Family history of psychiatric conditions and development of siblings of children with autism.

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.

Maternal intake of paracetamol during pregnancy and biomarkers of male fecundity in young adult sons.

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.

Mediating Factors in the Association of Maternal Educational Level With Pregnancy Outcomes: A Mendelian Randomization Study.

Importance: Lower educational attainment is associated with increased risk of adverse pregnancy outcomes, but it is unclear which pathways mediate this association. Objective: To investigate the association between educational attainment and pregnancy outcomes and the proportion of this association that is mediated through modifiable cardiometabolic risk factors. Design, Setting, and Participants: In this 2-sample mendelian randomization (MR) cohort study, uncorrelated (R2 < 0.01) single-nucleotide variants (formerly single-nucleotide polymorphisms) associated with the exposure (P < 5 × 10-8) and mediators and genetic associations with the pregnancy outcomes from genome-wide association studies were extracted. All participants were of European ancestry and were largely from Finland, Iceland, the United Kingdom, or the US. The inverse variance-weighted method was used in the main analysis, and the weighted median, weighted mode, and MR Egger regression were used in sensitivity analyses. In mediation analyses, the direct effect of educational attainment estimated in multivariable MR was compared with the total effect estimated in the main univariable MR analysis. Data were extracted between December 1, 2022, and April 30, 2023. Exposure: Genetically estimated educational attainment. The mediators considered were genetically estimated type 2 diabetes, body mass index, smoking, high-density lipoprotein cholesterol level, and systolic blood pressure. Main Outcomes and Measures: Ectopic pregnancy, hyperemesis gravidarum, gestational diabetes, preeclampsia, preterm birth, and offspring birth weight. Results: The analyses included 3 037 499 individuals with data on educational attainment, and those included in studies on pregnancy outcomes ranged from 141 014 for ectopic pregnancy to 270 002 with data on offspring birth weight. Each SD increase in genetically estimated educational attainment (ie, 3.4 years) was associated with an increased birth weight of 42 (95% CI, 28-56) g and an odds ratio ranging from 0.53 (95% CI, 0.46-0.60) for ectopic pregnancy to 0.81 (95% CI, 0.71-0.93) for preeclampsia. The combined proportion of the association that was mediated by the 5 cardiometabolic risk factors ranged from -17% (95% CI, -46% to 26%) for hyperemesis gravidarum to 78% (95% CI, 10%-208%) for preeclampsia. Sensitivity analyses accounting for pleiotropy were consistent with the main analyses. Conclusions and Relevance: In this MR cohort study, intervening for type 2 diabetes, body mass index, smoking, high-density lipoprotein cholesterol level, and systolic blood pressure may lead to reductions in several adverse pregnancy outcomes associated with lower levels of education. Such public health interventions would serve to reduce health disparities attributable to social inequalities.

Maternal medically diagnosed infection and antibiotic prescription during pregnancy and risk of childhood cancer: A population-based cohort study in Taiwan, 2004 to 2015.

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.

A scoping review of multigenerational impacts of grandparental exposures on mental health in grandchildren.

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.

Season of Conception and Risk of Cerebral Palsy.

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.

Per- and polyfluoroalkyl substances and sleep health in U.S. adults, NHANES 2005-2014.

BACKGROUND: 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. OBJECTIVE: To investigate the association between PFAS exposure and sleep health measures in U.S. adults. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Exposure to per- and polyfluoroalkyl substances in early pregnancy and risk of cerebral palsy in children.

BACKGROUND: Most cerebral palsy (CP) cases have an unexplained etiology, but a role for environmental exposures has been suggested. One purported environmental risk factor is exposure to endocrine-disrupting pollutants specifically per- and polyfluoroalkyl substances (PFAS). OBJECTIVES: We investigated the association between prenatal PFAS exposures and CP in Swedish children. METHODS: In this case-control study, 322 CP cases, 343 population controls, and 258 preterm controls were identified from a birth registry in combination with a CP follow-up program from 1995 to 2014 and linked to a biobank which contains serum samples from week 10-14 of pregnancy. Maternal serum concentrations of four PFAS compounds: perfluorohexane sulfonate (PFHxS), perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), and perfluorooctane sulfonate (PFOS) were analyzed using liquid chromatography-tandem-mass-spectrometry. We estimated odds ratios (ORs) and 95 % confidence intervals (CIs) for CP and each PFAS in quartiles and as continuous variables controlling for various sociodemographic and lifestyle factors. RESULTS: In crude and adjusted analyses, we did not find consistent evidence of associations between serum PFHxS, PFOA, PFNA, PFOS and concentrations in early pregnancy and CP, except in preterm infants. The ORs comparing the highest PFAS quartiles to the lowest were 1.05 (95 % CI: 0.63-1.76), 0.96 (95 % CI: 0.55-1.68), 0.71 (95 % CI: 0.41-1.25), and 1.17 (95 % CI: 0.61-2.26), for PFHxS, PFOA, PFNA, and PFOS, respectively. Some positive associations were observed for preterm infants, but the results were imprecise. Similar patterns were observed in analyses treating PFAS as continuous variables. CONCLUSIONS: In this study, we found little evidence that early pregnancy prenatal exposure to PFHxS, PFOA, PFNA, or PFOS increases the risk of CP. However, some positive associations were observed for preterm cases and warrant further investigation.

Hyperthyroidism in Danish Pregnant Women During a 20-Year Period.

