Perfluoroalkyl substances (PFASs) are widespread industrial pollutants that are extremely persistent in the environment. A previous study in the Danish National Birth Cohort (DNBC) found prenatal perfluorooctanoate (PFOA) exposure was associated with decreased birth weight, but had insufficient statistical power to evaluate adverse birth outcomes. Here, we conducted additional analyses in three samples originating from the DNBC for 3535 mothers and infant pairs to evaluate associations between prenatal PFASs exposures and low birth weight and preterm birth. Maternal plasma concentrations were measured for six types of PFASs in early pregnancy. Several PFASs were associated with a reduction in birth weight and gestational age. We estimated a nearly 2-fold increase in risks of preterm birth for the higher quartiles of PFOA and perflourooctanesulfonate (PFOS) exposure. In spline models, risk of preterm birth was increased for perfluorononanoic acid (PFNA), perfluoroheptane sulfonate (PFHpS) and perfluorodecanoic acid (PFDA) in higher exposure ranges. We also observed some elevated risks for low birth weight but these estimates were less precise. Our findings strengthen the evidence that in-utero PFASs exposures affect fetal growth. Future studies are needed to evaluate whether these associations persist with the decline of PFOA and PFOS in populations and should also investigate newer types of fluorinated compounds introduced more recently.

ImportanceLithium is a naturally occurring and trace element that has mood-stabilizing effects. Maternal therapeutic use of lithium has been associated with adverse birth outcomes. In animal models, lithium modulates Wnt/β-catenin signaling that is important for neurodevelopment. It is unknown whether exposure to lithium in drinking water affects brain health in early life.ObjectiveTo evaluate whether autism spectrum disorder (ASD) in offspring is associated with maternal exposure to lithium in drinking water during pregnancy.Design, Setting and ParticipantsThis nationwide population-based case-control study in Denmark identified 8842 children diagnosed with ASD born from 2000 through 2013 and 43 864 control participants matched by birth year and sex from the Danish Medical Birth Registry. These data were analyzed from March 2021 through November 2022.ExposuresGeocoded maternal residential addresses during pregnancy were linked to lithium level (range, 0.6 to 30.7 μg/L) in drinking water estimated using kriging interpolation based on 151 waterworks measurements of lithium across all regions in Denmark.Main Outcomes and MeasuresASD diagnoses were ascertained using International Statistical Classification of Diseases and Related Health Problems, Tenth Revision codes recorded in the Danish Psychiatric Central Register. The study team estimated odds ratios (ORs) and 95% CIs for ASD according to estimated geocoded maternal exposure to natural source of lithium in drinking water as a continuous (per IQR) or a categorical (quartile) variable, adjusting for sociodemographic factors and ambient air pollutants levels. The study team also conducted stratified analyses by birth years, child’s sex, and urbanicity.ResultsA total of 8842 participants with ASD (male, 7009 [79.3%]) and 43 864 control participants (male, 34 749 [79.2%]) were studied. Every IQR increase in estimated geocoded maternal exposure to natural source of lithium in drinking water was associated with higher odds for ASD in offspring (OR, 1.23; 95% CI, 1.17-1.29). Elevated odds among offspring for ASD were estimated starting from the second quartile (7.36 to 12.67 μg/L) of estimated maternal exposure to drinking water with lithium and the OR for the highest quartile (more than 16.78 μg/L) compared with the reference group (less than 7.39 μg/L) was 1.46 (95% CI, 1.35-1.59). The associations were unchanged when adjusting for air pollution exposures and no differences were apparent in stratified analyses.Conclusions and RelevanceEstimated maternal prenatal exposure to lithium from naturally occurring drinking water sources in Denmark was associated with an increased ASD risk in the offspring. This study suggests that naturally occurring lithium in drinking water may be a novel environmental risk factor for ASD development that requires further scrutiny.

