Association of tea and coffee consumption and biliary tract cancer risk: The Biliary Tract Cancers Pooling Project.

BACKGROUND AND AIMS: Tea and coffee are widely consumed beverages worldwide. We evaluated their association with biliary tract cancer (BTC) incidence. APPROACH AND RESULTS: We pooled data from 15 studies in the Biliary Tract Cancers Pooling Project to evaluate associations between tea and coffee consumption and biliary tract cancer development. We categorized participants as nondrinkers (0 cup/day), moderate drinkers (>0 and <3 cups/day), and heavy drinkers (≥3 cups/day). We estimated multivariable HRs and 95% CIs using Cox models. During 29,911,744 person-years of follow-up, 851 gallbladder, 588 intrahepatic bile duct, 753 extrahepatic bile duct, and 458 ampulla of Vater cancer cases were diagnosed. Individuals who drank tea showed a statistically significantly lower incidence rate of gallbladder cancer (GBC) relative to tea nondrinkers (HR=0.77; 95% CI, 0.64-0.91), and intrahepatic bile duct cancer (IHBDC) had an inverse association (HR=0.81; 95% CI, 0.66-1.00). However, no associations were observed for extrahepatic bile duct cancer (EHBDC) or ampulla of Vater cancer (AVC). In contrast, coffee consumption was positively associated with GBC, with a higher incidence rate for individuals consuming more coffee (HR<3 cups/day =1.29; 95% CI, 1.01-1.66; HR≥3 cups/day =1.49; 95% CI, 1.11-1.99, Ptrend=0.01) relative to coffee nondrinkers. However, there was no association between coffee consumption and GBC when restricted to coffee drinkers. There was little evidence of associations between coffee consumption and other biliary tract cancers. CONCLUSIONS: Tea consumption was associated with a lower incidence of GBC and possibly IHBDC. Further research is warranted to replicate the observed positive association between coffee and GBC.

Association between parental psychiatric disorders and risk of offspring autism spectrum disorder: a Swedish and Finnish population-based cohort study.

Background: Roughly more than one in six adults worldwide suffer from psychiatric conditions. Sporadic studies have associated parental psychiatric disorders with autism spectrum disorder in offspring. Comprehensively examining the association between parental psychiatric disorders and offspring autism spectrum disorder is needed to guide health policies, and to inform etiologic studies. Methods: We included all children born in Sweden and Finland 1997-2016. Diagnoses were clinically ascertained from National Registers through 2017. We calculated adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) for autism spectrum disorder in offspring of fathers and mothers with psychiatric disorders, in both parents jointly and across co-occurring conditions. Findings: Among 2,505,842 children, 33,612 were diagnosed with autism spectrum disorder, of which 20% had a parent with psychiatric disorders. The risk of autism spectrum disorder was increased across all psychiatric disorders in fathers (Sweden: aHR = 2.02, 95% CI = 1.92-2.12; Finland: aHR = 1.63, 95% CI = 1.50-1.77), mothers (Sweden: aHR = 2.34, 95% CI = 2.24-2.43; Finland aHR = 2.12, 95% CI = 1.92-2.28), or both parents (Sweden: aHR = 3.76, 95% CI = 3.48-4.07; Finland aHR = 3.61, 95% CI = 3.20-4.07), compared to neither parents. Co-occurrence of parental psychiatric disorders further increased risk (e.g., Sweden: for one, two or ≥three different diagnostic categories compared to no diagnosis, in fathers aHR = 1.81, 2.07, 2.52; in mothers aHR = 2.05, 2.63, 3.57). Interpretation: Psychiatric disorders in both parents conveyed the highest risk of offspring autism spectrum disorder, followed by mothers and then fathers. The risk increased with number of co-occurring disorders. All parental psychiatric disorders were associated with increased the risk of autism spectrum disorder. To reliably assess the risk of autism spectrum disorder in children, a comprehensive history incorporating the full range of parental psychiatric disorders is needed beyond solely focusing on familial autism spectrum disorder. Funding: Swedish-Research-Council-2021-0214.

Examining Sex Differences in Autism Heritability.

