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.

中文翻译：

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孕期和后代心血管疾病早期发作的母体糖尿病：基于人群的队列研究，随访40年。

目的评估孕前或孕期诊断为母亲的糖尿病与后半生的后代早期心血管疾病（CVD）之间的关系。设计基于人群的队列研究。设置丹麦国家卫生注册中心。参与者1977-2016年间丹麦所有243.2万无先天性心脏病的活产儿。随访从出生开始，一直持续到首次诊断为CVD，死亡，移民或2016年12月31日，以较早者为准。观察研究的暴露妊娠糖尿病，包括1型糖尿病（n = 22 055）和2型糖尿病（n = 6537），以及妊娠糖尿病（n = 26 272）。主要观察指标主要观察指标是医院诊断所定义的早发性CVD（不包括先天性心脏病）。研究了孕妇糖尿病与后代早期CVD风险之间的关联。使用Cox回归评估母亲的CVD病史或母亲的糖尿病并发症是否影响了这些关联。对日历年，性别，单身身份，产妇因素（胎龄，年龄，吸烟，受教育，同居，分娩时的住所，分娩前的CVD史）以及分娩前的CVD的父亲史进行了调整。将所有个体的累积发病率平均，并调整因素，同时将非CVD引起的死亡视为竞争事件。结果在长达40年的随访中，有1153名患有糖尿病的母亲的后代和91311名未患有糖尿病的母亲的后代被诊断出患有CVD。患有糖尿病的母亲的后代早期CVD的总体发生率增加了29％（危险比1.29（95％置信区间1.21至1.37）； 40岁以下未暴露于母体糖尿病的后代中的累积发生率13.07％（12.92％至13.21） ％），暴露后代与未暴露后代之间的累积发病率差异为4.72％（2.37％至7.06％）。同胞关系设计产生的结果与基于整个队列的未配对设计相似。妊娠糖尿病（1.34（1.25至1.43））和妊娠糖尿病（1.19（1.07至1.32））均与后代CVD发生率增加相关。我们还观察到特定的早期CVD的发生率有所不同，特别是心力衰竭（1.45（0.89至2.35）），高血压疾病（1.78（1.50至2.11）），深静脉血栓形成（1.82（1.38至2.41））和肺栓塞（1.91（1。31至2.80））。从儿童期到成年早期直至40岁，不同年龄组的CVD发生率均升高。在患有糖尿病并发症的母亲的后代中，增加的比率更为明显（1.60（1.25至2.05））。患有合并糖尿病的母亲的后代早期发生CVD的发生率较高（1.73（1.36至2.20））与合并CVD的附加影响有关，但不是由于糖尿病与CVD之间的相互作用对乘法量表的影响（P值互动0.94）。结论患有糖尿病的母亲的孩子，尤其是那些有CVD或糖尿病并发症史的母亲，从儿童期到成年早期都有较早的CVD发生率。如果母亲糖尿病确实与后代的CVD发生率增加有因果关系，则应进行预防，筛查，