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Background: Most cerebral palsy (CP) cases have an unexplained etiology, but a role for environmental exposures has been suggested. One purported environmental risk factor is exposure to endocrine-disrupting pollutants specifically per- and polyfluoroalkyl substances (PFAS)., Objectives: We investigated the association between prenatal PFAS exposures and CP in Swedish children., Methods: In this case-control study, 322 CP cases, 343 population controls, and 258 preterm controls were identified from a birth registry in combination with a CP follow-up program from 1995 to 2014 and linked to a biobank which contains serum samples from week 10-14 of pregnancy. Maternal serum concentrations of four PFAS compounds: perfluorohexane sulfonate (PFHxS), perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), and perfluorooctane sulfonate (PFOS) were analyzed using liquid chromatography-tandem-mass-spectrometry. We estimated odds ratios (ORs) and 95 % confidence intervals (CIs) for CP and each PFAS in quartiles and as continuous variables controlling for various sociodemographic and lifestyle factors., Results: In crude and adjusted analyses, we did not find consistent evidence of associations between serum PFHxS, PFOA, PFNA, PFOS and concentrations in early pregnancy and CP, except in preterm infants. The ORs comparing the highest PFAS quartiles to the lowest were 1.05 (95 % CI: 0.63-1.76), 0.96 (95 % CI: 0.55-1.68), 0.71 (95 % CI: 0.41-1.25), and 1.17 (95 % CI: 0.61-2.26), for PFHxS, PFOA, PFNA, and PFOS, respectively. Some positive associations were observed for preterm infants, but the results were imprecise. Similar patterns were observed in analyses treating PFAS as continuous variables., Conclusions: In this study, we found little evidence that early pregnancy prenatal exposure to PFHxS, PFOA, PFNA, or PFOS increases the risk of CP. However, some positive associations were observed for preterm cases and warrant further investigation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Perfluoroalkyl and polyfluoroalkyl substances (PFAS) are ubiquitous in the environment and accumulate in humans. PFAS are suspected to affect the neuropsychological function of children, but only few studies have evaluated the association with childhood attention and executive function., Objectives: To investigate the association between intrauterine exposure to PFAS and offspring attention and executive function., Methods: A total of 1593 children from the Danish National Birth Cohort, born 1996-2003, were included. The levels of 16 PFAS were measured in maternal plasma during pregnancy. At 5 years of age, the Test of Everyday Attention for Children at Five (TEACh-5) and the Behavior Rating Inventory of Executive Function (BRIEF) were performed. TEACh-5 scores were standardized to a mean of 0 and standard deviation (SD) of 1. BRIEF scores were standardized to a mean of 50 and a SD of 10. The associations between levels of seven PFAS and TEACh-5 and BRIEF were examined by multivariable linear regression adjusted for potential confounders., Results: Perfluorooctane sulfonamide (PFOSA) was associated with poorer selective attention [standardized mean difference (95% confidence interval) -0.5 (-0.7, -0.3), highest versus lowest quartile]. Other PFAS were not clearly associated with selective attention, and we found no clear associations between PFAS exposure and sustained attention. For parent rated executive function, perfluorooctanoate (PFOA) was associated with poorer scores, standardized mean difference 3.8 (95% confidence interval 1.6, 6.0), highest versus lowest quartile. Regarding other PFAS, the associations were less clear. We found no clear associations between any PFAS and executive function rated by preschool teachers., Conclusion: Intrauterine exposure to PFOSA was associated with poorer selective attention, while PFOA was associated with poorer executive function. Given the widespread nature of PFAS exposure, these findings may have public health implications, warranting further investigation., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Objective: To summarize the application of non-targeted metabolomics in epidemiological studies that assessed metabolite and metabolic pathway alterations associated with per- and polyfluoroalkyl substances (PFAS) exposure., Recent Findings: Eleven human