Importance: Autism spectrum disorder (ASD) is a neurodevelopmental disorder more prevalent in males than in females. The cause of ASD is largely genetic, but the association of genetics with the skewed sex ratio is not yet understood. To our knowledge, no large population-based study has provided estimates of heritability by sex. Objective: To estimate the sex-specific heritability of ASD. Design, Setting, and Participants: This was a population-based, retrospective analysis using national health registers of nontwin siblings and cousins from Sweden born between January 1, 1985, and December 31, 1998, with follow-up to 19 years of age. Data analysis occurred from August 2022 to November 2023. Main Outcomes and Measures: Models were fitted to estimate the relative variance in risk for ASD occurrence owing to sex-specific additive genetics, shared environmental effects, and a common residual term. The residual term conceptually captured other factors that promote individual behavioral variation (eg, maternal effects, de novo variants, rare genetic variants not additively inherited, or gene-environment interactions). Estimates were adjusted for differences in prevalence due to birth year and maternal and paternal age by sex. Results: The sample included 1 047 649 individuals in 456 832 families (538 283 males [51.38%]; 509 366 females [48.62%]). Within the entire sample, 12 226 (1.17%) received a diagnosis of ASD, comprising 8128 (1.51%) males and 4098 (0.80%) females. ASD heritability was estimated at 87.0% (95% CI, 81.4%-92.6%) for males and 75.7% (95% CI, 68.4%-83.1%) for females with a difference in heritability estimated at 11.3% (95% CI, 1.0%-21.6%). There was no support for shared environmental contributions. Conclusions and Relevance: These findings suggest that the degree of phenotypic variation attributable to genetic differences (heritability) differs between males and females, indicating that some of the underlying causes of the condition may differ between the 2 sexes. The skewed sex ratio in ASD may be partly explained by differences in genetic variance between the sexes.

Gestational age at birth and type 1 diabetes in childhood and young adulthood: a nationwide register study in Finland, Norway and Sweden.

AIMS/HYPOTHESIS: Children and adults born preterm have an increased risk of type 1 diabetes. However, there is limited information on risk patterns across the full range of gestational ages, especially after extremely preterm birth (23-27 weeks of gestation). We investigated the risk of type 1 diabetes in childhood and young adulthood across the full range of length of gestation at birth. METHODS: Data were obtained from national registers in Finland, Norway and Sweden. In each country, information on study participants and gestational age was collected from the Medical Birth Registers, information on type 1 diabetes diagnoses was collected from the National Patient Registers, and information on education, emigration and death was collected from the respective national register sources. Individual-level data were linked using unique personal identity codes. The study population included all individuals born alive between 1987 and 2016 to mothers whose country of birth was the respective Nordic country. Individuals were followed until diagnosis of type 1 diabetes, death, emigration or end of follow-up (31 December 2016 in Finland, 31 December 2017 in Norway and Sweden). Gestational age was categorised as extremely preterm (23-27 completed weeks), very preterm (28-31 weeks), moderately preterm (32-33 weeks), late preterm (34-36 weeks), early term (37-38 weeks), full term (39-41 weeks; reference) and post term (42-45 weeks). HRs and 95% CIs from country-specific covariate-adjusted Cox regression models were combined in a meta-analysis using a common-effect inverse-variance model. RESULTS: Among 5,501,276 individuals, 0.2% were born extremely preterm, 0.5% very preterm, 0.7% moderately preterm, 4.2% late preterm, 17.7% early term, 69.9% full term, and 6.7% post term. A type 1 diabetes diagnosis was recorded in 12,326 (0.8%), 6364 (0.5%) and 16,856 (0.7%) individuals at a median age of 8.2, 13.0 and 10.5 years in Finland, Norway and Sweden, respectively. Individuals born late preterm or early term had an increased risk of type 1 diabetes compared with their full-term-born peers (pooled, multiple confounder-adjusted HR 1.12, 95% CI 1.07, 1.18; and 1.15, 95% CI 1.11, 1.18, respectively). However, those born extremely preterm or very preterm had a decreased risk of type 1 diabetes (adjusted HR 0.63, 95% CI 0.45, 0.88; and 0.78, 95% CI 0.67, 0.92, respectively). These associations were similar across all three countries. CONCLUSIONS/INTERPRETATION: Individuals born late preterm and early term have an increased risk of type 1 diabetes while individuals born extremely preterm or very preterm have a decreased risk of type 1 diabetes compared with those born full term.

Hypertension and risk of endometrial cancer: a pooled analysis in the Epidemiology of Endometrial Cancer Consortium (E2C2).

BACKGROUND: The incidence rates of endometrial cancer (EC) are increasing, which may partly be explained by the rising prevalence of obesity, an established risk factor for EC. Hypertension, another component of metabolic syndrome, is also increasing in prevalence, and emerging evidence suggests that it may be associated with the development of certain cancers. The role of hypertension independent of other components of metabolic syndrome in the etiology of EC remains unclear. In this study we evaluated hypertension as an independent risk factor for EC and whether this association is modified by other established risk factors. METHODS: We included 15,631 EC cases and 42,239 controls matched on age, race, and study-specific factors from 29 studies in the Epidemiology of Endometrial Cancer Consortium. We used multivariable unconditional logistic regression models to estimate odds ratios (ORs) and 95% confidence intervals (CIs) to evaluate the association between hypertension and EC and whether this association differed by study design, race/ethnicity, body mass index, diabetes status, smoking status, or reproductive factors. RESULTS: Hypertension was associated with an increased risk of EC (OR=1.14, 95% CI:1.09-1.19). There was significant heterogeneity by study design (Phet<0.01), with a stronger magnitude of association observed among case-control vs. cohort studies. Stronger associations were also noted for pre-/peri-menopausal women and never users of postmenopausal hormone therapy. CONCLUSIONS: Hypertension is associated with EC risk independently from known risk factors. Future research should focus on biologic mechanisms underlying this association. IMPACT: This study provides evidence that hypertension may be an independent risk factor for EC.

