Preterm birth associated with increased risk of new-onset HF into adulthood
Association of Preterm Birth With Long-term Risk of Heart Failure Into Adulthood
Introduction and methods
Preterm birth (<37 weeks) is associated with cardiometabolic disorders, cardiovascular malformations, and cardiac remodeling that may predispose people to develop HF [1-3]. Also, adults who were born preterm have increased risk of known risk factors for HF such as hypertension, diabetes, lipid disorders, ischemic heart disease, and sleep-disordered breathing [4-9]. However, the long-term risk for the development of HF in adulthood in individuals born prematurely is unknown. Furthermore, it remains unclear what the relative contributions are of familial factors (genetic and/or environmental) vs. direct outcomes of preterm birth with regard to HF risk.
This study assessed 1) whether gestational age at birth is associated with increased risk of HF from childhood into mid-adulthood in a large population, 2) whether sex-specific differences existed, and 3) explored the possible influence of genetic and/or environmental factors by co-sibling analyses.
This study used the Swedish Birth Register to include 4 193 069 singleton births between 1973 to 2014. The cohort was followed up for the earliest diagnosis of HF from birth through December 31, 2015. HF was identified using the Swedish Hospital, Outpatient, or Cause of Death Registries. The primary analysis addressed whether preterm birth was associated with an increased risk of HF in adulthood across the age range of 0-43 years and in three age intervals (<1 years, 1-17 years, and 18-43 years). Individuals were stratified to gestational age at birth groups: extremely preterm births (22-27 weeks, n=8,324), moderately preterm births (28-33 weeks, n=44,373), late preterm births (34-36 weeks, n=157,342), early term births (37-38 weeks, n=740,391), full term births (39-41 weeks, n=2,896,444), and post term births (≥42 weeks, n=346,195). Also, the first 3 groups were combined to estimate HF risks for preterm infants (<37 weeks, n=210,039). The co-sibling analyses (n=3 530 215; 84.2% of the cohort) assessed potential confounding by unmeasured shared familial factors. The median age of the entire cohort at the end of the follow-up was 22.5 years (mean age was 22.2 ± 12.2 (SD) years).
- 4158 (0.1%) Individuals had HF (median age 15.4 ± 14.7 [SD] years at diagnosis).
- For the entire cohort (0-43 years), there was a ~2.7 fold increased risk of new-onset HF among individuals with preterm births (aHR 2.69, 95% CI: 2.43-2.97, P<0.001) and a 1.4 fold increased risk among those with early term births (aHR 1.40, 95% CI: 1.29-1.51, P<0.001) compared to full term births. Individuals with extremely preterm births had a ~13 fold increased risk for the development of HF (aHR 12.83, 95% CI: 9.55-17.25, P<0.001).
- Each additional week of gestation was associated with a 13% reduction in risk of new-onset HF compared to full term birth (aHR 0.87, 95% CI: 0.86-0.88, P<0.001).
- The estimated weighted percentages of HF cases among those born preterm was 64.5% and 92.7% among those born extremely preterm. 10.4% And 1.7% of HF cases in the entire population were associated with preterm and extremely preterm, respectively.
- Preterm birth was associated with an increased risk of HF at attained ages <1 year (HR 4.49, 95% CI: 3.86-5.43, P<0.001), 1-17 years (HR 3.42, 95% CI: 2.75-4.27, P<0.001), and 18-43 years (aHR 1.42, 95% CI: 1.19-1.71, P<0.001).
- Further stratification of 18-43 year old individuals for gestational age at birth demonstrated an increased risk for HF for extremely preterm births (aHR 4.72, 95% CI: 2.11-10.52, P<0.001), moderately preterm births (aHR 1.93, 95% CI: 1.37-2.71, P<0.001), and late preterm births (aHR 1.24, 95% CI: 1.00-1.54, P=0.05) compared to full term births. These associations remained significant when individuals with structural congenital cardiac anomalies were excluded (4.8% of the cohort).
- The absence of additive interaction suggested that preterm birth accounted for a similar number of HF cases among men and women.
- Co-sibling analyses to control for unmeasured shared familial factors between preterm and full term births showed similar elevated aHRs in the age groups below 1 year and 1-17 years compared to the primary analysis. However, there was not a significant difference between preterm and full term births in the group aged 18-43 years compared to the primary analysis (aHR 1.14 95% CI: 0.75-1.73 vs. aHR 1.42, 95% CI: 1.19-1.71, respectively).
This study demonstrated that preterm birth was associated with increased risk for HF into adulthood. The lower the gestational age of an infant at birth, the higher the risk for the development of HF. Co-sibling analyses suggested that the observed association between preterm birth and development of HF in 18-43 year old individuals might be largely due to shared familial determinants of preterm birth and development of HF in adulthood.