Mortality from external causes in late adolescence and early adulthood by gestational age and sex: a population-based cohort study in four Nordic countries.

BACKGROUND: External causes of death, such as accidents, substance use, and suicide, contribute substantially to mortality during adolescence and early adulthood and show marked sex differences. Individuals born preterm are at increased risk of mental disorders, and impaired cognitive and executive functions, potentially increasing their vulnerability to death from external causes. We investigated sex-specific associations between gestational age at birth and mortality from external causes during late adolescence and early adulthood. METHODS: Individual level data from national health registries in Denmark (1978-2001), Finland (1987-2003), Norway (1967-2002), and Sweden (1974-2001) were linked to form nationwide cohorts. In total, 6,924,697 participants were followed from age 15 years to a maximum of 50 years in 2016-2018. Gestational age was categorized as "very/moderately preterm" (23-33 weeks), "late preterm" (34-36 weeks), "early term" (37-38 weeks), "full term" (39-41 weeks), and "post term" (42-44 weeks). Outcomes were mortality from external causes overall and from the largest subgroups transport accidents, suicide, and drugs or alcohol. We estimated sex-specific hazard ratios (HRs), with full term as the reference, and pooled each country's estimates in meta-analyses. RESULTS: Across gestational ages mortality was higher for males than females. Individuals born very/moderately preterm had higher mortality from external causes, with HRs 1.11 (95% confidence interval [CI] 0.99-1.24) for males and 1.55 (95% CI 1.28-1.88) for females. Corresponding estimates for late preterm born were 1.11 (95% CI 1.04-1.18) and 1.15 (95% CI 1.02-1.29), respectively. Those born very/moderately preterm had higher mortality from transport accidents, but precision was low. For females, suicide mortality was higher following very/moderately preterm birth (HR 1.76, 95% CI 1.34-2.32), but not for males. Mortality from drugs or alcohol was higher in very/moderately and late preterm born males (HRs 1.23 [95% CI 0.99-1.53] and 1.29 [95% CI 1.16-1.45], respectively) and females (HRs 1.53 [95% CI 0.97-2.41] and 1.35 [95% CI 1.07-1.71], respectively, with some heterogeneity across countries). CONCLUSIONS: Mortality from external causes overall was higher in preterm than full term born among both males and females. A clear sex difference was seen for suicide, where preterm birth was a risk factor in females, but not in males.

Body mass index and risk of over 100 cancer forms and subtypes in 4.1 million individuals in Sweden: the Obesity and Disease Development Sweden (ODDS) pooled cohort study.

Background: Obesity, assessed by body mass index (BMI), is an established risk factor for 13 cancers. We aimed to identify further potential obesity-related cancers and to quantify their association with BMI relative to that of established obesity-related cancers. Methods: Using Cox regression models on 4,142,349 individuals in Sweden (mean age 27.1 years at weight measurement), we calculated hazard ratios (HRs) for the association between BMI and the risk of 122 cancers and cancer subtypes, grouped by topography and morphology. Cancers with a positive association (i.e., HR >1) at an α-level of 0.05 for obesity (BMI ≥30 kg/m2) vs. normal weight (BMI 18.5-24.9 kg/m2) or per 5 kg/m2 higher BMI, for which obesity is not an established risk factor, were considered potentially obesity related. Findings: After 100.2 million person-years of follow-up, 332,501 incident cancer cases were recorded. We identified 15 cancers in men and 16 in women as potentially obesity related. These were cancers of the head and neck, gastrointestinal tract, malignant melanoma, genital organs, endocrine organs, connective tissue, and haematological malignancies. Among these, there was evidence of differential associations with BMI between subtypes of gastric cancer, small intestine cancer, cervical cancer, and lymphoid neoplasms (P values for heterogeneity in HRs <0.05). The HR (95% confidence interval) per 5 kg/m2 higher BMI was 1.17 (1.15-1.20) in men and 1.13 (1.11-1.15) in women for potential obesity-related cancers (51,690 cases), and 1.24 (1.22-1.26) in men and 1.12 (1.11-1.13) in women for established obesity-related cancers (84,384 cases). Interpretation: This study suggests a large number of potential obesity-related cancers could be added to already established ones. Importantly, the magnitudes of the associations were largely comparable to those of the already established obesity-related cancers. We also provide evidence of specific cancer subtypes driving some associations with BMI. Studies accounting for cancer-specific confounders are needed to confirm these findings. Funding: Swedish Research Council, Swedish Cancer Society, Mrs. Berta Kamprad's Cancer Foundation, Crafoord Foundation, Cancer Research Foundation at the Department of Oncology, Malmö University Hospital, and China Scholarship Council.