Genome-wide association study identifies new loci associated with OCD.

To date, four genome-wide association studies (GWAS) of obsessive-compulsive disorder (OCD) have been published, reporting a high single-nucleotide polymorphism (SNP)-heritability of 28% but finding only one significant SNP. A substantial increase in sample size will likely lead to further identification of SNPs, genes, and biological pathways mediating the susceptibility to OCD. We conducted a GWAS meta-analysis with a 2-3-fold increase in case sample size (OCD cases: N = 37,015, controls: N = 948,616) compared to the last OCD GWAS, including six previously published cohorts (OCGAS, IOCDF-GC, IOCDF-GC-trio, NORDiC-nor, NORDiC-swe, and iPSYCH) and unpublished self-report data from 23andMe Inc. We explored the genetic architecture of OCD by conducting gene-based tests, tissue and celltype enrichment analyses, and estimating heritability and genetic correlations with 74 phenotypes. To examine a potential heterogeneity in our data, we conducted multivariable GWASs with MTAG. We found support for 15 independent genome-wide significant loci (14 new) and 79 protein-coding genes. Tissue enrichment analyses implicate multiple cortical regions, the amygdala, and hypothalamus, while cell type analyses yielded 12 cell types linked to OCD (all neurons). The SNP-based heritability of OCD was estimated to be 0.08. Using MTAG we found evidence for specific genetic underpinnings characteristic of different cohort-ascertainment and identified additional significant SNPs. OCD was genetically correlated with 40 disorders or traits-positively with all psychiatric disorders and negatively with BMI, age at first birth and multiple autoimmune diseases. The GWAS meta-analysis identified several biologically informative genes as important contributors to the aetiology of OCD. Overall, we have begun laying the groundwork through which the biology of OCD will be understood and described.

Female reproductive histories and the risk of chronic obstructive pulmonary disease.

BACKGROUND: Female reproductive factors may influence the development of chronic obstructive pulmonary disease (COPD) through the female hormonal environment, but studies on this topic are limited. This study aimed to assess whether age at menarche, number of children, infertility, miscarriage, stillbirth and age at natural menopause were associated with the risk of COPD. METHODS: Women from three cohorts with data on reproductive factors, COPD and covariates were included. Cause specific Cox regression models were adjusted for birth year, race, educational level, body mass index and pack years of smoking, stratified by asthma, and incorporating interaction between birth year and time. Between cohort differences and within cohort correlations were taken into account. RESULTS: Overall, 2 83 070 women were included and 10 737 (3.8%) developed COPD after a median follow-up of 11 (IQR 10-12) years. Analyses revealed a U shaped association between age at menarche and COPD (≤11 vs 13: HR 1.17, 95% CI 1.11 to 1.23; ≥16 vs 13: HR 1.24, 95% CI 1.21 to 1.27). Women with three or more children (3 vs 2: HR 1.14, 95% CI 1.12 to 1.17; ≥4 vs 2: HR 1.34, 95% CI 1.28 to 1.40), multiple miscarriages (2 vs 0: HR 1.28, 95% CI 1.24 to 1.32; ≥3 vs 0: HR 1.36, 95% CI 1.30 to 1.43) or stillbirth (1 vs 0: HR 1.38, 95% CI 1.25 to 1.53; ≥2 vs 0: HR 1.67, 95% CI 1.32 to 2.10) were at a higher risk of COPD. Among postmenopausal women, earlier age at natural menopause was associated with an increased risk of COPD (<40 vs 50-51: HR 1.69, 95% CI 1.63 to 1.75; 40-44 vs 50-51: HR 1.42, 95% CI 1.38 to 1.47). CONCLUSIONS: Multiple female reproductive factors, including age at menarche, number of children, miscarriage, stillbirth, and age at natural menopause were associated with the risk of COPD.

Preterm delivery and maternal obesity remain common complications in pregnancies with type 1 diabetes-A nationwide study in Sweden.

