Search

Background Nitrate contamination is seen in drinking water worldwide. Nitrate may pass the placental barrier. Despite suggestive evidence of fetal harm, the potential association between nitrate exposure from drinking water and pregnancy loss remains to be studied. We aimed to investigate if nitrate in drinking water was associated with the risk of pregnancy loss. Methods We conducted a nationwide cohort study of 100,410 pregnancies (enrolled around gestational week 11) in the Danish National Birth Cohort (DNBC) during 1996–2002. Spontaneous pregnancy losses before gestational week 22 were ascertained from the Danish National Patient Registry and DNBC pregnancy interviews. Using the national drinking water quality-monitoring database Jupiter, we estimated the individual and time-specific nitrate exposure by linking geocoded maternal residential addresses with water supply areas. The nitrate exposure was analyzed in spline models using a log-transformed continuous level or classified into five categories. We used Cox proportional hazards models to estimate associations between nitrate and pregnancy loss and used gestational age (days) as the time scale, adjusting for demographic, health, and lifestyle variables. Results No consistent associations were found when investigating the exposure as a categorical variable and null findings were also found in trimester specific analyses. In the spline model using the continuous exposure variable, a modestly increased hazard of pregnancy loss was observed for the first trimester at nitrate exposures between 1 and 10 mg/L, with the highest. adjusted hazard ratio at 5 mg/L of nitrate of 1.16 (95% CI: 1.01, 1.34). This trend was attenuated in the higher exposure ranges. Conclusion No association was seen between drinking water nitrate and the risk of pregnancy loss when investigating the exposure as a categorical variable. When we modelled the exposure as a continuous variable, a dose-dependent association was found between drinking water nitrate exposure in the first trimester and the risk of pregnancy loss. Very early pregnancy losses were not considered in this study, and whether survival bias influenced the results should be further explored.

Background Fetal exposure risk factors are associated with increased autism spectrum disorder (ASD) risk. New hypotheses regarding multigenerational risk for ASD have been proposed, but epidemiological evidence is largely lacking. We evaluated whether parental birth characteristics, including preterm birth and low birthweight, were associated with ASD risk in offspring. Methods We conducted a nationwide register-based cohort study that included 230 174 mother-child and 157 926 father-child pairs in Denmark. Logistic regression models were used to estimate odds ratios (OR) and 95% confidence intervals (CI) for offspring ASD according to parental preterm ( Results Offspring of mothers or fathers with adverse birth characteristics had about 31–43% higher risk for ASD (maternal preterm birth, OR = 1.31, 95% CI= 1.12, 1.55; maternal low birthweight, OR = 1.35, 95% CI: 1.17,1.57; paternal preterm birth, OR = 1.43, 95% CI = 1.18, 1.73; paternal low birthweight, OR = 1.38, 95% CI= 1.13, 1.70). Parents born very preterm ( Conclusions Offspring of parents born with adverse characteristics had an elevated risk for ASD. Transmission of ASD risk through maternal and paternal factors should be considered in future research on ASD aetiology.

PURPOSE OF REVIEW: Acetaminophen (or paracetamol) is one of the most commonly used medications during pregnancy. We reviewed recent epidemiological evidence regarding intrauterine exposure to acetaminophen and risk for asthma, neurodevelopment disorders, and reproductive health in childhood.RECENT FINDINGS: An increasing number of cohort studies have suggested that maternal use of acetaminophen during pregnancy was associated with increased risk for asthma; neurodevelopmental disorders, especially ADHD and behavioral problems; and genital malformations in the offspring. Oxidative stress and inflammation or endocrine effects are plausible shared biological mechanisms for the exposure to influence multiple developmental outcomes. We discussed methodological challenges that can threaten the validity of these observational data, including confounding and measurement errors. Novel statistical methods and research designs that can be used to mitigate these issues were introduced. Given the high prevalence of use, findings regarding intrauterine exposure to acetaminophen on multiple child health outcomes raise concerns. Research on causal and non-causal mechanisms that might explain these associations should be a priority.

In perinatal epidemiology, fetal deaths occur over the first timeline, from conception to birth or fetal death. Majority of other epidemiological research on human diseases focus on the second timeline, from birth to death. The transition from the first to the second timeline is not a fixed duration of time and it depends on when birth occurs. We discussed the complications when switching from the first to the second timeline in epidemiological studies of early life exposures, pregnancy events, and future health outcomes. Population-based studies often lack accurate data on the date of conception for most pregnancies and the complete count of fetal death, leading to chances for selection and misclassification biases. To address these problems, better research data and methodological advancement in study designs and biases evaluations are needed.

Discovering pathophysiologic networks in a blood-based approach may help to generate valuable tools for early treatment or preventive measures in autism. To date targeted or untargeted metabolomics approaches to identify metabolic features and pathways affecting fetal neurodevelopment have rarely been applied to pregnancy samples, that is, an early period potentially relevant for the development of autism spectrum disorders (ASD). We conducted a population-based study relying on autism diagnoses retrieved from California Department of Developmental Services record. After linking cases to and sampling controls from birth certificates, we retrieved stored maternal mid-pregnancy serum samples collected as part of the California Prenatal Screening Program from the California Biobank for children born 2004 to 2010 in the central valley of California. We retrieved serum for 52 mothers whose children developed autism and 62 population controls originally selected from all eligible children matched by birth year and child's sex. Also, we required that these mothers were relatively low or unexposed to air pollution and select pesticides during early pregnancy. We identified differences in metabolite levels in several metabolic pathways, including glycosphingolipid biosynthesis and metabolism, N-glycan and pyrimidine metabolism, bile acid pathways and, importantly, C21-steroid hormone biosynthesis and metabolism. Disturbances in these pathways have been shown to be relevant for neurodevelopment in rare genetic syndromes or implicated in previous studies of autism. This study provides new insight into maternal mid-pregnancy metabolic features possibly related to the development of autism and an incentive to explore whether these pathways and metabolites are useful for early diagnosis, treatment, or prevention. LAY SUMMARY: This study found that in mid-pregnancy the blood of mothers who give birth to a child that develops autism has some characteristic features that are different from those of blood samples taken from control mothers. These features are related to biologic mechanisms that can affect fetal brain development. In the future, these insights may help identify biomarkers for early autism diagnosis and treatment or preventive measures. Autism Res 2020, 13: 1258-1269. © 2020 International Society for Autism Research, Wiley Periodicals, Inc.

Background Zinc (Zn) has been suggested to impact fetal growth. However, the effect may be complicated by gestational diabetes mellitus (GDM) due to its impact on fetal growth and placental transport. This study aims to investigate whether GDM modifies the association between Zn levels and birth weight. Method A cohort matched by GDM was established in Taiyuan, China, between 2012 and 2016, including 752 women with GDM and 744 women without. Dietary Zn intake was assessed during pregnancy. Maternal blood (MB) and cord blood (CB) Zn levels were measured at birth. Birth weight was standardized as the z score and categorized as high (HBW, >4000 g) and low (LBW, Results 88.8% (N = 1328) of the population had inadequate Zn intake during pregnancy. In women with GDM, MB Zn level was inversely associated with birth weight (β = –.17; 95% confidence interval (CI), –0.34 to –0.01), while CB Zn level was positively associated with birth weight (β = .38; 95% CI, 0.06-0.70); suggestive associations were observed between MB Zn level and LBW (odds ratio 2.01; 95% CI, 0.95-4.24) and between CB Zn level and HBW (odds ratio 2.37; 95% CI, 1.08-5.21). Conclusions GDM may modify the associations between MB and CB Zn levels and birth weight in this population characterized by insufficient Zn intake. These findings suggest a previously unidentified path of adverse effects of GDM.

