Preterm birth and long-term risk of cardiovascular disease in mothers and offspring

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Currently about 1 of every 10 births in the US occurs preterm (gestational age <37 completed weeks), and because of advances in treatment, >95% of preterm infants survive to adulthood. Recent research has shown that both the mothers and offspring of preterm birth (PTB) have higher long-term risks of metabolic syndrome, a major risk factor for cardiovascular disease (CVD). Mothers who deliver preterm may also have higher long- term CVD incidence; however, the reported risks of CVD in adult offspring of PTB have been conflicting. A recent Trans-NIH Working Group highlighted a pressing need for studies that: (1) stratify long-term CVD risks by PTB subtype (e.g., spontaneous vs. indicated due to maternal/fetal conditions) to help elucidate underlying mechanisms and tailor long-term patient care; (2) allow longer follow-up into mid-adulthood or later when disease risks remain poorly understood; and (3) include large sample sizes to allow examination of long-term outcomes with high statistical power. We hypothesize that: (1) PTB is associated with higher long-term risks of CVD (i.e., ischemic heart disease, cerebrovascular disease, heart failure, peripheral vascular disease, aortic disease) among mothers and adult offspring, with increasing dose-response relationships by earlier gestational age; and (2) These associations exist for all major types of PTB, but are stronger for those related to placental insufficiency (e.g., preeclampsia or diabetes), which is associated with oxidative stress and inflammation, leading to structural microvascular changes. To address these hypotheses, we propose to conduct the first comprehensive examination of PTB and its subtypes in relation to CVD risks among mothers and their adult offspring. We will assemble and analyze national databases containing all ~2.3 million births to ~1.2 million mothers in Sweden during 1973-1995 and all inpatient and outpatient diagnoses of CVD through 2015. Our specific aims are to: (1) Examine PTB and its subtypes in relation to long-term risks of CVD and CVD-related outcomes (hypertension, diabetes, sleep apnea) in mothers and adult offspring; (2) determine if there are sociodemographic subgroups that are more susceptible to PTB effects on long-term risks; and (3) explore potential confounding effects of unmeasured familial (genetic and shared environmental) factors on PTB-CVD associations using co-relative analyses. The proposed research is significant because PTB is common and unprecedented numbers of survivors are now reaching adulthood (~400,000/year in the US); thus even modestly increased long-term risks translate into a large population health burden. It is innovative because it will provide the first comprehensive examination of PTB and its subtypes in relation to CVD risks, and use a co-relative design to disentangle familial confounding. It is highly cost-efficient because we will assemble these data from national registries that are unavailable or prohibitively costly to collect in the US. The results will have major impacts by establishing the long-term CVD risks associated with PTB and its subtypes among mothers and adult offspring, and informing clinical guidelines for better risk assessment and long-term care.