AIM: A primary goal of obstetric care of women with type 1 diabetes (T1D) is to reduce the risks of preterm birth (PTB). Besides hyperglycaemia, maternal obesity is an important risk factor for PTB in T1D. However, it's unclear if public health efforts decreased risks of maternal obesity and PTB in pregnancies with T1D. We examined time-trends over the last 20 years in the distribution of gestational ages at birth (GA) in offspring of women with T1D in Sweden, and in maternal BMI in the same mothers. METHODS: Population-based cohort study, using data from national registries in Sweden. To capture differences not only in the median values, we used quantile regression models to compare the whole distributions of GA's and early pregnancy BMI between deliveries in 1998-2007 (P1) and 2008-2016 (P2). Multivariable models were adjusted for differences in maternal age, smoking and education between periods 1 and 2. RESULTS: The study included 7639 offspring of women with T1D between 1998 and 2016. The 10% percentile GA, increased with 0.09 days (95% CI: -0.11 to 0.35) between P1 and P2. The 90% percentile for BMI was 1.20 kg/m2 higher (95% CI: 0.57 to 1.83) in P2. Risks of PTB remained stable over time also when adjusting for maternal BMI. CONCLUSION: Despite modern diabetes management, the distribution of GA, and consequently the risk of PTB in T1D, remained unchanged from 1998 to 2016. During the same time, maternal BMI increased, particularly in the already obese.

Maternal type 1 diabetes, preterm birth, and risk of intellectual disability in the offspring: A nation-wide study in Sweden.

OBJECTIVE: There are few data on long-term neurological or cognitive outcomes in the offspring of mothers with type 1 diabetes (T1D). The aims of this study were to examine if maternal T1D increases the risk of intellectual disability (ID) in the offspring, estimate the amount of mediation through preterm birth, and examine if the association was modified by maternal glycated hemoglobin (HbA1c). DESIGN: Population-based cohort study using population-based data from several national registries in Sweden. SETTING AND PARTICIPANTS: All offspring born alive in Sweden between the years 1998 and 2015. MAIN OUTCOME MEASURE: The risk of ID was estimated through hazard ratios with 95% confidence intervals (HR, 95% CI) from Cox proportional hazard models, adjusting for potential confounding. Risks were also assessed in mediation analyses and in subgroups of term/preterm births, in relation to maternal HbA1c and by severity of ID. RESULTS: In total, 1,406,441 offspring were included. In this cohort, 7,794 (0.57%) offspring were born to mothers with T1D. The risk of ID was increased in offspring of mothers with T1D (HR; 1.77, 1.43-2.20), of which 47% (95% CI: 34-100) was mediated through preterm birth. The HRs were not modified by HbA1c. CONCLUSION: T1D in pregnancy is associated with moderately increased risks of ID in the offspring. The risk is largely mediated by preterm birth, in particular for moderate/severe cases of ID. There was no support for risk-modification by maternal HbA1c.

Adult Attention-Deficit/Hyperactivity Disorder and the Risk of Dementia.

Importance: Evidence that adult attention-deficit/hyperactivity disorder (ADHD) is associated with an increased risk of dementia is scarce and inconsistent, and potential sources of bias are untested. Objective: To examine the association between adult ADHD and the risk of dementia. Design, Setting, and Participants: This prospective national cohort study consisted of 109 218 members of a nonprofit Israeli health maintenance organization born between 1933 and 1952 who entered the cohort on January 1, 2003, without an ADHD or dementia diagnosis and were followed up to February 28, 2020. Participants were aged 51 to 70 years in 2003. Statistical analysis was conducted from December 2022 to August 2023. Exposure: Adult ADHD was a time-varying covariate, classified as present from the age of the first diagnosis (using the International Classification of Diseases, Ninth Revision, and the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision); otherwise, absent. Main Outcome and Measures: Cox regression models were fitted to quantify the association between adult ADHD and the risk of incident dementia with hazard ratios (HRs) and their 95% CIs unadjusted and in the primary analysis, using inverse probability weights, adjusted for 18 sources of potential confounding. In 14 complementary analyses, subgroup and sensitivity analyses were implemented. Results: At the beginning of the follow-up, the sample of 109 218 participants had a mean (SD) age of 57.7 (5.5) years, 56 474 participants (51.7%) were female, and 52 744 (48.3%) were male. During follow-up, 730 participants (0.7%) received a diagnosis of adult ADHD, and 7726 (7.1%) received a diagnosis of dementia. Dementia occurred among 96 of 730 participants (13.2%) with adult ADHD and 7630 of 108 488 participants (7.0%) without adult ADHD. In the primary analysis, compared with the absence of adult ADHD, the presence of adult ADHD was statistically significantly (P < .001) associated with an increased dementia risk (unadjusted HR, 3.62 [95% CI, 2.92-4.49; P < .001]; adjusted HR, 2.77 [95% CI, 2.11-3.63; P < .001]). Twelve of the 14 complementary analyses did not attenuate the conclusions based on the results of the primary analysis. There was, however, no clear increase in the risk of dementia associated with adult ADHD among those who received psychostimulant medication, and evidence of reverse causation was mild. Conclusions and Relevance: In this cohort study of individuals born between 1933 and 1952 and followed up in old age, adult ADHD was associated with an increased risk of dementia. Policy makers, caregivers, patients, and clinicians may wish to monitor reliably for ADHD in old age.

