Search

Findings from studies of prenatal exposure to pesticides and adverse birth outcomes have been equivocal so far. We examined prenatal exposure to agricultural pesticides in relation to preterm birth and term low birthweight, respectively, in children born between 1998 and 2010, randomly selected from California birth records. We estimated residential exposure to agriculturally applied pesticides within 2 km of residential addresses at birth by pregnancy trimester for 17 individual pesticides and three chemical classes (organophosphates, pyrethroids, and carbamates). Among maternal addresses located within 2 km of any agricultural pesticide application, we identified 24,693 preterm and 220,297 term births, and 4412 term low birthweight and 194,732 term normal birthweight infants. First or second trimester exposure to individual pesticides (e.g., glyphosates, paraquat, imidacloprid) or exposure to 2 or more pesticides in the three chemical classes were associated with a small increase (3–7%) in risk for preterm birth; associations were stronger for female offspring. We did not find associations between term low birthweight and exposure to pesticides other than myclobutanil (OR: 1.11; 95% CI: 1.04–1.20) and possibly the pyrethroids class. Our improved exposure assessment revealed that first and second trimester exposure to pesticides is associated with preterm delivery but is rarely linked with term low birthweight. [ABSTRACT FROM AUTHOR]

Chemicals used or emitted by unconventional oil and gas development (UOGD) include reproductive/developmental toxicants. Associations between UOGD and certain birth defects were reported in a few studies, with none conducted in Ohio, which experienced a thirty-fold increase in natural gas production between 2010 and 2020. We conducted a registry-based cohort study of 965,236 live births in Ohio from 2010 to 2017. Birth defects were identified in 4653 individuals using state birth records and a state surveillance system. We assigned UOGD exposure based on maternal residential proximity at birth to active UOG wells and a metric specific to the drinking-water exposure pathway that identified UOG wells hydrologically connected to a residence ("upgradient UOG wells"). We estimated odds ratios (ORs) and 95% confidence intervals (CIs) for all structural birth defects combined and specific birth defect types using binary exposure metrics (presence/absence of any UOG well and presence/absence of an upgradient UOG well within 10 km), adjusting for confounders. Additionally, we conducted analyses stratified by urbanicity, infant sex, and social vulnerability. The odds of any structural defect were 1.13 times higher in children born to mothers living within 10 km of UOGD than those born to unexposed mothers (95%CI: 0.98–1.30). Odds were elevated for neural tube defects (OR: 1.57, 95%CI: 1.12–2.19), limb reduction defects (OR: 1.99, 95%CI: 1.18–3.35), and spina bifida (OR 1.93; 95%CI 1.25–2.98). Hypospadias (males only) was inversely related to UOGD exposure (OR: 0.62, 95%CI: 0.43–0.91). Odds of any structural defect were greater in magnitude but less precise in analyses using the hydrological-specific metric (OR: 1.30; 95%CI: 0.85–1.90), in areas with high social vulnerability (OR: 1.27, 95%CI: 0.99–1.60), and among female offspring (OR: 1.28, 95%CI: 1.06–1.53). Our results suggest a positive association between UOGD and certain birth defects, and findings for neural tube defects corroborate results from prior studies. [Display omitted] • Higher odds of neural tube defects in infants born near oil and gas development. • Higher odds of limb reduction defects in infants born near oil and gas development. • Higher odds of spina bifida in infants born near oil and gas development. • Lower odds of hypospadias in infants born near oil and gas development. • Greater risk in areas with high neighborhood social vulnerability. [ABSTRACT FROM AUTHOR]