studies published before April 1st, 2021 were identified through database searches (PubMed, Dimensions, Web of Science Core Collection, Embase, Scopus), and citation chaining (Citationchaser). The sample sizes of these studies ranged from 40 to 965, involving children and adolescents (n = 3), non-pregnant adults (n = 5), or pregnant women (n = 3). High-resolution liquid chromatography-mass spectrometry was the primary analytical platform to measure both PFAS and metabolome. PFAS were measured in either plasma (n = 6) or serum (n = 5), while metabolomic profiles were assessed using plasma (n = 6), serum (n = 4), or urine (n = 1). Four types of PFAS (perfluorooctane sulfonate(n = 11), perfluorooctanoic acid (n = 10), perfluorohexane sulfonate (n = 9), perfluorononanoic acid (n = 5)) and PFAS mixtures (n = 7) were the most studied. We found that alterations to tryptophan metabolism and the urea cycle were most reported PFAS-associated metabolomic signatures. Numerous lipid metabolites were also suggested to be associated with PFAS exposure, especially key metabolites in glycerophospholipid metabolism which is critical for biological membrane functions, and fatty acids and carnitines which are relevant to the energy supply pathway of fatty acid oxidation. Other important metabolome changes reported included the tricarboxylic acid (TCA) cycle regarding energy generation, and purine and pyrimidine metabolism in cellular energy systems., Conclusions: There is growing interest in using non-targeted metabolomics to study the human physiological changes associated with PFAS exposure. Multiple PFAS were reported to be associated with alterations in amino acid and lipid metabolism, but these results are driven by one predominant type of pathway analysis thus require further confirmation. Standardizing research methods and reporting are recommended to facilitate result comparison. Future studies should consider potential differences in study methodology, use of prospective design, and influence from confounding bias and measurement errors., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Per- and polyfluoroalkyl substances (PFAS) are widespread persistent pollutants. Evidence regarding neurodevelopmental effects of PFAS have been mixed. The relation between PFAS exposure and anatomical markers that have been suggested to correlate with fetal brain development have not been studied., Objectives: We investigated the association between prenatal PFAS exposures and three craniofacial features in children measured at 5 years of age., Methods: Measures of palpebral fissure length (PFL), philtrum groove, and upper-lip thickness were generated from standardized digital facial photographs from 656 children in the Danish National Birth Cohort. PFL was classified into two groups (shorter; normal), and the philtrum (grooved; smooth; normal) and upper-lip (thick; thin; normal) measures into three groups each. Six PFAS were measured in maternal plasma ( median = 8 gestational wk). Multinomial logistic regression was used to estimate the odds ratio (OR) and 95% confidence interval (CI) for each facial feature using the normal group as the reference according to log 2 -PFAS concentration (in nanograms per milliliter) or PFAS tertiles, adjusting for potential confounders, including maternal alcohol intake and smoking. Stratified analyses by maternal alcohol intake or child's sex were performed., Results: Prenatal exposure to each PFAS was associated with elevated odds for a shorter PFL, with the strongest association observed for perfluorodecanoic acid (PFDA; per doubling OR = 2.02 ; 95% CI: 1.11, 3.70). Some nonlinear associations were found for philtrum measures: the second tertile of PFDA and perfluorononanoic acid were associated with grooved philtrum, whereas the second tertile of perfluoroheptane sulfonate with smooth philtrum. The associations between PFAS exposure and a shorter PFL were stronger among mothers who consumed alcohol in the first trimester, some sex-specific associations were noted for philtrum and upper-lip measures., Discussion: Prenatal PFAS exposures might influence fetal craniofacial development. A larger study is needed to replicate the potential modifying effects observed for alcohol exposure and to clarify whether associations of craniofacial markers observed reflect specific neurologic deficits. https://doi.org/10.1289/EHP9478.