Ethnic Differences in the Association Between Age at Natural Menopause and Risk of Type 2 Diabetes Among Postmenopausal Women: A Pooled Analysis of Individual Data From 13 Cohort Studies.

OBJECTIVE: To investigate associations between age at natural menopause, particularly premature ovarian insufficiency (POI) (natural menopause before age 40 years), and incident type 2 diabetes (T2D) and identify any variations by ethnicity. RESEARCH DESIGN AND METHODS: We pooled individual-level data of 338,059 women from 13 cohort studies without T2D before menopause from six ethnic groups: White (n = 177,674), Chinese (n = 146,008), Japanese (n = 9,061), South/Southeast Asian (n = 2,228), Black (n = 1,838), and mixed/other (n = 1,250). Hazard ratios (HRs) of T2D associated with age at menopause were estimated in the overall sample and by ethnicity, with study as a random effect. For each ethnic group, we further stratified the association by birth year, education level, and BMI. RESULTS: Over 9 years of follow-up, 20,064 (5.9%) women developed T2D. Overall, POI (vs. menopause at age 50-51 years) was associated with an increased risk of T2D (HR 1.31; 95% CI 1.20-1.44), and there was an interaction between age at menopause and ethnicity (P < 0.0001). T2D risk associated with POI was higher in White (1.53; 1.36-1.73), Japanese (4.04; 1.97-8.27), and Chinese women born in 1950 or later (2.79; 2.11-3.70); although less precise, the risk estimates were consistent in women of South/Southeast Asian (1.46; 0.89-2.40), Black (1.72; 0.95-3.12), and mixed/other (2.16; 0.83-5.57) ethnic groups. A similar pattern, but with a smaller increased risk of T2D, was observed with early menopause overall (1.16; 1.10-1.23) and for White, Japanese, and Chinese women born in 1950 or later. CONCLUSIONS: POI and early menopause are risk factors for T2D in postmenopausal women, with considerable variation across ethnic groups, and may need to be considered in risk assessments of T2D among women.

Gestational age at birth and hospitalisations for infections among individuals aged 0-50 years in Norway: a longitudinal, register-based, cohort study.

Background: Preterm birth is associated with increased risk of childhood infections. Whether this risk persists into adulthood is unknown and limited information is available on risk patterns across the full range of gestational ages. Methods: In this longitudinal, register-based, cohort study, we linked individual-level data on all individuals born in Norway (January 01, 1967-December 31, 2016) to nationwide hospital data (January 01, 2008-December 31, 2017). Gestational age was categorised as 23-27, 28-31, 32-33, 34-36, 37-38, 39-41, and 42-44 completed weeks. The analyses were stratified by age at follow-up: 0-11 months and 1-5, 6-14, 15-29, and 30-50 years. The primary outcome was hospitalisation due to any infectious disease, with major infectious disease groups as secondary outcomes. Adjusted hospitalisation rate ratios (RRs) for any infection and infectious disease groups were estimated using negative binomial regression. Models were adjusted for year of birth, maternal age at birth, parity, and sex, and included an offset parameter adjusted for person-time at risk. Findings: Among 2,695,830 individuals with 313,940 hospitalisations for infections, we found a pattern of higher hospitalisation risk in lower gestational age groups, which was the strongest in childhood but still evident in adulthood. Comparing those born very preterm (28-31) and late preterm (34-36) to full-term (39-41 weeks), RRs (95% confidence interval) for hospitalisation for any infectious disease at ages 1-5 were 3.3 (3.0-3.7) and 1.7 (1.6-1.8), respectively. At 30-50 years, the corresponding estimates were 1.4 (1.2-1.7) and 1.2 (1.1-1.3). The patterns were similar for the infectious disease groups, including bacterial and viral infections, respiratory tract infections (RTIs), and infections not attributable to RTIs. Interpretation: Increasing risk of hospitalisations for infections in lower gestational age groups was most prominent in children but still evident in adolescents and adults. Possible mechanisms and groups that could benefit from vaccinations and other prevention strategies should be investigated. Funding: St. Olav's University Hospital and Norwegian University of Science and Technology, Norwegian Research Council, Liaison Committee for education, research and innovation in Central Norway, European Commission, Academy of Finland, Sigrid Jusélius Foundation, Foundation for Pediatric Research, and Signe and Ane Gyllenberg Foundation.

Paternal and maternal psychiatric history and risk of preterm and early term birth: A nationwide study using Swedish registers.

