In utero exposure to perfluoroalkyl and polyfluoroalkyl substances and attention and executive function in the offspring: A study in the Danish National Birth Cohort.

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.

Early Life Exposure to Perfluoroalkyl Substances (PFAS) and ADHD: A Meta-Analysis of Nine European Population-Based Studies.

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.

Head circumference at birth and intellectual disability: a nationwide cohort study.

BACKGROUND: Intellectual disability (ID) is a prevalent chronic disability affecting up to 1-3% of the general population. Small head circumference at birth, a surrogate measure of foetal cerebral growth, may be a risk factor for ID. We aimed to investigate the association between the full distribution of head circumference at birth and ID. METHODS: This cohort study was based on Danish nationwide registries and included all Danish singletons born alive from 1997 to 2013. Follow-up ended at October 2015. The data was analysed using a Cox proportional hazards regression model adjusted for a large number of potential confounders. RESULTS: The cohort comprised 986,909 infants. Neither microcephaly nor macrocephaly at birth was consistently associated with the risk of ID. Within the normal range of head circumference, larger head circumference was associated with a decreased risk of ID (HR per standard deviation increase in head circumference z score 0.85, 95% CI 0.81-0.88). The association detected within the normal range was consistent in all sensitivity analyses. CONCLUSIONS: Intrauterine brain growth restriction may be a risk factor for ID.

Head circumference at birth and school performance: a nationwide cohort study of 536,921 children.

BACKGROUND: Early measures of cognitive function are of great public health interest. We aimed to estimate the association between head circumference at birth, a measure of cerebral size, and school performance. METHODS: We conducted a nationwide cohort study of all liveborn singletons in Denmark, 1997-2005. The association between birth head circumference z score and test scores in reading and mathematics from a nationwide mandatory computer-based school test program (7-16 years) was estimated by multivariable linear regression adjusted for potential confounders. RESULTS: The cohort included 536,921 children. Compared to normocephalic children, children with microcephaly [<-2 standard deviations (SD)] had lower mean reading scores: second grade: -0.08 SD (95% CI -0.10 to -0.06), eighth grade: -0.07 SD (95% CI -0.10 to -0.04). Macrocephaly (>+2 SD) was associated with higher scores. In normocephalic children, each SD increase in head circumference was associated with a 0.03 SD (95% CI 0.03 to 0.04) increase in mean reading scores. The results were similar across grades within both reading and mathematics. CONCLUSION: Prenatal brain growth may be causally related to childhood school performance. The demonstrated differences are unlikely to be clinically relevant at the individual level but may be important at a public health level.

Associations of Fetal Growth Outcomes with Measures of the Combined Xenoestrogenic Activity of Maternal Serum Perfluorinated Alkyl Acids in Danish Pregnant Women.

BACKGROUND: Higher concentrations of single perfluorinated alkyl acids (PFAAs) have been associated with lower birth weight (BW), but few studies have examined the combined effects of PFAA mixtures. PFAAs have been reported to induce estrogen receptor (ER) transactivity, and estrogens may influence human fetal growth. We hypothesize that mixtures of PFAAs may affect human fetal growth by disrupting the ER. OBJECTIVES: We aimed to study the associations between the combined xenoestrogenic activity of PFAAs in pregnant women's serum and offspring BW, length, and head circumference. METHODS: We extracted the actual mixture of PFAAs from the serum of 702 Danish pregnant women (gestational wk 11­13) enrolled in the Aarhus Birth Cohort (ABC) using solid phase extraction, high-performance liquid chromatography (HPLC), and weak anion exchange. PFAA-induced xenoestrogenic receptor transactivation (XER) was determined using the stable transfected MVLN cell line. Associations between XER and measures of fetal growth were estimated using multivariable linear regression with primary adjustment for maternal age, body mass index (BMI), educational level, smoking, and alcohol intake, and sensitivity analyses with additional adjustment for gestational age (GA) (linear and quadratic). RESULTS: On average, an interquartile range (IQR) increase in XER was associated with a [Formula: see text] [95% confidence interval (CI): [Formula: see text], [Formula: see text]] decrease in BW and a [Formula: see text] (95% CI: 0.1, 0.5) decrease in birth length. Upon additional adjustment for GA, the estimated mean differences were [Formula: see text] (95% CI: [Formula: see text], 4) and [Formula: see text] (95% CI: [Formula: see text], 0.0), respectively. CONCLUSION: Higher-serum PFAA-induced xenoestrogenic activities were associated with lower BW and length in offspring, suggesting that PFAA mixtures may affect fetal growth by disrupting ER function. https://doi.org/10.1289/EHP1884.

