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The association between intrauterine growth restriction and cardiovascular disease (CVD) later in life might be confounded by familial factors. We conducted a binational register-based cohort study to assess associations of birth weight for gestational age (GA), a proxy for intrauterine growth restriction, and GA with CVD risk in early adulthood, before and after addressing familial factors via sibling comparison. We included 3,410,334 live nonmalformed singleton births from Sweden (1973–1996) and Denmark (1978–1998). During a median follow-up period of 10 years from age 18 years onwards, 29,742 individuals developed incident CVD (hypertension, ischemic heart disease, or cerebrovascular disease). Compared with individuals born with appropriate birth weight for GA (AGA; 10th–90th percentiles) or full term (39–40 gestational weeks), individuals born severely small for GA (SGA; ≤3rd percentile) or preterm (22–36 weeks) were at increased risk of CVD (hazard ratio (HR) = 1.38 (95% confidence interval (CI): 1.32, 1.45) and HR = 1.31 (95% CI: 1.25, 1.38), respectively). The association was attenuated when comparing individuals born SGA with their AGA siblings (HR = 1.11, 95% CI: 0.99, 1.25) but remained robust when comparing individuals born preterm with their term siblings (HR = 1.21, 95% CI: 1.07, 1.37). Our findings suggest that both SGA and preterm birth are associated with CVD risk in early adulthood, with greater familial confounding noted for SGA birth. [ABSTRACT FROM AUTHOR]

Objective: To evaluate associations between gestational diabetes mellitus (GDM) and various incident cardiovascular disease (CVD) end points, considering the effects of the mediating role of type 2 diabetes and shared environmental/familial factors.Research Design and Methods: This population-based cohort study included 10,02,486 parous women in Denmark during 1978-2016. We used Cox regression to 1) examine the associations of GDM with overall and type-specific CVDs using full-cohort and sibling-matched analysis, 2) quantify the impact of type 2 diabetes after GDM using mediation analysis, and 3) assess whether these associations were modified by prepregnancy obesity or maternal history of CVD.Results: Women with a history of GDM had a 40% increased overall CVD risk (hazard ratio [HR] 1.40, 95% CI 1.35-1.45). Sibling-matched analyses yielded similar results (HR 1.44, 95% CI 1.28-1.62). The proportion of association between GDM and overall CVD explained by subsequent type 2 diabetes was 23.3% (15.4-32.8%). We observed increased risks of specific CVDs, including 65% increased stroke risk and more than twofold risks for myocardial infarction, heart failure, and peripheral artery disease. The elevated overall risks were more pronounced among women with GDM and prepregnancy obesity or maternal history of CVD.Conclusions: A history of GDM was associated with increased risks of overall and specific CVDs. Increased risks were partly explained by subsequent type 2 diabetes, and the need to identify other pathways remains important. Continuous monitoring of women with a history of GDM, especially those with prepregnancy obesity or maternal history of CVD, may provide better opportunities to reduce their cardiovascular risk. [ABSTRACT FROM AUTHOR]

Background: Atopic diseases are characterized by dysregulated inflammatory response, which may incur the onset of peripartum mental disorders, but the impact remains unknown. This study examined whether and to what extent the history of atopic diseases is associated with newly onset peripartum mental disorders. Methods: Using population‐based registries, we identified all primiparous women who gave birth to live singletons in Denmark during 1978–2016 (n = 937,422). The exposure was hospital contact due to the three major types of atopic diseases—asthma, atopic dermatitis, and allergic rhinitis—before conception. The primary outcome was any hospital contact for mental disorder during pregnancy and 1‐year postpartum, which was further classified into affective disorders, neurotic, stress‐related and somatoform disorders, and substance abuse. The follow‐up started from the date of conception and ended at the date of the first diagnosis of mental disorders, 1‐year postpartum, death, emigration, or December 31, 2016, whichever came first. Cox regression was used, adjusted for calendar year, age at childbirth, education, residence, and Charlson comorbidity index. Results: A total of 24,016 (2.6%) women received diagnosis of at least one of the three atopic diseases before conception (asthma, 1.7%; atopic dermatitis, 0.6%; and allergic rhinitis, 0.8%). Exposure to asthma, atopic dermatitis, or allergic rhinitis was associated with a 37% increased overall risk of peripartum mental disorders (hazard ratio [HR], 1.37; 95% confidence interval [CI], 1.27–1.49). Higher risks were observed among women with more frequent hospital contacts for atopic disease (HR, 1.80; 95% CI, 1.37–2.35; ≥5 times), and with recent hospital contacts for atopic disease (HR, 1.74; 95% CI, 1.48–2.06; within 2 years before conception). Specific associations were observed between asthma and neurotic, stress‐related and somatoform disorders (HR, 1.40; 95% CI, 1.21–1.62), and between atopic dermatitis and substance abuse (HR, 1.62; 95% CI, 1.12–2.34). Conclusions: History of asthma, atopic dermatitis, and allergic rhinitis before conception was associated with increased risks of peripartum mental disorders. Women who have atopic diseases before pregnancy may benefit from systematic mental health monitoring. [ABSTRACT FROM AUTHOR]