Background: Maternal per- and polyfluoroalkyl substances (PFAS) exposure has been associated with placental function and fetal growth measures. However, few studies have simultaneously investigated paternal and maternal exposure effects., Objectives: We evaluated the associations of paternal or maternal PFAS levels with placental function and fetal growth measures., Methods: We studied six PFAS measured in matched parental serums collected within 3 days before delivery in a birth cohort from LaiZhouWan, China. Outcomes evaluated include cord serum estradiol (n = 351), testosterone (n = 349), placental P450aromatase (n = 125), and birth weight (n = 369). Multiple linear regression was applied to estimate the associations for these outcomes according to paternal or maternal PFAS level after adjusting for socio-demographic confounders. Co-adjustment analysis of both paternal and maternal PFAS in the same model was performed., Results: Maternal and paternal PFAS levels were correlated (Spearman's r = 0.23-0.45). Maternal PFAS were associated with increased estradiol (e.g., , Pfoa: β = 0.03, 95%CI: 0.00, 0.07), testosterone (e.g., , Pfua: β = 0.14, 95%CI: 0.00, 0.27), and P450aromatase (e.g., , Pfoa: β = 0.13, 95%CI: 0.04, 0.22). Maternal PFAS were also associated with a lower mean of birth weight but the estimated 95% CI included the null. Paternal PFAS were not associated with any of the outcomes evaluated., Conclusions: Several maternal PFAS were associated with fetal steroid hormones and placental enzymes. Despite a correlation of PFAS level within the couples, no association was found for paternal PFAS exposure on these outcomes. The findings suggest the intrauterine PFAS exposure effect on fetal endocrine hormones and growth is unlikely to be confounded by exposure sources or familial factors shared within the couples., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Perfluoroalkyl substances (PFAS) are suggested to interfere with thyroid hormone during pregnancy and influence fetal neurodevelopment. Epidemiological evidence regarding behavioral difficulties in childhood associated with prenatal PFAS exposure has been inconclusive., Objective: We evaluated the association between prenatal PFAS exposure and behavioral difficulties at 7 and 11 years, and investigated the potential mediating role of maternal thyroid hormones., Methods: Using pooled samples in the Danish National Birth Cohort established between 1996 and 2002, we estimated the associations between concentrations of six types of PFAS in maternal plasma (median, 8 gestational weeks) and child behavioral assessments from the Strength and Difficulties Questionnaire (SDQ), reported by parents at 7 years (n = 2421), and by parents (n = 2070) and children at 11 years (n = 2071). Behavioral difficulties were defined as having a composite SDQ score above the 90th percentile for total difficulties and externalizing or internalizing behaviors. We used logistic regression to estimate the adjusted Odds Ratio (OR) by doubling increase of prenatal PFAS (ng/ml). The possible mediating effect of maternal thyroid function classified based on thyroid stimulating hormone (TSH) and free thyroxine (fT4) levels were evaluated., Results: Prenatal perfluorononanoic acid (PFNA) was consistently associated with total and externalizing behavioral difficulties in all three SDQ measures reported by parents (OR = 1.40, 95% CI: 1.14-1.73 for age 7; OR = 1.27, 95% CI: 1.05-1.53 for age 11) or children (OR = 1.32, 95% CI: 1.11-1.58) while no consistent associations were observed for other types of PFAS. A small magnitude of natural indirect effects via maternal thyroid dysfunction (ORs ranged from 1.01 to 1.03) of several PFAS were observed for parent-reported total and externalizing behaviors at 7 years only., Discussion: Prenatal PFNA exposure was associated with externalizing behavioral difficulties in childhood in repeated SDQ measures at 7 and 11 years. The slight mediating effects of maternal thyroid hormones in early gestation warrant further evaluation., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Introduction: To date, the evidence for an association between perfluoroalkyl substances (PFAS) exposure and attention deficit and hyperactivity disorder (ADHD) is inconclusive., Objective: We investigated the association between early life exposure to perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA), and ADHD in a collaborative study including nine European population-based studies, encompassing 4,826 mother-child pairs., Methods: Concentrations of PFOS and PFOA were measured in maternal serum/plasma during pregnancy, or in breast milk, with different timing of sample collection in each cohort. We used a validated pharmacokinetic model of pregnancy and lactation to estimate concentrations of PFOS and PFOA in children at birth and at 3, 6, 12, and 24 months of age. We classified ADHD using recommended cutoff points for each instrument used to derive symptoms scores. We used multiple imputation for missing covariates, logistic regression to model the association between PFAS exposure and ADHD in each study, and combined all adjusted study-specific effect estimates using random-effects meta-analysis., Results: A total of 399 children were classified as having ADHD, with a prevalence ranging from 2.3% to 7.3% in the studies. Early life exposure to PFOS or PFOA was not associated with ADHD during childhood [odds ratios (ORs) ranging from 0.96 (95% CI: 0.87, 1.06) to 1.02 (95% CI: 0.93, 1.11)]. Results from stratified models suggest potential differential effects of PFAS related to child sex and maternal education., Conclusion: We did not identify an increased prevalence of ADHD in association with early life exposure to PFOS and PFOA. However, stratified analyses suggest that there may be an increased prevalence of ADHD in association with PFAS exposure in girls, in children from nulliparous women, and in children from low-educated mothers, all of which warrant further exploration. https://doi.org/10.1289/EHP5444.