Conditioning on Parity in Studies of Perfluoroalkyl Acids and Time to Pregnancy: An Example from the Danish National Birth Cohort.

BACKGROUND: Previous studies have investigated the associations between perfluoroalkyl acids (PFAAs) in women and time to pregnancy (TTP). Inconsistent results may be explained by differences in conditioning on parity. OBJECTIVES: We used causal directed acyclic graphs to illustrate potential confounding related to previous pregnancies and exposure measurement error due to differences in the interpregnancy interval in pregnancy-based studies that include parous women. We exemplified the potential importance of these issues using data from the Danish National Birth Cohort. METHODS: We used discrete time survival models to estimate associations between maternal plasma PFAAs in early pregnancy and TTP in 638 nulliparous and 613 parous women. RESULTS: PFAA quartiles were not associated with the TTP in nulliparous women. In parous women, higher PFAA quartiles were associated with longer TTP. The strongest associations were estimated for perfluorohexane sulfonate and perfluorooctane sulfonate. PFAA concentrations were higher in women with longer interpregnancy intervals. Accounting for the interpregnancy interval attenuated the estimated associations. CONCLUSIONS: Associations between PFAAs and TTP in parous women may be biased by confounders related to previous pregnancies and exposure measurement error. To avoid these biases, studies that include parous women may need to condition on a) common causes of PFAAs and the TTP in the index pregnancy, b) previous births (a descendant of a collider), c) PFAA levels or common causes of PFAA levels and the TTP in the previous pregnancy (to alleviate collider stratification bias caused by conditioning on previous births), and d) the interpregnancy interval (in pregnancy-based studies). Alternatives would be to restrict studies to nulliparous women or to use toxicokinetic modeling to correct exposure estimates in parous women. These recommendations may be extended to studies of other chemicals with similar toxicokinetic properties. https://doi.org/10.1289/EHP1493.

Directed acyclic graphs: a tool for causal studies in paediatrics.

Many paediatric clinical research studies, whether observational or interventional, have as an eventual aim the identification or quantification of causal relationships. One might ask: does screen time influence childhood obesity? Could overuse of paracetamol in infancy cause wheeze? How does breastfeeding affect later cognitive outcomes? In this review, we present causal directed acyclic graphs (DAGs) to a paediatric audience. DAGs are a graphical tool which provide a way to visually represent and better understand the key concepts of exposure, outcome, causation, confounding, and bias. We use clinical examples, including those outlined above, framed in the language of DAGs, to demonstrate their potential applications. We show how DAGs can be most useful in identifying confounding and sources of bias, demonstrating inappropriate statistical adjustments for presumed biases, and understanding threats to validity in randomised controlled trials. We believe that a familiarity with DAGs, and the concepts underlying them, will be of benefit both to the researchers planning studies, and practising clinicians interpreting them.

Head circumference at birth and childhood developmental disorders in a nationwide cohort in Denmark.

BACKGROUND: Early markers of Attention Deficit Hyperactivity Disorder (ADHD) and Autism Spectrum Disorder (ASD) may improve the understanding and early recognition of these disorders. We aimed to estimate the association between head circumference at birth, a measure of cerebral size at birth, and the risk of ADHD and ASD. METHODS: We present a register-based cohort study of all Danish singletons born alive between 1997 and 2013. Cox proportional hazards regression was used for the statistical analyses. Sibling-matched analyses were performed to account for unmeasured confounding shared by siblings. RESULTS: The analyses included 986 909 new-borns. Compared to normocephalic children, microcephaly was associated with an increased risk of ADHD (hazard ratio [HR] 1.22, 95% confidence interval [CI] 1.12, 1.32). Macrocephaly was associated with a decreased risk of ADHD (HR 0.90, 95% CI 0.82, 0.99). Neither microcephaly nor macrocephaly were associated with ASD (HR 1.06, 95% CI 0.94, 1.19 and 1.03, 95% CI 0.90, 1.19). The largest difference was found within the normocephalic children. A head circumference at the lower limit of normocephaly compared to a head circumference at the upper limit was associated with an increased risk of ADHD (HR 1.52, 95% CI 1.43, 1.63). The sibling analyses confirmed the increased risk of ADHD with decreasing head circumference in the normocephalic children. No other clear associations were present in the sibling analyses. CONCLUSIONS: Within normocephalic children, smaller head circumference at birth was associated with a higher risk of ADHD. Restricted foetal brain growth may be a risk factor for the development of ADHD but not ASD.