Paracetamol is suggested to have endocrine disrupting properties possibly affecting fetal programming of reproductive health that might lead to impaired semen quality and changes in reproductive hormones. In this longitudinal study, we included 1058 young adult men born 1998–2000 into the Danish National Birth Cohort with follow-up at 18–21 years of age. The exposure, maternal intake of paracetamol, was modelled in three ways: dichotomized, trimester-specific, and as duration of exposure categorized into: short (1–2 weeks), medium (3–9 weeks) or long duration (>9 weeks) vs. no intake. Outcomes included semen characteristics, self-measured testis volume, and reproductive hormone levels. We used negative binominal regression to estimate the percentage difference and 95% confidence interval (CI) for each outcome. In total, 547 (48%) sons were prenatally exposed to paracetamol due to maternal intake at least once. Maternal intake of paracetamol during pregnancy was not associated with any of the biomarkers in the dichotomized or trimester-specific exposure models. For duration of exposure, sons of mothers with long duration of maternal intake of paracetamol showed tendencies towards lower semen concentration (-14% [95% CI: -31%; 8%]), a higher proportion of nonprogressive and immotile spermatozoa (8% [95% CI: -4%; 21%]) and higher DNA Fragmentation Index (16% [95% CI: -1%; 36%]) compared to son of mothers with no intake. Maternal intake of paracetamol during pregnancy was not clearly associated with biomarkers of male fecundity in adult sons. However, it cannot be ruled out that long duration of maternal intake of paracetamol might be associated with impaired semen characteristics. • Paracetamol in utero might affect reproductive health through endocrine disruption. • This large cohort study found no clear effect on biomarkers of fecundity in sons. • It cannot be excluded that prolonged intake might impair semen quality. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Outdoor air pollution has been linked to poor sleep health, but limited studies have investigated the relationship between solid cooking fuels and sleep health in adults. Therefore, we analyzed data from the China Health and Retirement Survey (CHARLS), a national survey of about 17,000 residents aged over 45. Participants were restricted to those who participated in CHARLS 2011, 2013 and 2015 (n = 8,668). Sleep health was indicated by self-reported average sleep hours at night and the numbers of unrested days/week in CHARLS 2015. We analyzed cooking fuel types reported and assessed the duration of solid fuels usage as consistent (indicated use in all three surveys or 6 + years) or inconsistent use (indicated use in one or two surveys or 1–4 years). We found consistent use of solid fuels was associated with a shorter sleep duration (OR = 1.17 95% CI 1.01, 1.35 for ≤ 6 h vs. 7–9 h/day) and higher frequencies of feeling unrested (OR = 1.32 95% CI 1.12, 1.55 for ≥ 5 days/week vs. none) compared with cleaner fuels use. The associations for inconsistent solid fuels use and sleep health were in the similar direction but smaller in magnitude. Further research is needed to confirm our findings and evaluate the exposure impact of specific fuel types to inform intervention strategies. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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

Per- and polyfluoroalkyl substances (PFAS) are synthetic chemicals that induce oxidative inflammatory responses and disrupt the endocrine and central nervous systems, all of which can influence sleep. To investigate the association between PFAS exposure and sleep health measures in U.S. adults. We analyzed serum concentration data of four PFAS [perfluorooctane sulfonic acid (PFOS), perfluorooctanoic acid (PFOA), perfluorohexane sulfonic acid (PFHxS), and perfluorononanoic acid (PFNA)] reported for 8913 adults in NHANES 2005–2014. Sleep outcomes, including trouble sleeping, having a diagnosis of sleep disorder, and recent daily sleep duration classified as insufficient or excessive sleep (<6 or >9 h/day) were examined. Weighted logistic regression was used to estimate the association between the sleep outcomes and each PFAS modeled continuously (log2) or in exposure tertiles. We applied quantile g-computation to estimate the effect of the four PFAS as a mixture on the sleep outcomes. We conducted a quantitative bias analysis to assess the potential influence of self-selection and uncontrolled confounding. We observed some inverse associations between serum PFAS and trouble sleeping or sleep disorder, which were more consistent for PFOS (e.g., per log2-PFOS (ng/ml) and trouble sleeping OR = 0.93, 95%CI: 0.89, 0.98; sleep disorder OR = 0.89, 95%CI: 0.83, 0.95). Per quartile increase of the PFAS mixture was inversely associated with trouble sleeping and sleep disorder. No consistent associations were found for sleep duration across analyses. Our bias analysis suggests that the finding on sleep disorder could be explained by a moderate level of self-selection and negative confounding effects. We found no evidence to suggest exposure to four legacy PFAS worsened self-reported sleep health among U.S. adults. While some inverse associations between specific PFAS and sleep disorder were observed, self-selection and uncontrolled confounding biases may play a role in these findings. • Evidence does not suggest PFAS influence worsened sleep health in adults. • Some inverse associations of PFOS or PFAS mixture and sleep disorder was observed. • Self-selection and uncontrolled confounding biases may contribute to the finding. [ABSTRACT FROM AUTHOR]