Importance: Maternal immune activation during pregnancy is associated with increased risks of several mental disorders in offspring during childhood, but little is known about how maternal autoimmune diseases during pregnancy are associated with mental health in offspring during and after childhood. Objective: To investigate the association between maternal autoimmune diseases before childbirth and risk of mental disorders among offspring up to early adulthood. Design, Setting, and Participants: This population-based nationwide cohort study used data from Danish national registers on singletons born in Denmark from 1978 to 2015 with up to 38 years of follow-up. Data analyses were conducted from March 1, 2020, through September 30, 2021. Exposures: Maternal autoimmune disease diagnosed before or during pregnancy according to the Danish National Patient Register. Main Outcomes and Measures: The main outcome was mental disorders, defined by hospital diagnoses, in offspring. Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% CIs for mental disorders. Results: Of the 2 254 234 singleton infants included in the study (median age, 16.7 years [IQR, 10.5-21.7 years]; 51.28% male), 2.26% were born to mothers with autoimmune diseases before childbirth. Exposed participants had an increased risk of overall mental disorders compared with their unexposed counterparts (HR, 1.16; 95% CI, 1.13-1.19; incidence, 9.38 vs 7.91 per 1000 person-years). Increased risks of overall mental disorders in offspring were seen in different age groups for type 1 diabetes (1-5 years: HR, 1.35 [95% CI, 1.17-1.57]; 6-18 years: HR, 1.24 [95% CI, 1.15-1.33]; >18 years: HR, 1.19 [95% CI, 1.09-1.30]) and rheumatoid arthritis (1-5 years: HR, 1.42 [95% CI, 1.16-1.74]; 6-18 years: HR, 1.19 [95% CI, 1.05-1.36]; >18 years: HR, 1.28 [95% CI, 1.02-1.60]). Regarding specific mental disorders, increased risk after exposure to any maternal autoimmune disorder was observed for organic disorders (HR, 1.54; 95% CI, 1.21-1.94), schizophrenia (HR, 1.35; 95% CI, 1.21-1.51), obsessive-compulsive disorder (HR, 1.42; 95% CI, 1.24-1.63), mood disorders (HR, 1.12; 95% CI, 1.04-1.21), and a series of neurodevelopmental disorders (eg, childhood autism [HR, 1.21; 95% CI, 1.08-1.36] and attention-deficit/hyperactivity disorder [HR, 1.19; 95% CI, 1.12-1.26]). Conclusions and Relevance: In this cohort study in Denmark, prenatal exposure to maternal autoimmune diseases was associated with increased risks of overall and type-specific mental disorders in offspring. Maternal type 1 diabetes and rheumatoid arthritis during pregnancy were associated with offspring's mental health up to early adulthood. Individuals prenatally exposed to autoimmune disease may benefit from long-term surveillance for mental disorders.

Background Nitrosatable drugs commonly prescribed during pregnancy can react with nitrite to form N-nitroso compounds which have been associated with an increased risk of stillbirth. Whether maternal residential drinking water nitrate modifies this association is unknown. We investigated, if household drinking water nitrate was associated with stillbirth, and if it modified the association between nitrosatable prescription drug intake and the risk of stillbirth. Methods We conducted an individual-level register- and population-based cohort study using 652,810 women with the first recorded singleton pregnancy in the Danish Medical Birth Registry between 1997 and 2017. Nitrosatable drug exposure was recorded by use of the Danish National Patient Registry defined as women with a first redeemed prescription of a nitrosatable drug the first 22 weeks of pregnancy. The reference group was women with no redeemed prescription of a nitrosatable drug in this period. The average individual drinking water nitrate concentration level (mg/L) was calculated in the same period. We categorized nitrosatable drugs as secondary amines, tertiary amines, and amides. Cox hazard regression was used to estimate crude and adjusted hazard ratios with 95% confidence intervals for stillbirth stratified into five categories of nitrate concentrations: ≤1 mg/L, > 1- ≤ 2 mg/L, > 2- ≤ 5 mg/L, > 5- ≤ 25 mg/L, and > 25 mg/L. Results Drinking water nitrate exposure in the population was not associated with the risk of stillbirth. Among 100,244 women who had a nitrosatable prescription drug redeemed ≤22 weeks of pregnancy of pregnancy, 418 (0.42%) had a stillbirth compared to 1993 stillbirths (0.36%) among 552,566 referent women. Women with any nitrosatable prescription drug intake and > 1- ≤ 2 mg/L nitrate concentration had an increased risk of stillbirth [adjusted hazard ratio 1.55 (95% confidence interval, 1.15–2.09)] compared with referent women. In the stratified analyses, the highest risk of stillbirth was found among women with secondary amine intake and > 25 mg/L nitrate concentrations [adjusted hazard ratio 3.11 (95% CI, 1.08–8.94)]. Conclusions The association between nitrosatable prescription drug intake and the risk of stillbirth may depend on the level of nitrate in household drinking water. Evaluations of the effect of nitrosatable drug intake on perinatal outcomes might consider nitrate exposure from drinking water.

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.

Importance Maternal diabetes has been suggested as a risk factor for attention-deficit/hyperactivity disorder and autism in offspring, but evidence on its association with the full spectrum of psychiatric disorders remains lacking. Objective To investigate the associations between maternal diabetes diagnosed before or during pregnancy and 10 types of psychiatric disorders in offspring during the first 4 decades of life. Design, setting, and participants This population-based cohort study used data from several Danish nationwide medical and administrative registries in Denmark on all 2 413 335 live births from 1978 to 2016. Data were analyzed between October 1, 2019, and July 15, 2021. Exposures Any maternal diabetes diagnosis during pregnancy (56 206 offspring [2.3%]) and 3 diabetes subtypes (pregestational type 1 diabetes, 22 614 offspring [1.0%]; pregestational type 2 diabetes, 6713 offspring [0.3%]; and gestational diabetes, 26 879 offspring [1.1%]). Main outcomes and measures Outcomes included 10 types of psychiatric disorders: any psychiatric disorder, substance use disorders, schizophrenia, mood disorders, anxiety disorders, eating disorders, personality disorders, intellectual disorders, developmental disorders, and behavioral disorders. Hazard ratios (HRs) and 95% CIs were computed using Cox proportional hazards regression models. Covariates included maternal and paternal history of any psychiatric disorder, offspring sex, calendar period of birth, singleton status, and several maternal characteristics during pregnancy (ie, age, parity, educational level, smoking, cohabitation, residence, and body mass index). Sibship design and competing risk analyses were also conducted. Results A total of 2 413 335 individuals (1 239 148 male participants [51%]; age range, 1-39 years; median age, 19.0 years [IQR, 5.8-20.8 years]) were included in this study. During the 39-year follow-up time, 151 208 offspring (6.4%) received a diagnosis of a psychiatric disorder. Offspring born to mothers with any diabetes diagnosis during pregnancy were at increased risk of developing any psychiatric disorder (HR, 1.15; 95% CI, 1.10-1.20), schizophrenia (HR, 1.55; 95% CI, 1.15-2.08), anxiety disorders (HR, 1.22; 95% CI, 1.09-1.36), intellectual disabilities (HR, 1.29; 95% CI, 1.11-1.50), developmental disorders (HR, 1.16; 95% CI, 1.03-1.30), and behavioral disorders (HR, 1.17; 95% CI, 1.08-1.27) compared with offspring born to mothers without a diabetes diagnosis during pregnancy. No association was observed for substance use disorders, mood disorders, eating disorders, and personality disorders. Conclusions and relevance This study shows a pattern that suggests that prenatal exposure to maternal diabetes during pregnancy was associated with increased risk of psychiatric disorders overall and most specific psychiatric disorders in offspring in their first 4 decades of life.

