth cohort in Puerto Rico. Phthalate metabolites were measured in multiple maternal urine collected during pregnancy. Neurodevelopment was measured at 6, 12, and 24 months of age using the Battelle Developmental Inventory-2nd edition (BDI), which provides scores for adaptive, personal-social, communication, motor, and cognitive domains. Multivariable linear regression was used to examine associations between phthalate metabolite concentrations and BDI scores, adjusting for maternal age, maternal education, child age, and specific gravity. Sex-specificity was assessed with sex X exposure interaction terms and stratified models. Results show that all five domains were significantly associated with mono-3-carboxypropyl phthalate (MCPP) at age 24 months, suggesting a holistic developmental delay related to this metabolite. Sex-specificity existed for all timepoints (p-interaction < 0.2), in general, showing stronger associations among boys. For example, metabolites of a recent phthalate replacement, di-2-ethylhexyl terephthalate (DEHTP), were differentially associated with the adaptive domain (boys −7.53%/IQR, 95% CI: −14.58, −0.48 vs. girls −0.85%/IQR, 95% CI: −5.08, 3.37), and the cognitive domain (boys −6.05%/IQR, 95% CI: −10.88, −1.22 vs. girls −1.93%/IQR, 95%CI: −4.14, 0.28) at 6 months. To conclude, gestational exposure to phthalates and phthalate replacements was associated with neurodevelopmental delay across multiple domains, with differences by sex and child age.

Examining the association between prenatal maternal stress and infant non-nutritive suck.

BACKGROUND: This study examined the relationship between prenatal maternal stress (PREMS) and non-nutritive suck (NNS) and tested its robustness across 2 demographically diverse populations. METHODS: The study involved 2 prospective birth cohorts participating in the national Environmental influences on Child Health Outcomes (ECHO) Program: Illinois Kids Development Study (IKIDS) and ECHO Puerto Rico (ECHO-PROTECT). PREMS was measured during late pregnancy via the 10-item Perceived Stress Scale (PSS-10). NNS was sampled from 1- to 8-week-olds using a custom pacifier for ~5 min. RESULTS: Overall, 237 mother-infant dyads completed this study. Despite several significant differences, including race/ethnicity, income, education, and PREMS levels, significant PREMS-NNS associations were found in the 2 cohorts. In adjusted linear regression models, higher PREMS, measured through PSS-10 total scores, related to fewer but longer NNS bursts per minute. CONCLUSIONS: A significant association was observed between PREMS and NNS across two diverse cohorts. This finding is important as it may enable the earlier detection of exposure-related deficits and, as a result, earlier intervention, which potentially can optimize outcomes. More research is needed to understand how NNS affects children's neurofunction and development. IMPACT: In this double-cohort study, we found that higher maternal perceived stress assessed in late pregnancy was significantly associated with fewer but longer sucking bursts in 1- to 8-week-old infants. This is the first study investigating the association between prenatal maternal stress (PREMS) and infant non-nutritive suck (NNS), an early indicator of central nervous system integrity. Non-nutritive suck is a potential marker of increased prenatal stress in diverse populations. Non-nutritive suck can potentially serve as an early indicator of exposure-related neuropsychological deficits allowing for earlier interventions and thus better prognoses.

Association between Quality of Maternal Prenatal Food Source and Preparation and Breastfeeding Duration in the Environmental Influences on Child Health Outcome (ECHO) Program.

This study examined the relationship between maternal food source and preparation during pregnancy and the duration of breastfeeding among 751 mother-child dyads in the United States. The data collected from the Environmental influences on Child Health Outcomes (ECHO) Program included twelve cohorts of mothers (age ≥ 18) who delivered infant(s). Three categories of maternal food source and preparation including, High, Moderate, or Low Food Source Quality were derived from the mother report. The mean duration of breastfeeding differed strongly across the three categories. The High Food Source Quality group breastfed an average of 41 weeks, while shorter durations were observed for the Moderate (26 weeks) and Low (16 weeks) Food Source Quality groups. Cox proportional hazards models were used to estimate the relative hazard of time to breastfeeding cessation for each participant characteristic. The full model adjusted for clustering/cohort effect for all participant characteristics, while the final model adjusted for the subset of characteristics identified from variable reduction modeling. The hazard of breastfeeding cessation for those in the High Food Source Quality group was 24% less than the Moderate group (RH = 0.76; 95% CI, 0.63-0.92). Pregnant women in the High Food Source Quality group breastfed longer than the Moderate and Low groups. We encourage more detailed studies in the future to examine this relationship longitudinally.