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. • We identified factors that may predict residential mobility in early childhood. • Address at birth, address at diagnosis, and LexisNexis records were compared. • Over 20% of case and control children moved in their first year of life. • Pesticide exposure estimates based on different addresses were moderately correlated. • Public records may be used to augment address information in record linkage studies. [ABSTRACT FROM AUTHOR]

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. We evaluated the associations of paternal or maternal PFAS levels with placental function and fetal growth measures. 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. 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. 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. [Display omitted] • We compared paternal and maternal PFAS effect on placental function and fetal growth measures. • Maternal PFAS were associated with increased cord serum E2 or T and placental P450arom. • The associations between paternal PFAS and the fetal outcomes studied were null. • The results of maternal PFAS are unlikely due to confounders shared within the family. [ABSTRACT FROM AUTHOR]

Meta-analysis is a powerful analytic method for summarizing effect estimates across studies. However, conventional meta-analysis often assumes a linear exposure-outcome relationship and does not account for variability over the exposure ranges. In this work, we first used simulation techniques to illustrate that the linear-based meta-analytical approach may result in oversimplistic effect estimation based on three plausible non-linear exposure-outcome curves (S-shape, inverted U-shape, and M-shape). We showed that subgroup meta-analysis that stratifies on exposure levels can investigate non-linearity and identify the consistency of effect magnitudes in these simulated examples. Next, we examined the heterogeneity of effect estimates across exposure ranges in two published linear-based meta-analyses of prenatal exposure to per- and polyfluoroalkyl substances (PFAS) on changes in mean birth weight or risk of preterm birth. The re-analysis found some varying effect sizes and potential heterogeneity when restricting to different PFAS exposure ranges, but findings were sensitive to the cut-off choices used to rank the exposure levels. Finally, we discussed methodological challenges and recommendations for detecting and interpreting potential non-linear associations in meta-analysis. Using meta-analysis without accounting for exposure range could contribute to literature inconsistency for exposure-induced health effects and impede evidence-based policymaking. Therefore, investigating result heterogeneity by exposure range is recommended., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objectives: Quantitative bias analysis (QBA) methods evaluate the impact of biases arising from systematic errors on observational study results. This systematic review aimed to summarize the range and characteristics of QBA methods for summary-level data published in the peer-reviewed literature., Study Design and Setting: We searched MEDLINE, Embase, Scopus, and Web of Science for English-language articles describing QBA methods. For each QBA method, we recorded key characteristics, including applicable study designs, bias(es) addressed; bias parameters, and publicly available software. The study protocol was preregistered on the Open Science Framework (https://osf.io/ue6vm/)., Results: Our search identified 10,249 records, of which 53 were articles describing 57 QBA methods for summary-level data. Of the 57 QBA methods, 53 (93%) were explicitly designed for observational studies, and 4 (7%) for meta-analyses. There were 29 (51%) QBA methods that addressed unmeasured confounding, 19 (33%) misclassification bias, 6 (11%) selection bias, and 3 (5%) multiple biases. Thirty-eight (67%) QBA methods were designed to generate bias-adjusted effect estimates and 18 (32%) were designed to describe how bias could explain away observed findings. Twenty-two (39%) articles provided code or online tools to implement the QBA methods., Conclusion: In this systematic review, we identified a total of 57 QBA methods for summary-level epidemiologic data published in the peer-reviewed literature. Future investigators can use this systematic review to identify different QBA methods for summary-level epidemiologic data., Plain Language Summary: Quantitative bias analysis (QBA) methods can be used to evaluate the impact of biases on observational study results. However, little is known about the full range and characteristics of available methods in the peer-reviewed literature that can be used to conduct QBA using information reported in manuscripts and other publicly available sources without requiring the raw data from a study. In this systematic review, we identified 57 QBA methods for summary-level data from observational studies. Overall, there were 29 methods that addressed unmeasured confounding, 19 that addressed misclassification bias, six that addressed selection bias, and three that addressed multiple biases. This systematic review may help future investigators identify different QBA methods for summary-level data., Competing Interests: Declaration of competing interest In the past 36 months, T.L.L. served as a member of the Amgen Methods Advisory Council, for which he received consulting fees and travel support. J.S.R. reported receiving grants from the US Food and Drug Administration; Johnson and Johnson; Medical Device Innovation Consortium; Agency for Healthcare Research and Quality; National Heart, Lung, and Blood Institute; and Arnold Ventures outside the submitted work and is also is an expert witness at the request of relator attorneys, the Greene Law Firm, in a qui tam suit alleging violations of the False Claims Act and Anti-Kickback Statute against Biogen Inc. that was settled in September 2022. M.M.J reported receiving grants from the US Food and Drug Administration; Agency for Healthcare Research and Quality; National Heart, Lung, and Blood Institute; National Center for Advancing Translational Sciences; National Institute on Drug Abuse; and American Cancer Society. J.D.W. is supported by Arnold Ventures, Johnson & Johnson through the Yale Open Data Access project, and the National Institute on Alcohol Abuse and Alcoholism of the National Institutes of Health under award 1K01AA028258 and previously served as a consultant to Hagens Berman Sobol Shapiro LLP and Dugan Law Firm APLC., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Younger siblings (SIBS) of children with autism exhibit a wide range of clinical and subclinical symptoms including social, cognitive, language, and adaptive functioning delays. Identifying factors linked with this phenotypic heterogeneity is essential for improving understanding of the underlying biology of the heterogenous outcomes and for early identification of the most vulnerable SIBS. Prevalence of neurodevelopmental (NDD) and neuropsychiatric disorders (NPD) is significantly elevated in families of children with autism. It remains unknown, however, if the family history associates with the developmental outcomes among the SIBS. We quantified history of the NDDs and NPDs commonly reported in families of children with autism using a parent interview and assessed autism symptoms, verbal, nonverbal, and adaptive skills in a sample of 229 SIBS. Multiple regression analyses were used to examine links between family history and phenotypic outcomes, whereas controlling for birth year, age, sex, demographics, and parental education. Results suggest that family history of schizophrenia, depression, anxiety, bipolar disorder, and intellectual disability associate robustly with dimensional measures of social affect, verbal and nonverbal IQ, and adaptive functioning in the SIBS. Considering family history of these disorders may improve efforts to predict long-term outcomes in younger siblings of children with autism and inform about familial factors contributing to high phenotypic heterogenetity in this cohort., (© 2024 The Author(s). Autism Research published by International Society for Autism Research and Wiley Periodicals LLC.)