Background: Per- and polyfluoroalkyl substances (PFAS) are widespread persistent organic pollutants and endocrine disruptors. High doses of perfluorooctanesulfonic acid (PFOS) and perfluorooctanoic acid (PFOA) exposure can cause pregnancy loss and infant deaths in animals, but the associations between PFAS exposures and risk of miscarriage in humans are not well studied., Methods: Using a case-control study nested within the Danish National Birth Cohort (DNBC, 1996-2002), we compared 220 pregnancies ending in miscarriage during weeks 12-22 of gestation, with 218 pregnancies resulting in live births. Levels of seven types of PFAS [PFOS, PFOA, perfluorohexane sulfonate (PFHxS), perfluoroheptane sulfonate (PFHpS), perfluorononanoic acid (PFNA), perfluorodecanoic acid (PFDA), and perfluorooctanesulfonic acid (PFOSA)] were measured in maternal plasma collected in early gestation (mean gestational week 8). We estimated the odds ratios (ORs) and 95% confidence intervals (CIs) for miscarriage and each PFAS as a continuous variable or in quartiles, controlling for maternal age, parity, socio-occupational status, smoking and alcohol intake, gestational week of blood sampling, and maternal history of miscarriage. Stratification by parity and PFAS mixture analyses using weighted quantile sum (WQS) regression were also conducted., Results: We observed a monotonic increase in odds for miscarriage associated with increasing PFOA and PFHpS levels. The ORs comparing the highest PFOA or PFHpS quartile to the lowest were 2.2 (95% CI: 1.2, 3.9) and 1.8 (95% CI: 1.0, 3.2). The ORs were also elevated for the second or third quartile of PFHxS or PFOS, but no consistent exposure-outcome pattern emerged. An interquartile range (IQR) increment in the WQS index of seven PFAS was associated with 64% higher odds for miscarriage (95% CI: 1.15, 2.34). The associations were stronger in parous women, while findings were inconsistent among nulliparous women., Conclusion: Maternal exposures to higher levels of PFOA, PFHpS, and PFAS mixtures were associated with the risk of miscarriage and particularly among parous women. Larger replication studies among nulliparous women are needed to allay concerns about confounding by reproductive history. https://doi.org/10.1289/EHP6202.