BACKGROUND: Women with psychiatric diagnoses are at increased risk of preterm birth (PTB), with potential life-long impact on offspring health. Less is known about the risk of PTB in offspring of fathers with psychiatric diagnoses, and for couples where both parents were diagnosed. In a nationwide birth cohort, we examined the association between psychiatric history in fathers, mothers, and both parents and gestational age. METHODS AND FINDINGS: We included all infants live-born to Nordic parents in 1997 to 2016 in Sweden. Psychiatric diagnoses were obtained from the National Patient Register. Data on gestational age were retrieved from the Medical Birth Register. Associations between parental psychiatric history and PTB were quantified by relative risk (RR) and two-sided 95% confidence intervals (CIs) from log-binomial regressions, by psychiatric disorders overall and by diagnostic categories. We extended the analysis beyond PTB by calculating risks over the whole distribution of gestational age, including "early term" (37 to 38 weeks). Among the 1,488,920 infants born throughout the study period, 1,268,507 were born to parents without a psychiatric diagnosis, of whom 73,094 (5.8%) were born preterm. 4,597 of 73,500 (6.3%) infants were born preterm to fathers with a psychiatric diagnosis, 8,917 of 122,611 (7.3%) infants were born preterm to mothers with a pscyhiatric diagnosis, and 2,026 of 24,302 (8.3%) infants were born preterm to both parents with a pscyhiatric diagnosis. We observed a shift towards earlier gestational age in offspring of parents with psychiatric history. The risks of PTB associated with paternal and maternal psychiatric diagnoses were similar for different psychiatric disorders. The risks for PTB were estimated at RR 1.12 (95% CI [1.08, 1.15] p < 0.001) for paternal diagnoses, at RR 1.31 (95% CI [1.28, 1.34] p < 0.001) for maternal diagnoses, and at RR 1.52 (95% CI [1.46, 1.59] p < 0.001) when both parents were diagnosed with any psychiatric disorder, compared to when neither parent had a psychiatric diagnosis. Stress-related disorders were associated with the highest risks of PTB with corresponding RRs estimated at 1.23 (95% CI [1.16, 1.31] p < 0.001) for a psychiatry history in fathers, at 1.47 (95% CI [1.42, 1.53] p < 0.001) for mothers, and at 1.90 (95% CI [1.64, 2.20] p < 0.001) for both parents. The risks for early term were similar to PTB. Co-occurring diagnoses from different diagnostic categories increased risk; for fathers: RR 1.10 (95% CI [1.07, 1.13] p < 0.001), 1.15 (95% CI [1.09, 1.21] p < 0.001), and 1.33 (95% CI [1.23, 1.43] p < 0.001), for diagnoses in 1, 2, and ≥3 categories; for mothers: RR 1.25 (95% CI [1.22, 1.28] p < 0.001), 1.39 (95% CI [1.34, 1.44] p < 0.001) and 1.65 (95% CI [1.56, 1.74] p < 0.001). Despite the large sample size, statistical precision was limited in subgroups, mainly where both parents had specific psychiatric subtypes. Pathophysiology and genetics underlying different psychiatric diagnoses can be heterogeneous. CONCLUSIONS: Paternal and maternal psychiatric history were associated with a shift to earlier gestational age and increased risk of births before full term. The risk consistently increased when fathers had a positive history of different psychiatric disorders, increased further when mothers were diagnosed and was highest when both parents were diagnosed.

Is there a link between infertility, miscarriage, stillbirth, and premature or early menopause? Results from pooled analyses of 9 cohort studies.

BACKGROUND: Some reproductive factors (such as age at menarche and parity) have been shown to be associated with age at natural menopause, but there has been little quantitative analysis of the association between infertility, miscarriage, stillbirth, and premature (<40 years) or early menopause (40-44 years). In addition, it has been unknown whether the association differs between Asian and non-Asian women, although the age at natural menopause is younger among Asian women. OBJECTIVE: This study aimed to investigate the association of infertility, miscarriage, and stillbirth with age at natural menopause, and whether the association differed by race (Asian and non-Asian). STUDY DESIGN: This was a pooled individual participant data analysis from 9 observational studies contributing to the InterLACE consortium. Naturally postmenopausal women with data on at least 1 of the reproductive factors (ie, infertility, miscarriage, and stillbirth), age at menopause, and confounders (ie, race, education level, age at menarche, body mass index, and smoking status) were included. A multinomial logistic regression model was used to estimate relative risk ratios and 95% confidence intervals for the association of infertility, miscarriage, and stillbirth with premature or early menopause, adjusting for confounders. Between-study difference and within-study correlation were taken into account by including study as a fixed effect and indicating study as a cluster variable. We also examined the association with number of miscarriages (0, 1, 2, ≥3) and stillbirths (0, 1, ≥2), and tested whether the strength of association differed between Asian and non-Asian women. RESULTS: A total of 303,594 postmenopausal women were included. Their median age at natural menopause was 50.0 years (interquartile range, 47.0-52.0). The percentages of women with premature and early menopause were 2.1% and 8.4%, respectively. The relative risk ratios (95% confidence intervals) of premature and early menopause were 2.72 (1.77-4.17) and 1.42 (1.15-1.74) for women with infertility; 1.31 (1.08-1.59) and 1.37 (1.14-1.65) for women with recurrent miscarriages; and 1.54 (1.52-1.56) and 1.39 (1.35-1.43) for women with recurrent stillbirths. Asian women with infertility, recurrent miscarriages (≥3), or recurrent stillbirths (≥2) had higher risk of premature and early menopause compared with non-Asian women with the same reproductive history. CONCLUSION: Histories of infertility and recurrent miscarriages and stillbirths were associated with higher risk of premature and early menopause, and the associations differed by race, with stronger associations for Asian women with such reproductive history.