Background: The prevalence of cardiovascular disease (CVD) has been increasing in children, adolescents, and young adults in recent decades. Exposure to adverse intrauterine environment in fetal life may contribute to the elevated risk of early-onset CVD. Many studies have shown that maternal hypertensive disorders of pregnancy (HDP) are associated with increased risks of congenital heart disease, high blood pressure, increased BMI, and systemic vascular dysfunction in offspring. However, empirical evidence on the association between prenatal exposure to maternal HDP and early-onset CVD in childhood and adolescence remains limited.Methods and Findings: We conducted a population-based cohort study using Danish national health registers, including 2,491,340 individuals born in Denmark from 1977 to 2018. Follow-up started at birth and ended at the first diagnosis of CVD, emigration, death, or 31 December 2018, whichever came first. Exposure of maternal HDP was categorized as preeclampsia or eclampsia (n = 68,387), gestational hypertension (n = 18,603), and pregestational hypertension (n = 15,062). Outcome was the diagnosis of early-onset CVD from birth to young adulthood (up to 40 years old). We performed Cox proportional hazards regression to evaluate the associations and whether the association differed by maternal history of CVD or diabetes before childbirth. We further assessed the association by timing of onset and severity of preeclampsia. The median follow-up time was 18.37 years, and 51.3% of the participants were males. A total of 4,532 offspring in the exposed group (2.47 per 1,000 person-years) and 94,457 in the unexposed group (2.03 per 1,000 person-years) were diagnosed with CVD. We found that exposure to maternal HDP was associated with an increased risk of early-onset CVD (hazard ratio [HR]: 1.23; 95% CI = 1.19 to 1.26; P < 0.001). The HRs for preeclampsia or eclampsia, gestational hypertension, and pregestational hypertension were 1.22 (95% CI, 1.18 to 1.26; P < 0.001), 1.25 (95% CI, 1.17 to 1.34; P < 0.001), and 1.28 (95% CI, 1.15 to 1.42; P < 0.001), respectively. We also observed increased risks for type-specific CVDs, in particular for hypertensive disease (HR, 2.11; 95% CI, 1.96 to 2.27; P < 0.001) and myocardial infarction (HR, 1.49; 95% CI, 1.12 to 1.98; P = 0.007). Strong associations were found among offspring of mothers with CVD history (HR, 1.67; 95% CI, 1.41 to 1.98; P < 0.001) or comorbid diabetes (HR, 1.56; 95% CI, 1.34 to 1.83; P < 0.001). When considering timing of onset and severity of preeclampsia on offspring CVD, the strongest association was observed for early-onset and severe preeclampsia (HR, 1.48, 95% CI, 1.30 to 1.67; P < 0.001). Study limitations include the lack of information on certain potential confounders (including smoking, physical activity, and alcohol consumption) and limited generalizability in other countries with varying disparities in healthcare.Conclusions: Offspring born to mothers with HDP, especially mothers with CVD or diabetes history, were at increased risks of overall and certain type-specific early-onset CVDs in their first decades of life. Further research is warranted to better understand the mechanisms underlying the relationship between maternal HDP and early-onset CVD in offspring. [ABSTRACT FROM AUTHOR]

Aim: To investigate the association between a maternal history of spontaneous abortion and intellectual disability in children. Method: This cohort study included 1 778 786 children (913 340 males, 865 085 females, 361 missing data; mean age 15y 2mo, SD 8y 11mo, range birth to 40y) born in Denmark between 1977 and 2016. Cox proportional hazard regression was used to estimate the hazard ratios (HRs) of intellectual disability. Results: The overall HR of intellectual disability for children with a maternal history of spontaneous abortion was 1.17 (95% confidence interval [CI] 1.12–1.22) and the risk for multiple spontaneous abortions (HR=1.30, 95% CI 1.20–1.40) was higher than for a single spontaneous abortion (HR=1.13, 95% CI 1.07–1.18). When only cases of inpatient intellectual disability were included, the estimates increased slightly: the overall HR was 1.22 (95% CI 1.12–1.32), the HR for multiple spontaneous abortions was 1.37 (95% CI 1.20–1.58), and the HR for a single spontaneous abortion was 1.17 (95% CI 1.07–1.28). The risks were similar regardless of whether spontaneous abortion occurred before or after the index delivery. Estimates were nearly unchanged after adjusting for preterm birth, low birthweight, or Apgar score. Interpretation: Children born to mothers with spontaneous abortion, especially multiple spontaneous abortions, may be at a higher risk of intellectual disability in later life, regardless of whether spontaneous abortion occurred before or after the index delivery. The findings have clinical implications for targeted early intervention of children with intellectual disability. What this paper addsA maternal history of spontaneous abortion was associated with a risk of intellectual disability in offspring.The risk was higher in children whose mothers previously had multiple spontaneous abortions.Similar risks were observed regardless of whether spontaneous abortion occurred before or after childbirth. What this paper adds: A maternal history of spontaneous abortion was associated with a risk of intellectual disability in offspring.The risk was higher in children whose mothers previously had multiple spontaneous abortions.Similar risks were observed regardless of whether spontaneous abortion occurred before or after childbirth. [ABSTRACT FROM AUTHOR]

Maternal hypertensive disorders during pregnancy (HDP) have been associated with neuropsychiatric problems in offspring. We aim to investigate the associations between specific types of maternal HDP and offspring neurodevelopmental disorders and further examine whether the timing of onset and severity of HDP would affect these associations. The study population consisted of 4,489,044 live-born singletons in Denmark during 1978–2012 and Sweden during 1987–2010. Maternal HDP was categorized into chronic hypertension, gestational hypertension, and pre-eclampsia; pre-eclampsia was further stratified according to timing (early-onset, late-onset), or severity (moderate, severe) of the disease. Neurodevelopmental disorders, including attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and intellectual disability (ID), were defined by ICD-coded register diagnosis. Cox regression was used to calculate hazard ratios (HR) while adjusting for potential confounders, and sibling analyses assessed the influence of unmeasured shared familial factors. Maternal HDP was associated with increased risks of ADHD (HR, 1.24; 95% confidence interval [CI], 1.20–1.28), ASD (1.29 [1.24–1.34]), and ID (1.58 [1.50–1.66]) in offspring, respectively, which was mostly driven by pre-eclampsia. The strongest associations were observed for early-onset and severe pre-eclampsia, and the corresponding HRs for ADHD, ASD and ID were 1.93 [1.73–2.16], 1.86 [1.61–2.15], and 3.99 [3.42–4.65], respectively. The results were similar in the sibling analyses. The associations between maternal HDP and offspring neurodevelopmental disorders were consistent across the subgroups of sex, preterm status, parity, maternal age and psychiatric disorders. Maternal HDP, especially early-onset pre-eclampsia, are associated with increased risks of ADHD, ASD, and ID in particular, independent of shared familial factors. [ABSTRACT FROM AUTHOR]