Background: Maternal thyroid hormones are essential for fetal brain development in early gestation. Perfluoroalkyl substances (PFASs)-widespread and persistent pollutants-have been suggested to interfere with maternal thyroid hormones in the second or third trimesters, but evidence for an association in the early pregnancy period is sparse., Objectives: Our goal was to evaluate the gestational-week specific associations of maternal thyroid-stimulating hormone (TSH) and free thyroxine (fT4) levels with plasma concentrations of six PFAS chemicals in the first and second pregnancy trimester., Methods: A cross-sectional analysis was conducted using 1,366 maternal blood samples collected between gestational weeks (GWs) 5 and 19 (median, 8 gestational weeks) in the Danish National Birth Cohort (DNBC) during 1996-2002. We estimated the percentage changes of serum TSH and fT4 levels according to concentrations (in nanograms per milliliter) of six PFAS chemicals modeled as per interquartile range (IQR) increase or by exposure quartiles. Moreover, we contrasted the estimated week-specific TSH or fT4 levels by PFAS quartile and estimated ORs for binary high or low TSH and fT4 status based on the week-specific distribution according to IQR increase of PFAS., Results: TSH levels followed a U-curve trend in early pregnancy with a nadir at GW10, whereas fT4 levels were less fluctuated in the samples. There were no apparent associations between any of the PFASs and changes of average TSH or fT4 levels in total samples. In gestational-week-specific analyses, we found that the estimated TSH values were higher among the highest perfluorooctane sulfonate (PFOS), perfluorooctanoic acid (PFOA), perfluorohexane sulfonate (PFHxS), and perfluoroheptane sulfonate (PFHpS) quartiles compared with the lower quartiles from GW5 to GW10, but the difference became null or even reversed after GW10. For binary outcomes, perfluorodecanoic acid (PFDA) was associated with high fT4 status before GW10 [ OR = 1.46 (95% CI: 1.04, 2.05)]., Conclusions: We observed some gestational-week-specific associations between high exposure to several PFAS and TSH level in early gestations. Further research of the biology and the potential clinical impact regarding thyroid hormones disruptions in early pregnancy is needed. https://doi.org/10.1289/EHP5482.

Background: It remains unsettled whether prenatal exposure to perfluoroalkyl substances (PFASs) affects human reproductive health through potential endocrine disruption., Objectives: We aimed to explore the associations between prenatal exposure to several PFASs and various aspects of pubertal development in boys and girls., Methods: We studied two samples ([Formula: see text] and 445) from the Puberty Cohort, nested within the Danish National Birth Cohort (DNBC), measuring PFAS in maternal plasma from early gestation. Data on pubertal development were collected biannually from the age of 11 y until full maturation, using web-based questionnaires. Outcomes were age at menarche, voice break, first ejaculation, and Tanner stages 2 to 5 for pubic hair, breast, genital development, and a combined puberty indicator. A regression model for censored data was used to estimate mean difference (months) in age at achieving the pubertal outcomes across tertiles of PFAS concentrations and with a doubling of PFAS concentrations (continuous). For perfluorooctanoic acid (PFOA) and perfluorooctanesulfonic acid (PFOS), a meta-analysis was used to provide a weighted average of the point estimates from samples 1 and 2., Results: Overall, prenatal exposure to PFOS, perfluorohexane sulfonate (PFHxS), perfluoroheptane sulfonate (PFHpS), perfluorononanoic acid (PFNA), and perfluorodecanoic acid (PDFA) (girls) and PFHxS and PFHpS (boys) was associated with lower mean age at puberty marker onset. PFDA and PFNA exposure was associated with higher mean age at onset of puberty in boys. Nonmonotonic associations in girls (PFOS, PFHpS, PFDA) and boys (PFDA, PFNA) were observed, showing larger mean age differences for the combined puberty indicator in the middle tertile [girls: PFOS: [Formula: see text] mo, 95% confidence interval (CI): [Formula: see text], [Formula: see text]; PFHpS: [Formula: see text] mo, 95% CI: [Formula: see text], 1.85; PFDA: [Formula: see text] mo, 95% CI: [Formula: see text], 1.83; and boys: PFNA: 4.45 mo, 95% CI: [Formula: see text], 10.21; PFDA: 4.59 mo, 95% CI: [Formula: see text], 10.11] than in the highest tertile with the lowest as reference., Conclusions: Our population-based cohort study suggests sex-specific associations of altered pubertal development with prenatal exposure to PFASs. These findings are novel, and replication is needed. https://doi.org/10.1289/EHP3567.

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.

