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Purpose The aim of this study was to examine whether use of regular aspirin and/or other non-steroidal anti-inflammatory drugs (NSAIDs) is associated with the development of age-related macular degeneration (AMD). Methods In the California Teachers Study cohort (N = 88,481) we identified diagnoses of AMD up to December 31, 2012 by linkage to statewide hospital discharge records. Aspirin, ibuprofen, other NSAIDs, and acetaminophen use and comprehensive risk factor information were collected via self-administered questionnaires at baseline in 1995–1996 and a follow-up questionnaire in 2005–2006. We employed Cox proportional hazard regression to model AMD risk. Results We did not find any associations between AMD and frequency and duration of aspirin or ibuprofen use reported at baseline. In the subsample with more specific information on medication use, we observed a 20% decrease in risk of AMD among low-dose aspirin users (HR 0.81, 95% CI 0.70–0.95) and a 55% decrease among cyclooxygenase-2 (COX-2) inhibitor users (HR 0.45, 95% CI 0.26–0.78) during 6.3 years of average follow-up. Conclusion The decrease in risk of intermediate- or late-stage AMD among women who reported regular use of low-dose aspirin or specific COX-2 inhibitors suggests a possible protective role for medications with COX-2 inhibitory properties or aspirin at doses used for cardiovascular disease prevention.

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.

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.

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.

Background: The relationship between adherence to traditional Chinese postpartum practices (known as “doing-the-month”) and postpartum depression (PPD) remains unknown. Practices including restrictions on diet, housework and social activity, personal hygiene, and cold contact, could introduce biological, psychological, and socio-environmental changes during postpartum.Methods: The cross-sectional study included 955 postpartum women in obstetric clinics in Hunan Province of China between September 2018 to June 2019. Thirty postpartum practices were collected by a self-report online structured questionnaire. Postpartum depression symptoms were assessed by the Chinese version of the Edinburgh Postnatal Depression Scale (EPDS). Multivariable linear regression was used to estimate the differences in EPDS scores according to adherence to postpartum practices. Firth's bias-reduced logistic regression was employed to analyze the binary classification of having PPD symptoms (EPDS ≥ 10).Results: Overall, both moderate and low adherence to postpartum practices appeared to be associated with higher EPDS scores (adjusted difference 1.07, 95% CI 0.20, 1.94 for overall moderate adherence; and adjusted difference 1.72, 95% CI 0.84, 2.60 for overall low adherence). In analyses by practice domain, low adherence to housework-related and social activity restrictions was associated with having PPD symptoms compared with high adherence (OR 1.61, 95% CI 1.07, 2.43).Conclusions: Low adherence to traditional Chinese postpartum practices was associated with higher EPDS scores indicating PPD symptoms, especially in the domain of housework-related and social activity restrictions. Psychosocial stress and unsatisfactory practical support related to low adherence to postpartum practices might contribute to PPD. Longitudinal study and clinical assessment would be needed to confirm these findings.

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.

Background: Fetal exposure risk factors are associated with increased ASD risk. New hypotheses regarding transgenerational risk for ASD have been proposed, but epidemiological evidence is still lac...

Sustained and inadequately controlled hypertension can promote the development of age-related macular degeneration (AMD) through multiple biologic pathways. Epidemiologic studies of high blood pressure, antihypertensive therapies, and the risk of AMD thus far have been inconclusive. However, few studies evaluated risks according to the use of different classes of antihypertensive drugs or took combinations of use into account. We performed a prospective cohort study by linking the California Teachers Study (CTS) cohort (N = 88 481) to statewide hospital discharge records up to December 31, 2012. History of high blood pressure, regular use of antihypertensive medications, and comprehensive risk factor information was collected via self-administered questionnaires at baseline in 1995-1996, and information on specific classes of antihypertensive drugs was provided by a subsample of CTS participants who completed a follow-up questionnaire in 2000. We identified 1762 female teachers with AMD during 14.8 years of follow-up on average. Applying Cox proportional hazard regression, we estimated increased risks of AMD among women treated for hypertension at baseline (HR = 1.15, 95% CI: 1.03, 1.30); the magnitude of the association increased with longer duration of antihypertensive treatment. In the subsample with more specific information on type of medication use, we estimated a 45% increased risk of AMD among women receiving diuretics as monotherapy compared to women with medications more potent than diuretics (HR = 1.45, 95% CI 1.10, 1.90). In women treated with a combination of antihypertensive drugs, we observed no increased risk of AMD for any individual class of drugs.