While associations between maternal infections during pregnancy and childhood leukemia in offspring have been extensively studied, the evidence for other types of childhood cancers is limited. Additionally, antibiotic exposure during pregnancy could potentially increase the risk of childhood cancers. Our study investigates associations between maternal infections and antibiotic prescriptions during pregnancy and the risk of childhood cancer in Taiwan. We conducted a population-based cohort study using the Taiwan Maternal and Child Health Database (TMCHD), linked with national health and cancer registries. The study included 2 267 186 mother-child pairs, and the median follow-up time was 7.96 years. Cox proportional hazard models were utilized to estimate effects. Maternal infections during pregnancy were associated with a moderate increase in the risk of childhood hepatoblastoma (adjusted hazard ratio [HR] = 1.34; 95% confidence interval [CI]: 0.90-1.98) and a weaker increase in the risk of childhood acute lymphoblastic leukemia (ALL) (adjusted HR = 1.15; 95% CI: 0.99-1.35). Antibiotic prescriptions during pregnancy were also associated with an elevated risk of childhood ALL (adjusted HR = 1.30; 95% CI: 1.04-1.63), particularly with tetracyclines (adjusted HR = 2.15; 95% CI: 1.34-3.45). Several specific antibiotics were also associated with an increased risk of hepatoblastoma and medulloblastoma. Children exposed in utero to antibiotic prescription or both infections and antibiotics during pregnancy were at higher risk of developing ALL. Our findings suggest that there are associations between maternal infections, antibiotic use during pregnancy and the risk of several childhood cancers in addition to ALL and highlight the importance of further research in this area., (© 2023 UICC.)