Direct additive genetics and maternal effect contribute to the risk of Tourette disorder.

BACKGROUND: Risk for Tourette disorder, and chronic motor or vocal tic disorders (referenced here inclusively as CTD), arise from a combination of genetic and environmental factors. While multiple studies have demonstrated the importance of direct additive genetic variation for CTD risk, little is known about the role of cross-generational transmission of genetic risk, such as maternal effect, which is not transmitted via the inherited parental genomes. Here, we partition sources of variation on CTD risk into direct additive genetic effect (narrow-sense heritability) and maternal effect. METHODS: The study population consists of 2 522 677 individuals from the Swedish Medical Birth Register, who were born in Sweden between 1 January 1973 and 31 December 2000, and followed for a diagnosis of CTD through 31 December, 2013. We used generalised linear mixed models to partition the liability of CTD into: direct additive genetic effect, genetic maternal effect and environmental maternal effect. RESULTS: We identified 6227 (0.2%) individuals in the birth cohort with a CTD diagnosis. A study of half-siblings showed that maternal half-siblings had twice higher risk of developing a CTD compared with paternal ones. We estimated 60.7% direct additive genetic effect (95% credible interval, 58.5% to 62.4%), 4.8% genetic maternal effect (95% credible interval, 4.4% to 5.1%) and 0.5% environmental maternal effect (95% credible interval, 0.2% to 7%). CONCLUSIONS: Our results demonstrate genetic maternal effect contributes to the risk of CTD. Failure to account for maternal effect results in an incomplete understanding of the genetic risk architecture of CTD, as the risk for CTD is impacted by maternal effect which is above and beyond the risk from transmitted genetic effect.

Hypertensive conditions of pregnancy, preterm birth, and premenopausal breast cancer risk: a premenopausal breast cancer collaborative group analysis.

PURPOSE: Women with preeclampsia are more likely to deliver preterm. Reports of inverse associations between preeclampsia and breast cancer risk, and positive associations between preterm birth and breast cancer risk are difficult to reconcile. We investigated the co-occurrence of preeclampsia/gestational hypertension with preterm birth and breast cancer risk using data from the Premenopausal Breast Cancer Collaborative Group. METHODS: Across 6 cohorts, 3096 premenopausal breast cancers were diagnosed among 184,866 parous women. We estimated multivariable hazard ratios (HR) and 95% confidence intervals (CI) for premenopausal breast cancer risk using Cox proportional hazards regression. RESULTS: Overall, preterm birth was not associated (HR 1.02, 95% CI 0.92, 1.14), and preeclampsia was inversely associated (HR 0.86, 95% CI 0.76, 0.99), with premenopausal breast cancer risk. In stratified analyses using data from 3 cohorts, preterm birth associations with breast cancer risk were modified by hypertensive conditions in first pregnancies (P-interaction = 0.09). Preterm birth was positively associated with premenopausal breast cancer in strata of women with preeclampsia or gestational hypertension (HR 1.52, 95% CI: 1.06, 2.18), but not among women with normotensive pregnancy (HR = 1.09, 95% CI: 0.93, 1.28). When stratified by preterm birth, the inverse association with preeclampsia was more apparent, but not statistically different (P-interaction = 0.2), among women who did not deliver preterm (HR = 0.82, 95% CI 0.68, 1.00) than those who did (HR = 1.07, 95% CI 0.73, 1.56). CONCLUSION: Findings support an overall inverse association of preeclampsia history with premenopausal breast cancer risk. Estimates for preterm birth and breast cancer may vary according to other conditions of pregnancy.

Associations of life course obesity with endometrial cancer in the Epidemiology of Endometrial Cancer Consortium (E2C2).