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.

Offspring neurodevelopmental outcomes born to parents with chronic inflammatory arthritis using antirheumatic therapies: A scoping review.

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.

Association Between Estimated Geocoded Residential Maternal Exposure to Lithium in Drinking Water and Risk for Autism Spectrum Disorder in Offspring in Denmark.

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/ß-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.

Residential proximity to unconventional oil and gas development and birth defects in Ohio.

BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: Our results suggest a positive association between UOGD and certain birth defects, and findings for neural tube defects corroborate results from prior studies.

Parental Age and Childhood Risk for Cerebral Palsy in California.

OBJECTIVE: To investigate the associations between maternal or paternal age at the time of delivery and offspring's risk for cerebral palsy (CP) in California. STUDY DESIGN: We conducted a population-based, case-control study that included 8736 singleton CP cases and 90 250 singleton controls, matched by sex and birth year, selected from California birth certificate records from 1994 to 2010. We estimated OR and 95% CIs for CP diagnosis according to maternal and paternal age recorded on the birth certificates. Causal mediation analysis was performed to estimate direct and indirect effects of parental ages on CP with preterm delivery as a potential mediator. RESULTS: Children born to younger mothers (≤19 years) or older mothers (35-39 years; ≥40 years) had a greater risk of CP compared with children of mothers aged 25-29 years (ORs ranging from 1.13 to 1.59). Compared with paternal age 25-29 years, older paternal age (40-44 years; ≥45 years) also was associated with an increased risk for CP independent of maternal age. When analyzing jointly using both parents of ages 20-34 years as the reference, the greatest risk was estimated for older parents (≥35 years). Preterm birth was estimated to mediate 19%-34% of the total effects between maternal or paternal age and offspring CP risk. CONCLUSIONS: Young maternal age and an older age in either or both parents were associated with a greater risk of CP in their children. Although preterm birth was a mediator, additional factors related to parental age need further exploration to explain risk of CP.

Joint association of smoking and physical activity with mortality in elderly hypertensive patients: A Chinese population-based cohort study in 2007-2018.

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.

Developmental Milestones of Infancy and Associations with Later Childhood Neurodevelopmental Outcomes in the Adolescent Brain Cognitive Development (ABCD) Study.

The age at attaining infancy developmental milestones has been associated with later neurodevelopmental outcomes, but evidence from large and diverse samples is lacking. We investigated this by analyzing data of 5360 singleton children aged 9-10 from 17 states in the US enrolled in the Adolescent Brain Cognitive Development (ABCD) study during 2016-2020. Delays in four milestones (first roll over, unaided sitting, unaided walking, and speaking first words) were defined using the 90th percentile of age at attainment reported by children's biological mothers. Childhood neurocognitive function was measured by research assistants using the NIH toolbox, and children reported their behavioral problems using the Brief Problem Monitor. Linear mixed-effects models were employed to investigate the association between delays in single or multiple milestones and childhood neurobehavioral outcomes. Delays in first roll over, unaided sitting, or walking were associated with poorer childhood neurocognitive function, while delay in speaking first words was associated with both poorer neurocognitive function and behavioral problems. Children who had delays in both motor and language milestones had the worst neurocognitive function and behavioral outcomes. Our results suggest that delays in motor and language milestone attainment during infancy are predictive of childhood neurobehavioral outcomes.

Drinking water nitrate and risk of pregnancy loss: a nationwide cohort study.

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.

Cardiovascular disease and risk of lung cancer incidence and mortality: A nationwide matched cohort study.

Purpose: Previous studies have suggested a link between cardiovascular disease (CVD) and the subsequent development of lung cancer. However, empirical evidence on the association of CVDs, particularly type-specific CVDs, with lung cancer incidence and survival remains limited. Methods: The cohort study included 306,285 patients with CVD and 1,222,140 individuals without CVD. We performed stratified Cox regression to estimate the hazard ratio (HR). Results: During up to 42 years of follow-up, 243 (0.08%) and 537 (0.04%) participants were diagnosed with lung cancer among CVD patients and matched individuals, respectively. Patients with CVD had a 67% increased risk of lung cancer (HR: 1.67, 95% confidence interval [CI]: 1.42-1.96). The increased risks were observed in patients with heart disease (1.93, 1.30-2.85), vascular disease (1.88, 1.35-2.61), and hypertensive disease (1.46, 1.15-1.85), respectively. Patients with CVD had a 95% increased risk of lung cancer mortality (1.95, 1.50-2.55), particularly vascular disease (3.24, 1.74-6.02) and heart disease (2.29, 1.23-4.26). Patients with CVD diagnosed in middle adulthood (>40 years old) tended to have a higher incidence risk (3.44, 2.28-5.19) and mortality (3.67, 1.80-7.46) than those diagnosed at younger ages. Conclusions: Our findings on the association of CVD diagnosis, especially heart and vascular disease, with increased risk of lung cancer incidence and mortality suggest that CVD contributes to the development and worsening of lung cancer survival. In particular, people with CVD diagnosed in middle adulthood (>40 years old) would benefit from early preventive evaluation and screening for lung cancer.

Health Effects Associated with Exposures to Endocrine Disrupting Chemicals.

A number of recent studies have shown that human exposures to a wide range of endocrine-disrupting chemicals (EDCs) may increase the risk of disease across the lifespan by altering the homeostasis or action of endogenous hormones, or other signaling chemicals of the endocrine system [...].