Prenatal Exposure to Perfluoroalkyl Substances and IQ Scores at Age 5; a Study in the Danish National Birth Cohort.

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.

Congenital Heart Defects and Measures of Prenatal Brain Growth: A Systematic Review.

BACKGROUND: We summarize the evidence for an association between congenital heart defects and prenatal brain growth through a systematic literature review. Congenital heart defects are among the most common malformations, affecting approximately six per 1000 live births. The association between congenital heart defects and long-term neurodevelopmental disorders is well established. Increasing evidence suggests an association between impaired prenatal brain growth and neurodevelopmental disorders in children with congenital heart defects. METHODS: Systematic literature searches were performed in PubMed and EMBASE. We included original studies comparing fetuses or newborns with congenital heart defects to reference fetuses or newborns with respect to brain biometrics, including biparietal diameter, brain volume, and head circumference at birth. The study characteristics and the results were extracted and presented in tables. No meta-analysis was undertaken. RESULTS: Twenty-eight studies were included. All except two studies found an association between congenital heart defects and measures of reduced prenatal brain growth. The strongest evidence concerned hypoplastic left heart syndrome, tetralogy of Fallot, and transposition of the great arteries. CONCLUSIONS: The literature suggests an association between congenital heart defects and measures of impaired prenatal brain growth. However, most studies were small and failed to include important potential confounding factors and to address other sources of potential bias as well. Future large-scale studies that address potential confounders are warranted.

Paracetamol use during pregnancy and attention and executive function in offspring at age 5 years.

Methods: We studied 1491 mothers and children enrolled in the Danish National Birth Cohort (DNBC; 1996-2002). Prenatal paracetamol use was prospectively recorded in three telephone interviews. Trained psychologists assessed child's attention function using the Test of Everyday Attention for Children at Five (TEACh-5). Parents and preschool teachers completed Behaviour Rating Inventory of Executive Function (BRIEF) to assess executive functions. We estimated the differences of composite mean outcome scores, and odds ratios (OR) for subnormal attention or executive function (defined as 1 standard deviation below the mean), adjusting for maternal IQ, maternal mental health, indications for paracetamol use and other potential confounders. Results: First trimester use of paracetamol was associated with poorer attention scores in childhood [mean difference -0.34, 95% confidence interval (CI) -0.63, -0.05 for overall attention, and -0.25, 95% CI -0.50, 0.01 for selective attention]. Children prenatally exposed to paracetamol were also at a higher risk for subnormal overall attention (OR = 1.5, 95% CI 1.0, 2.5), selective attention difficulties (OR = 1.5, 95% CI 1.0, 2.4), and parent-rated subnormal executive function (metacognition index, OR = 1.5, 95% CI 0.9, 2.3). The risks for subnormal overall attention or executive function were elevated with longer duration of paracetamol use in pregnancy. Conclusions: We found some evidence that maternal paracetamol use during pregnancy was associated with poorer attention and executive function in 5-year-olds.

Congenital Heart Defects and Indices of Placental and Fetal Growth in a Nationwide Study of 924 422 Liveborn Infants.