BACKGROUND: Adult obesity is a strong risk factor for endometrial cancer (EC); however, associations of early life obesity with EC are inconclusive. We evaluated associations of young adulthood (18-21 years) and adulthood (at enrolment) body mass index (BMI) and weight change with EC risk in the Epidemiology of Endometrial Cancer Consortium (E2C2). METHODS: We pooled data from nine case-control and 11 cohort studies in E2C2. We performed multivariable logistic regression analyses to estimate odds ratios (OR) and 95% confidence intervals (95% CI) for BMI (kg/m2) in young adulthood and adulthood, with adjustment for BMI in adulthood and young adulthood, respectively. We evaluated categorical changes in weight (5-kg increments) and BMI from young adulthood to adulthood, and stratified analyses by histology, menopausal status, race and ethnicity, hormone replacement therapy (HRT) use and diabetes. RESULTS: We included 14 859 cases and 40 859 controls. Obesity in adulthood (OR = 2.85, 95% CI = 2.47-3.29) and young adulthood (OR = 1.26, 95% CI = 1.06-1.50) were positively associated with EC risk. Weight gain and BMI gain were positively associated with EC; weight loss was inversely associated with EC. Young adulthood obesity was more strongly associated with EC among cases diagnosed with endometrioid histology, those who were pre/perimenopausal, non-Hispanic White and non-Hispanic Black, among never HRT users and non-diabetics. CONCLUSIONS: Young adulthood obesity is associated with EC risk, even after accounting for BMI in adulthood. Weight gain is also associated with EC risk, whereas weight loss is inversely associated. Achieving and maintaining a healthy weight over the life course is important for EC prevention efforts.

Maternal rheumatoid arthritis and risk of autism in the offspring.

BACKGROUND: Maternal Rheumatoid Arthritis (RA) is suggested to increase the risk of Autism Spectrum Disorder (ASD) in the offspring, mainly through inflammation/autoimmunity, but the association is unclear. A prospective population-based cohort study was implemented to examine the association between maternal RA and offspring ASD. METHODS: We included all children born alive in Sweden from 1995 to 2015, followed up through 2017. Diagnoses of ASD and RA were clinically ascertained from National Patient Register. We quantified the association by hazard ratios (HR) and two-sided 95% confidence intervals (CI), from Cox regression after detailed adjustment for potential confounders. We examined RA serostatus, etiological subgroups and the timing of exposure. To closer examine the underlying mechanism for the association, we included a negative control group for RA, arthralgia, with similar symptomology as RA but free from inflammation/autoimmunity. RESULTS: Of 3629 children born to mothers with RA, 70 (1.94%) were diagnosed with ASD, compared to 28 892 (1.92%) of 1 503 908 children born to mothers without RA. Maternal RA before delivery was associated with an increased risk of offspring ASD (HR = 1.43, 95% CI 1.11-1.84), especially for seronegative RA (HR = 1.61, 95% CI 1.12-2.30). No similar association was observed for paternal RA, maternal sisters with RA, or RA diagnosed after delivery. Maternal arthralgia displayed as high risks for offspring ASD as did maternal RA (HR = 1.41, 95% CI 1.24-1.60). CONCLUSIONS: In Sweden, maternal RA before delivery was associated with an increased risk of offspring ASD. The comparable association between maternal arthralgia and ASD risk suggests other pathways of risk than autoimmunity/inflammation, acting jointly or independently of RA.

Dietary omega-3 fatty acids and endometrial cancer risk in the Epidemiology of Endometrial Cancer Consortium: An individual-participant meta-analysis.

BACKGROUND: Limited data from prospective studies suggest that higher dietary intake of long-chain omega-3 polyunsaturated fatty acids (LCn3PUFA), which hold anti-inflammatory properties, may reduce endometrial cancer risk; particularly among certain subgroups characterized by body mass and tumor pathology. MATERIALS AND METHODS: Data from 12 prospective cohort studies participating in the Epidemiology of Endometrial Cancer Consortium were harmonized as nested case-control studies, including 7268 endometrial cancer cases and 26,133 controls. Habitual diet was assessed by food frequency questionnaire, from which fatty acid intakes were estimated. Two-stage individual-participant data mixed effects meta-analysis estimated adjusted odds ratios (OR) and 95% confidence intervals (CI) through logistic regression for associations between study-specific energy-adjusted quartiles of LCn3PUFA and endometrial cancer risk. RESULTS: Women with the highest versus lowest estimated dietary intakes of docosahexaenoic acid, the most abundant LCn3PUFA in diet, had a 9% increased endometrial cancer risk (Quartile 4 vs. Quartile 1: OR 1.09, 95% CI: 1.01-1.19; P trend = 0.04). Similar elevated risks were observed for the summary measure of total LCn3PUFA (OR 1.07, 95% CI: 0.99-1.16; P trend = 0.06). Stratified by body mass index, higher intakes of LCn3PUFA were associated with 12-19% increased endometrial cancer risk among overweight/obese women and no increased risk among normal-weight women. Higher associations appeared restricted to White women. The results did not differ by cancer grade. CONCLUSION: Higher dietary intakes of LCn3PUFA are unlikely to reduce endometrial cancer incidence; rather, they may be associated with small to moderate increases in risk in some subgroups of women, particularly overweight/obese women.

Rates of Spontaneous Abortion in Israel Before and During the COVID-19 Pandemic.

This cross-sectional study uses electronic health record data to compare monthly incidence rates of spontaneous abortion in Israel before and during the COVID-19 pandemic.