Peripheral artery disease (PAD) affects hundreds of millions worldwide and predicts stroke, ischemic heart disease, and premature mortality. Traditional PAD risk factors include diabetes, hypertension, hyperlipidemia, smoking, and physical inactivity. Adverse pregnancy outcomes are established predictors of other cardiovascular diseases in women, but their long-term associations with PAD and potential causal mechanisms are incompletely characterized. The authors aimed to determine PAD risk associated with five major adverse pregnancy outcomes using population-based data and to assess whether shared familial factors could explain observed associations.
The study used the Swedish Medical Birth Register to identify 2,201,638 women with a singleton delivery during 1973–2015; after excluding 192 women with prior PAD, 2,201,446 women were included. Follow-up extended from first delivery through December 31, 2018, providing up to 46 years of observation and 54 million person-years of follow-up. Median follow-up time after delivery was 25 years. During follow-up, 13,211 women (0.6%) were diagnosed with PAD (median age at diagnosis 62 years). Censoring occurred at death (n = 74,761) or emigration (n = 92,904).
Five major adverse pregnancy outcomes were ascertained from prenatal and birth records: preterm delivery (gestational age <37 weeks), small for gestational age (birth weight <10th percentile for gestational age), preeclampsia (with or without complications), other hypertensive disorders of pregnancy (gestational or chronic hypertension), and gestational diabetes. Gestational age estimation relied on last menstrual period in the 1970s and ultrasound from the 1980s onward. These registry-derived measures have documented high reliability and positive predictive values near 90% for several outcomes.
PAD was identified using ICD diagnostic codes from the Swedish Hospital and Outpatient Registers and available primary care records. Codes spanned ICD-8/9 and ICD-10 eras as applicable. PAD diagnoses were recorded across settings: 27.3% in inpatient care, 21.8% in specialty outpatient care, and 50.9% in primary care, as available. The Swedish Hospital Register has nationwide coverage from 1987 and a reported positive predictive value of 98% for PAD diagnoses.
Analyses adjusted for maternal age (used as the Cox model time axis), calendar year of delivery, parity, education, employment and income, country of origin, smoking (0, 1–9, ≥10 cigarettes/day), BMI (continuous and categorical), and pre-pregnancy diagnoses of hypertension, diabetes, or hyperlipidemia. Smoking and BMI were available beginning in 1982 for subsets of the cohort (67% and 56% respectively). Missing data were multiply imputed with 20 imputations; a sensitivity analysis restricted to women with complete data (N = 1,209,163) was also reported.
Cox proportional hazards regression estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for PAD associated with each adverse pregnancy outcome. Outcomes were modeled as time-dependent “ever” exposures, updated at each delivery. Analyses examined associations across the full follow-up and within intervals (<10, 10–19, 20–29, and 30–46 years after delivery). Two adjusted models were run for each exposure: (1) adjusting for sociodemographic factors, parity, and traditional PAD risk factors, and (2) additionally adjusting for other adverse pregnancy outcomes.
To assess potential confounding by unmeasured shared familial factors (genetic or environmental), co-sibling analyses were conducted among 1,198,476 women (54% of cohort) with at least one full sister who had a singleton delivery. Stratified Cox models used sister sets as strata, thereby controlling for familial baseline hazards.
Across 54 million person-years, 13,211 women were diagnosed with PAD. The distribution of diagnoses by setting was reported as 27.3% inpatient, 21.8% specialty outpatient, and 50.9% primary care. Overall, 667,774 women (30.4%) experienced at least one adverse pregnancy outcome. The most common outcomes were small for gestational age (14.4% of women) and preterm delivery (8.9%).
All five adverse pregnancy outcomes were associated with significantly increased long-term risk of PAD. Reported adjusted HRs at 30–46 years after delivery were:
All reported p-values for these associations were <0.01. Women with multiple adverse pregnancy outcomes had further increases in PAD risk. Incidence rate differences, attributable fraction in the exposed (AFe), and population attributable fraction (PAF) were computed, though specific values for these measures beyond HRs are not detailed here.
The study modeled adverse pregnancy outcomes as time-updated exposures across successive deliveries and examined risk across life-course intervals up to 46 years. Secondary analyses included examination of spontaneous versus medically indicated preterm delivery (systematically recorded from 1990) and associations by the total number of adverse pregnancy outcomes (0, 1, 2, ≥3), adjusted for parity and covariates.
Co-sibling (within-family) analyses that stratified on sister sets and adjusted for the same covariates found that the observed associations between adverse pregnancy outcomes and PAD were largely unexplained by shared familial (genetic and/or environmental) factors. This suggests that the associations are not fully attributable to measured or unmeasured familial confounders shared by sisters.
The authors note several limitations: the study population was restricted to Sweden and therefore requires replication in other populations; ascertainment relied on diagnostic codes which may incur some misclassification; smoking and BMI data were only available from 1982 onward for subsets of the cohort; and certain detailed results (e.g., full incidence rate differences, AFe, PAF numeric values, and some subgroup results) are reported in the full manuscript but are not reproduced in this summary.
In this large national cohort, all five major adverse pregnancy outcomes were associated with increased long-term risk of peripheral artery disease, with elevated risks persisting up to 46 years after delivery. Associations were strongest for gestational diabetes and remained after adjustment for sociodemographic and traditional cardiovascular risk factors, and were largely not explained by shared familial factors. The authors conclude that women with adverse pregnancy outcomes may warrant earlier cardiovascular risk assessment and prolonged clinical follow-up to reduce PAD and broader cardiovascular disease risk. Replication in other populations and consideration of misclassification inherent to registry-based diagnoses were recommended by the authors.