Associations between biomarkers of prenatal metals exposure and non-nutritive suck among infants from the PROTECT birth cohort in Puerto Rico.

Background/Aim: Infant non-nutritive suck (NNS) has been used as an early marker of neonatal brain function. Although there is an established relationship between prenatal exposure to certain metals and brain development, the association between metal exposure and NNS has not been explored. Therefore, in this study we assessed associations between maternal urinary metal(loid) concentrations and NNS measurements among infants from the Puerto Rico PROTECT birth cohort. We hypothesized that maternal urinary metal(loid) concentrations are significantly associated with infant NNS measures in a sex-dependent manner. Methods: We measured urinary concentrations of 14 metal(loid)s in pregnant women at up to three time points in pregnancy. The geometric mean of each metal(loid) for each pregnant woman was calculated and used as an exposure measurement across gestation. NNS measurements (duration, frequency, amplitude, bursts/min, cycles/burst, cycles/min) were collected from infants between 4 and 6 (±2 weeks) weeks of age using our custom research pacifier. Linear regression was used to estimate associations between urinary metal(loid) concentrations across pregnancy and continuous NNS variables. Sex-specific effects were estimated using interaction terms between NNS variables and infant sex. Results: We observed significant positive associations between mercury, manganese, and tin with NNS duration (mercury: %Δ = 1.08, 95% CI: 0.42, 1.74; manganese: %Δ = 0.67, 95% CI: 0.15, 1.20; tin: %Δ = 0.83, 95% CI: 0.17, 1.49) and NNS cycles/burst (mercury: %Δ = 1.85, 95% CI: 0.58, 3.11; manganese: (%Δ = 1.37, 95% CI: 0.40, 2.34; tin: %Δ = 1.68, 95% CI: 0.46, 2.91). Furthermore, the association between NNS cycles/min with cadmium (%Δ = 8.06, 95% CI: 3.33, 12.78), manganese (%Δ = 4.44, 95% CI: 1.40, 7.47), and tin (%Δ = 4.50, 95% CI: 0.81, 8.18) were in the opposite direction from its association with zinc (%Δ = -9.30, 95% CI: -14.71, -3.89), as well as with copper (%Δ = -6.58, 95% CI: -12.06, -1.10). For the sex-stratified analysis, the negative associations between metal(loid)s and NNS duration were predominantly driven by male infants; however, the negative associations between metal(loid)s and NNS bursts/min were mainly driven by female infants. Conclusion: We observed significant associations between prenatal metal(loid) exposure and NNS measurements among infants from the ongoing Puerto Rico PROTECT cohort. Similar to previous studies that have demonstrated associations between NNS and subsequent neurodevelopment, this study highlights the potential of NNS as a quantitative index to measure altered neurodevelopment from prenatal metal(loid) exposures. We believe this study will inform future efforts aimed at reducing health risks related to early life metal exposures, such as developing early identification of metal-induced adverse outcomes in child neurodevelopment.

Non-nutritive suck and airborne metal exposures among Puerto Rican infants.