Background: Perfluoroalkyl substances (PFASs) are widespread persistent organic compounds that have been suggested to affect neurodevelopment., Objective: We aimed to evaluate whether prenatal exposure to PFASs is associated with IQ in children., Methods: We studied 1,592 pregnancies enrolled in the Danish National Birth Cohort (DNBC) during 1996-2002. Sixteen PFASs were measured in maternal plasma collected in early gestation. Child IQ was assessed at 5 y of age using the Wechsler Primary and Preschool Scales of Intelligence-Revised (WPPSI-R) administered by trained psychologists. Using multivariable linear regression models, we estimated the differences in child IQ scores according to PFAS concentration [per natural-log (ng/mL) unit increase or values categorized in quartiles]., Results: Perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) were detected in all samples, and five additional PFASs were quantified in >80% of the samples. Overall, we found no strong associations between a natural-log unit increase in each of the seven PFASs we evaluated and child IQ scores. A few positive and negative associations were found in the sex-stratified PFAS quartile analyses, but the patterns were inconsistent., Conclusion: Overall, we did not find consistent evidence to suggest prenatal exposure to PFASs to be associated with child IQ scores at 5 y of age in the DNBC. Some of the sex-specific observations warrant further investigation. Additional studies should examine offspring IQ at older ages and assess other functional cognitive and neuropsychiatric measures in addition to intelligence. Postnatal exposures to PFASs and mixture effects for PFASs and PFASs with other environmental pollutants should also be considered in future research. https://doi.org/10.1289/EHP2754.

Purpose of Review: We reviewed and summarized the epidemiological evidence for the influence that pre- and postnatal exposures to perfluoroalkyl substances (PFASs) may have on health outcomes in offspring, with a particular focus on birth outcomes and postnatal growth, immunomodulatory effects and neurodevelopment., Recent Findings: PFASs are persistent organic pollutants that have been widely produced and used in a range of commercial products since the 1950s. Human exposures to PFASs are nearly ubiquitous globally, but studies that addressed potential health effects of PFASs have only begun to accumulate in recent years. Animal studies suggest adverse effects resulting from developmental encompasses prenatal exposures to PFASs. In humans, the developing fetus is exposed to PFASs via active or passive placenta transfer, while newborns might be exposed via breastfeeding or PFAS in the home environment. Overall, epidemiological findings are consistent and suggest possible associations with fetal and postnatal growth and immune function, while the findings on neurodevelopmental endpoints to date are rather inconclusive. Methodological challenges and future directions for PFASs-focused research are discussed.

Background: Perfluoroalkyl acids (PFAAs) are persistent and bioaccumulating compounds, which are spread all over the globe. We aimed to compare the PFAA concentrations in serum from pregnant women in five birth cohorts from four countries (Denmark, China, Norway, and Greenland)., Methods: Serum samples were obtained from the following five birth cohorts including a total of 4718 pregnant women: the Danish National Birth Cohort (DNBC, years 1996-2002, Denmark), the Aarhus Birth Cohort (ABC, years 2008-2013, Denmark), the Shanghai Birth Cohort (SBC, years 2013-2015, China), the Northern Norway Mother-Child Contaminant Cohort (MISA, years 2007-2009, Norway), and the Greenlandic Birth Cohort (ACCEPT, years 2010-2013, Greenland). The samples were analyzed using liquid chromatography triple-quadrupole mass spectrometry. To ensure comparability, all samples except for the MISA samples were measured in the same laboratory. We adjusted the log-transformed PFAA concentrations for age and parity using analysis of covariance., Results and Discussion: The geometric mean (GM) of the summed concentrations of the seven most abundant PFAAs (∑PFAA) was 35ng/mL in the DNBC, 25 ng/mL in the SBC, 18ng/mL in the ACCEPT, 12ng/mL in the MISA cohort, and 12ng/mL in the ABC. The DNBC concentration was highest presumably because these samples were taken in earlier years (i.e. 1996-2002) than the samples from the other cohorts (i.e. 2007-2015), and at a time when the production of PFAAs were at the highest. When excluding the DNBC samples, we found that the concentrations of all the perfluorinated sulfonic acids (PFSAs) and one of the four perfluorinated carboxylic acids (PFCAs) were highest in the Greenlandic women, whereas the other three PFCAs were highest in the Chinese women., Conclusion: The concentration and composition of serum PFAAs were similar for the Danish ABC women and the Norwegian MISA women but were otherwise different across the cohorts. The different exposure profiles might partly be related to differences in lifestyle and diet. As the concentrations and compositional patterns vary between the countries, we suggest that the health implications associated with high PFAA exposure might also differ between the countries., (Copyright © 2016 Elsevier GmbH. All rights reserved.)