Understanding risk factors for endometrial cancer in young women.

BACKGROUND: The American Cancer Society recommends physicians inform average risk women about endometrial cancer (EC) risk on reaching menopause, but new diagnoses are rising fastest in women <50 years. Educating these women about EC risks requires knowledge of risk factors. However, EC in young women is rare and challenging to study in single study populations. METHODS: We included 13,846 incident EC patients (1,639 < 50 years) and 30,569 matched control individuals from the Epidemiology of Endometrial Cancer Consortium. We used generalized linear models to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for 6 risk factors and EC risk. We created a risk score to evaluate the combined associations and population attributable fractions of these factors. RESULTS: In younger and older women, we observed positive associations with BMI and diabetes, and inverse associations with age at menarche, oral contraceptive use, and parity. Current smoking was associated with reduced risk only in women ≥50 years (PHet<0.01). BMI was the strongest risk factor [OR≥35 vs <25 kg/m2=5.57 (95% CI:4.33-7.16) for <50 years; OR≥35 vs <25 kg/m2=4.68 (95% CI : 4.30-5.09) for ≥50 years; PHet=0.14]. Possessing ≥4 risk factors was associated with ∼9-fold increased risk in women <50 years and ∼4-fold increased risk in women ≥50 years (PHet<0.01). Together, 59.1% of ECs in women <50 and 55.6% in women ≥50 were attributable to these factors. CONCLUSIONS: Our data confirm younger and older women share common EC risk factors. Early educational efforts centered on these factors may help mitigate the rising EC burden in young women.

Time trends of the association of body mass index with mortality in 3.5 million young Swedish adults.

PURPOSE: We investigated time trends of the obesity-mortality association, accounting for age, sex, and cause-specific deaths. METHODS: We analysed pooled nationwide data in Sweden for 3,472,310 individuals aged 17-39 years at baseline in 1963-2016. Cox regression and flexible parametric survival models investigated BMI-mortality associations in sub-groups of sex and baseline calendar years (men: <1975, 1975-1985, ≥1985 and women: <1985, 1985-1994, ≥1995). RESULTS: Comparing men with obesity vs. normal weight, all-cause and "other-cause" mortality associations decreased over periods; HR (95% CI) 1.92 (1.83-2.01) and 1.70 (1.58-1.82) for all-cause and 1.72 (1.58-1.87) and 1.40 (1.28-1.53) for "other-cause" mortality in <1975 and ≥1985, but increased for CVD mortality; HR 2.71 (2.51-2.94) and 3.91 (3.37-4.53). Higher age at death before 1975 coincided with more obesity-related deaths at higher ages. Furthermore, the all-cause mortality association for different ages in men showed no clear differences between periods (p-interaction=0.09), suggesting no calendar effect after accounting for attained age. Similar, but less pronounced, results were observed in women. Associations with cancer mortality showed no clear trends in men or in women. CONCLUSIONS: Accounting for differences in age and death causes between calendar periods when investigating BMI-mortality time trends may avoid misinterpreting the risks associated with obesity over time.

Cohort profile: The Obesity and Disease Development Sweden (ODDS) study, a pooled cohort.