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.

Cancer patients are at lower risk of developing Parkinson’s disease (PD) compared with the general population. One explanation is the negative association between smoking and PD, but PD risk is also lower for cancers not related to smoking. Another explanation is survival bias where death from cancer may act as a competing risk. We conducted a large population-based case-control study in Denmark and investigated whether cancer diagnosis reduced the risk of developing PD even after adjusting for important risk factors including smoking, physical activity, and lifetime oestrogen status. Using probabilistic bias analysis we quantified the influence of survival bias. We estimated negative point estimates (ORs) between cancers and PD for all cancers except skin, female breast, and ill-defined and unspecified 0.85 (95% CI 0.59–1.21); smoking-related cancers 0.75 (95% CI 0.45–1.23); and cancers not related to smoking 0.82 (95% CI 0.49–1.38) that are very similar to those previously reported for a much larger Danish register only based study, even though our confidence intervals include the null. These effect estimates shifted towards the null after accounting for survival bias but most bias-adjusted ORs remained below 1 within the range of priors considered in simulations. Overall, cancer patients have a lower risk of developing PD even after controlling for cancer-related lifestyles factors and correcting for survival bias.

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

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.

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 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.

Objective: To study the influence of occupational pesticide use on Parkinson's disease (PD) in a population with information on various occupational, residential, and household sources of pesticide exposure. Methods: In a population-based case control study in Central California, we used structured interviews to collect occupational history details including pesticide use in jobs, duration of use, product names, and personal protective equipment use from 360 PD cases and 827 controls. We linked reported products to California's pesticide product label database and identified pesticide active ingredients and occupational use by chemical class including fungicides, insecticides, and herbicides. Employing unconditional logistic regression, we estimated odds ratios and 95% confidence intervals for PD and occupational pesticide use. Results: Ever occupational use of carbamates increased risk of PD by 455%, while organophosphorus (OP) and organochlorine (OC) pesticide use doubled risk. PD risk increased 110–211% with ever occupational use of fungicides, herbicides, and insecticides. Using any pesticide occupationally for >10years doubled the risk of PD compared with no occupational pesticide use. Surprisingly, we estimated higher risks among those reporting use of personal protective equipment (PPE). Conclusions: Our findings provide additional evidence that occupational pesticide exposures increase PD risk. This was the case even after controlling for other sources of pesticide exposure. Specifically, risk increased with occupational use of carbamates, OPs, and OCs, as well as of fungicides, herbicides, or insecticides. Interestingly, some types of PPE use may not provide adequate protection during pesticide applications. Keywords: Occupational pesticide use, Parkinson's disease, Case control study

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: 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.

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.

Recent epidemiological studies suggest that prenatal exposure to acetaminophen (APAP) is associated with increased risk of Autism Spectrum Disorder (ASD), a neurodevelopmental disorder affecting 1 in 59 children in the US. Maternal and prenatal exposure to pesticides from food and environmental sources have also been implicated to affect fetal neurodevelopment. However, the underlying mechanisms for ASD are so far unknown, likely with complex and multifactorial etiology. The aim of this study was to explore the potential effects of APAP and pesticide exposure on development with regards to the etiology of ASD by highlighting common genes and biological pathways. Genes associated with APAP, pesticides, and ASD through human research were retrieved from molecular and biomedical literature databases. The interaction network of overlapping genetic associations was subjected to network topology analysis and functional annotation of the resulting clusters. These genes were over-represented in pathways and biological processes (FDR p < 0.05) related to apoptosis, metabolism of reactive oxygen species (ROS), and carbohydrate metabolism. Since these three biological processes are frequently implicated in ASD, our findings support the hypothesis that cell death processes and specific metabolic pathways, both of which appear to be targeted by APAP and pesticide exposure, may be involved in the etiology of ASD. This novel exposures-gene-disease database mining might inspire future work on understanding the biological underpinnings of various ASD risk factors.

