Risk for AF in Middle Age in Patients Born Prematurely or Large for Gestational Age

Preterm birth and being large for gestational age (LGA) are associated with an increased risk for atrial fibrillation (AF) up to the age of 49 years, according to a study in JAMA Pediatrics.

The population-based study used prospective data from several nationwide registers in Denmark, Sweden, and Finland to evaluate whether preterm birth, being small for gestational age (SGA), or being LGA are associated with AF risk in childhood and adulthood.

All live singleton births were identified in Denmark from 1978 through 2016 (n=2,332,882) and in Sweden from 1973 through 2014 (n=4,171,006). Additionally, there was a random sample of 90% live singletons in Finland from 1987 through 2014 (n=1,636,116). The analysis included 8,012,433 births after the exclusion of births with missing or implausible gestational age, birth weight, or sex.

AF was the outcome and was defined as AF or atrial flutter. Follow-up was initiated at birth and ended at the first AF diagnosis, emigration, death, or the latest date with available data, whichever came first.

Among the cohort, 378,917 participants were born preterm (4.7%), 800,959 were SGA (10.0%), and 802,759 were LGA (10.0%). Participants’ maximum age at the end of follow-up was 49 years (median, 21 years; IQR, 11.7-30.7 years). In the 174.4 million person-years of follow-up, 11,464 individuals had AF (0.14%), with a median age at diagnosis of 29.3 years (IQR, 22.3-36.4 years).

An inverse, mostly linear association was observed between gestational age and the risk for AF. Preterm birth was associated with an increased risk for AF, with adjusted hazard ratios (HRs) of 1.30 (95% CI, 1.18-1.42) in the population analysis and 1.29 (95% CI, 1.08-1.55) in the sibling analysis.

The risk for AF increased significantly according to birth weight for gestational age from the 50th percentile. Individuals who were born SGA had a lower AF risk (adjusted HR, 0.93; 95% CI, 0.88-0.99) and those born LGA had an increased AF risk (adjusted HR, 1.55; 95% CI, 1.46-1.63), compared with individuals born appropriate for gestational age (AGA). Only being LGA was associated with AF risk in the sibling analysis. For the population and sibling analyses, AF risk was higher for severe LGA vs moderate LGA.

Being SGA was associated with a higher risk for AF in the first 18 years of follow-up (adjusted HR, 1.27; 95% CI, 1.07-1.50) and with a lower risk afterward (adjusted HR, 0.90; 95% CI, 0.84-0.96). The association between LGA and risk for AF was similar in both periods.

Compared with term AGA births, the risk for AF was increased by 71% among preterm LGA births, 55% for term LGA births, 31% in preterm AGA births, and 25% in preterm SGA births. AF risk was 9% lower for term SGA vs term AGA births. The HRs were generally higher during the first 18 years of follow-up compared with later in these analyses.

In sensitivity analyses, the associations of preterm birth, being SGA, and being LGA with AF risk were not different based on the child’s sex or country of birth.

Among several limitations, some asymptomatic, paroxysmal, or mild cases of AF could have been missed, and residual confounding is possible. Furthermore, the findings apply only to children and young adults, and the population was predominantly White with universal free health care systems.

“Further studies with longer follow-up and that may elucidate the underlying mechanisms for the observed associations are warranted,” wrote the study authors. “As the prevalence of LGA births is reported to increase over time, the possible long-term health effects of being born LGA may become increasingly important.”

Disclosure: One study author declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.