PURPOSE: The Obesity and Disease Development Sweden (ODDS) study was designed to create a large cohort to study body mass index (BMI), waist circumference (WC) and changes in weight and WC, in relation to morbidity and mortality. PARTICIPANTS: ODDS includes 4 295 859 individuals, 2 165 048 men and 2 130 811 women, in Swedish cohorts and national registers with information on weight assessed once (2 555 098 individuals) or more (1 740 761 individuals), in total constituting 7 733 901 weight assessments at the age of 17-103 years in 1963-2020 (recalled weight as of 1911). Information on WC is available in 152 089 men and 212 658 women, out of whom 108 795 have repeated information on WC (in total 512 273 assessments). Information on morbidity and mortality was retrieved from national registers, with follow-up until the end of 2019-2021, varying between the registers. FINDINGS TO DATE: Among all weight assessments (of which 85% are objectively measured), the median year, age and BMI (IQR) is 1985 (1977-1994) in men and 2001 (1991-2010) in women, age 19 (18-40) years in men and 30 (26-36) years in women and BMI 22.9 (20.9-25.4) kg/m2 in men and 23.2 (21.2-26.1) kg/m2 in women. Normal weight (BMI 18.5-24.9 kg/m2) is present in 67% of assessments in men and 64% in women and obesity (BMI≥30 kg/m2) in 5% of assessments in men and 10% in women. The median (IQR) follow-up time from the first objectively measured or self-reported current weight assessment until emigration, death or end of follow-up is 31.4 (21.8-40.8) years in men and 19.6 (9.3-29.0) years in women. During follow-up, 283 244 men and 123 457 women died. FUTURE PLANS: The large sample size and long follow-up of the ODDS Study will provide robust results on anthropometric measures in relation to risk of common diseases and causes of deaths, and novel findings in subgroups and rarer outcomes.

Association of infertility and recurrent pregnancy loss with the risk of dementia.

Emerging evidence has shown the association between female reproductive histories (e.g., menarche age, parity, premature and early menopause) and the risk of dementia. However, little attention has been given to infertility and pregnancy loss. To examine the associations of infertility, recurrent miscarriages, and stillbirth with the risk of dementia, this study used data from four cohorts in the International Collaboration for a Life Course Approach to Reproductive Health and Chronic Disease Events. Women with data on at least one of the reproductive exposures of interest, dementia, and all covariates were included. Histories of infertility, miscarriage, and stillbirth were self-reported. Dementia (including Alzheimer's disease) was identified through surveys, aged care, pharmaceutical, hospital, and death registry data. Cause-specific Cox regression models were used to estimate the hazard ratios of dementia, accounting for well-established risk factors of dementia, study variability, and within-study correlation. Overall, 291,055 women were included at a median (interquartile range) age of 55.0 (47.0-62.0) at baseline. During the median (interquartile range) follow-up period of 13.0 (12.0-14.0) years, 3334 (1.2%) women developed dementia. Compared to women without stillbirth, a history of recurrent stillbirths (≥ 2) was associated with 64% higher risk of dementia (adjusted hazard ratio = 1.64, 95% confidence interval: 1.46-1.85). Compared to women without miscarriage, women with recurrent miscarriages (≥ 3) were at 22% higher risk of dementia (adjusted hazard ratio = 1.22, 95% confidence interval: 1.19-1.25). These findings suggest that recurrent stillbirths is a risk factor for dementia and may need to be considered in risk assessment of dementia in women.

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.

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.

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.

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.

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.

Hypertension and Risk of Endometrial Cancer: A Pooled Analysis in the Epidemiology of Endometrial Cancer Consortium (E2C2).

BACKGROUND: The incidence rates of endometrial cancer are increasing, which may partly be explained by the rising prevalence of obesity, an established risk factor for endometrial cancer. 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 endometrial cancer remains unclear. In this study, we evaluated hypertension as an independent risk factor for endometrial cancer and whether this association is modified by other established risk factors. METHODS: We included 15,631 endometrial cancer 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 ORs and 95% confidence intervals (CI) to evaluate the association between hypertension and endometrial cancer 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 endometrial cancer (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 versus cohort studies. Stronger associations were also noted for pre-/perimenopausal women and never users of postmenopausal hormone therapy. CONCLUSIONS: Hypertension is associated with endometrial cancer 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 endometrial cancer.

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.

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.

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.

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.

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.