Acetaminophen is the most common over-the-counter pain and fever medication used by pregnant women. While European studies suggest acetaminophen exposure in pregnancy could affect childhood asthma development, findings are less consistent in other populations. We evaluated whether maternal prenatal acetaminophen use is associated with childhood asthmatic symptoms (asthma diagnosis, wheeze, dry cough) in a Los Angeles cohort of 1201 singleton births. We estimated risk ratio (RR) and 95% confidence interval (CI) for childhood asthmatic outcomes according to prenatal acetaminophen exposure. Effect modification by maternal race/ethnicity and psychosocial stress during pregnancy was evaluated. The risks for asthma diagnosis (RR = 1.39, 95% CI 0.96, 2.00), wheezing (RR = 1.25, 95% CI 1.01, 1.54) and dry cough (RR =1.35, 95% CI 1.06, 1.73) were higher in children born to mothers who ever used acetaminophen during pregnancy compared with non-users. Black/African American and Asian/Pacific Islander children showed a greater than two-fold risk for asthma diagnosis and wheezing associated with the exposure. High maternal psychosocial stress also modified the exposure-outcome relationships. Acetaminophen exposure during pregnancy was associated with childhood asthmatic symptoms among vulnerable subgroups in this cohort. A larger study that assessed prenatal acetaminophen exposure with other social/environmental stressors and clinically confirmed outcomes is needed.

Paracetamol (N-acetyl-p-aminophenol (APAP), otherwise known as acetaminophen) is the active ingredient in more than 600 medications used to relieve mild to moderate pain and reduce fever. APAP is widely used by pregnant women as governmental agencies, including the FDA and EMA, have long considered APAP appropriate for use during pregnancy when used as directed. However, increasing experimental and epidemiological research suggests that prenatal exposure to APAP might alter fetal development, which could increase the risks of some neurodevelopmental, reproductive and urogenital disorders. Here we summarize this evidence and call for precautionary action through a focused research effort and by increasing awareness among health professionals and pregnant women. APAP is an important medication and alternatives for treatment of high fever and severe pain are limited. We recommend that pregnant women should be cautioned at the beginning of pregnancy to: forego APAP unless its use is medically indicated; consult with a physician or pharmacist if they are uncertain whether use is indicated and before using on a long-term basis; and minimize exposure by using the lowest effective dose for the shortest possible time. We suggest specific actions to implement these recommendations. This Consensus Statement reflects our concerns and is currently supported by 91 scientists, clinicians and public health professionals from across the globe., A growing body of research suggests that prenatal exposure to paracetamol (APAP) might alter development and increase the risk of some reproductive, urogenital and neurodevelopmental disorders. This Consensus Statement calls for precautionary action, including a focused research effort, increasing awareness among health professionals and pregnant women and, whenever possible, minimizing use.

Purpose: Nitrosatable drugs can react with nitrite in the stomach and form N-nitroso compounds. Exposure to nitrosatable drugs has been associated with congenital malformations and preterm birth, but use during pregnancy as a cause of fetal death is not well-known. We examined if prenatally nitrosatable drug use is associated with risk of stillbirth. Methods: A nationwide cohort was conducted using 554 844 women with singleton and first recorded pregnancies regardless of previous pregnancy history from the Danish Medical Birth Register from 1996 to 2015. Exposure was recorded by use of the Danish National Prescription Register and defined as women who had redeemed a prescribed nitrosatable drug in the first 22 weeks of pregnancy. The reference group was women with no redeemed prescribed nitrosatable drug in this time period. We categorized nitrosatable drugs as secondary amines, tertiary amines, and amides. Cox hazard regression was used to estimate crude and adjusted hazard ratios (aHRs) with 95% confidence intervals (CIs) for stillbirth. Results: Among the 84 720 exposed women, 348 had a stillbirth compared with 1690 stillbirths among the 470 124 unexposed women. Women who used any prescribed nitrosatable drug were more likely to have a stillbirth compared with unexposed women (aHRs 1.24; 95% CI, 1.03-1.49). Conclusion: Nitrosatable drug use during the first 22 weeks of pregnancy might increase risk of stillbirth. The findings should be interpreted cautiously because of important unmeasured factors that might influence the observed association, including maternal vitamin C intake, dietary, and other sources of nitrate/nitrite intake.

Frequent maternal use of acetaminophen in pregnancy has been linked to attention-deficit/hyperactivity disorder (ADHD) in children, but concerns regarding uncontrolled confounding remain. In this article, we illustrate use of the negative control exposure (NCE) approach to evaluate uncontrolled confounding bias in observational studies on pregnancy drug safety and explain the causal assumptions behind the method. We conducted an NCE analysis and evaluated the associations between maternal acetaminophen use during different exposure periods and ADHD among 8,856 children born in 1993–2005 to women enrolled in the Nurses’ Health Study II cohort. Information on regular maternal acetaminophen use was collected prospectively in biennial questionnaires. A total of 721 children (8.1%) in the cohort had been diagnosed with ADHD as reported by the mothers. Our NCE analysis suggested that only acetaminophen use at the time of pregnancy was associated with childhood ADHD (odds ratio = 1.34, 95% confidence interval: 1.05, 1.72), and the effect estimates for the 2 NCE periods (about 4 years before and 4 years after the pregnancy) were null. Our findings corroborate those of prior reports suggesting that prenatal acetaminophen exposure may influence neurodevelopment. The lack of an association between acetaminophen use in the pre- and postpregnancy exposure periods and ADHD provides assurance that uncontrolled time-invariant factors do not explain this association.

Key Points Question Are there associations between gestational age, analyzed in 6 subgroups covering the full range of gestational duration, and the rate of neuropsychiatric diagnoses? Findings In this Danish, nationwide, registry-based cohort study, shortened gestational duration was associated with the rate of both child-onset and adult-onset neuropsychiatric diseases. Beyond the traditional threshold of fetal maturity (≥37 weeks), the early term group (37-38 weeks) had a slightly elevated rate of multiple neuropsychiatric disorders compared with the full-term group, whereas the late-term and postterm groups had the lowest rates for most disorders except pervasive developmental disorders. Meaning These findings suggest that neuropsychiatric disorders might be associated with factors related to early development and that interventions focusing on perinatal risk factors and obstetric practices might lower the risk for neuropsychiatric disorders in the population., This cohort study evaluates associations between 6 gestational age groups and rates of 9 major types and 8 subtypes of childhood-onset and adult-onset neuropsychiatric disorders using data from a Danish nationwide registry., Importance Nonoptimal gestational durations could be associated with neurodevelopmental disabilities, yet evidence regarding finer classification of gestational age and rates of multiple major neuropsychiatric disorders beyond childhood is limited. Objective To comprehensively evaluate associations between 6 gestational age groups and rates of 9 major types and 8 subtypes of childhood and adult-onset neuropsychiatric disorders. Design, Setting, and Participants This cohort study evaluated data from a nationwide register of singleton births in Denmark from January 1, 1978, to December 31, 2016. Data analyses were conducted from October 1, 2019, through November 15, 2020. Exposures Gestational age subgroups were classified according to data from the Danish Medical Birth Register: very preterm (20-31 completed weeks), moderately preterm (32-33 completed weeks), late preterm (34-36 completed weeks), early term (37-38 completed weeks), term (39-40 completed weeks, reference), and late or postterm (41-45 completed weeks). Main Outcomes and Measures Neuropsychiatric diagnostic records (International Statistical Classification of Diseases and Related Health Problems, Tenth Revision codes F00-F99) were ascertained from the Danish Psychiatric Central Register up to August 10, 2017. Poisson regression was used to estimate the incidence rate ratio (IRR) and 95% CI for neuropsychiatric disorders, adjusting for selected sociodemographic factors. Results Of all 2 327 639 singleton births studied (1 194 925 male newborns [51.3%]), 22 647 (1.0%) were born very preterm, 19 801 (0.9%) were born moderately preterm, 99 488 (4.3%) were born late preterm, 388 416 (16.7%) were born early term, 1 198 605 (51.5%) were born at term, and 598 682 (25.7%) were born late or postterm. A gradient of decreasing IRRs was found from very preterm to late preterm for having any or each of the 9 neuropsychiatric disorders (eg, very preterm: IRR, 1.49 [95% CI, 1.43-1.55]; moderately preterm: IRR, 1.23 [95% CI, 1.18-1.28]; late preterm: IRR, 1.17 [95% CI, 1.14-1.19] for any disorders) compared with term births. Individuals born early term had 7% higher rates (IRR, 1.07 [95% CI, 1.06-1.08]) for any neuropsychiatric diagnosis and a 31% higher rate for intellectual disability (IRR, 1.31 [95% CI, 1.25-1.37]) compared with those born at term. The late or postterm group had lower IRRs for most disorders, except pervasive developmental disorders, for which the rate was higher for postterm births compared with term births (IRR, 1.06 [95% CI, 1.03-1.09]). Conclusions and Relevance Higher incidences of all major neuropsychiatric disorders were observed across the spectrum of preterm births. Early term and late or postterm births might not share a homogeneous low risk with individuals born at term. These findings suggest that interventions that address perinatal factors associated with nonoptimal gestation might reduce long-term neuropsychiatric risks in the population.