Background: Fetal exposure risk factors are associated with increased autism spectrum disorder (ASD) risk. New hypotheses regarding multigenerational risk for ASD have been proposed, but epidemiological evidence is largely lacking. We evaluated whether parental birth characteristics, including preterm birth and low birthweight, were associated with ASD risk in offspring.Methods: We conducted a nationwide register-based cohort study that included 230 174 mother-child and 157 926 father-child pairs in Denmark. Logistic regression models were used to estimate odds ratios (OR) and 95% confidence intervals (CI) for offspring ASD according to parental preterm (<37 weeks) and low birthweight (<2500 g) status, with or without adjustment for certain grandmaternal sociodemographic factors. Mediation analyses were performed for selected parental and offspring health-related factors.Results: Offspring of mothers or fathers with adverse birth characteristics had about 31-43% higher risk for ASD (maternal preterm birth, OR = 1.31, 95% CI= 1.12, 1.55; maternal low birthweight, OR = 1.35, 95% CI: 1.17,1.57; paternal preterm birth, OR = 1.43, 95% CI = 1.18, 1.73; paternal low birthweight, OR = 1.38, 95% CI= 1.13, 1.70). Parents born very preterm (<32 weeks) marked a nearly 2-fold increase in ASD risk in their children. These associations were slightly attenuated upon adjustment for grandmaternal sociodemographic factors. Mediation analyses suggested that parental social-mental and offspring perinatal factors might explain a small magnitude of the total effect observed, especially for maternal birth characteristic associations.Conclusions: Offspring of parents born with adverse characteristics had an elevated risk for ASD. Transmission of ASD risk through maternal and paternal factors should be considered in future research on ASD aetiology. [ABSTRACT FROM AUTHOR]

Background: Socioeconomic disparities in infant mortality have persisted for decades in high-income countries and may have become stronger in some populations. Therefore, new understandings of the mechanisms that underlie socioeconomic differences in infant deaths are essential for creating and implementing health initiatives to reduce these deaths. We aimed to explore whether and the extent to which preterm birth (PTB) and small for gestational age (SGA) at birth mediate the association between maternal education and infant mortality.Methods and Findings: We developed a population-based cohort study to include all 1,994,618 live singletons born in Denmark in 1981-2015. Infants were followed from birth until death, emigration, or the day before the first birthday, whichever came first. Maternal education at childbirth was categorized as low, medium, or high. An inverse probability weighting of marginal structural models was used to estimate the controlled direct effect (CDE) of maternal education on offspring infant mortality, further split into neonatal (0-27 days) and postneonatal (28-364 days) deaths, and portion eliminated (PE) by eliminating mediation by PTB and SGA. The proportion eliminated by eliminating mediation by PTB and SGA was reported if the mortality rate ratios (MRRs) of CDE and PE were in the same direction. The MRRs between maternal education and infant mortality were 1.63 (95% CI 1.48-1.80, P < 0.001) and 1.19 (95% CI 1.08-1.31, P < 0.001) for low and medium versus high education, respectively. The estimated proportions of these total associations eliminated by reducing PTB and SGA together were 55% (MRRPE = 1.27, 95% CI 1.15-1.40, P < 0.001) for low and 60% (MRRPE = 1.11, 95% CI 1.01-1.22, P = 0.037) for medium versus high education. The proportions eliminated by eliminating PTB and SGA separately were, respectively, 46% and 11% for low education (versus high education) and 48% and 13% for medium education (versus high education). PTB and SGA together contributed more to the association of maternal educational disparities with neonatal mortality (proportion eliminated: 75%-81%) than with postneonatal mortality (proportion eliminated: 21%-23%). Limitations of the study include the untestable assumption of no unmeasured confounders for the causal mediation analysis, and the limited generalizability of the findings to other countries with varying disparities in access and quality of perinatal healthcare.Conclusions: PTB and SGA may play substantial roles in the relationship between low maternal education and infant mortality, especially for neonatal mortality. The mediating role of PTB appeared to be much stronger than that of SGA. Public health strategies aimed at reducing neonatal mortality in high-income countries may need to address socially related prenatal risk factors of PTB and impaired fetal growth. The substantial association of maternal education with postneonatal mortality not accounted for by PTB or SGA could reflect unaddressed educational disparities in infant care or other factors. [ABSTRACT FROM AUTHOR]