Background: We previously demonstrated an association between plasma perfluorooctane sulfonate (PFOS) and perfluorooctanoate (PFOA) and longer time to pregnancy (TTP) in a sample from the Danish National Birth Cohort (DNBC, 1996-2002). In this study we investigated this association in a new sample from the same cohort., Methods: Sample 1 consisted of 440 women, and Sample 2 consisted of 1161 women from whom we previously published the associations between PFOS or PFOA and TTP. We performed sample-specific and pooled analyses using discrete-time survival analyses to estimate fecundability ratios according to PFOS and PFOA quartiles, adjusted for potential confounders chosen guided by a directed acyclic graph. We also estimated odds ratios for infertility (TTP > 12 months or infertility treatment) according to PFOS and PFOA by multivariable logistic regression., Results: In Sample 1 PFOS was not associated with lower fecundability ratios or infertility, and there was a tendency towards longer TTP with increasing PFOA only in parous women. In Sample 2 previously reported associations were again seen. In the pooled analyses including both parous and nulliparous women fecundability ratios were 13-22 % lower for the three higher quartiles of PFOS or PFOA compared to the reference quartile., Conclusions: The pooled analyses were driven by the larger old sample, but we did not corroborate our previous finding of an association between high PFOS and longer TTP in the new sample. The tendency towards an association for PFOA and TTP in parous women may be due to reverse causation. Results from the new sample are more in line with the recent literature.

Background: Perfluoroalkyl substances (PFASs) are persistent pollutants found to be endocrine disruptive and neurotoxic in animals. Positive correlations between PFASs and neurobehavioral problems in children were reported in cross-sectional data, but findings from prospective studies are limited., Objectives: We investigated whether prenatal exposure to PFASs is associated with attention deficit/hyperactivity disorder (ADHD) or childhood autism in children., Methods: Among 83,389 mother-child pairs enrolled in the Danish National Birth Cohort during 1996-2002, we identified 890 ADHD cases and 301 childhood autism cases from the Danish National Hospital Registry and the Danish Psychiatric Central Registry. From this cohort, we randomly selected 220 cases each of ADHD and autism, and we also randomly selected 550 controls frequency matched by child's sex. Sixteen PFASs were measured in maternal plasma collected in early or mid-pregnancy. We calculated risk ratios (RRs) using generalized linear models, taking into account sampling weights., Results: Perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) were detected in all samples; four other PFASs were quantified in ≥ 90% of the samples. We did not find consistent evidence of associations between mother's PFAS plasma levels and ADHD [per natural log nanograms per milliliter increase: PFOS RR = 0.87 (95% CI: 0.74, 1.02); PFOA RR = 0.98 (95% CI: 0.82, 1.16)] or autism [per natural log nanograms per milliliter increase: PFOS RR = 0.92 (95% CI: 0.69, 1.22); PFOA RR = 0.98 (95% CI: 0.73, 1.31)]. We found positive as well as negative associations between higher PFAS quartiles and ADHD in models that simultaneously adjusted for all PFASs, but these estimates were imprecise., Conclusions: In this study we found no consistent evidence to suggest that prenatal PFAS exposure increases the risk of ADHD or childhood autism in children.

