Modeling the U.S. National Burden of Severe Hemolytic Disease of the Fetus and Newborn

OBJECTIVE: To estimate the national burden of severe hemolytic disease of the fetus and newborn (HDFN) attributed to the three most clinically significant alloantibodies (anti-D, anti-K, and anti-c) using a large data set of prenatal antibody screens in U.S. pregnancies. METHODS: Prenatal red blood cell alloantibody results were extracted from a national laboratory firm from 2010 to 2021 and normalized to the U.S. population race, ethnicity, and regional distributions based on Census data. Prevalence of critical alloantibody titers, pregnancy continuation rates, distribution of paternal race and ethnicity, allele prevalence of antigen in paternal race and ethnicity, and rate of disease were used to estimate the burden of disease using Monte Carlo simulations. RESULTS: There were 8,809,993 pregnancies included in the cohort. Normalization of the cohort to U.S. births resulted in an estimated national prevalence of any high-risk antibodies of 686.5 per 100,000 pregnancies (27.9 per 100,000 for anti-c, 596.1 per 100,000 for anti-D, and 62.5 per 100,000 for anti-K), with 63.9 per 100,000 (1.9 for anti-c, 20.6 for anti-D, and 41.3 for anti-K) of those reaching critical levels. The estimated national burden of severe HDFN attributed to any high-risk antibody was 2.4 per 100,000 pregnancies (95% CI, 2.0-2.9). Among all pregnancies with critical titers, 3.8% (95% CI, 3.1-4.5) were estimated to result in severe HDFN. CONCLUSION: This study provides contemporary national estimates of severe HDFN in the United States, demonstrating that, although alloimmunization is relatively common, progression to severe HDFN remains rare.