Background: Whether labour epidural analgesia impacts risk of neurodevelopmental disorders in offspring is unsettled, raising public and scientific concerns. We explored the association between maternal labour epidural analgesia and autism spectrum disorder, and specific developmental disorder, attention-deficit hyperactivity disorder, intellectual disability, and epilepsy in offspring.Methods: This nationwide population-based cohort study included 624 952 live-born singletons delivered by women who intended to deliver vaginally (i.e. vaginal and intrapartum Caesarean deliveries) in Denmark from 2005 to 2016. A total of 80 862 siblings discordant for exposure to labour epidural analgesia were analysed in a sibling-matched analysis. Both full-cohort and sibling-matched analyses were performed to estimate hazard ratios (HRs) of offspring risk of autism spectrum disorder, specific developmental disorder, attention-deficit hyperactivity disorder, intellectual disability, and epilepsy, according to exposure to labour epidural analgesia, adjusted for maternal socio-economic, pregnancy, and perinatal covariates.Results: In the full cohort, maternal labour epidural analgesia was associated with autism spectrum disorder in offspring (HR 1.11; 95% confidence interval [CI]: 1.04-1.18); however, in the sibling-matched analysis, no association with autism spectrum disorder was found (HR 1.03; 95% CI: 0.84-1.27). The association between labour epidural analgesia and specific developmental disorder (HR 1.12; 95% CI: 1.03-1.22) in the full cohort also disappeared in the sibling-matched analysis (HR 1.01; 95% CI: 0.78-1.31). No association between maternal labour epidural analgesia and the remaining neurodevelopmental disorders was found overall (attention-deficit hyperactivity disorder, HR 0.98; 95% CI: 0.92-1.03; intellectual disability, HR 0.98; 95% CI: 0.85-1.14; epilepsy, HR 0.89; 95% CI: 0.79-1.00) or in the sibling-matched analyses.Conclusions: Our findings did not support an association between maternal attention-deficit hyperactivity disorder and autism spectrum disorder, specific developmental disorder, attention-deficit hyperactivity disorder, intellectual disability, or epilepsy. [ABSTRACT FROM AUTHOR]

Importance: Maternal infection is common during pregnancy and is an important potential cause of fetal genetic and immunological abnormalities. Maternal infection has been reported to be associated with childhood leukemia in previous case-control or small cohort studies., Objective: To evaluate the association of maternal infection during pregnancy with childhood leukemia among offspring in a large study., Design, Setting, and Participants: This population-based cohort study used data from 7 Danish national registries (including the Danish Medical Birth Register, the Danish National Patient Registry, the Danish National Cancer Registry, and others) for all live births in Denmark between 1978 and 2015. Swedish registry data for all live births between 1988 and 2014 were used to validate the findings for the Danish cohort. Data were analyzed from December 2019 to December 2021., Exposures: Maternal infection during pregnancy categorized by anatomic locations identified from the Danish National Patient Registry., Main Outcomes and Measures: The primary outcome was any leukemia; secondary outcomes were acute lymphoid leukemia (ALL) and acute myeloid leukemia (AML). Offspring childhood leukemia was identified in the Danish National Cancer Registry. Associations were first assessed in the whole cohort using Cox proportional hazards regression models, adjusted for potential confounders. A sibling analysis was performed to account for unmeasured familial confounding., Results: This study included 2 222 797 children, 51.3% of whom were boys. During the approximately 27 million person-years of follow-up (mean [SD], 12.0 [4.6] years per person), 1307 children were diagnosed with leukemia (ALL, 1050; AML, 165; or other, 92). Children born to mothers with infection during pregnancy had a 35% increased risk of leukemia (adjusted hazard ratio [HR], 1.35 [95% CI, 1.04-1.77]) compared with offspring of mothers without infection. Maternal genital and urinary tract infections were associated with a 142% and 65% increased risk of childhood leukemia, with HRs of 2.42 (95% CI, 1.50-3.92) and 1.65 (95% CI, 1.15-2.36), respectively. No association was observed for respiratory tract, digestive, or other infections. The sibling analysis showed comparable estimates to the whole-cohort analysis. The association patterns for ALL and AML were similar to that for any leukemia. No association was observed for maternal infection and brain tumors, lymphoma, or other childhood cancers., Conclusions and Relevance: In this cohort study of approximately 2.2 million children, maternal genitourinary tract infection during pregnancy was associated with childhood leukemia among offspring. If confirmed in future studies, our findings may have implications for understanding the etiology and developing preventive measures for childhood leukemia.

Importance: Maternal immune activation during pregnancy is associated with increased risks of several mental disorders in offspring during childhood, but little is known about how maternal autoimmune diseases during pregnancy are associated with mental health in offspring during and after childhood., Objective: To investigate the association between maternal autoimmune diseases before childbirth and risk of mental disorders among offspring up to early adulthood., Design, Setting, and Participants: This population-based nationwide cohort study used data from Danish national registers on singletons born in Denmark from 1978 to 2015 with up to 38 years of follow-up. Data analyses were conducted from March 1, 2020, through September 30, 2021., Exposures: Maternal autoimmune disease diagnosed before or during pregnancy according to the Danish National Patient Register., Main Outcomes and Measures: The main outcome was mental disorders, defined by hospital diagnoses, in offspring. Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% CIs for mental disorders., Results: Of the 2 254 234 singleton infants included in the study (median age, 16.7 years [IQR, 10.5-21.7 years]; 51.28% male), 2.26% were born to mothers with autoimmune diseases before childbirth. Exposed participants had an increased risk of overall mental disorders compared with their unexposed counterparts (HR, 1.16; 95% CI, 1.13-1.19; incidence, 9.38 vs 7.91 per 1000 person-years). Increased risks of overall mental disorders in offspring were seen in different age groups for type 1 diabetes (1-5 years: HR, 1.35 [95% CI, 1.17-1.57]; 6-18 years: HR, 1.24 [95% CI, 1.15-1.33]; >18 years: HR, 1.19 [95% CI, 1.09-1.30]) and rheumatoid arthritis (1-5 years: HR, 1.42 [95% CI, 1.16-1.74]; 6-18 years: HR, 1.19 [95% CI, 1.05-1.36]; >18 years: HR, 1.28 [95% CI, 1.02-1.60]). Regarding specific mental disorders, increased risk after exposure to any maternal autoimmune disorder was observed for organic disorders (HR, 1.54; 95% CI, 1.21-1.94), schizophrenia (HR, 1.35; 95% CI, 1.21-1.51), obsessive-compulsive disorder (HR, 1.42; 95% CI, 1.24-1.63), mood disorders (HR, 1.12; 95% CI, 1.04-1.21), and a series of neurodevelopmental disorders (eg, childhood autism [HR, 1.21; 95% CI, 1.08-1.36] and attention-deficit/hyperactivity disorder [HR, 1.19; 95% CI, 1.12-1.26])., Conclusions and Relevance: In this cohort study in Denmark, prenatal exposure to maternal autoimmune diseases was associated with increased risks of overall and type-specific mental disorders in offspring. Maternal type 1 diabetes and rheumatoid arthritis during pregnancy were associated with offspring's mental health up to early adulthood. Individuals prenatally exposed to autoimmune disease may benefit from long-term surveillance for mental disorders.