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 Questionnaire (SDQ) responses were collected during the 11-year follow-up. We estimated risk ratios for behavioral problems including total difficulties as well as 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 (r = 0.49) behaviors. 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.

OBJECTIVE: Thyroid hormones are crucial developmental factors, and thyroid disease in pregnant women is a concern. Overweight and obesity are also important health concerns, and we hypothesized that in utero exposure to maternal thyroid disease could programme the foetus to development of adiposity.DESIGN: Cohort and case-cohort studies.PARTICIPANTS: Pregnant women from the Danish National Birth Cohort and their 7-year-old children.MEASUREMENTS: Maternal thyroid disease (hyperthyroidism and hypothyroidism) was assessed from registrations of diagnoses and treatment (n = 71 706) or from the measurement of thyroid-stimulating hormone (TSH) in a stored blood sample from the early pregnancy (n = 7624). Maternal prepregnancy body mass index (BMI) and child BMI at 7 years of age were used to define overweight and obesity, and associations were evaluated using regression models adjusting for potential confounders.RESULTS: No association was found between maternal thyroid disease in pregnancy and child overweight (hyperthyroidism: adjusted risk ratio (aRR): 1.02 (95% confidence interval (CI): 0.58-1.82); hypothyroidism: 1.31 (0.86-1.97)) or obesity (hyperthyroidism: 0.96 (0.53-1.75); hypothyroidism: 1.25 (0.76-2.05)). On the other hand, pregnant women with hypothyroidism in early pregnancy had a higher risk of being overweight (aRR: 1.20 (95% CI: 1.03; 1.41)) and obese (1.45 (1.07; 1.96)), whereas women with hyperthyroidism had a lower risk of being overweight (0.79 (0.64; 0.98)).CONCLUSIONS: Results provide no evidence that maternal thyroid disease in pregnancy programmes adiposity in the child, but corroborate an association between maternal thyroid disease and adiposity in the mother.

DAL’s contribution to this paper is supported by the European Research Council under the European Union’s Seventh Framework Programme (FP7/2007–2013/ERC grant agreement no 669545) and a UK National Institute of Health Senior Investigator (NF-0616-10102). TC’s contribution is supported by European Union’s Horizon 2020 research and innovation programme under grant agreement No 733206 (LifeCycle). MLV has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 707404. The opinions expressed in this document refect only the author’s view. The European Commission is not responsible for any use that may be made of the information it contains. The INfancia y Medio Ambiente (INMA)-Sabadell cohort was funded by grants from Instituto de Salud Carlos III (Red INMA G03/176; CB06/02/0041; CP18/00018; PI041436; PI081151; PI1100610 incl. FEDER funds). ISGlobal acknowledge support from the Spanish Ministry of Science and Innovation through the “Centro de Excelencia Severo Ochoa 2019–2023” Program (CEX2018-000806-S). SA is funded by a Juan de la Cierva—Incorporación Postdoctoral Contract awarded by Ministry of Economy, Industry and Competitiveness (IJCI-2017-34068). JJ holds Miguel Servet-II contract (CPII19/00015) awarded by the Instituto de Salud Carlos III (Co-funded by European Social Fund “Investing in your future”). MC holds a Miquel ServetI cotract (CP16/00128) awarded by the Instituto de Salud Carlos III (co-funded by European Social Fund "Investing in your future"). The INMA-Asturias cohort is funded by grants from Instituto de Salud Carlos III (FISS PI 04/2018, FISS PI09/02311, FISS PI13/02429, FISS PI18/00909 including FEDER funds) and University of Oviedo. This study was funded by Instituto de Salud Carlos III through the projects ‘CP14/00108 & PI16/00261’ (co-funded by European Regional Development Fund ‘A way to make Europe’) (…), Alemany, S., Avella-García, C., Liew, Z., García-Esteban, R., Inoue, K., Cadman, T., López-Vicente, M., González, L., Riaño Galán, I., Andiarena, A., Casas, M., Margetaki, K., Strandberg-Larsen, K., Lawlor, D.A., El Marroun, H., Tiemeier, H., Iñiguez, C., Tardón, A., Santa-Marina, L., Júlvez, J., Porta, D., Chatzi, L., Sunyer, J.

Acetaminophen (or paracetamol) is one of the most commonly used medications during pregnancy. We reviewed recent epidemiological evidence regarding intrauterine exposure to acetaminophen and risk for asthma, neurodevelopment disorders, and reproductive health in childhood.An increasing number of cohort studies have suggested that maternal use of acetaminophen during pregnancy was associated with increased risk for asthma; neurodevelopmental disorders, especially ADHD and behavioral problems; and genital malformations in the offspring. Oxidative stress and inflammation or endocrine effects are plausible shared biological mechanisms for the exposure to influence multiple developmental outcomes. We discussed methodological challenges that can threaten the validity of these observational data, including confounding and measurement errors. Novel statistical methods and research designs that can be used to mitigate these issues were introduced. Given the high prevalence of use, findings regarding intrauterine exposure to acetaminophen on multiple child health outcomes raise concerns. Research on causal and non-causal mechanisms that might explain these associations should be a priority.

The purpose of this review is to summarize the application of untargeted metabolomics to identify the perturbation of metabolites or metabolic pathways associated with air pollutant exposures.Twenty-three studies were included in this review, in adults, children, or pregnant women. The most commonly measured air pollutant is particulate matter smaller than 2.5 μm. Size-fractioned particles, particle chemical species, gas pollutants, or organic compounds were also investigated. The reviewed studies used a wide range of air pollution measurement techniques and metabolomics analyses. Identified metabolites were primarily related to oxidative stress and inflammatory responses, and a few were related to the alterations of steroid metabolic pathways. The observed metabolic perturbations can differ by disease status, sex, and age. Air pollution-related metabolic changes were also associated with health outcomes in some studies. Our review shows that air pollutant exposures are associated with metabolic pathways primarily related to oxidative stress, inflammation, as assessed through untargeted metabolomics in 23 studies. More metabolomic studies with larger sample sizes are needed to identify air pollution components most responsible for adverse health effects, elaborate on mechanisms for subpopulation susceptibility, and link air pollution exposure to specific adverse health effects.