BACKGROUND: Congenital heart defects (CHDs) have been associated with placental anomalies. The nature and the consequences of this association remain poorly understood. We aimed to estimate the associations between all major subtypes of CHD and placental weight at birth, and the association between placental weight and measures of both overall and cerebral growth in fetuses with CHD, as well. METHODS: We included all 924 422 liveborn Danish singletons, 1997 to 2011. CHD was present in 7569. We compared mean differences in placental weight z score between newborns with CHD and newborns without CHD by multivariable linear regression adjusted for potential confounders. RESULTS: CHD was associated with a mean z score difference of -0.04 (95% confidence interval, -0.07 to -0.02). Some subtypes were associated with smaller placental size at birth: tetralogy of Fallot, -0.45 (95% confidence interval, -0.58 to -0.31); double-outlet right ventricle, -0.48 (95% confidence interval, -0.87 to -0.10); major ventricular septal defects, -0.41 (95% confidence interval, -0.52 to -0.29). Placental weight z score was associated with birth weight and head circumference z scores in all subtypes. In the 3 mentioned subtypes, the mean deviations from the population mean head circumference and birth weight z scores were reduced by up to 66% with adjustment for placental weight z score. CONCLUSIONS: Three subtypes of CHD were associated with lower placental weight, and placental weight was associated with measures of both overall growth and cerebral growth in fetuses with all subtypes of CHD. In certain subtypes, the described deviations in fetal growth were reduced by up to two-thirds after adjustment for placental weight z score.

Microarray-Based Analysis of Methylation of 1st Trimester Trisomic Placentas from Down Syndrome, Edwards Syndrome and Patau Syndrome.

Methylation-based non-invasive prenatal testing of fetal aneuploidies is an alternative method that could possibly improve fetal aneuploidy diagnosis, especially for trisomy 13(T13) and trisomy 18(T18). Our aim was to study the methylation landscape in placenta DNA from trisomy 13, 18 and 21 pregnancies in an attempt to find trisomy-specific methylation differences better suited for non-invasive prenatal diagnosis. We have conducted high-resolution methylation specific bead chip microarray analyses assessing more than 450,000 CpGs analyzing placentas from 12 T21 pregnancies, 12 T18 pregnancies and 6 T13 pregnancies. We have compared the methylation landscape of the trisomic placentas to the methylation landscape from normal placental DNA and to maternal blood cell DNA. Comparing trisomic placentas to normal placentas we identified 217 and 219 differentially methylated CpGs for CVS T18 and CVS T13, respectively (delta ß>0.2, FDR<0.05), but only three differentially methylated CpGs for T21. However, the methylation differences was only modest (delta ß<0.4), making them less suitable as diagnostic markers. Gene ontology enrichment analysis revealed that the gene set connected to theT18 differentially methylated CpGs was highly enriched for GO terms related to"DNA binding" and "transcription factor binding" coupled to the RNA polymerase II transcription. In the gene set connected to the T13 differentially methylated CpGs we found no significant enrichments.

Determinants of serum levels of perfluorinated alkyl acids in Danish pregnant women.

Humans are exposed to perfluorinated alkyl acids (PFAAs) from food, drinking water, air, dust, and consumer products. PFAAs are persistent and bio-accumulative. In the present study, we aimed to establish how the serum levels of PFAAs differ according to age, pre-pregnancy body mass index (BMI), previous miscarriages, educational level, country of birth, smoking, and alcohol intake. We included 1438 Danish pregnant nulliparous women from the Aarhus Birth Cohort. The women gave a blood serum sample between week 11 and 13 of pregnancy. Sixteen PFAAs were extracted from serum using solid phase extraction and analyzed by liquid chromatography/tandem mass spectrometry. Multivariable linear regression analysis was used to determine the associations between individual characteristics of the women and their levels of seven PFAAs that were detected in at least 50% of the samples. The total concentration of the PFAAs (∑PFAA) was higher in older women. On average, normal weight women had a higher ∑PFAA level than underweight, overweight, and obese women. Higher levels were also observed for women without previous miscarriages, women with a high educational level, women born in Denmark (as opposed to women born elsewhere but currently living in Denmark), non-smokers, and women who consumed alcohol before or during pregnancy. These associations were similar for all the studied PFAAs, although the levels of perfluoroundecanoic acid varied more across the categories of age, BMI, education, smoking, and alcohol consumption than any other PFAAs measured.

Perfluoroalkyl and polyfluoroalkyl substances and measures of human fertility: a systematic review.