Several studies have reported associations between prenatal acetaminophen exposure and behavioral outcomes in young children. We aimed to evaluate the associations of prenatal and postnatal exposures to acetaminophen with behavioral problems in children at age 11 years, using behavioral measures reported by parents and children. We studied 40,934 mother-child pairs from the Danish National Birth Cohort enrolled during 1996-2002. Parent-reported and child-reported Strengths and Difficulties Questionnaires (SDQ) were collected during the 11-year follow-up. We estimated risk ratios for behavioral problems including total difficulties, and internalizing or externalizing behaviors following prenatal (during pregnancy) or postnatal (within the first 18 months after birth) acetaminophen exposure. Parent-reported and child-reported SDQ scores were moderately correlated; higher for externalizing (r=0.59) than internalizing behaviors (r=0.49). Prenatal acetaminophen exposure was associated with 10-40% higher risks for total difficulties and internalizing and externalizing problems based on parent- or child-reported SDQ with the association being stronger for greater cumulative weeks of acetaminophen use. Postnatal exposure was associated with 16-19% higher risks for parent-reported internalizing behaviors, but the associations were weak or null for child-reported scores except for prosocial behavior. Our study corroborates published associations between prenatal exposures to acetaminophen and behavioral problems and extends the literature to early adolescence.

Cerebral palsy (CP) is the most common neuro-motor disability in young children. Disruptions of maternal hormone function during pregnancy have been linked to CP risk. We investigated whether prenatal exposure to pesticide compounds with endocrine-disrupting action affect CP risk. We conducted a case-control study of 3905 CP cases and 39,377 controls born between 1998 and 2010 in California to mothers who lived in proximity (within 2 km) to any agricultural pesticide application recorded in the California Pesticide Use Reporting (PUR) system. We focused on 23 pesticides considered endocrine disruptors that are frequently used, and we found that exposure to any of the 23 pesticides in the first trimester was associated with elevated CP risks in female offspring (OR = 1.19; 95% CI: 1.05–1.35) but not males (OR = 0.99; 95% CI: 0.89–1.09) compared to the unexposed offspring. Positive associations were estimated for 15 pesticides suspected to affect the estrogen and 7 pesticides suspected to affect the thyroid hormone system. Our study suggests that first trimester exposure to pesticides that are suspected endocrine disruptors are associated with CP risk in female offspring. Pesticide exposures in early pregnancy may have sex-specific influences on the neuro-motor development of the fetus by interfering with endocrine systems.

Objective: The aim of PARENTs was to determine whether imaging of the placenta by novel multi-parametric MRI techniques in early pregnancy could help predict adverse pregnancy outcomes due to ischemic placental disease (IPD). Additionally, we sought to determine maternal characteristics and environmental risk factors that contribute to IPD and secondary adverse pregnancy outcomes. Study Design: Potential subjects in their first trimester of pregnancy, who agreed to MRI imaging of the placenta and measures of assessment of environmental pollution, were recruited into PARENTs, a prospective population-based cohort study. Participants were seen at three study visits during pregnancy and again at their delivery from 2015 to 2019. We collected data from interviews, chart abstractions, and imaging. Maternal biospecimens (serum, plasma, and urine) at antepartum study visits and delivery specimens (placenta, cord, and maternal blood) were collected, processed, and stored. The primary outcome was a composite of IPD, which included any of the following: placental abruption, hypertensive disease of pregnancy, fetal growth restriction (FGR), or a newborn of small-for-gestational-age (SGA). Results: In this pilot cohort, of the 190 subjects who completed pregnancy to viable delivery, 50 (26%) developed IPD. Among demographic characteristics, having a history of prior IPD in multiparous women was associated with the development of IPD. In the multiple novel perfusion measurements taken of the in vivo placenta using MRI, decreased high placental blood flow (hPBF; ml/100g/min) in early pregnancy (between 14-16 weeks) was found to be significantly associated with the later development of IPD. Conclusion: Successful recruitment of the PARENTs prospective cohort demonstrated the feasibility and acceptability of the use of MRI in human pregnancy to study the placenta in vivo and at the same time collect environmental exposure data. Analysis is ongoing and we hope these methods will assist researchers in the design of prospective imaging studies of pregnancy.