What is the efficacy of treatments for hemolytic disease of the newborn (HDN) in the fetus?

Updated: Dec 28, 2017
  • Author: Sameer Wagle, MBBS, MD; Chief Editor: Muhammad Aslam, MD  more...
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Initial attempts to suppress Rh antibody production with Rh hapten, Rh-positive RBC stroma, and administration of promethazine were unsuccessful. Extensive plasmapheresis with partial replacement using 5% albumin (therapeutic plasma exchange) and intravenous immunoglobulin (IVIG) or the administration of IVIG at 1 g/kg body weight weekly has been shown to be moderately effective. The mechanism of action appears to be blockage of Fc receptors in the placenta, reducing antibody transport across to the fetus, Fc receptors on the phagocytes in the fetal reticuloendothelial system, and feedback inhibition of maternal antibody synthesis. However, antibody-dependent cell-mediated cytotoxicity and rebound elevation of antibody concentration, alteration of placental blood flow during the procedure, and postpartum hemorrhage have been noted after plasma exchange. [41]

A more recent retrospective study comprising 5 pregnant women with severe HDFN due to RBC alloimmunization reported successful treatment with a combined regimen of therapeutic plasma exchange, IVIG, and intrauterine transfusion (IUT) early in the pregnancies. [68]  The women underwent 3 plasma exchange procedures during weeks 10-13 of pregnancy, following by weekly IVIG infusions; the fetuses received RBC units that fully matched the maternal phenotype to the D, C, E, K, Fy, Jk, and S antigen groups. All the women delivered healthy infants at 33-38 weeks' gestation. [68]

However, these techniques only postpone the need for percutaneous umbilical blood sampling (PUBS) and IVT until 20-22 weeks' gestation, when these procedures can be performed at a more acceptable risk. A review of IVIG use shows its usefulness in preventing the onset of fetal hydrops and in delaying the need for IUT. [69] Thus, a combined approach of plasmapheresis that starts at 12 weeks' gestation 3 times in that week, followed by IVIG at a loading dose of 2 g/kg after the third plasmapheresis, and then continued IVIG 1 g/kg/wk until 20 weeks' gestation has been suggested for at-risk fetuses prior to 20 weeks' gestation and can also be used later in gestation if IVT cannot be performed or if hydrops is unresponsive to IVT. [41]

One report indicated that treatment of fetuses with severe alloimmunization using IVT combined with fetal IVIG therapy at 1 g/kg/dose starting from the third IVT helped in reducing the frequency of IVT and improving signs of hydrops. [70] A case report shows successful treatment of severe anemia and hydrops in a fetus with alloimmunization due to anti-M antibody with fetal intraperitoneal IVIG injections 2 g/kg given weekly starting 30 weeks. [71] However, this was a case report, and a randomized controlled trial is needed before this can become standard of care.

Similar regimens of tests and treatment are used in the management of pregnancies affected by nonRhD alloimmunization, such as anti-Rhc, anti-K (K1), and anti-M. Once the mother is diagnosed with an antibody associated with hemolytic disease, an indirect Coombs titer is performed, along with paternal testing for involved antigen and zygosity. Maternal titers are repeated (monthly until 28 weeks' gestation and then every 2 wk) until a threshold for fetal anemia is reached (1:8 for Kell and 1:32 for rest).

Fetal antigen typing is performed via amniocentesis or cell-free fetal DNA in maternal plasma if the father is found to be heterozygous (100% for K1, 65% for M). When the fetus is known to be antigen positive, surveillance for severe fetal anemia is performed, with weekly MCA Doppler screening as early as 16-18 weeks and IUT is carried out if it exceeds 1.5 MOM with a delivery by 38 weeks' gestation. [72]

Maternal alloantibodies to paternal leukocytes have been shown to result in Fc blockade and to reduce the severity of fetal hemolytic anemia. This may be used in the future.

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