Context: Hyperthyroidism in pregnancy is a clinical concern, and surveillance of any change in the occurrence of hyperthyroidism in pregnancy is important, especially when a mandatory iodine fortification (IF) program is implemented such as in Denmark in the year 2000., Objective: To investigate any change in the occurrence of hyperthyroidism and the use of antithyroid drugs (ATDs) in Danish pregnant women during a 20-year period before and after the implementation of IF., Methods: A nationwide register-based cohort (1997-2016) and 2 birth cohorts with biochemical data (the Danish National Birth Cohort, 1997-2003, and the North Denmark Region Pregnancy Cohort, 2011-2015) were used to study maternal use of ATDs in pregnancy and frequency of early pregnancy biochemical hyperthyroidism during a 20-year period prior to and after the implementation of mandatory IF., Results: In the nationwide cohort, the adjusted odds ratio (aOR) for treatment with ATDs was 1.51 (95% CI, 1.30-1.74) after mandatory IF (2001-2004) compared with baseline (1997-1999). The increase was more pronounced in the previously moderately iodine-deficient West Denmark (aOR 1.67; 95% CI, 1.36-2.04) than the mildly deficient East Denmark (aOR 1.30; 95% CI, 1.06-1.60) and returned to baseline levels at the end of follow-up in both regions. No time-related difference in early pregnancy biochemical hyperthyroidism was observed., Conclusion: The use of ATDs in Danish pregnant women increased following the implementation of IF and then leveled out. Results comply with observations in the general Danish population and suggest that IF influences the occurrence of autoimmune hyperthyroidism in younger individuals., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose of Review: The multigenerational effects of grandparental exposures on their grandchildren's mental health and neurodevelopment are gaining research attention. We conducted a scoping review to summarize the current epidemiological studies investigating pregnancy-related and environmental factors that affected grandparental pregnancies and mental health outcomes in their grandchildren. We also identified methodological challenges that affect these multigenerational health studies and discuss opportunities for future research., Recent Findings: We performed a literature search using PubMed and Embase and included 18 articles for this review. The most investigated grandparental pregnancy-related factors were the grandparental age of pregnancy (N = 6), smoking during pregnancy (N = 4), and medication intake (N = 3). The most frequently examined grandchild outcomes were autism spectrum disorder (N = 6) and attention-deficit/hyperactivity disorder (N = 4). Among these studies, grandparental smoking and the use of diethylstilbestrol were more consistently reported to be associated with neurodevelopmental disorders, while the findings for grandparental age vary across the maternal or paternal line. Grandmaternal weight, adverse delivery outcomes, and other spatial-temporal markers of physical and social environmental stressors require further scrutiny. The current body of literature has suggested that mental and neurodevelopmental disorders may be outcomes of unfavorable exposures originating from the grandparental generation during their pregnancies. To advance the field, we recommend research efforts into setting up multigenerational studies with prospectively collected data that span through at least three generations, incorporating spatial, environmental, and biological markers for exposure assessment, expanding the outcome phenotypes evaluated, and developing a causal analytical framework including mediation analyses specific for multigenerational research., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Importance: Cerebral palsy (CP) is the most prevalent neuromotor disability in childhood, but for most cases the etiology remains unexplained. Seasonal variation in the conception of CP may provide clues for their potential etiological risk factors that vary across seasons., Objective: To evaluate whether the month or season of conception is associated with CP occurrence., Design, Setting, and Participants: This statewide cohort study examined more than 4 million live births that were registered in the California birth records during 2007 to 2015 and were linked to CP diagnostic records (up to year 2021). Statistical analyses were conducted between March 2022 and January 2023., Exposures: The month and season of conception were estimated based on the child's date of birth and the length of gestation recorded in the California birth records., Main Outcomes and Measures: CP status was ascertained from the diagnostic records obtained from the Department of Developmental Services in California. Poisson regression was used to estimate the relative risk (RR) and 95% CI for CP according to the month or the season of conception, adjusting for maternal- and neighborhood-level factors. Stratified analyses were conducted by child's sex and neighborhood social vulnerability measures, and the mediating role of preterm birth was evaluated., Results: Records of 4 468 109 children (51.2% male; maternal age: 28.3% aged 19 to 25 years, 27.5% aged 26 to 30 years; maternal race and ethnicity: 5.6% African American or Black, 13.5% Asian, 49.8% Hispanic or Latinx of any race, and 28.3% non-Hispanic White) and 4697 with CP (55.1% male; maternal age: 28.3% aged 19 to 25 years, 26.0% aged 26 to 30 years; maternal race and ethnicity: 8.3% African American or Black, 8.6% Asian, 54.3% Hispanic or Latinx of any race, and 25.8% non-Hispanic White) were analyzed. Children conceived in winter (January to March) or spring (April to June) were associated with a 9% to 10% increased risk of CP (winter: RR, 1.09 [95% CI, 1.01-1.19]; spring: RR, 1.10 [95% CI, 1.02-1.20]) compared with summer (July to September) conceptions. Analyses for specific months showed similar results with children conceived in January, February, and May being at higher risk of CP. The associations were slightly stronger for mothers who lived in neighborhoods with a high social vulnerability index, but no child sex differences were observed. Only a small portion of the estimated association was mediated through preterm birth., Conclusions and Relevance: In this cohort study in California, children conceived in winter and spring had a small increase in CP risk. These findings suggest that seasonally varying environmental factors should be considered in the etiological research of CP.