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 To evaluate the associations between maternal diabetes diagnosed before or during pregnancy and early onset cardiovascular disease (CVD) in offspring during their first four decades of life. Design Population based cohort study. Setting Danish national health registries. Participants All 2 432 000 liveborn children without congenital heart disease in Denmark during 1977-2016. Follow-up began at birth and continued until first time diagnosis of CVD, death, emigration, or 31 December 2016, whichever came first. Exposures for observational studies Pregestational diabetes, including type 1 diabetes (n=22 055) and type 2 diabetes (n=6537), and gestational diabetes (n=26 272). Main outcome measures The primary outcome was early onset CVD (excluding congenital heart diseases) defined by hospital diagnosis. Associations between maternal diabetes and risks of early onset CVD in offspring were studied. Cox regression was used to assess whether a maternal history of CVD or maternal diabetic complications affected these associations. Adjustments were made for calendar year, sex, singleton status, maternal factors (parity, age, smoking, education, cohabitation, residence at childbirth, history of CVD before childbirth), and paternal history of CVD before childbirth. The cumulative incidence was averaged across all individuals, and factors were adjusted while treating deaths from causes other than CVD as competing events. Results During up to 40 years of follow-up, 1153 offspring of mothers with diabetes and 91 311 offspring of mothers who did not have diabetes were diagnosed with CVD. Offspring of mothers with diabetes had a 29% increased overall rate of early onset CVD (hazard ratio 1.29 (95% confidence interval 1.21 to 1.37); cumulative incidence among offspring unexposed to maternal diabetes at 40 years of age 13.07% (12.92% to 13.21%), difference in cumulative incidence between exposed and unexposed offspring 4.72% (2.37% to 7.06%)). The sibship design yielded results similar to those of the unpaired design based on the whole cohort. Both pregestational diabetes (1.34 (1.25 to 1.43)) and gestational diabetes (1.19 (1.07 to 1.32)) were associated with increased rates of CVD in offspring. We also observed varied increased rates of specific early onset CVDs, particularly heart failure (1.45 (0.89 to 2.35)), hypertensive disease (1.78 (1.50 to 2.11)), deep vein thrombosis (1.82 (1.38 to 2.41)), and pulmonary embolism (1.91 (1.31 to 2.80)). Increased rates of CVD were seen in different age groups from childhood to early adulthood until age 40 years. The increased rates were more pronounced among offspring of mothers with diabetic complications (1.60 (1.25 to 2.05)). A higher incidence of early onset CVD in offspring of mothers with diabetes and comorbid CVD (1.73 (1.36 to 2.20)) was associated with the added influence of comorbid CVD but not due to the interaction between diabetes and CVD on the multiplicative scale (P value for interaction 0.94). Conclusions Children of mothers with diabetes, especially those mothers with a history of CVD or diabetic complications, have increased rates of early onset CVD from childhood to early adulthood. If maternal diabetes does have a causal association with increased CVD rate in offspring, the prevention, screening, and treatment of diabetes in women of childbearing age could help to reduce the risk of CVD in the next generation.

Key Points Question Is grandparental age at the time of birth of the parent associated with the risk for autism spectrum disorders (ASDs) in the grandchildren? Findings This Danish national population-based cohort study across 3 generations observed transgenerational associations suggesting that ASD risk in children was elevated if their mothers were born to young (≤19 years) grandparents or if their fathers were born to young (≤19 years) and older (≥40 years) grandparents, compared with children whose parents were born to grandparents aged 25 to 29 years. These associations observed for grandparental hage were independent of possible parental age associations with ASD risk in children. Meaning These findings suggest that the risk of ASD associated with young or advanced grandparental age might be transmitted across generations, which should be considered in future research of the causes of ASD., This cohort study estimates the associations between grandparental age at the time their children were born and the risk of autism spectrum disorders in their grandchildren., Importance Advanced parental age has been associated with autism spectrum disorders (ASDs) in children. However, little is known about the association between grandparental age at the time of birth of the parent and the risk of ASD in the grandchildren. Objective To estimate the associations between parental and grandparental age and ASD risk in children. Design, Setting, and Participants This population-based, multigenerational cohort study used data from Danish national health registries. A parental age cohort was constructed to evaluate the association between parental age and ASD in 1 476 783 singleton children born from 1990 to 2013, and a multigenerational cohort was also constructed including 362 438 fathers and 458 234 mothers born from 1973 to 1990 for whom information on grandparental age was available. Data analyses were conducted from November 1, 2018, through February 7, 2020. Exposures Parental age at childbirth and grandparental age at the time of the birth of the parent. Main Outcomes and Measures Diagnoses of ASD in children were obtained from the Danish Psychiatric Central Register (1994-2017). Logistic regression analysis was used to estimate the associations between parental or grandparental age and ASD in children. Results Of the 1 476 783 children born from 1990 to 2013, 758 066 (51.3%) were male, and 27 616 (1.9%) had ASD (20 467 [74.1%] were male). Advanced paternal or maternal age over 30 years was monotonically associated with increased ASD risk, with odds ratios (ORs) of 1.56 (95% CI, 1.45-1.68) for maternal age 40 years and older and 1.57 (95% CI, 1.39-1.78) for paternal age 50 years and older, compared with parents aged 25 to 29 years. In the multigenerational cohort, 9364 grandchildren (1.7%) had ASD. This study found U-shaped associations, in that ASD risk was higher among grandchildren of younger (≤19 years) maternal grandmothers (OR, 1.68; 95% CI, 1.52-1.85), younger maternal grandfathers (OR, 1.50; 95% CI, 1.26-1.78), and younger paternal grandmothers (OR, 1.18; 95% CI, 1.04-1.34), and older (≥40 years) paternal grandmothers (OR, 1.40; 95% CI, 1.03-1.90) compared with the grandchildren of grandparents who were aged 25 to 29 years at the time of giving birth to the parents. Conclusions and Relevance These findings corroborate previous studies suggesting that advanced parental age is independently associated with increased ASD risk in children. This study also found that children with young maternal grandparents and children with young and old paternal grandparents had elevated ASD risk. Possible transmission of ASD risk across generations should be considered in etiological research on ASD.

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.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.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.

This study explored the association between exposure to acetaminophen during pregnancy and pubertal development using data from 15,822 boys and girls in the longitudinal Puberty Cohort, nested within the Danish National Birth Cohort. Use of acetaminophen was reported 3 times during pregnancy and 6 months postpartum. In total, 54% of mothers indicated use at least once during pregnancy. Between 2012 and 2017, sons and daughters provided information on a wide range of pubertal milestones - including Tanner stages, axillary hair growth, and age at menarche or voice break and first ejaculation - every 6 months from 11 years of age until full sexual maturation. Data were analyzed using a regression model for interval-censored data, providing adjusted mean monthly differences in age at attaining the pubertal milestones according to intrauterine cumulative (weeks) and trimester-specific acetaminophen exposure. Our results suggested a tendency towards slightly earlier attainment of almost all studied markers of female pubertal development with increasing number of weeks of exposure (i.e., about 1.5-3 months earlier age at pubic hair, axillary hair, and acne development comparing unexposed with those prenatally exposed for more than 12 weeks). Male pubertal development had no strong association with acetaminophen exposure.

Children whose mothers experienced childhood abuse are more likely to suffer various neurodevelopmental deficits. Whether an association exists specifically for attention deficit hyperactivity disorder (ADHD) is unknown. We examined the association of maternal experience of childhood abuse with ADHD in offspring, assessed by maternal report of diagnosis and validated with the ADHD Rating Scale-IV in a subsample, in the Nurses’ Health Study II (n = 49,497 mothers; n = 7,607 case offspring; n = 102,151 control offspring). We examined whether 10 adverse perinatal circumstances (e.g., prematurity, smoking) or socioeconomic factors accounted for a possible association. Exposure to abuse was associated with greater prevalence of ADHD in offspring (8.7% of offspring of women exposed to severe abuse vs. 5.5% of offspring of women not abused, P = 0.0001) and with greater risk for ADHD when the model was adjusted for demographic factors (male offspring, risk ratio (RR) = 1.6, 95% confidence interval (CI): 1.3, 1.9; female offspring, RR = 2.3, 95% CI: 1.7, 3.0). After adjustment for perinatal factors, the association of maternal childhood abuse with ADHD in offspring was slightly attenuated (male offspring, RR = 1.5, 95% CI: 1.2, 1.8; female offspring, RR = 2.1, 95% CI: 1.6, 2.8). We identified an association between maternal experience of childhood abuse and risk for ADHD in offspring, which was not explained by several important perinatal risk factors or socioeconomic status.

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.