Sleep disorders, oftentimes co-occurring with other mental and neurological disorders in the elderly, have been previously linked to short-term exposures to air pollution. Here we assessed such associations among 395,651 elderly Chinese in Ningbo, China where air pollution exposures are high and the proportion of elderly in the population is growing. We utilized a regional health information database in China (2008–2017) that collected information on hospital visits for sleep disorders among the elderly (age 60+). Measures of daily air pollution concentrations including nitrogen dioxide (NO2), sulfur dioxide (SO2), ozone (O3), inhalable particles (PM10), and ambient fine particulate matter (PM2.5) were generated from seven environmental air quality monitoring sites in the study area. We used a generalized additive model to evaluate the associations between hospital visits for sleep disorders and short-term air pollution exposures for up to 7 days prior to a hospital visit. Short-term exposure to multiple air pollutants was associated with hospital visits for sleep disorders in an elderly population; with the strongest associations during 2–3 days prior to a clinic visits for traffic-related pollutants including air quality index (AQI), PM2.5, PM10, and NO2 and for SO2 and O3 for 5 days prior to the visits. Our study based on large health care record system suggested that short-term air pollution exposures are associated with sleep disorders in the elderly. Considering the individual covariates that could not be adjusted in time-series analyses, future studies with individual level data and an ability to evaluate the severity of sleep disorders and their relation to mental and physical health in general and air pollution are needed. An aging population with increasing health problems and the frequency of high and very high air pollution events in China make our findings very health policy relevant.

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.

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.

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

Background: It has been debated whether mild analgesics, mainly paracetamol, adversely affect aspects of neurodevelopment. We examined whether mother's use of paracetamol, aspirin or ibuprofen in pregnancy is associated with increased risk of cerebral palsy (CP) in the child.Method: We included 185 617 mother-child pairs from the Danish National Birth Cohort and the Norwegian Mother and Child Cohort Study. We created harmonized definitions of analgesic use in pregnancy, as well as indications for analgesic use and other potential confounders. Children with CP were identified in nationwide registers. We estimated the average causal effect of analgesics on risk of CP using marginal structural models with stabilized inverse probability weights.Results: Paracetamol use was reported in 49% of all pregnancies, aspirin in 3% and ibuprofen in 4%. Prenatal exposure to paracetamol ever in pregnancy was associated with increased risk of overall CP [adjusted odds ratio (aOR) 1.3, 95% confidence interval (CI): 1.0-1.7] and unilateral spastic CP (aOR 1.5, 95% CI: 1.0-2.2). The association appeared to be driven by an increased risk of unilateral spastic CP in children exposed in second trimester (aOR 1.6, 95% CI: 1.0-2.5). Children ever prenatally exposed to aspirin in pregnancy had an elevated risk of bilateral spastic CP (aOR 2.4, 95% CI: 1.1-5.3) compared with unexposed.Conclusion: We observed an increased risk of spastic CP in children prenatally exposed to paracetamol and aspirin. Although we controlled for several important indications for analgesic use, we cannot exclude the possibility of confounding by underlying diseases.

Maternal obesity has been associated with increased risk of offspring behavioral problems. We examined whether this association could be explained by familial factors by comparing associations for maternal body mass index (BMI) with associations for paternal BMI. We studied 38,314 children born to mothers enrolled in the Danish National Birth Cohort during 1996-2002. Data on maternal BMI was collected at 15 weeks of gestation, and paternal BMI was assessed when the child was 18 months old. When the child was 7 years old, the Strengths and Difficulties Questionnaire was completed by the parents. We estimated odds ratios for behavioral problems in offspring born to overweight/obese parents, and we found that maternal BMI was associated with offspring behavioral problems. Maternal BMI of 25.0-29.9 was associated with a 33% (odds ratio = 1.33, 95% confidence interval: 1.13, 1.57) higher risk of total difficulties in offspring, and maternal BMI of ≥30.0 was associated with an 83% (odds ratio = 1.83, 95% confidence interval: 1.49, 2.25) higher risk. Paternal obesity was also associated with higher risk of offspring behavioral problems, but stronger associations were observed with maternal prepregnancy obesity. Our results suggest that part of the association between maternal BMI and behavioral problems can be accounted for by genetic and social factors, but environmental risk factors may also contribute to the etiology of behavioral problems.