Introduction: Most women with rheumatic diseases discontinue antirheumatic therapies in anticipation of, or during pregnancy due to concerns around medication safety and fetal wellbeing., Objective: We performed a scoping review of available evidence investigating the risks of adverse offspring neurodevelopmental outcomes amongst parents with chronic inflammatory arthritis, taking antirheumatic therapies during conception or pregnancy., Methods: We designed a scoping review protocol and search strategy a priori in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. We performed an exhaustive search in Cochrane Library, Embase, Google Scholar, Medline, and Web of Science for relevant literature in January 2023. Articles needed to include offspring neurodevelopmental outcomes born to parents with CIA who took antirheumatic therapies during conception or pregnancy. Independent reviewers extracted data from eligible articles using a standard abstraction tool and performed critical appraisal of study quality., Results: Six studies were included for full data abstraction. Use of Nonsteroidal Anti-inflammatory Drugs, Tumor Necrosis Factor Alpha inhibitors, and exposure to methotrexate during early first trimester of pregnancy did not seem to increase risk for adverse offspring neurodevelopmental outcomes. Corticosteroid use during pregnancy seemed to pose an increased risk for attention deficit hyperactive disorders in offspring., Conclusion: Use of some antirheumatic therapies during pregnancy may not be associated with adverse offspring neurodevelopmental outcomes. Further investigations are needed to elucidate if other confounding factors affect long term offspring health outcomes born to parents with chronic inflammatory arthritis., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

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

Background: Although associations of physical activity and smoking with mortality have been well-established, the joint impact of physical activity and smoking on premature mortality among elderly hypertensive population was still unclear. This study aimed to assess association of physical activity, smoking, and their interaction with all-cause and cardiovascular disease (CVD) mortality risk in elderly hypertensive patients., Methods: We included 125,978 Chinese hypertensive patients aged 60-85 years [mean (SD) age, 70.5 (6.9) years] who had records in electronic health information system of Minhang District of Shanghai, China in 2007-2015. Cox regression was used to estimate individual and joint association of smoking and physical activity on all-cause and CVD mortality. Interactions were measured both additively and multiplicatively. Additive interaction was evaluated by relative excess risk due to interaction (RERI), attributable proportion due to interaction (AP) and synergy index (S)., Results: Among 125,978 elderly hypertensive patients (median age 70.1), 28,250 deaths from all causes and 13,164 deaths from CVD were observed during the follow-up up to 11 years. There was an additive interaction between smoking and physical inactivity [RERI: all-cause 0.19 (95% CI: 0.04-0.34), CVD 0.28 (0.06-0.50); AP: all-cause 0.09 (0.02-0.16), CVD 0.14 (0.04-0.23); S: all-cause 1.21 (1.04-1.42), CVD 1.36 (1.06-1.75)], while the concurrence of both risk factors was associated with more than 2-fold risk of death [hazard ratio (HR): all-cause 2.10 (1.99-2.21), CVD 2.19 (2.02-2.38)]., Conclusion: Our study suggested that smoking and physical inactivity together may have amplified association on premature death compared to the sum of their individual associations, highlighting the importance of improving behavioral factors in combination and promoting a comprehensive healthy lifestyle in hypertensive elderly., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Yang, Xu, Liu, Li, Liew, Liu, Huang, Zhu, Zhang, Chen, Hao, Qin and Yu.)