Background: Cardiovascular disease (CVD) is increasing in youths, but there is limited knowledge about the etiology of early-onset CVD. We aimed to examine the association between maternal education before childbirth and CVD risk in offspring during early adulthood (20 to 40 years of age)., Methods: This population-based cohort study included 112,3600 subjects born in Denmark during 1977 to 1996., Results: Compared with offspring born to mothers with high education, offspring born to mothers with low or medium education had 27% (hazard ratio, 1.27; 95% confidence interval, 1.23-1.30) or 12% (1.12; 1.09-1.15) increased overall risk of early-onset CVD, respectively. Increased risks were observed for most type-specific CVDs: in particular, for myocardial infarction (low [2.03; 1.55-2.65] or medium education [1.52; 1.16-1.99]), heart failure (low [1.59; 1.24-2.03] or medium education [1.51; 1.19-1.92]), and ischemic stroke (low [1.50; 1.28-1.76] or medium education [1.29; 1.10-1.51]). We observed high incidences of CVD in offspring of mothers with comorbid CVD (low [1.67; 1.51-1.86] or medium education [1.46; 1.29-1.64]), compared with those of mothers with high education and no history of CVD., Conclusions: Low maternal education before childbirth, especially with maternal comorbid CVD, is significantly associated with increased risk of overall CVD and most type-specific CVDs in offspring in early adulthood. The influence of maternal education on future offspring CVD should be taken into consideration in the assessment of CVD risks from early decades of life., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Importance: The associations of maternal history of spontaneous abortion (SA) and stillbirth with congenital heart disease (CHD) remain elusive., Objective: To evaluate the associations of maternal history of pregnancy loss with CHD in offspring and the role of maternal type 2 diabetes., Design, Setting, and Participants: This population-based cohort study included singleton live offspring born between January 1, 1977, and December 31, 2016, identified through Danish national health registries. Statistical analysis was performed from October 1, 2019, through September 1, 2021., Exposures: Maternal history of SA, with frequency varying from 1 or 2 to 3 or more episodes, and maternal history of single and multiple stillbirths., Main Outcomes and Measures: Overall CHD identified by hospital diagnosis. Cox proportional hazard regression was used to estimate the hazard ratio (HR) of CHD. Diabetes was evaluated as a potential confounder and a potential effect modifier., Results: Among 1 642 534 included offspring (mean [SD] age, 14.11 [8.39] years; 843 265 male [51.35%]), 246 669 (15.02%) were born to mothers with a history of SA and 9750 (0.59%) were born to mothers with a history of stillbirth. The HRs of CHD were 1.16 (95% CI, 1.13-1.20) for offspring with a maternal history of SA and 1.49 (95% CI, 1.32-1.68) for offspring with a maternal history of stillbirth. Significant dose-response associations were observed among offspring with a maternal history of 3 or more episodes of SA (HR, 1.60; 95% CI, 1.39-1.84) and those with maternal history of multiple stillbirths (HR, 2.75; 95% CI, 1.63-4.65). If only inpatient CHD cases were included, the risk of CHD was higher than that found in the main analysis, with HRs of 1.24 (95% CI, 1.19-1.30) for maternal history of SA and 1.78 (95% CI, 1.51-2.11) for maternal history of stillbirth. The observed associations were strengthened by maternal prepregnancy type 2 diabetes (HR for maternal history of SA, 1.65 [95% CI, 1.37-1.97]; HR for maternal history of stillbirth, 1.74 [95% CI, 1.06-2.85])., Conclusions and Relevance: These findings suggest that offspring born to mothers with a previous SA or stillbirth, especially multiple episodes, or with prepregnancy type 2 diabetes were at a higher risk of being diagnosed with CHD. These findings may help identify women at increased risk in whom detailed fetal heart assessment may be cost-effective and highlight the importance of screening for type 2 diabetes in women of reproductive age.