Air pollution has been shown to impact multiple measures of neurodevelopment in young children. Its effects on particularly vulnerable populations, such as ethnic minorities, however, is less studied. To address this gap in the literature, we assess the associations between infant non-nutritive suck (NNS), an early indicator of central nervous system integrity, and air pollution exposures in Puerto Rico. Among infants aged 0-3 months enrolled in the Center for Research on Early Childhood Exposure and Development (CRECE) cohort from 2017 to 2019, we examined associations between exposure to fine particulate matter (PM2.5) and its components on infant NNS in Puerto Rico. NNS was assessed using a pacifier attached to a pressure transducer, allowing for real-time visualization of NNS amplitude, frequency, duration, cycles/burst, cycles/min and bursts/min. These data were linked to 9-month average prenatal concentrations of PM2.5 and components, measured at three community monitoring sites. We used linear regression to examine the PM2.5-NNS association in single pollutant models, controlling for infant sex, maternal age, gestational age, and season of birth in base and additionally for household smoke exposure, age at testing, and NNS duration in full models. Among 198 infants, the average NNS amplitude and burst duration was 17.1 cmH2O and 6.1 s, respectively. Decreased NNS amplitude was consistently and significantly associated with 9-month average exposure to sulfur (-1.026 ± 0.507), zinc (-1.091 ± 0.503), copper (-1.096 ± 0.535) vanadium (-1.157 ± 0.537), and nickel (-1.530 ± 0.501). Decrements in NNS frequency were associated with sulfur exposure (0.036 ± 0.018), but not other examined PM components. Our findings provide new evidence that prenatal maternal exposure to specific PM components are associated with impaired neurodevelopment in Puerto Rican infants soon after birth.

Associations of gestational phthalate exposure and non-nutritive suck among infants from the Puerto Rico Testsite for Exploring Contamination Threats (PROTECT) birth cohort study.

BACKGROUND: Infant non-nutritive suck (NNS), or sucking on a pacifier with no nutrients being delivered, has been used as in index of brain function and has been linked to subsequent neurodevelopment. Yet, no data are available connecting NNS to environmental exposures in utero. The goal of this study was to examine the relationship between gestational exposure to phthalates (a group of chemicals found in personal care products, PVC plastics, and other products) and NNS among infants in a birth cohort study in Puerto Rico. METHODS: Urinary phthalate metabolite levels were measured in women at up to three time points in pregnancy as a measure of in utero exposure to the child. We calculated the geometric mean of each metabolite for each woman as a measure of exposure across gestation. Infants had their NNS sampled using our custom research pacifier between 4-6 (± 2 weeks) weeks of age, yielding the following NNS dependent measures: cycles/burst, frequency, amplitude, bursts/min, and cycles/min. RESULTS: Two hundred and eight mother-infant dyads completed this study We used multiple linear regression to assess associations between individual phthalate metabolites and NNS measurements, adjusting for infant sex, birthweight, and urinary specific gravity. An interquartile range (IQR) increase in mono carboxyisononyl phthalate across pregnancy was associated with 3.5% (95%CI: -6.2, -0.8%) lower NNS frequency and 8.9% (0.6, 17.3%) higher NNS amplitude. Similarly, an IQR increase in mono-2-ethylhexyl phthalate was also associated with 3.4% (-6.5, -0.2%) lower NNS frequency, while an IQR increase in di-2-ethylhexyl terephthalate metabolites was associated with 11.2% (2.9, 19.5%) higher NNS amplitude. Gestational exposure to phthalates may alter NNS amplitude and frequency in full-term infants. These findings indicate that the infants may be increasing their NNS amplitude to compensate for their slower NNS frequency. These preliminary findings could have important clinical implications for earlier detection of exposure-related deficits in neurofunction as well as implications for subsequent neurodevelopment and related interventions.

Cohort profile: Center for Research on Early Childhood Exposure and Development in Puerto Rico.

PURPOSE: Puerto Rican children experience high rates of asthma and obesity. Further, infants born in Puerto Rico are more at risk for being born prematurely compared with infants on the mainland USA. Environmental exposures from multiple sources during critical periods of child development, potentially modified by psychosocial factors, may contribute to these adverse health outcomes. To date, most studies investigating the health effects of environmental factors on infant and child health have focused on single or individual exposures. PARTICIPANTS: Infants currently in gestation whose mother is enrolled in Puerto Rico Testsite for Exploring Contamination Threats (PROTECT) cohort, and infants and children already born to mothers who participated in the PROTECT study. FINDINGS TO DATE: Data collection and processing remains ongoing. Demographic data have been collected on 437 mother-child pairs. Birth outcomes are available for 420 infants, neurodevelopmental outcomes have been collected on 319 children. Concentrations of parabens and phenols in maternal spot urine samples have been measured from 386 mothers. Center for Research on Early Childhood Exposure and Development mothers have significantly higher urinary concentrations of dichlorophenols, triclosan and triclocarban, but lower levels of several parabens compared with reference values from a similar population drawn from the National Health and Nutrition Examination Survey. FUTURE PLANS: Data will continue to be collected through recruitment of new births with a target of 600 children. Seven scheduled follow-up visits with existing and new participants are planned. Further, our research team continues to work with healthcare providers, paediatricians and early intervention providers to support parent's ability to access early intervention services for participants.