Background The prevalence of cardiovascular disease (CVD) has been increasing in children, adolescents, and young adults in recent decades. Exposure to adverse intrauterine environment in fetal life may contribute to the elevated risk of early-onset CVD. Many studies have shown that maternal hypertensive disorders of pregnancy (HDP) are associated with increased risks of congenital heart disease, high blood pressure, increased BMI, and systemic vascular dysfunction in offspring. However, empirical evidence on the association between prenatal exposure to maternal HDP and early-onset CVD in childhood and adolescence remains limited. Methods and findings We conducted a population-based cohort study using Danish national health registers, including 2,491,340 individuals born in Denmark from 1977 to 2018. Follow-up started at birth and ended at the first diagnosis of CVD, emigration, death, or 31 December 2018, whichever came first. Exposure of maternal HDP was categorized as preeclampsia or eclampsia (n = 68,387), gestational hypertension (n = 18,603), and pregestational hypertension (n = 15,062). Outcome was the diagnosis of early-onset CVD from birth to young adulthood (up to 40 years old). We performed Cox proportional hazards regression to evaluate the associations and whether the association differed by maternal history of CVD or diabetes before childbirth. We further assessed the association by timing of onset and severity of preeclampsia. The median follow-up time was 18.37 years, and 51.3% of the participants were males. A total of 4,532 offspring in the exposed group (2.47 per 1,000 person-years) and 94,457 in the unexposed group (2.03 per 1,000 person-years) were diagnosed with CVD. We found that exposure to maternal HDP was associated with an increased risk of early-onset CVD (hazard ratio [HR]: 1.23; 95% CI = 1.19 to 1.26; P < 0.001). The HRs for preeclampsia or eclampsia, gestational hypertension, and pregestational hypertension were 1.22 (95% CI, 1.18 to 1.26; P < 0.001), 1.25 (95% CI, 1.17 to 1.34; P < 0.001), and 1.28 (95% CI, 1.15 to 1.42; P < 0.001), respectively. We also observed increased risks for type-specific CVDs, in particular for hypertensive disease (HR, 2.11; 95% CI, 1.96 to 2.27; P < 0.001) and myocardial infarction (HR, 1.49; 95% CI, 1.12 to 1.98; P = 0.007). Strong associations were found among offspring of mothers with CVD history (HR, 1.67; 95% CI, 1.41 to 1.98; P < 0.001) or comorbid diabetes (HR, 1.56; 95% CI, 1.34 to 1.83; P < 0.001). When considering timing of onset and severity of preeclampsia on offspring CVD, the strongest association was observed for early-onset and severe preeclampsia (HR, 1.48, 95% CI, 1.30 to 1.67; P < 0.001). Study limitations include the lack of information on certain potential confounders (including smoking, physical activity, and alcohol consumption) and limited generalizability in other countries with varying disparities in healthcare. Conclusions Offspring born to mothers with HDP, especially mothers with CVD or diabetes history, were at increased risks of overall and certain type-specific early-onset CVDs in their first decades of life. Further research is warranted to better understand the mechanisms underlying the relationship between maternal HDP and early-onset CVD in offspring., Chen Huang and co-workers study associations between maternal hypertensive disorders and cardiovascular disease in offspring., Author summary Why was this study done? The prevalence of cardiovascular disease (CVD) has been increasing in children, adolescents, and young adults in recent decades in developed countries. Maternal hypertensive disorders of pregnancy (HDP) is associated with an increased risk of congenital heart disease and a number of risk factors of CVD in offspring. Little is known about whether and to what extent prenatal exposure to HDP affects the development of early-onset CVD in offspring from birth to adolescence and beyond. What did the researchers do and find? We conducted a population-based cohort study that included all 2,491,340 live births in Denmark from 1977 to 2018 and followed them from birth to early adulthood (up to 40 years). We found that individuals born to mothers with HDP had a 23% increased risk of early-onset CVD in offspring, especially of those mothers with a history of CVD (67% increased risk) or diabetes (56% increased risk). What do these findings mean? Offspring born to mothers with HDP, especially mothers with CVD or diabetes, are at an increased risk of early-onset CVD from birth to early adulthood. These findings suggest that better management of maternal HDP, particularly in early phase of pregnancy, may improve cardiovascular health of children and adolescents and beyond, in terms of reducing the risk of early-onset CVD. Further research is warranted to better understand the mechanisms underlying the relationship between maternal HDP and early-onset CVD in offspring in early decades of life.

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. This research was primarily supported by a grant from the European Community’s Seventh Framework Program (FP7/2007–2013) under grant agreement Developmental Neurotoxicity Assessment of Mixtures in Children (DENAMIC) no. 282957. M.-A.V. is the recipient of a Research Scholars J1 Award from the Fonds de recherche du Québec–Santé. Norwegian Human Milk Study (HUMIS) research was funded by a grant from the Norwegian Research Council, under the NEVRINOR program grant agreement no. 226402; by PROTECTion against Endocrine Disruptors: Detection, mixtures, health effects, risk assessment and communication, and by European Union (EU) Horizon 2020 Marie Skłodowska-Curie Actions Innovative Training Networks–European Training Network no. 722634. We thank Anteneh Desalegn for his work in the HUMIS biobank. The study was approved by the Regional Ethics Committee for Medical Research in Norway (ref. S-02122) and the Norwegian Data Inspectorate (refs. 2002/1398), and participation did not occur until after informed consent was obtained. The Infancia y Medio Ambiente (INMA) study was funded by grants from the EU: NEWGENERIS FP6-2003-Food-3-A-016320, FP7-ENV-2011 cod 282957, HEALTH.2010.2.4.5-1; and by grants from Spain: Instituto de Salud Carlos III (Red INMA G03/176 and CB06/02/0041, FIS-FEDER:PI 03/1615, PI04/1509, PI04/1112, PI04/1436, PI04/1931, PI/04/2018, PI05/1079, PI05/1052, PI06/0867, PI06/1213, PI07/0314, PI/08/1151, PI09/02647, FIS-PI041436, FIS-PI081151, FISS-PI042018, FISS-PI09/02311, FISPI06/0867 FIS-PS09/00090, FIS-PI07/0252, PS09/00090, PI11/01007, PI11/02591, PI11/02038, PI13/1944, PI13/2032, PI14/00891, PI14/01687, PI16/1288, PI17/00663 and Miguel Servet-FEDER: CP11/00178, MS13/00054, and MSII16/00051), Generalitat de Catalunya-CIRIT 1999SGR 00241, La Fundació La Marató de TV3 (090430), Alicia Koplowitz Foundation 2017, Conselleria de Sanitat Generalitat Valenciana, Department of Health of the Basque Government (2005111093 and 2009111069), Provincial Government of Gipuzkoa (DFG06/004 and DFG08/001), Obra Social Cajastur, Universidad de Oviedo, Consejería de Salud de la Junta de Andalucía (grant no. 183/07), EU Commission (QLK4-1999-01422, QLK4-2002-00603, and CONTAMED FP7-ENV-212502), and Fundación Roger Torné. Global Health Institute Barcelona (ISGlobal) is a member of the CERCA Programme, Generalitat de Catalunya. A full roster of the INMA Project Investigators can be found at http://www.proyectoinma.org/presentacion-inma/listadoinvestigadores/en_listado-investigadores.html. The INUENDO study was funded by the European Commission’s Seventh and Fifth Framework Programmes (FP7-ENV-2008-1-226217 and QLK4-CT-2001-00202). The polychorinated biphenyl (PCB) cohort was funded by the U.S. National Institutes of Health (grants R01 CA096525 and R03 TW007152), the EU Seventh Framework Programme FP7/2007-2023 (grant agreement OBELIX, no. 227391), Slovak Research and Development Agency (grants APVT-21-016804, APVV-0571-12, APVV-0444-11), and by the ITMS project (no. 26240120033) based on the supporting operational research and development program from the European Regional Development Fund. This research was primarily supported by a grant from the European Community’s Seventh Framework Program (FP7/2007–2013) under grant agreement Developmental Neurotoxicity Assessment of Mixtures in Children (DENAMIC) no. 282957. M.-A.V. is the recipient of a Research Scholars J1 Award from the Fonds de recherche du Québec–Santé. Norwegian Human Milk Study (HUMIS) research was funded by a grant from the Norwegian Research Council, under the NEVRINOR program grant agreement no. 226402; by PROTECTion against Endocrine Disruptors: Detection, mixtures, health effects, risk assessment and communication, and by European Union (EU) Horizon 2020 Marie Skłodowska-Curie Actions Innovative Training Networks–European Training Network no. 722634. We thank Anteneh Desalegn for his work in the HUMIS biobank. The study was approved by the Regional Ethics Committee for Medical Research in Norway (ref. S-02122) and the Norwegian Data Inspectorate (refs. 2002/1398), and participation did not occur until after informed consent was obtained. The Infancia y Medio Ambiente (INMA) study was funded by grants from the EU: NEWGENERIS FP6-2003-Food-3-A-016320, FP7-ENV-2011 cod 282957, HEALTH.2010.2.4.5-1; and by grants from Spain: Instituto de Salud Carlos III (Red INMA G03/176 and CB06/02/0041, FIS-FEDER:PI 03/1615, PI04/1509, PI04/1112, PI04/1436, PI04/1931, PI/04/2018, PI05/1079, PI05/1052, PI06/0867, PI06/1213, PI07/0314, PI/08/1151, PI09/02647, FIS-PI041436, FIS-PI081151, FISS-PI042018, FISS-PI09/02311, FISPI06/0867 FIS-PS09/00090, FIS-PI07/0252, PS09/00090, PI11/01007, PI11/02591, PI11/02038, PI13/1944, PI13/2032, PI14/00891, PI14/01687, PI16/1288, PI17/00663 and Miguel Servet-FEDER: CP11/00178, MS13/00054, and MSII16/00051), Generalitat de Catalunya-CIRIT 1999SGR 00241, La Fundació La Marató de TV3 (090430), Alicia Koplowitz Foundation 2017, Conselleria de Sanitat Generalitat Valenciana, Department of Health of the Basque Government (2005111093 and 2009111069), Provincial Government of Gipuzkoa (DFG06/004 and DFG08/001), Obra Social Cajastur, Universidad de Oviedo, Consejería de Salud de la Junta de Andalucía (grant no. 183/07), EU Commission (QLK4-1999-01422, QLK4-2002-00603, and CONTAMED FP7-ENV-212502), and Fundación Roger Torné. Global Health Institute Barcelona (ISGlobal) is a member of the CERCA Programme, Generalitat de Catalunya. A full roster of the INMA Project Investigators can be found at http://www.proyectoinma.org/presentacion-inma/listadoinvestigadores/en_listado-investigadores.html. The INUENDO study was funded by the European Commission’s Seventh and Fifth Framework Programmes (FP7-ENV-2008-1-226217 and QLK4-CT-2001-00202). The polychorinated biphenyl (PCB) cohort was funded by the U.S. National Institutes of Health (grants R01 CA096525 and R03 TW007152), the EU Seventh Framework Programme FP7/2007-2023 (grant agreement OBELIX, no. 227391), Slovak Research and Development Agency (grants APVT-21-016804, APVV-0571-12, APVV-0444-11), and by the ITMS project (no. 26240120033) based on the supporting operational research and development program from the European Regional Development Fund.

