Adverse pregnancy outcomes and long-term risk of peripheral artery disease: A cohort study

Background Women with adverse pregnancy outcomes have higher subsequent cardiovascular risks, but their long-term risks of peripheral artery disease (PAD) and potential causality are unclear. A better understanding of such risks is needed to improve early risk stratification, clinical care, and long-term cardiovascular health. We sought to determine long-term risks of PAD associated with 5 major adverse pregnancy outcomes in a large population-based cohort, and to assess for familial confounding using co-sibling analyses. Methods and findings A national cohort study was conducted of all 2,201,446 women with a singleton delivery in Sweden in 1973–2015, followed up for PAD identified from nationwide inpatient and outpatient diagnoses linked through 2018. Cox regression was used to compute hazard ratios (HRs) for PAD associated with preterm delivery, small for gestational age, preeclampsia, other hypertensive disorders, and gestational diabetes, adjusting for other maternal factors (age, year of delivery, parity, socioeconomic factors, body mass index, smoking, and prior history of hypertension, diabetes, or hyperlipidemia). Co-sibling analyses assessed for potential confounding by shared familial (genetic and/or environmental) factors. In 54 million person-years of follow-up, 13,211 (0.6%) women were diagnosed with PAD (median age, 62 years). All adverse pregnancy outcomes were associated with significantly increased long-term risk of PAD. At 30–46 years following delivery, adjusted HRs for PAD associated with specific adverse pregnancy outcomes were: gestational diabetes, 3.83 (95% CI [3.20,4.59]; p < 0.001); small for gestational age, 1.74 (95% CI [1.65,1.83]; p < 0.001); other hypertensive disorders, 1.61 (95% CI [1.21,2.15]; p = 0.001); preterm delivery, 1.58 (95% CI [1.48,1.70]; p < 0.001); and preeclampsia, 1.28 (95% CI [1.20,1.37]; p < 0.001). These findings were largely unexplained by shared familial factors. Women with multiple adverse pregnancy outcomes had further increases in risk. This study was limited to Sweden and will need replication in other populations, and was based on diagnostic codes which may involve some misclassification. Conclusions In this large national cohort, all adverse pregnancy outcomes were associated with increased risk for PAD up to 46 years later. Women with adverse pregnancy outcomes need early preventive actions and long-term clinical follow-up to reduce their risk of PAD and other associated cardiovascular diseases.