Perfluoroalkyl and polyfluoroalkyl substances (PFASs) are found widespread in the environment and humans. The relation of PFASs to fertility has now been examined in a relatively large number of epidemiologic studies and a synthesis is in order. The aim of this study was to assess the current human epidemiologic evidence on the association between exposure to PFASs and measures of human fertility, with particular emphasis on perfluorooctane sulfonate (PFOS) and perfluorooctanoate (PFOA). Systematic literature searches were initially conducted in MEDLINE and EMBASE and subsequently in references and citations of included papers. Studies were included if they assessed exposure to PFASs in biological samples in relation to reproductive hormones, semen characteristics, or time to pregnancy (TTP). Study characteristics and results were abstracted to predefined forms, and the studies were assessed for the risk of bias and confounding. Sixteen studies investigated the association between PFAS exposure in men and semen parameters, reproductive hormone levels, or TTP. There was a lack of consistent results among the numerous investigated exposure-outcome combinations. However, subtle associations between higher PFOS and lower testosterone or abnormal semen morphology cannot be excluded. Eleven studies assessed the association between PFAS exposure in women and TTP or reproductive hormones levels. Four of eight studies found prolonged TTP with higher PFOS or PFOA, but only one study found an association when restricting to nulliparous women. In men, there is little evidence of an association between PFAS exposure and semen quality or levels of reproductive hormones. For PFOS and PFOA, the literature indicates an association with female fecundability in parous women, which is most likely not causal.

Congenital Heart Defects and Measures of Fetal Growth in Newborns with Down Syndrome or 22q11.2 Deletion Syndrome.

OBJECTIVES: To estimate the association between congenital heart defects (CHD) and indices of fetal growth in Down and 22q11.2 deletion syndromes. STUDY DESIGN: We established 2 Danish nationwide cohorts of newborn singletons with either Down syndrome (n = 670) or 22q11.2 deletion syndrome (n = 155), born 1997-2011. In both cohorts, we analyzed the association between CHD, CHD severity, and indices of fetal growth by multivariable linear regression adjusted for potential confounders. We report mean differences in gestational age specific z-scores compared with newborns without CHD. RESULTS: Down syndrome and 22q11.2 deletion syndrome were both associated with lower mean birth weight and head circumference z-scores. We found no association between CHD or CHD severity and indices of fetal growth. In Down syndrome, the association between any CHD and the mean difference in head circumference z-score was 0.03 (95% CI -0.12, 0.18), and the estimate regarding birth weight z-score was 0.09 (95% CI -0.08, 0.25). The corresponding estimates in 22q11.2 deletion syndrome were 0.00 (95% CI -0.33, 0.32) and -0.09 (95% CI -0.45, 0.26). CONCLUSIONS: We found no association between CHD and fetal growth measures in newborns with Down syndrome or 22q11.2 deletion syndrome. Thus, in certain subtypes of CHD, the contribution of genetic factors to prenatal growth impairment may be more important than circulatory disturbances.

Time trends of perfluorinated alkyl acids in serum from Danish pregnant women 2008-2013.

We aimed to estimate the levels and time trends of perfluorinated alkyl acids (PFAAs) in serum of 1533 Danish pregnant nulliparous women between 2008 and 2013. The selection criterion of only including nulliparous women was chosen to avoid confounding from parity. The serum samples were analyzed for sixteen PFAAs using solid phase extraction and liquid chromatography tandem mass spectrometry (LC-MS/MS). We investigated the time trends for seven PFAAs, which were detected in more than 50% of the samples: perfluorohexane sulfonate (PFHxS), perfluoroheptane sulfonate (PFHpS), perfluorooctane sulfonate (PFOS), perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), perfluorodecanoic acid (PFDA), and perfluoroundecanoic acid (PFUnA). We found that the serum levels of all seven PFAAs decreased during the period from 2008 to 2013; on average PFHxS decreased with 7.0% per year, PFHpS with 14.8%, PFOS with 9.3%, PFOA with 9.1%, PFNA with 6.2%, PFDA with 6.3%, and PFUnA with 7.1% per year. Adjustment for maternal age, body mass index (BMI), educational level and gestational age at blood sampling did not change the time trends much. To our knowledge, we are the first to report decreasing trends of PFNA, PFDA and PFUnA since year 2000, thereby indicating that the phase-out of these compounds are beginning to show an effect on human serum levels.