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.

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.

Background: Maternal exposure to traffic-related air pollution during pregnancy has been shown to increase the risk of adverse birth outcomes and neurodevelopmental disorders. By utilizing high-resolution metabolomics (HRM), we investigated perturbations of the maternal serum metabolome in response to traffic-related air pollution to identify biological mechanisms. Methods: We retrieved stored mid-pregnancy serum samples from 160 mothers who lived in the Central Valley of California known for high air particulate levels. We estimated prenatal traffic-related air pollution exposure (carbon monoxide, nitric oxides, and particulate matter

OBJECTIVE: Acetaminophen (paracetamol), a medication commonly used in pregnancy, has hormonal effects, as has been suggested in experimental studies. Developmental exposure to endocrine disruptors could predispose individuals to weight gain. This study evaluated the associations between prenatal acetaminophen exposure and overweight in childhood.METHODS: A total of 30,127 (age 7) and 24,934 (age 11) children in the Danish National Birth Cohort born during 1996 to 2002 were studied. Mothers reported acetaminophen use in telephone interviews conducted during pregnancy, and children's BMI and waist circumference were reported by parents at 7 and 11 years. Differences for BMI z score and waist circumference were estimated, as well as risk ratios for overweight in girls and boys adjusting for indications of use and other confounders.RESULTS: There were no consistent associations found for prenatal acetaminophen exposure and BMI z score or waist circumference in girls and boys at both ages. Prenatal acetaminophen exposure was associated with overweight in girls at age 11 (risk ratio 1.31, 95% CI: 1.10-1.56, if exposed in all three trimesters; P CONCLUSIONS: There was no strong association between prenatal acetaminophen exposure and childhood BMI, but the findings on frequent prenatal exposure to acetaminophen and overweight in girls warrant further investigation.

Studies of environmental exposures and childhood cancers that rely on records often only use maternal address at birth or address at cancer diagnosis to assess exposures in early childhood, possibly leading to exposure misclassification and questionable validity due to residential mobility during early childhood. Our objective was to assess patterns and identify factors that may predict residential mobility in early childhood, and examine the impact of mobility on early childhood exposure assessment for agriculturally applied pesticides and childhood cancers in California. We obtained the addresses at diagnosis of all childhood cancer cases born in 1998-2011 and diagnosed at 0-5 years of age (n = 6478) from the California Cancer Registry (CCR), and their birth addresses from linked birth certificates. Controls were randomly selected from California birth records and frequency matched (20:1) to all cases by year of birth. We obtained residential histories from a public-record database LexisNexis for both case (n = 3877 with age at diagnosis 1-5 years) and control (n = 99,262) families. Logistic regression analyses were conducted to assess the socio-demographic factors in relation to residential mobility in early childhood. We employed a Geographic Information System (GIS)-based system to estimate children's first year of life exposures to agriculturally applied pesticides based on birth vs diagnosis address or residential histories based upon Lexis-Nexis Public Records and assessed agreement between exposure measures using Spearman correlations and kappa statistics. Over 20% of case and control children moved in their first year of life, and 55% of children with cancer moved between birth and diagnosis. Older age at diagnosis, younger maternal age, lower maternal education, not having a Hispanic ethnic background, use of public health insurance, and non-metropolitan residence at birth were predictors of higher residential mobility. There was moderate to strong correlation (Spearman correlation = 0.76-0.83) and good agreement (kappa = 0.75-0.81) between the first year of life exposure estimates for agricultural pesticides applied within 2 km of a residence relying on an address at birth or at diagnosis or LexisNexis addresses; this did not differ by outcome status, but agreement decreased with decreasing buffer size, and increasing distance moved or age at diagnosis. These findings suggest that residential addresses collected at one point in time may represent residential history in early childhood to a reasonable extent; nevertheless, they exposure misclassification in the first year of life remains an issue. Also, the highest proportion of women not captured by LexisNexis were Hispanic women born in Mexico and those living in the lowest SES neighborhoods, i.e. possibly those with the higher environmental exposures, as well as younger women and those with less than high school education. Though LexisNexis only captures a sub-population, its data may be useful for augmenting address information and assessing the extent of exposure misclassification when estimating environmental exposures in large record linkage studies. Future research should investigate how to correct for exposure misclassification introduced by residential mobility that is not being captured by records.