AIM: Although birth asphyxia is a major risk factor for neonatal and childhood morbidity and mortality, it has not been investigated much in relation to attention deficit hyperactivity disorder (ADHD). We examined whether birth asphyxia measured by the pH of the blood in the umbilical artery cord was associated with childhood ADHD.METHOD: A population-based cohort of 295 687 children born in Finland between 1991 and 2002 was followed until December 31, 2007. ADHD was identified by the International Classification of Diseases, 10th edition, as a diagnosis of hyperkinetic disorder. We examined the risk of ADHD with varying pH values using Cox regression, taking time trends into consideration.RESULTS: When compared to the reference group, a pH value below 7.10 was significantly associated with an increased risk of ADHD. The strongest risks were observed among children with a pH value CONCLUSION: Birth asphyxia, defined by low pH value, may predict an increased risk of ADHD in childhood. The association between the pH value and ADHD was homogenous when stratified by gestational age and the Apgar score.

© 2017 Informa UK Limited, trading as Taylor & Francis Group. Objective: To evaluate whether early folic acid or multivitamin supplementation during pregnancy prevents diagnosis of hyperkinetic disorders (HKD), treatment for attention deficit hyperactivity disorder (ADHD), and ADHD-like behaviors reported by parents participating in the DNBC for children at age 7. Methods: HKD diagnosis and ADHD medication use data were obtained from the Danish National Hospital, Central Psychiatric and Pharmaceutical registers. We estimated hazard ratios (HRs) for HKD diagnosis and ADHD medication use and risk ratios (RRs) for parent-reported ADHD behavior collected with the Strength and Difficulties Questionnaire (SDQ), comparing children whose mothers took folic acid or multivitamin supplements early in pregnancy defined as starting periconceptionally (4 weeks prior to their last menstrual period (LMP)) through 8 weeks after their LMP (4–8 weeks), to children whose mothers indicated no supplement use for the same entire period. Results: We identified 384 children (1.1%) with a hospital diagnosis for HKD and 642 children (1.8%) treated with ADHD medication. We found no association between risk of HKD diagnosis or intake of ADHD medication and early maternal folic acid use. However, early multivitamin use was associated with an approximately 30% reduction in risk for HKD diagnosis (aHR: 0.70, 95% CI: 0.52–0.96) and 21% reduction in treatment with ADHD medication (aHR: 0.79, 95% CI: 0.62–0.98). We observed a reduced risk in parent-reported ADHD behaviors, but these results were attenuated after adjustment. Conclusion: Our data suggest that multivitamin use in early pregnancy may reduce risk for HKD diagnosis and treatment for ADHD in the offspring.

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

BACKGROUND: Prenatal maternal smoking has been associated with attention-deficit/hyperactivity disorder (ADHD) in children, but the causal nature of this association is still under scrutiny. We examined the association with maternal smoking and nicotine replacement use during pregnancy, using association with paternal smoking as a marker of potential genetic or social confounding. METHODS: We included 84 803 singletons who participated in the Danish National Birth Cohort. Information on parental smoking was reported by the mothers during pregnancy. Children with ADHD were identified from the Danish Psychiatric Central Register, the Danish National Patient Register, and the Register of Medicinal Product Statistics by the International Classification of Diseases, 10th Revision diagnosis or medication. We also used hyperactivity/inattention score of the parent-reported Strengths and Difficulties Questionnaire, included in the 7-year follow-up of the National Birth Cohort. RESULTS: Maternal and paternal smoking during pregnancy were associated with an elevated risk of ADHD defined by hospital diagnosis, medication, and hyperactivity/inattention score, but the association was stronger for maternal smoking than for paternal smoking. Compared with children born to nonsmoking mothers and smoking fathers, children born of smoking mothers and nonsmoking fathers had a higher risk of ADHD (adjusted hazard ratio = 1.26; 95% confidence interval, 1.03 to 1.53). We also saw a higher risk of ADHD in children of mothers who used nicotine replacement during pregnancy. CONCLUSIONS: Our findings indicate that the association between prenatal maternal smoking and ADHD may overestimate a causal link, but nicotine exposure or related factors may still play a causal role.

Introduction: A number of studies indicate that acetaminophen taken during pregnancy may have a programming effect on the fetal brain development. The potential adverse consequences may only surface to clinical detection years later. Should we act on these findings now or do we wait for additional evidence?Areas covered: We argue for action inspired by these well analyzed studies that are based on five prospective cohorts data collected from different countries. Several analytical options have been employed especially to address confounding, and all analyses have consistently suggested that confounding alone is an unlikely explanation for this disturbing observation.Expert opinion: Acetaminophen is often used for minor symptom or discomfort where the treatment has no strong indication and carries little, if any risk for the pregnant women. The harm of doing nothing may well exceed the harm for taking precautionary actions considering the consequences at stake.