Investigating the impact of Hurricane Maria on an ongoing birth cohort in Puerto Rico.

Prior to Hurricane Maria, Puerto Rico already had 200+ hazardous waste sites, significant contamination of water resources, and among the highest rates of preterm birth in the US. To address these issues, the Puerto Rico Testsite for Exploring Contamination Threats (PROTECT) Center was formed in 2010 to investigate prenatal environmental exposures, particularly phthalates, and adverse birth outcomes. Recent work from the PROTECT study confirms that in utero exposure to certain phthalates is associated with shorter gestation and increased risk of preterm birth. However, previous research also suggests that pregnant women who experience a natural disaster such as Hurricane Maria are at higher risk of adverse birth outcomes, but it is unknown whether this is due to stress, hazardous exposures, or a combination of factors. Thus, the aim of this analysis was to characterize hurricane-related changes in phthalate exposures and experiences within the PROTECT cohort. Among 176 participants who were pregnant during or within 5 months after Maria, 122 completed a questionnaire on hurricane-related experiences. Questionnaire results and biomarkers of exposure suggest that participants did not have regular access to fresh foods and water during hurricane recovery, and almost half reported structural damage to their home. In addition, biomarker concentrations of phthalates commonly used in food packaging were higher among participants post-hurricane, while phthalates commonly used in personal care products were lower compared to pre-hurricane levels. Hurricane-related increases in phthalate exposure, as well as widespread structural damage, food and water shortages, and long-term absence of electricity and cell phone service, likely increased the risk of adverse birth outcomes among this already vulnerable population.

Determinants and characterization of exposure to phthalates, DEHTP and DINCH among pregnant women in the PROTECT birth cohort in Puerto Rico.

BACKGROUND: As a result of evidence suggesting phthalate toxicity, their use has decreased in recent years. However, new phthalates and non-phthalate replacements have emerged in their place, with unknown potential impacts on health. METHODS: We measured 15 phthalate, two di(2-ethylhexyl)terephthalate (DEHTP), and two di(isononyl)cyclohexane-1,2-dicarboxylate (DINCH) urinary metabolites, collected up to three times during pregnancy from 994 women in Northern Puerto Rico (2011-2017). We used tests of linear trend to assess changes in concentrations over time and linear mixed models to identify predictors of exposure (sociodemographic characteristics, drinking water sources, diet, product use). RESULTS: Several phthalate metabolites decreased over the study period indicating decreased exposure, while the geometric mean of DEHTP metabolites (molecular sum) increased threefold between 2014 and 2017. Intraclass correlations revealed low to moderate reproducibility of these biomarkers across pregnancy. Several metabolites were associated with maternal age, income, education, pre-pregnancy BMI, drinking public water, use of cleaning and personal care products, and ice cream consumption. DINCH metabolite concentrations remained low throughout the study period. CONCLUSION: Although exposure to some phthalates may be decreasing, exposure to replacements, such as DEHTP, is increasing. Additional studies are needed to further characterize sources of phthalate replacement chemicals and potential exposure-related health effects among vulnerable populations.

Interactions between chemicals and non-chemical stressors: The modifying effect of life events on the association between triclocarban, phenols and parabens with gestational length in a Puerto Rican cohort.