Congenital Heart Defects and Indices of Fetal Cerebral Growth in a Nationwide Cohort of 924 422 Liveborn Infants.

BACKGROUND: Neurodevelopmental disorders are the most common and distressful comorbidities associated with congenital heart defects (CHD). Head circumference at birth (HC), a proxy for prenatal cerebral growth, is an established risk factor for neurodevelopmental disorders. METHODS AND RESULTS: In a nationwide cohort, we included all 924 422 liveborn Danish singletons, 1997 to 2011. CHD was present in 5519. The association between CHD and growth indices was analyzed by multivariable linear regression, adjusted for potential confounders. We report mean differences in gestational age-specific z scores in comparison with the general population. CHD was associated with lower HC z scores, -0.10 (95% confidence interval [CI], -0.13 to -0.08). Several CHD subtypes were associated with smaller HC, eg, hypoplastic left heart syndrome, -0.39 (95% CI, -0.58 to -0.21); common arterial trunk, -0.41 (95% CI, -0.74 to -0.09); and major ventricular septal defects, -0.25 (95% CI, -0.35 to -0.15). Other single-ventricle defects, transposition of the great arteries, tetralogy of Fallot, and anomalous pulmonary venous return, were also associated with smaller HC. Transposition of the great arteries was associated with smaller HC relative to birth weight, -0.26 (95% CI, -0.39 to -0.13). Major ventricular septal defects were associated with larger HC relative to birth weight. The results were consistent under various conditions, eg, when siblings of infants with CHD (n=5311) or infants with other major malformations (n=24 974) were used as the reference. CONCLUSIONS: Several subtypes of CHD were associated with smaller HC. The associations with major ventricular septal defects, common arterial trunk, and anomalous pulmonary venous return have not previously been described. Only infants with transposition of the great arteries had smaller HC relative to birth weight.

Perfluoroalkyl Acids in Maternal Serum and Indices of Fetal Growth: The Aarhus Birth Cohort.

BACKGROUND: Previous studies indicated an association between intrauterine exposure to perfluorooctane sulfonate (PFOS) or perfluorooctanoate (PFOA) and lower birth weight. However, these perfluoroalkyl acids (PFAAs) have to some extent been substituted by other compounds on which little is known. OBJECTIVES: We investigated the association between specific PFAAs and birth weight, birth length, and head circumference at birth. METHODS: We studied 1,507 mothers and their children from the Aarhus Birth Cohort (2008-2013). Nulliparous women were included during pregnancy, and serum levels of 16 PFAAs were measured between 9 and 20 completed gestational weeks (96% within 13 weeks). For compounds with quantifiable values in > 50% of samples (7 compounds), we report the associations with birth weight, birth length, and head circumference at birth determined by multivariable linear regression. RESULTS: Estimated mean birth weights were lower among women with serum perfluorohexane sulfonate, perfluoroheptane sulfonate, and PFOS concentrations above the lowest exposure quartile, but we found no consistent monotonic dose-response patterns. These associations were stronger when the population was restricted to term births (n = 1,426). For PFOS, the birth weight estimates for the highest versus lowest quartile were -50 g (95% CI: -123, 23 g) in all births and -62 g (95% CI: -126, 3 g) in term births. For the other PFAAs, the direction of the associations was inconsistent, and no overall association with birth weight was apparent. No PFAAs were associated with birth length or head circumference at birth. CONCLUSIONS: Overall, we did not find strong or consistent associations between PFAAs and birth weight or other indices of fetal growth, though estimated mean birth weights were lower among those with exposures above the lowest quartile for some compounds. CITATION: Bach CC, Bech BH, Nohr EA, Olsen J, Matthiesen NB, Bonefeld-Jørgensen EC, Bossi R, Henriksen TB. 2016. Perfluoroalkyl acids in maternal serum and indices of fetal growth: the Aarhus Birth Cohort. Environ Health Perspect 124:848-854; http://dx.doi.org/10.1289/ehp.1510046.