Pregnancy loss in major fetal congenital heart disease: incidence, risk factors and timing

B M. Jepson, Division of Pediatric Cardiology, Department of Pediatrics, University of Utah, Salt Lake City, UT, USA.
T D. Metz, Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, University of Utah, Salt Lake City, UT, USA.
T A. Miller, Division of Pediatric Cardiology, Maine Medical Center, Portland, ME, USA.
S L. Son, Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, University of Colorado, Aurora, CO, USA.
Z Ou, Division of Epidemiology, Department of Internal Medicine, University of Utah, Salt Lake City, UT, USA.


OBJECTIVE: Fetuses with congenital heart disease (CHD) are at increased risk of pregnancy loss compared to the general population. We aimed to identify pregnancy loss incidence, timing and risk factors in major fetal CHD overall and by cardiac diagnosis. METHODS: We performed a retrospective, population-level, cohort study of fetuses and infants diagnosed with major CHD between 1997-2018 identified by the Utah Birth Defect Network, excluding terminations and minor cardiovascular diagnoses (e.g., isolated aortic/pulmonary pathology and isolated septal defects). Pregnancy loss incidence and timing were recorded overall and by CHD diagnosis with stratification by isolated CHD versus presence of an additional fetal diagnosis (genetic diagnosis and/or extracardiac malformation). Adjusted pregnancy loss risks were calculated and risk factors assessed in multivariable models for the overall cohort and prenatal diagnosis sub-cohort. RESULTS: Of 9351 UBDN cases with a cardiovascular code, we identified 3251 with major CHD resulting in a study cohort of 3120 after excluding terminations (n=131). There were 2956 (94.7%) livebirths and 164 (5.3%) pregnancy losses which occurred at a median of 27.3 weeks' gestation. Of study cases, 1848 (59%) had isolated CHD and 1272 (41%) had an additional fetal diagnosis (736 [58%] genetic diagnosis, 536 [42%] extracardiac malformation). Observed pregnancy loss incidence was highest in hypoplastic left heart syndrome (HLHS, 10.7%), double outlet right ventricle with normally related great vessels or not otherwise specified (10.5%), and Ebstein anomaly (9.9%). Adjusted pregnancy loss risk overall was 5.3% (95% CI 3.7-7.6; aRR 9.0, 95% CI 6.0-13.0, based on 0.6% general population risk) and 1.4% (95% CI 0.9-2.3; aRR 2.0, 95% CI 1.0-6.0) in isolated CHD. Variables associated with pregnancy loss in multivariable analyses included female sex (aOR 1.6, 95% CI 1.1-2.3), Hispanic ethnicity (aOR 1.6, 95% CI 1.0-2.5), hydrops (aOR 6.7, 95% CI 4.3-10.5), additional fetal diagnosis (aOR 6.3, 95% CI 4.1-10), atrioventricular valve regurgitation ≥ moderate (aOR 3.6, 95% CI 1.3-8.8), and ventricular dysfunction (aOR 3.8, 95% CI 1.2-11.1). Diagnostic groups associated with pregnancy loss were HLHS and variants (aOR 3.0, 95% CI 1.7-5.3) and other single ventricles (aOR 2.4, 95% CI 1.1-4.9). Time-to-pregnancy loss analysis demonstrated a steeper survival curve for cases with an additional fetal diagnosis compared to cases with isolated CHD (p<0.0001). CONCLUSIONS: Pregnancy loss risk is higher in major fetal CHD compared to the general population, driven by CHD type and additional fetal diagnoses. Recognition of pregnancy loss incidence, risk factors and timing may inform patient counseling, antenatal surveillance, and delivery planning. This article is protected by copyright. All rights reserved.