The potential etiological role of early acetaminophen exposure on Autism Spectrum Conditions (ASC) and Attention-Deficit/Hyperactivity Disorder (ADHD) is inconclusive. We aimed to study this association in a collaborative study of six European population-based birth/child cohorts. A total of 73,881 mother-child pairs were included in the study. Prenatal and postnatal (up to 18 months) acetaminophen exposure was assessed through maternal questionnaires or interviews. ASC and ADHD symptoms were assessed at 4-12 years of age using validated instruments. Children were classified as having borderline/clinical symptoms using recommended cutoffs for each instrument. Hospital diagnoses were also available in one cohort. Analyses were adjusted for child and maternal characteristics along with indications for acetaminophen use. Adjusted cohort-specific effect estimates were combined using random-effects meta-analysis. The proportion of children having borderline/clinical symptoms ranged between 0.9 and 12.9% for ASC and between 1.2 and 12.2% for ADHD. Results indicated that children prenatally exposed to acetaminophen were 19% and 21% more likely to subsequently have borderline or clinical ASC (OR = 1.19, 95% CI 1.07-1.33) and ADHD symptoms (OR = 1.21, 95% CI 1.07-1.36) compared to non-exposed children. Boys and girls showed higher odds for ASC and ADHD symptoms after prenatal exposure, though these associations were slightly stronger among boys. Postnatal exposure to acetaminophen was not associated with ASC or ADHD symptoms. These results replicate previous work and support providing clear information to pregnant women and their partners about potential long-term risks of acetaminophen use., (© 2021. The Author(s).)

Purpose of Review: 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., Recent Findings: 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.

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.

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.

Purpose of Review: Despite a call for better understanding of the role of environmental pollutant influences on mental health and the tremendous public health burden of mental health, this issue receives far less attention than many other effects of pollutants. Here we summarize the body of literature on non-occupational environmental pollutant exposures and adult depression, anxiety, and suicide-in PubMed, Embase, Web of Science, and PsychINFO through the end of year 2018., Recent Findings: One hundred twelve articles met our criteria for further review. Of these, we found 88 articles on depression, 33 on anxiety, and 22 on suicide (31 articles covered multiple outcomes). The earliest article was published in 1976, and the most frequent exposure of interest was air pollution (n = 33), followed by secondhand smoke (n = 20), metals (n = 18), noise (n = 17), and pesticides (n = 10). Other exposures studied less frequently included radiation, magnetic fields, persistent organic pollutants (POPs), volatile organic compounds, solvents, and reactive sulfur compounds. The current literature, although limited, clearly suggests many kinds of environmental exposures may be risk factors for depression, anxiety, and suicide. For several pollutants, important limitations exist with many of the studies. Gaps in the body of research include a need for more longitudinal, life-course studies, studies that can measure cumulative exposures as well as shorter-term exposures, studies that reduce the possibility of reverse causation, and mechanistic studies focused on neurotoxic exposures.

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

Background: 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., Competing Interests: The authors have declared that no competing interests exist.

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., (© 2019 S. Karger AG, Basel.)

Background: Previous autism spectrum disorder (ASD) and air pollution studies focused on pregnancy exposures, but another vulnerable period is immediate postnatally. Here, we examined early life exposures to air pollution from the pre- to the postnatal period and ASD/ASD subtypes in the Danish population., Methods: With Danish registers, we conducted a nationwide case-control study of 15,387 children with ASD born 1989-2013 and 68,139 population controls matched by birth year and sex identified from the birth registry. We generated air dispersion model (AirGIS) estimates for NO2, SO2, PM2.5 and PM10 at mothers' home from 9 months before to 9 months after pregnancy and calculated odds ratios (OR) and 95% confidence intervals (CI), adjusting for parental age, neighborhood socio-economic indicators, and maternal smoking using conditional logistic regression., Results: In models that included all exposure periods, we estimated adjusted ORs for ASD per interquartile range (IQR) increase for 9 month after pregnancy with NO2 of 1.08 (95% CI: 1.01, 1.15) and with PM2.5 of 1.06 (95% CI: 1.01, 1.11); associations were smaller for PM10 (1.04; 95% CI: 1.00, 1.09) and strongest for SO2 (1.21; 95% CI: 1.13, 1.29). Also, associations for pollutants were stronger in more recent years (2000-2013) and in larger cities compared with provincial towns/rural counties. For particles and NO2, associations were only specific to autism and Asperger diagnoses., Conclusion: Our data suggest that air pollutant exposure in early infancy but not during pregnancy increases the risk of being diagnosed with autism and Asperger among children born in Denmark., Competing Interests: Conflicts of interest: None declared.

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., (© 2015 International Society for Autism Research, Wiley Periodicals, Inc.)