BACKGROUND: Phenols and parabens are common additives to consumer products. There is evidence of adverse birth outcomes in association with prenatal exposure to these chemicals, in addition to psychosocial factors. We previously reported an increase in gestational length with bisphenol-A, methylparaben and propylparaben, and a decrease in gestational length with triclocarban. OBJECTIVES: We examined the modifying effect of psychosocial stress on the association between chemicals and gestational length in up to 752 women among a pregnancy cohort study. METHODS: Urinary biomarkers were measured at up to three time points in pregnancy. Multiple linear regression models were conducted to investigate the association between gestational length and the interaction between average exposure biomarkers and LES. Multiple linear regression models regressing the exposure biomarkers in relation to gestational length were also stratified by LES, Negative LES, and Positive LES, based on the subjective ratings of events. Results were transformed into the change in gestational length for an inter-quartile-range difference in the exposure. RESULTS: Of the four psychosocial stress measures, only the life events score (LES) was a significant modifier. Associations between triclocarban, bisphenol-S, methyl- and propylparaben in relation to gestational length were stronger among women with negative Total LES scores. Among women with negative Total LES scores, bisphenol-S and triclocarban were associated with a 3-5 day decrease in gestational length [(-3.15; 95% CI: -6.06, -0.24); (-4.68; 95% CI: -8.47, -0.89)], whereas methylparaben and propylparaben were associated with a 2-3 day increase in gestational length [(2.21; 95% CI: 0.02, 4.40); (2.92; 95% CI: 0.58, 5.26)]. Significant interactions were driven by negative life events, but the association with triclocarban was driven by few positive life events. CONCLUSIONS: Associations between exposure biomarkers and gestational length were stronger in the presence of negative life events. This provides evidence that stress makes the body more vulnerable to chemical exposure.

Impact of Hurricanes Irma and Maria on Puerto Rico Maternal and Child Health Research Programs.

Puerto Rico was hit by two major hurricanes in September 2017 causing great devastation, losing over 90% of the power grid, wireless communication and access to potable water, and destroying many homes. Our research programs: Puerto Rico Testsite for Exploring Contamination Threats (PROTECT), Center for Research on Early Childhood Exposure and Development in Puerto Rico (CRECE), Zika in Infants and Pregnancy (ZIP), and Environmental Influences on Child Health Outcomes (ECHO) are ongoing observational cohort studies that have been investigating environmental risk factors for perinatal health outcomes among Puerto Rican mothers and infants. Our projects paused operations for about two weeks, to begin recovery process and become a source of assistance, retaining 95% of study participants across all research programs. We joined with various groups to ensure the safety and welfare of team members, study participants, community health center partners, and members of the surrounding communities. We learned important lessons about the impact of these hurricanes and the difficulties of the recovery. Major challenges post-hurricanes were access to care and nutrition, maternal stress, and environmental damage. We understood the need to integrate disaster preparedness into our programs' operating procedures and future applications, recognizing that these events will recur. We will grow resilience among our staff, maternal and child health partners, and participants by building on the experience of these two storms.

The association of urinary organophosphate ester metabolites and self-reported personal care and household product use among pregnant women in Puerto Rico.

BACKGROUND: Organophosphate esters (OPEs) are widely detected among U.S. pregnant women. OPEs, some of which are present in nail polish, have been associated with adverse reproductive health outcomes. More research is needed to investigate associations with OPEs and personal care products (PCP) use. METHODS: Pregnant women (18-40 years) were recruited from two hospitals and five prenatal clinics in Northern Puerto Rico (n = 148 women) between 2011 and 2015. Concentrations of bis(2-chloroethyl) phosphate (BCEtP), bis(1-chloro-2-propyl) phosphate (BCPP), bis(1,3-dichloro-2-propyl) phosphate (BDCPP), di-n-butyl phosphate (DNBP), di-benzyl phosphate (DBzP), di-cresyl phosphate (DCP), DPHP, and 2,3,4,5-tetrabromobenzoic acid (TBBA) were measured twice during pregnancy. Participants completed questionnaires on PCP and household products (HP) use. Associations among products and metabolite concentrations (n = 296 observations) were assessed using linear mixed models. RESULTS: BCEtP, BCPP, BDCPP and DPHP were detected frequently (≥77%). Correlations among metabolites (0.16 ≤ r ≤ 0.35) and Intraclass correlation coefficients (ICCs) (0.03 ≤ ICC≤0.34) were weak-to-moderate. Suntan lotion was associated with a 110% increase in BDCPP. DPHP increased with perfume (51%) and nail polish (49%) use. BCPP increased 46% with pesticide use in home. CONCLUSION: Biomarkers of OPEs were often detected among pregnant women. Associations with PCP and HP use suggest OPEs may be used in such products, specifically in perfume and nail polish. Further investigation into these products is warranted.