Aims/hypothesis: We aimed to investigate the associations between maternal diabetes before or during pregnancy and the risk of high refractive error (RE) in offspring until the age of 25 years., Methods: This nationwide register-based cohort study comprised 2,470,580 individuals born in 1977-2016. The exposure was maternal diabetes during or before pregnancy (type 1 diabetes, type 2 diabetes and gestational diabetes). Cox regression was used to examine the association between maternal diabetes and the risk of high RE in offspring from birth until the age of 25 years, adjusting for multiple potential confounders., Results: During up to 25 years of follow-up, 553 offspring of mothers with diabetes and 19,695 offspring of mothers without diabetes were diagnosed with high RE. Prenatal exposure to maternal diabetes was associated with a 39% increased risk of high RE: HR 1.39 (95% CI 1.28, 1.51), p < 0.001; standardised cumulative incidence in unexposed offspring at 25 years of age 1.18% (95% CI 1.16%, 1.19%); cumulative incidence difference 0.72% (95% CI 0.51%, 0.94%). The elevated risks were observed for hypermetropia (HR 1.37 [95% CI 1.24, 1.51], p < 0.001), myopia (HR 1.34 [95% CI 1.08, 1.66], p = 0.007) and astigmatism (HR 1.58 [95% CI 1.29, 1.92], p < 0.001). The increased risks were more pronounced among offspring of mothers with diabetic complications (HR 2.05 [95% CI 1.60, 2.64], p < 0.001), compared with those of mothers with diabetes but no diabetic complications (HR 1.18 [95% CI 1.02, 1.37], p = 0.030)., Conclusions/interpretation: Our findings suggest that maternal diabetes during pregnancy is associated with an increased risk of high RE in offspring, in particular among those of mothers with diabetic complications. Early ophthalmological screening should be recommended in offspring of mothers with diabetes diagnosed before or during pregnancy., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: This study aimed to examine the association of a mother's loss of a close relative before or during pregnancy with intellectual disability (ID) in the offspring., Methods: We performed a nationwide population-based cohort study based on Danish national registries. All live-born singletons born in Denmark during the 1978-2016 period (n = 2,216,601) were followed up starting from birth to 38 years of age. Log-linear Poisson regression was used to estimate the association between maternal bereavement (the death of an older child, a partner, or a parent 1 year before or during pregnancy) and the risk of ID in the offspring., Results: Maternal bereavement during or before pregnancy was associated with an increased risk of ID (incidence rate ratio [IRR] = 1.15; 95% confidence interval [CI] = 1.04-1.28). The risk of ID was increased by 27% when maternal bereavement occurred during pregnancy (IRR = 1.27; 95% CI = 1.08-1.49). When stratifying on the child's sex, we also observed an increased risk of ID associated with maternal bereavement during pregnancy both for male (IRR = 1.25; 95% CI = 1.02-1.53) and for female (IRR = 1.31; 95% CI = 1.02-1.69), respectively. The IRRs for unnatural death of a relative were also elevated (IRR = 1.22; 95% CI = 0.91-1.64) in general, although the difference was not statistically significant., Conclusions: Our findings suggest that prenatal stress due to maternal loss of a close relative may increase the risk of offspring's ID of both sexes, in particular when the loss happened during pregnancy., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Psychosomatic Society.)

Importance: Maternal diabetes has been suggested as a risk factor for attention-deficit/hyperactivity disorder and autism in offspring, but evidence on its association with the full spectrum of psychiatric disorders remains lacking., Objective: To investigate the associations between maternal diabetes diagnosed before or during pregnancy and 10 types of psychiatric disorders in offspring during the first 4 decades of life., Design, Setting, and Participants: This population-based cohort study used data from several Danish nationwide medical and administrative registries in Denmark on all 2 413 335 live births from 1978 to 2016. Data were analyzed between October 1, 2019, and July 15, 2021., Exposures: Any maternal diabetes diagnosis during pregnancy (56 206 offspring [2.3%]) and 3 diabetes subtypes (pregestational type 1 diabetes, 22 614 offspring [1.0%]; pregestational type 2 diabetes, 6713 offspring [0.3%]; and gestational diabetes, 26 879 offspring [1.1%])., Main Outcomes and Measures: Outcomes included 10 types of psychiatric disorders: any psychiatric disorder, substance use disorders, schizophrenia, mood disorders, anxiety disorders, eating disorders, personality disorders, intellectual disorders, developmental disorders, and behavioral disorders. Hazard ratios (HRs) and 95% CIs were computed using Cox proportional hazards regression models. Covariates included maternal and paternal history of any psychiatric disorder, offspring sex, calendar period of birth, singleton status, and several maternal characteristics during pregnancy (ie, age, parity, educational level, smoking, cohabitation, residence, and body mass index). Sibship design and competing risk analyses were also conducted., Results: A total of 2 413 335 individuals (1 239 148 male participants [51%]; age range, 1-39 years; median age, 19.0 years [IQR, 5.8-20.8 years]) were included in this study. During the 39-year follow-up time, 151 208 offspring (6.4%) received a diagnosis of a psychiatric disorder. Offspring born to mothers with any diabetes diagnosis during pregnancy were at increased risk of developing any psychiatric disorder (HR, 1.15; 95% CI, 1.10-1.20), schizophrenia (HR, 1.55; 95% CI, 1.15-2.08), anxiety disorders (HR, 1.22; 95% CI, 1.09-1.36), intellectual disabilities (HR, 1.29; 95% CI, 1.11-1.50), developmental disorders (HR, 1.16; 95% CI, 1.03-1.30), and behavioral disorders (HR, 1.17; 95% CI, 1.08-1.27) compared with offspring born to mothers without a diabetes diagnosis during pregnancy. No association was observed for substance use disorders, mood disorders, eating disorders, and personality disorders., Conclusions and Relevance: This study shows a pattern that suggests that prenatal exposure to maternal diabetes during pregnancy was associated with increased risk of psychiatric disorders overall and most specific psychiatric disorders in offspring in their first 4 decades of life.

