# Characterization of severity of hemolytic disease of the fetus and newborn due to Rhesus antigen alloimmunization

## TL;DR

This study characterizes the severity of hemolytic disease in newborns caused by Rhesus antigen antibodies, finding that most cases are mild but some require serious interventions.

## Contribution

The study introduces a novel severity index to classify real-world cases of hemolytic disease of the fetus and newborn due to Rhesus antigen alloantibodies.

## Key findings

- Most neonates with Rhesus antigen hemolytic disease had minimal severity, but nearly 7% required invasive interventions or faced mortality.
- Severely affected neonates were more likely to be born via cesarean and at lower gestational ages.
- The HDFN Severity Index effectively categorizes disease severity and could aid in managing future pregnancies.

## Abstract

Clinical manifestations of hemolytic disease of the fetus and newborn include anemia, hyperbilirubinemia, hydrops fetalis, kernicterus, and fetal or neonatal demise. More than 50 antibodies are linked to hemolytic disease of the fetus and newborn, with Rhesus (including D and c) and Kell antigens carrying the highest risk of disease. To date, a multicenter, comprehensive evaluation of hemolytic disease of the fetus and newborn due to Rhesus antigen alloantibodies in the United States has not been undertaken.

This study aimed to implement a novel severity index to characterize the real-world disease spectrum of hemolytic disease of the fetus and newborn due to alloantibodies from the Rhesus class.

This retrospective cohort study was conducted in neonates with commercial insurance available through Optum's deidentified Clinformatics® Data Mart Database (Clinformatics®) and Merative MarketScan® Commercial Claims and Encounters (CCAE) Database from 2000 to 2022. Neonatal and maternal records were linked algorithmically by shared family identifier. A hierarchical severity index was developed for neonates with a Rhesus antigen hemolytic disease of the fetus and newborn diagnosis code in the first 30 days of life, using antenatal and neonatal diagnoses and treatments: Severe (neonatal death, hydrops fetalis, intrauterine transfusion); Moderate (neonatal exchange transfusion); Mild (neonatal simple transfusion); Minimal (neonatal phototherapy or hyperbilirubinemia). Maternal, antenatal, and perinatal demographic and clinical characteristics were summarized descriptively by severity.

In Clinformatics® and Commercial Claims and Encounters Database, respectively, 1927 and 1268 neonates met the inclusion criteria. Most (93.1% Clinformatics®; 93.5% CCAE Database) displayed minimal severity, although in both databases nearly 40% of these neonates still required phototherapy. More neonates were mildly affected (3.3% Clinformatics®; 2.2% Commercial Claims and Encounters Database) than moderately (1.0% Clinformatics®; 1.1% Commercial Claims and Encounters Database). In Clinformatics® and Commercial Claims and Encounters Database, respectively, severe hemolytic disease of the fetus and newborn affected 2.6% and 3.2% of neonates, 54% and 46% of whom received exchange or simple transfusions. Severely affected neonates were more commonly delivered by cesarean delivery and at a lower gestational age (34.1 weeks Clinformatics®; 35.4 weeks Commercial Claims and Encounters Database) than those minimally affected (38.5 weeks Clinformatics®; 38.4 weeks Commercial Claims and Encounters Database).

Results across 2 real-world US databases found that although most neonates affected by hemolytic disease of the fetus and newborn due to Rhesus antigen alloantibodies did not require intervention beyond phototherapy, nearly 7% experienced disease severity requiring invasive intervention or resulting in neonatal mortality. More severely affected neonates had lower gestational age at birth, higher rates of cesarean delivery and neonatal intensive care unit admission, and longer length of hospital stay at birth compared with minimally affected neonates. The HDFN Severity Index is a useful tool to characterize hemolytic disease of the fetus and newborn and may be valuable alongside guideline-driven care in subsequent pregnancies.