Effect of Screening for Red Cell Antibodies, Other Than Anti-D, to Detect Hemolytic Disease of the Fetus and Newborn: A Population Study in The Netherlands

Abstract

Hemolytic disease of the fetus and newborn (HDFN) is a serious disorder resulting from maternal red blood cell alloantibodies directed against fetal red cells. Alloimmunization against the D antigen has been responsible for most cases of severe HDFN but, as methods of preventing D immunization have developed, alloantibodies other than anti-D, namely anti-K and anti-c in particular, have emerged as an important cause of severe HDFN. This report details the effect of a first-trimester antibody screening program instituted in the Netherlands to detect antibodies other than anti-D in a timely manner. Among 305,000 consecutive pregnancies in an 18-month period, there were 1002 with such alloantibodies. In a parallel-coverage validation study, patients with HDFN due to antibodies other than anti-D that were missed on screening were identified retrospectively. The prevalence of positive antibody screens on first-trimester screening was 1,232 per 100,000, of which 20% were not confirmed by the reference laboratory and 47% had no clinical consequences; only 7% involved anti-D antibodies. The frequency of clinically relevant alloantibodies other than anti-D was 328 per 100,000, of which 191 per 100,000 were at risk of HDFN. The most common antibodies were anti-E, followed by anti-K and anti-C. Severe HDFN resulting from immunization to antigens other than D and requiring intrauterine or postnatal transfusions developed in 21 of 567 (3.7%) of the pregnancies that were at risk; the antibodies were anti-K in 11.6%; anti-c in 8.5%; anti-E in 1.1%; and Rh antibodies other than anti-C, anti-D, or anti-E in 3.8%. All fetuses or children identified as being affected were treated promptly. Two children had complications from the transfusions; one was born at 34 weeks after 4 intrauterine transfusions, and one developed necrotizing enterocolitis after an exchange transfusion at birth. There was no mortality directly related to HDFN. The coverage validation study showed the screening program to be 75% sensitive. Five of 8 cases that were missed at screening were due to anti-C, and delay-related permanent damage occurred in 2 of the affected children; one had kernicterus and suffered permanent brain damage and one had intracerebral bleeding caused by asphyxia that was possibly related to severe antenatal anemia. Screening proved to be 99.8% specific, and its positive predictive value for detecting severe HDFN was 3.7. An estimated 15,000 pregnant women would need to be screened in order to detect one fetus at risk of severe HDFN. A single first-trimester red cell alloantibody screen detects most cases at risk of severe HDFM and would seem to be warranted as part of routine prenatal care. Its performance might be improved by repeated testing of C-negative pregnant women at week 30.