Background: No previous study has examined the effect of maternal hypothyroidism on a broad spectrum of cardiovascular disease (CVD) endpoints in the offspring., Methods: A nationwide population-based cohort study based on the linkage of several Danish nationwide registries was conducted to explore whether maternal hypothyroidism is associated with offspring's CVD. Altogether 1,041,448 singletons born between the 1st of January 1978 and the 31st of December 1998 were investigated from the age of 8 years to the 31st of December 2016. Exposure was maternal diagnosis of hypothyroidism across lifespan and the outcome of interest was a CVD diagnosis in the offspring. Cox regression models were performed to estimate the hazard ratios (HRs) of CVD., Results: Offspring born to mothers with hypothyroidism had an increased risk of CVD (hazard ratios (HR)=1.23, 95% confidence interval (CI): 1.12-1.35), and of several subcategories of CVD including hypertension, arrhythmia, and acute myocardial infarction in offspring. The magnitude of association was the most pronounced in an exposure occur during pregnancy (HR=1.71, 95% CI: 1.10-2.67), which is consistent across all the subgroup analysis, including sibling analysis., Conclusions: Maternal hypothyroidism is associated with an increased risk of CVD in offspring. Thyroid hormone insufficiency during pregnancy may predominantly contribute to the observed associations; however, the effects of a shared genetic background and a time-stable familial environment/lifestyle factors cannot be excluded., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Miao, Liu, Yuan, Madsen, Yu, László, Liang, Ji and Li.)

Importance: Nonoptimal gestational durations could be associated with neurodevelopmental disabilities, yet evidence regarding finer classification of gestational age and rates of multiple major neuropsychiatric disorders beyond childhood is limited., Objective: To comprehensively evaluate associations between 6 gestational age groups and rates of 9 major types and 8 subtypes of childhood and adult-onset neuropsychiatric disorders., Design, Setting, and Participants: This cohort study evaluated data from a nationwide register of singleton births in Denmark from January 1, 1978, to December 31, 2016. Data analyses were conducted from October 1, 2019, through November 15, 2020., Exposures: Gestational age subgroups were classified according to data from the Danish Medical Birth Register: very preterm (20-31 completed weeks), moderately preterm (32-33 completed weeks), late preterm (34-36 completed weeks), early term (37-38 completed weeks), term (39-40 completed weeks, reference), and late or postterm (41-45 completed weeks)., Main Outcomes and Measures: Neuropsychiatric diagnostic records (International Statistical Classification of Diseases and Related Health Problems, Tenth Revision codes F00-F99) were ascertained from the Danish Psychiatric Central Register up to August 10, 2017. Poisson regression was used to estimate the incidence rate ratio (IRR) and 95% CI for neuropsychiatric disorders, adjusting for selected sociodemographic factors., Results: Of all 2 327 639 singleton births studied (1 194 925 male newborns [51.3%]), 22 647 (1.0%) were born very preterm, 19 801 (0.9%) were born moderately preterm, 99 488 (4.3%) were born late preterm, 388 416 (16.7%) were born early term, 1 198 605 (51.5%) were born at term, and 598 682 (25.7%) were born late or postterm. A gradient of decreasing IRRs was found from very preterm to late preterm for having any or each of the 9 neuropsychiatric disorders (eg, very preterm: IRR, 1.49 [95% CI, 1.43-1.55]; moderately preterm: IRR, 1.23 [95% CI, 1.18-1.28]; late preterm: IRR, 1.17 [95% CI, 1.14-1.19] for any disorders) compared with term births. Individuals born early term had 7% higher rates (IRR, 1.07 [95% CI, 1.06-1.08]) for any neuropsychiatric diagnosis and a 31% higher rate for intellectual disability (IRR, 1.31 [95% CI, 1.25-1.37]) compared with those born at term. The late or postterm group had lower IRRs for most disorders, except pervasive developmental disorders, for which the rate was higher for postterm births compared with term births (IRR, 1.06 [95% CI, 1.03-1.09])., Conclusions and Relevance: Higher incidences of all major neuropsychiatric disorders were observed across the spectrum of preterm births. Early term and late or postterm births might not share a homogeneous low risk with individuals born at term. These findings suggest that interventions that address perinatal factors associated with nonoptimal gestation might reduce long-term neuropsychiatric risks in the population.

Importance: Advanced parental age has been associated with autism spectrum disorders (ASDs) in children. However, little is known about the association between grandparental age at the time of birth of the parent and the risk of ASD in the grandchildren., Objective: To estimate the associations between parental and grandparental age and ASD risk in children., Design, Setting, and Participants: This population-based, multigenerational cohort study used data from Danish national health registries. A parental age cohort was constructed to evaluate the association between parental age and ASD in 1 476 783 singleton children born from 1990 to 2013, and a multigenerational cohort was also constructed including 362 438 fathers and 458 234 mothers born from 1973 to 1990 for whom information on grandparental age was available. Data analyses were conducted from November 1, 2018, through February 7, 2020., Exposures: Parental age at childbirth and grandparental age at the time of the birth of the parent., Main Outcomes and Measures: Diagnoses of ASD in children were obtained from the Danish Psychiatric Central Register (1994-2017). Logistic regression analysis was used to estimate the associations between parental or grandparental age and ASD in children., Results: Of the 1 476 783 children born from 1990 to 2013, 758 066 (51.3%) were male, and 27 616 (1.9%) had ASD (20 467 [74.1%] were male). Advanced paternal or maternal age over 30 years was monotonically associated with increased ASD risk, with odds ratios (ORs) of 1.56 (95% CI, 1.45-1.68) for maternal age 40 years and older and 1.57 (95% CI, 1.39-1.78) for paternal age 50 years and older, compared with parents aged 25 to 29 years. In the multigenerational cohort, 9364 grandchildren (1.7%) had ASD. This study found U-shaped associations, in that ASD risk was higher among grandchildren of younger (≤19 years) maternal grandmothers (OR, 1.68; 95% CI, 1.52-1.85), younger maternal grandfathers (OR, 1.50; 95% CI, 1.26-1.78), and younger paternal grandmothers (OR, 1.18; 95% CI, 1.04-1.34), and older (≥40 years) paternal grandmothers (OR, 1.40; 95% CI, 1.03-1.90) compared with the grandchildren of grandparents who were aged 25 to 29 years at the time of giving birth to the parents., Conclusions and Relevance: These findings corroborate previous studies suggesting that advanced parental age is independently associated with increased ASD risk in children. This study also found that children with young maternal grandparents and children with young and old paternal grandparents had elevated ASD risk. Possible transmission of ASD risk across generations should be considered in etiological research on ASD.

