Adverse pregnancy outcomes and long-term risk of cardiovascular disease in women

Pregnancy is a "natural stress test" that may reveal higher cardiovascular disease (CVD) risks in early adulthood, potentially long before the emergence of clinical CVD. Up to one-third of all pregnancies are affected by an adverse pregnancy outcome (APO), defined as preeclampsia, other hypertensive disorders, gestational diabetes, fetal growth restriction, and/or preterm delivery. Consequently, APOs affect >40 million women worldwide each year and nearly 30% of all women during their reproductive years. However, long-term CVD risks associated with APOs remain poorly understood and not well integrated into clinical practice. A better understanding could facilitate earlier interventions in young women and alter their long-term trajectory of CVD. Prior studies have been limited by insufficient phenotyping of APOs and CVD, follow-up time, and statistical power to assess long-term risks. Large cohorts are needed with prospective phenotyping of APOs and CVD before, during, and after pregnancy, and long-term follow-up. We hypothesize that APOs are associated with higher long-term CVD risks (ischemic heart disease, stroke, heart failure, arrhythmias, peripheral vascular disease) across the life course, independently of familial factors. To test this hypothesis, we propose to conduct the first comprehensive assessment of prospectively phenotyped APOs and long-term CVD risks in a large cohort with up to 48 years of follow-up. We will analyze national registry data for all 4.7 M pregnancies in 2.5 M women in Sweden during 1973-2017 and all inpatient and outpatient CVD diagnoses and mortality through 2020. Sweden is an ideal setting because it has linkable individual-level data for the entire population needed to enable this first-of-its-kind study, and CVD rates and mechanisms are comparable to the US. Our aims are to (1) determine associations between 4 major APOs (preeclampsia, other hypertensive disorders, gestational diabetes, fetal growth restriction) and long-term CVD risks across the life course; (2) identify high-risk subgroups of women who are most susceptible to effects of APOs on long-term CVD risks; (3) assess the influence of shared familial (genetic and/or environmental) factors; and (4) develop an integrated model for association of all 5 major APOs (including preterm delivery) with long-term CVD risks. The proposed research is significant because CVD is the leading cause of death in women worldwide, and APOs are common and potentially important sentinels of long-term CVD risks, yet such risks are understudied and poorly integrated into clinical practice. It is innovative because it will provide the first comprehensive assessment of prospectively phenotyped APOs and long-term CVD risks, utilize co-relative designs to disentangle familial confounding, and develop an integrated model for all 5 major APOs using unparalleled data for 2.5 M women. It is highly cost-efficient because we will leverage data from national registries in Sweden that are unavailable or prohibitively costly to assemble in the US. The results will will help improve women's health by identifying the long-term CVD risks associated with APOs needed to guide early prevention and long-term clinical care.