Background Socioeconomic disparities in infant mortality have persisted for decades in high-income countries and may have become stronger in some populations. Therefore, new understandings of the mechanisms that underlie socioeconomic differences in infant deaths are essential for creating and implementing health initiatives to reduce these deaths. We aimed to explore whether and the extent to which preterm birth (PTB) and small for gestational age (SGA) at birth mediate the association between maternal education and infant mortality. Methods and findings We developed a population-based cohort study to include all 1,994,618 live singletons born in Denmark in 1981–2015. Infants were followed from birth until death, emigration, or the day before the first birthday, whichever came first. Maternal education at childbirth was categorized as low, medium, or high. An inverse probability weighting of marginal structural models was used to estimate the controlled direct effect (CDE) of maternal education on offspring infant mortality, further split into neonatal (0–27 days) and postneonatal (28–364 days) deaths, and portion eliminated (PE) by eliminating mediation by PTB and SGA. The proportion eliminated by eliminating mediation by PTB and SGA was reported if the mortality rate ratios (MRRs) of CDE and PE were in the same direction. The MRRs between maternal education and infant mortality were 1.63 (95% CI 1.48–1.80, P < 0.001) and 1.19 (95% CI 1.08–1.31, P < 0.001) for low and medium versus high education, respectively. The estimated proportions of these total associations eliminated by reducing PTB and SGA together were 55% (MRRPE = 1.27, 95% CI 1.15–1.40, P < 0.001) for low and 60% (MRRPE = 1.11, 95% CI 1.01–1.22, P = 0.037) for medium versus high education. The proportions eliminated by eliminating PTB and SGA separately were, respectively, 46% and 11% for low education (versus high education) and 48% and 13% for medium education (versus high education). PTB and SGA together contributed more to the association of maternal educational disparities with neonatal mortality (proportion eliminated: 75%–81%) than with postneonatal mortality (proportion eliminated: 21%–23%). Limitations of the study include the untestable assumption of no unmeasured confounders for the causal mediation analysis, and the limited generalizability of the findings to other countries with varying disparities in access and quality of perinatal healthcare. Conclusions PTB and SGA may play substantial roles in the relationship between low maternal education and infant mortality, especially for neonatal mortality. The mediating role of PTB appeared to be much stronger than that of SGA. Public health strategies aimed at reducing neonatal mortality in high-income countries may need to address socially related prenatal risk factors of PTB and impaired fetal growth. The substantial association of maternal education with postneonatal mortality not accounted for by PTB or SGA could reflect unaddressed educational disparities in infant care or other factors., Bo Fu and colleagues analyse factors that may mediate associations between maternal education and child health., Author summary Why was this study done? Infant mortality in high-income countries has decreased in recent decades. However, socioeconomic inequality in infant mortality remains and may have become stronger in some populations. This study provides in-depth knowledge on the underlying pathways from maternal socioeconomic inequality to infant mortality, which is important for developing preventive strategies to reduce potentially preventable deaths. What did the researchers do and find? We conducted a national population-based cohort study that included all 1.99 million live singletons born in Denmark in 1981–2015. Using modern modeling methods for causal mediation analysis, we found that preterm birth and restricted fetal growth may mediate the association between low maternal education and infant mortality. The mediated effects through preterm birth and restricted fetal growth were substantial for neonatal mortality but not for postneonatal mortality. The effect through preterm birth seemed to be greater than that through restricted fetal growth. What do these findings mean? Public health strategies could aim to reduce educational differences in the death of newborns in high-income countries by addressing socially related risk factors for preterm birth and impaired fetal growth, such as the accessibility and quality of maternity and perinatal care, or maternal lifestyle factors. The substantial direct impact of low maternal education on postneonatal death not explained by preterm birth or restricted fetal growth could be due to unaddressed educational inequality in infant care or other factors such as housing conditions, the quality of medical care, or the use of specialized medical care.

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. SUMMARY: 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.

Perfluoroalkyl substances (PFASs) were put on the market more than 50 years ago. They were not believed to enter biological systems or to be biologically active and it came as a big surprise when they were found in wildlife. Later, they were found in humans and are now ubiquitously present in many populations. It is of concern but we still do not know how serious the potential health problems are.

Context: Abnormal maternal thyroid function in pregnancy may impair fetal brain development, but more evidence is needed to refine and corroborate the hypothesis.Objective: To estimate the association between maternal thyroid function in early pregnancy and neuropsychological performance of the child at 5 years of age.Design: Follow-up study.Participants: A cohort of 1153 women and their children sampled from the Danish National Birth Cohort. Maternal thyroid-stimulating hormone (TSH) and free thyroxine (fT4) were measured in stored biobank sera from early pregnancy.Main outcomes measures: Child neuropsychological test results (Wechsler Intelligence Scale/Test of Everyday Attention), test of motor function (Movement Assessment Battery), and results of parent and teacher reports (Behavior Rating Inventory of Executive Function/Strengths and Difficulties Questionnaire).Results: Altogether 145 children (12.6%) were born to mothers with abnormal thyroid function in the early pregnancy. High maternal TSH and low fT4 were associated with lower child verbal intelligence quotient (adjusted mean difference TSH ≥ 10 mIU/L vs 0.1 to 2.49 mIU/L, -8.9 [95% confidence interval (CI), -15 to -2.4]; fT4 < 10 pmol/l vs 12.0 to 18.99 pmol/l, -13 [95% CI, -19 to -7.3]). Abnormal maternal thyroid function was also associated with adverse motor function and teacher-reported problems of executive function and behavior, and these associations were dominated by exposure to maternal hypothyroxinemia.Conclusions: Maternal thyroid hormone abnormalities were associated with adverse neuropsychological function of the child at 5 years of age. For intelligence, marked hypothyroidism was important, whereas for motor function and executive and behavior problems, maternal hypothyroxinemia was predominant.

Acetaminophen (paracetamol) is the most commonly used pain and fever medication during pregnancy. Previously, a positive ecological correlation between acetaminophen use and autism spectrum disorders (ASD) has been reported but evidence from larger studies based on prospective data is lacking. We followed 64,322 children and mothers enrolled in the Danish National Birth Cohort (DNBC; 1996–2002) for average 12.7 years to investigate whether acetaminophen use in pregnancy is associated with increased risk of ASD in the offspring. Information on acetaminophen use was collected prospectively from three computer-assisted telephone interviews. We used records from the Danish hospital and psychiatric registries to identify diagnoses of ASD. At the end of follow up, 1,027 (1.6%) children were diagnosed with ASD, 345 (0.5%) with infantile autism. We found that 31% of ASD (26% of infantile autism) have also been diagnosed with hyperkinetic disorders. More than 50% women reported ever using acetaminophen in pregnancy. We used Cox proportional hazards model to estimate hazard ratio (HR) and 95% confident interval (CI). Prenatal use of acetaminophen was associated with an increased risk of ASD accompanied by hyperkinetic symptoms (HR = 1.51 95% CI 1.19–1.92), but not with other ASD cases (HR = 1.06 95% CI 0.92–1.24). Longer duration of use (i.e., use for >20 weeks in gestation) increased the risk of ASD or infantile autism with hyperkinetic symptoms almost twofold. Maternal use of acetaminophen in pregnancy was associated with ASD with hyperkinetic symptoms only, suggesting acetaminophen exposure early in fetal life may specifically impact this hyperactive behavioral phenotype. Autism Res 2016, 9: 951–958. © 2015 International Society for Autism Research, Wiley Periodicals, Inc.

Purpose Some studies have suggested that maternal acetaminophen use during pregnancy is associated with asthma in the offspring, and coffee consumption may modify the toxicity of acetaminophen. We aim to examine whether pregnancy maternal acetaminophen use increases the risk for offspring asthma, and whether such a potential association could be modified by maternal coffee consumption. Methods We included 63 652 live-born singletons enrolled in the Danish National Birth Cohort. Maternal acetaminophen use and coffee consumption during pregnancy were assessed prospectively via the enrolment questionnaire and three computer-assisted telephone interviews. Asthma cases were identified by using the Danish National Patient Register and the Danish National Prescription Registry. We estimated the hazard ratios (HRs) for asthma according to prenatal acetaminophen and coffee exposure using Cox proportional hazards regression model. Results After adjusting for potential confounders, acetaminophen use during pregnancy was associated with an increased risk of offspring asthma (HR = 1.16, 95% confidence interval (CI): 1.11–1.22). Coffee drinking during pregnancy was associated with a slightly decreased risk (HR = 0.94, 95%CI: 0.90–0.99). But there was no strong evidence of effect measure modification of acetaminophen use on offspring asthma by coffee consumption. Conclusions Acetaminophen use during pregnancy was associated with a modest increased risk for offspring asthma, which was not modified by coffee consumption. Copyright © 2015 John Wiley & Sons, Ltd.