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OBJECTIVE:To evaluate the associations between maternal diabetes diagnosed before or during pregnancy and early onset cardiovascular disease (CVD) in offspring during their first four decades of life. DESIGN:Population based cohort study. SETTING:Danish national health registries. PARTICIPANTS:All 2 432 000 liveborn children without congenital heart disease in Denmark during 1977-2016. Follow-up began at birth and continued until first time diagnosis of CVD, death, emigration, or 31 December 2016, whichever came first. EXPOSURES FOR OBSERVATIONAL STUDIES:Pregestational diabetes, including type 1 diabetes (n=22 055) and type 2 diabetes (n=6537), and gestational diabetes (n=26 272). MAIN OUTCOME MEASURES:The primary outcome was early onset CVD (excluding congenital heart diseases) defined by hospital diagnosis. Associations between maternal diabetes and risks of early onset CVD in offspring were studied. Cox regression was used to assess whether a maternal history of CVD or maternal diabetic complications affected these associations. Adjustments were made for calendar year, sex, singleton status, maternal factors (parity, age, smoking, education, cohabitation, residence at childbirth, history of CVD before childbirth), and paternal history of CVD before childbirth. The cumulative incidence was averaged across all individuals, and factors were adjusted while treating deaths from causes other than CVD as competing events. RESULTS:During up to 40 years of follow-up, 1153 offspring of mothers with diabetes and 91 311 offspring of mothers who did not have diabetes were diagnosed with CVD. Offspring of mothers with diabetes had a 29% increased overall rate of early onset CVD (hazard ratio 1.29 (95% confidence interval 1.21 to 1.37); cumulative incidence among offspring unexposed to maternal diabetes at 40 years of age 13.07% (12.92% to 13.21%), difference in cumulative incidence between exposed and unexposed offspring 4.72% (2.37% to 7.06%)). The sibship design yielded results similar to those of the unpaired design based on the whole cohort. Both pregestational diabetes (1.34 (1.25 to 1.43)) and gestational diabetes (1.19 (1.07 to 1.32)) were associated with increased rates of CVD in offspring. We also observed varied increased rates of specific early onset CVDs, particularly heart failure (1.45 (0.89 to 2.35)), hypertensive disease (1.78 (1.50 to 2.11)), deep vein thrombosis (1.82 (1.38 to 2.41)), and pulmonary embolism (1.91 (1.31 to 2.80)). Increased rates of CVD were seen in different age groups from childhood to early adulthood until age 40 years. The increased rates were more pronounced among offspring of mothers with diabetic complications (1.60 (1.25 to 2.05)). A higher incidence of early onset CVD in offspring of mothers with diabetes and comorbid CVD (1.73 (1.36 to 2.20)) was associated with the added influence of comorbid CVD but not due to the interaction between diabetes and CVD on the multiplicative scale (P value for interaction 0.94). CONCLUSIONS:Children of mothers with diabetes, especially those mothers with a history of CVD or diabetic complications, have increased rates of early onset CVD from childhood to early adulthood. If maternal diabetes does have a causal association with increased CVD rate in offspring, the prevention, screening, and treatment of diabetes in women of childbearing age could help to reduce the risk of CVD in the next generation.

BackgroundSocioeconomic 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 findingsWe 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.ConclusionsPTB 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.

We investigated the association between maternal grandmaternal early pregnancy body mass index (BMI) and grandoffspring stillbirth risk in a Swedish population-based 3-generation cohort of 176 908 grandmothers (F0), 197 579 mothers (F1), and 316 459 grandoffspring (F2) born 1997-2016. There were 998 stillbirths (risk, 3.2 per 1000 births). Compared with grandmaternal BMI 18.5-24.9, adjusted relative risks (RRs) of grandoffspring stillbirth for BMIs of 25.0-29.9 and ≥30.0 were, respectively, 1.41 (95% CI, 1.15-1.72) and 1.62 (95% CI, 1.14-2.30). RRs for corresponding maternal (F1) BMI categories were, respectively, 1.32 (95% CI, 1.06-1.65) and 1.77 (95% CI, 1.39-2.25). Maternal BMI mediated only 19% of this relationship. Grandmaternal preeclampsia and maternal small-for-gestational age (SGA) birth were related to increased F2 stillbirth risk but did not mediate the association between grandmaternal BMI and grandoffspring stillbirth risk. To explore whether this association was explained by factors shared within families, we studied the relationship of maternal full sisters' BMI and stillbirth risk in 101 368 pregnancies. Stillbirth RRs for full sisters' BMI 25.0-29.9 and ≥30.0 compared with 18.5-24.9 were, respectively, 0.76 (95% CI, 0.51-1.13) and 0.88 (95% CI, 0.55-1.40). In conclusion, grandmaternal overweight and obesity were associated with grandoffspring stillbirth. This association is not fully explained by shared familial factors. [ABSTRACT FROM AUTHOR]

Objectives: To investigate the association between maternal early pregnancy body mass index (BMI) and offspring bipolar disorder (BPD). Methods: We conducted a nationwide cohort study among 1,507,056 non‐malformed singleton live‐births in Sweden born 1983–2004. Using national registries with prospectively recorded information, we followed participants for a BPD diagnosis from ages 13 to up to 35 years. We compared BPD risks by early pregnancy BMI using hazard ratios (HR) with 95% confidence intervals (CI) from adjusted Cox models. We also conducted sibling‐controlled analyses among 874,047 full siblings. Results: There were 9970 BPD diagnoses. Risk of BPD was 0.72% through 25 years of age. Maternal early pregnancy BMI was positively associated with offspring BPD risk. Compared with normal BMI (18.5–24.9), adjusted HR (95% CI) for overweight (BMI 25–29.9), obesity grade 1 (BMI 30–34.9), and obesity grades 2–3 (BMI ≥35) were 1.08 (1.02, 1.15), 1.26 (1.14, 1.40), and 1.31 (1.07, 1.60), respectively. Adjusted HR per unit BMI was 1.015 (95% CI 1.009, 1.021). A similar trend was observed among siblings. Pregnancy and neonatal complications did not substantially mediate the association between maternal obesity (BMI ≥30) and offspring BPD. Conclusions: Maternal BMI ≥25 is associated with offspring BPD risk in a dose–response manner. [ABSTRACT FROM AUTHOR]