Health Care Use and Recurrence Rate in Hemolytic Disease of the Fetus and Newborn: Retrospective Cohort Study (Preprint)

BACKGROUND Hemolytic disease of the fetus and newborn (HDFN) is a life-threatening condition resulting from maternal-fetal erythrocyte antigen incompatibility. Although anti–Rhesus D (RhD) prophylaxis has reduced RhD-associated cases, HDFN persists due to non-RhD antibodies and gaps in prevention. Population-based data on maternal and neonatal outcomes and recurrence patterns are limited. OBJECTIVE This study aimed to characterize maternal and neonatal outcomes, health care use patterns, and recurrence rates of HDFN across pregnancies. METHODS We conducted a retrospective cohort study of 464,711 pregnancies within the Kaiser Permanente Southern California system from January 1, 2008, to June 30, 2022. HDFN diagnoses were confirmed using validated natural language processing–assisted manual chart review and followed through 2023. Maternal characteristics, neonatal outcomes, and health care use were compared by HDFN status, and recurrence patterns were evaluated among individuals with ≥2 pregnancies. Chi-square tests and Wilcoxon rank-sum tests were used to compare characteristics between HDFN and non-HDFN pregnancies. Statistical significance was defined as P<.05. RESULTS Among all pregnancies, 139 of 464,711 (0.03%) were diagnosed with HDFN. Women with HDFN were more likely than those without HDFN to be older (aged ≥35 years; n=42, 30.2% vs n=97,146, 20.9%) and multiparous (n=121, 87.1% vs n=264,766, 57%). Infants affected by HDFN had higher rates of preterm birth (n=40, 28.4% vs n=42,240, 9.5%), low birth weight (<2500 g; n=22, 15.6% vs n=31,740, 7.1%), and neonatal jaundice (n=92, 65.2% vs n=162,465, 36.4%) than non-HDFN infants. Delivery hospitalizations (median 5.0, IQR 2.0-7.5 days vs median 2.0, IQR 1.0-2.0 days) and neonatal intensive care unit stays (median 4.0, IQR 0.0-7.0 days vs median 0.0, IQR 0.0-0.0 days) were longer, and maternal nondelivery hospitalizations were more frequent (n=27, 19.4% vs n=23,228, 5%) among pregnancies complicated by HDFN. Among women with a prior HDFN-affected pregnancy, 83.3% (n=25) experienced recurrence in a subsequent pregnancy. Of these recurrent cases, 32% (n=8) were severe, and 75% (n=6) involved fetal anemia requiring at least 1 intrauterine transfusion. CONCLUSIONS HDFN was rare but was associated with substantial maternal and neonatal morbidity, including higher rates of preterm birth, increased neonatal intensive care unit admissions, and greater health care use. Recurrence was frequent and clinically significant, underscoring the importance of early surveillance and proactive management strategies.