Only 60-70% of fertilized eggs may result in a live birth, and very early fetal loss mainly goes unnoticed. Outcomes that can only be ascertained in live-born children will be missing for those who do not survive till birth. In this article, we illustrate a common bias structure (leading to 'live-birth bias') that arises from studying the effects of prenatal exposure to environmental factors on long-term health outcomes among live births only in pregnancy cohorts. To illustrate this we used prenatal exposure to perfluoroalkyl substances (PFAS) and attention-deficit/hyperactivity disorder (ADHD) in school-aged children as an example. PFAS are persistent organic pollutants that may impact human fecundity and be toxic for neurodevelopment. We simulated several hypothetical scenarios based on characteristics from the Danish National Birth Cohort and found that a weak inverse association may appear even if PFAS do not cause ADHD but have a considerable effect on fetal survival. The magnitude of the negative bias was generally small, and adjusting for common causes of the outcome and fetal loss can reduce the bias. Our example highlights the need to identify the determinants of pregnancy loss and the importance of quantifying bias arising from conditioning on live birth in observational studies., (© The Author 2015; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Perfluoroalkyl substances (PFASs) are persistent pollutants and endocrine disruptors that may affect fetal brain development. We investigated whether prenatal exposure to PFASs increases the risk of congenital cerebral palsy (CP). The source population for this study includes 83,389 liveborn singletons and mothers enrolled in the Danish National Birth Cohort during 1996-2002. We identified 156 CP cases by linking the cohort to the Danish National Cerebral Palsy Register, and we randomly selected 550 controls using a case-cohort design. We measured 16 PFASs in maternal plasma collected in early or midpregnancy, and 6 PFASs were quantifiable in more than 90% of the samples. We found a higher risk of CP in boys with higher maternal PFAS levels; per 1-unit (natural-log ng/mL) increase, the risk ratios were 1.7 (95% confidence interval: 1.0, 2.8) for perfluorooctane sulfonate and 2.1 (95% confidence interval: 1.2, 3.6) for perfluorooctanoic acid. We also observed a dose-response pattern of CP risk in boys per quartile of maternal level of perfluorooctane sulfonate and perfluorooctanoic acid (P for trend < 0.01). PFASs were associated with both unilateral and bilateral spastic CP subphenotypes. No association between PFASs and CP was found in girls. Prenatal exposures to PFASs may increase the risk of CP in boys, but the finding is novel and replication is needed., (© The Author 2014. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Perfluoroalkyl substances (PFASs) are persistent pollutants found to be endocrine disruptive and neurotoxic in animals. Positive correlations between PFASs and neurobehavioral problems in children were reported in cross-sectional data, but findings from prospective studies are limited. Objectives: We investigated whether prenatal exposure to PFASs is associated with attention deficit/hyperactivity disorder (ADHD) or childhood autism in children. Methods: Among 83,389 mother-child pairs enrolled in the Danish National Birth Cohort during 1996-2002, we identified 890 ADHD cases and 301 childhood autism cases from the Danish National Hospital Registry and the Danish Psychiatric Central Registry. From this cohort, we randomly selected 220 cases each of ADHD and autism, and we also randomly selected 550 controls frequency matched by child's sex. Sixteen PFASs were measured in maternal plasma collected in early or mid-pregnancy. We calculated risk ratios (RRs) using generalized linear models, taking into account sampling weights. Results: Perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) were detected in all samples; four other PFASs were quantified in ≥ 90% of the samples. We did not find consistent evidence of associations between mother's PFAS plasma levels and ADHD [per natural log nanograms per milliliter increase: PFOS RR = 0.87 (95% CI: 0.74, 1.02); PFOA RR = 0.98 (95% CI: 0.82, 1.16)] or autism [per natural log nanograms per milliliter increase: PFOS RR = 0.92 (95% CI: 0.69, 1.22); PFOA RR = 0.98 (95% CI: 0.73, 1.31)]. We found positive as well as negative associations between higher PFAS quartiles and ADHD in models that simultaneously adjusted for all PFASs, but these estimates were imprecise. Conclusions: In this study we found no consistent evidence to suggest that prenatal PFAS exposure increases the risk of ADHD or childhood autism in children. Citation: Liew Z, Ritz B, von Ehrenstein OS, Bech BH, Nohr EA, Fei CY, Bossi R, Henriksen TB, Bonefeld-Jørgensen EC, Olsen J. 2015. Attention deficit/hyperactivity disorder and childhood autism in association with prenatal exposure to perfluoroalkyl substances: a nested case–control study in the Danish National Birth Cohort. Environ Health Perspect 123:367-373; http://dx.doi.org/10.1289/ehp.1408412 [ABSTRACT FROM AUTHOR]