Recent studies have shown that certain pharmacological agents used by fathers before conception may increase the risk of adverse neonatal outcomes in offspring. However, little is known about the effect of paternal use of antiepileptic drugs (AEDs) on congenital anomalies in children. Based on Danish national registers, we conducted a cohort study of 733, 282 singletons born from 1997 to 2008, with follow-up throughout 2013. The children whose fathers used AEDs during the 3 months before conception were categorized as the exposed. Logistic regression model was used to examine association between paternal AEDs use before conception and the risk of congenital anomalies in offspring. Compared with unexposed children, the exposed had a 23% increased risk of congenital anomalies (odds ratios (OR) 1.23, 95% confidence interval [CI] 1.10-1.37) after adjusting for potential confounders. When extending the exposure window to 1 year before conception to the end of pregnancy, except for those using AEDs during 3 months before conception (the susceptible period of exposure), the increased risks were also observed in children whose fathers were former users (i.e., those using AEDs only from 1 year to 3 months before conception) (OR 1.29, 95%CI 1.03-1.61) and later users (i.e., those using AEDs only during pregnancy) (OR 1.35, 95%CI 1.12-1.65). This study suggested that the mildly increased risk of congenital anomalies in the offspring associated with paternal AEDs use before conception may be attributable to the underlying indications related to AEDs use.

Background: Cerebral palsy (CP) is the most common physical developmental disability in childhood with a prevalence of 2 to 3 per 1000 live births. β2-adrenoreceptor agonist (β2AA) are widely used for the treatment of asthma. Maternal use of β2AAs may increase the risk of adverse neuro-psychiatric health outcomes in the offspring. No study, however, has evaluated the effect of prenatal exposure to β2AAs on the risk of CP., Objective: To examine the association between prenatal exposure to β2AAs and the risk of childhood cerebral palsy., Methods: This population-based cohort study included all live singleton births in Denmark from January 1, 1997 to December 31, 2003. The information on outpatient prescriptions of β2AAs was extracted from Danish National Prescription Registry. Children born to mothers who used β2AAs from 30 days before pregnancy until delivery were categorized as the exposed. To differentiate the effect of β2AAs from the underlying indications, the exposure window was further extended to 2 years before pregnancy and the exposed groups were re-defined to represent different periods of exposure to maternal use of β2AAs (use only before pregnancy, use only during pregnancy, and use both before and during pregnancy). Cases of CP were identified from the Danish Cerebral Palsy Register. Logistic regression was used to estimate incidence odds ratio (OR) of CP., Results: Among all the 442,278 singletons, 19,616 (4.44%) were exposed to β2AAs in utero (from 30 days before pregnancy until delivery). The risk of childhood CP was 0.21% in exposed and 0.19% in unexposed group, yielding an adjusted OR (aOR) 1.12 (95% confidence interval (CI): 0.82, 1.53). When extending the exposure time window to 2 years prior to pregnancy, no overall significant association was observed regardless of the exposure period. However, an increased risk of CP (aOR = 1.41, 95%CI: 0.92, 2.18) for maternal β2AAs use during pregnancy was observed in female offspring, especially in those born at term (aOR = 1.65, 95%CI: 1.02, 2.67). This increase was mainly attributed to an increased risk in those born to mothers who used β2AAs both before and during pregnancy (aOR = 1.81, 95%CI: 0.99, 3.33)., Conclusions: We observed an association between maternal β2AAs use during pregnancy and an increased risk of CP in female offspring, but we could not rule out confounding by the underlying indications for β2AAs., Competing Interests: The authors have declared that no competing interests exist.

Background: Mortality in children under five years has been widely studied, whereas mortality at 5-9 years has received little attention. Using unique data from national registers in three Nordic countries, we aimed to characterize mortality directionality in children aged 0 to 9 years., Methods and Findings: The cohort study included all children born in Denmark from 1973 to 2008 (n = 2,433,758), Sweden from 1973 to 2006 (n = 3,400,212), and a random sample of 89.3% of children born in Finland from 1987 to 2007 (n = 1,272,083). Children were followed from 0 to 9 years, and cumulative mortality and mortality rates were compared by age, gender, cause of death, and calendar periods. Among the 7,105,962 children, there were 48,299 deaths during study period. From 1981-1985 to 2001-2005, all-cause mortality rates were reduced by between 34% and 62% at different ages. Overall mortality rate ratio between boys and girls decreased from 1.25 to 1.21 with the most prominent reduction in children aged 5-9 years (from 1.59 to 1.19). Neoplasms, diseases of the nervous system and transport accidents were the most frequent cause of death after the first year of life. These three leading causes of death declined by 42% (from 6.2 to 3.6 per 100,000 person years), 43% (from 3.7 to 2.1) and 62% (from 3.9 to 1.5) in boys, and 25% (from 4.1 to 3.1 per 100000 person years), 42% (from 3.4 to 1.9) and 63% (from 3.0 to 1.1) in girls, respectively. Mortality from neoplasms was the highest in each age except infants when comparing cause-specific mortality, and half of deaths from diseases of the nervous system occurred in infancy. Mortality rate due to transport accidents increased with age and was highest in boys aged 5-9 years., Conclusions: Mortality rate in children aged 0-9 years has been decreasing with diminished difference between genders over the past decades. Our results suggest the importance of further research on mortality by causes of neoplasms, and causes of transport accidents-especially in children aged 5-9 years.