Department of Biostatistics, School of Public Health, and The Key Laboratory of Public Health Safety of Ministry of Education, Fudan University, Shanghai, China.
Ministry of Education-Shanghai Key Laboratory of Children's Environmental Health, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
PLoS Med. 2021 Sep 28;18(9):e1003805. doi: 10.1371/journal.pmed.1003805. eCollection 2021 Sep.
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.
背景:近几十年来,儿童、青少年和年轻人中心血管疾病(CVD)的患病率一直在上升。胎儿期暴露于不利的宫内环境可能会增加早发性 CVD 的风险。许多研究表明,母亲妊娠高血压疾病(HDP)与后代先天性心脏病、高血压、BMI 增加和全身血管功能障碍的风险增加有关。然而,关于母亲 HDP 产前暴露与儿童和青少年早发性 CVD 之间的关联的实证证据仍然有限。
方法和发现:我们使用丹麦国家健康登记处进行了一项基于人群的队列研究,该研究包括 1977 年至 2018 年期间在丹麦出生的 2491340 人。随访从出生开始,至首次诊断为 CVD、移民、死亡或 2018 年 12 月 31 日(以先发生者为准)结束。母亲 HDP 的暴露情况分为子痫前期或子痫(n=68387)、妊娠期高血压(n=18603)和孕前高血压(n=15062)。结局是从出生到成年早期(40 岁以下)的早发性 CVD 诊断。我们使用 Cox 比例风险回归来评估关联,以及该关联是否因母亲产前 CVD 或糖尿病病史而有所不同。我们还通过子痫前期发病时间和严重程度来评估关联。中位随访时间为 18.37 年,参与者中 51.3%为男性。暴露组中有 4532 名(每 1000 人年 2.47 人)和未暴露组中有 94457 名(每 1000 人年 2.03 人)被诊断为 CVD。我们发现,母亲 HDP 暴露与早发性 CVD 风险增加相关(风险比[HR]:1.23;95%置信区间[CI]:1.19 至 1.26;P<0.001)。子痫前期或子痫、妊娠期高血压和孕前高血压的 HR 分别为 1.22(95%CI,1.18 至 1.26;P<0.001)、1.25(95%CI,1.17 至 1.34;P<0.001)和 1.28(95%CI,1.15 至 1.42;P<0.001)。我们还观察到特定类型 CVD 的风险增加,特别是高血压疾病(HR,2.11;95%CI,1.96 至 2.27;P<0.001)和心肌梗死(HR,1.49;95%CI,1.12 至 1.98;P=0.007)。在有 CVD 病史的母亲(HR,1.67;95%CI,1.41 至 1.98;P<0.001)或合并糖尿病的母亲(HR,1.56;95%CI,1.34 至 1.83;P<0.001)的后代中发现了强烈的关联。当考虑子痫前期发病时间和严重程度对后代 CVD 的影响时,我们发现早发性和严重的子痫前期与后代 CVD 的关联最强(HR,1.48;95%CI,1.30 至 1.67;P<0.001)。研究局限性包括缺乏某些潜在混杂因素(包括吸烟、身体活动和饮酒)的信息,以及在其他国家存在医疗保健差异的情况下的普遍适用性有限。
结论:母亲 HDP,尤其是有 CVD 或糖尿病病史的母亲所生的后代,在其生命的最初几十年中,整体和某些特定类型的早发性 CVD 风险增加。需要进一步研究以更好地理解母亲 HDP 与后代早发性 CVD 之间关系的潜在机制。
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