Hemolytic disease of the newborn (anti-Rhc) is a form of hemolytic disease of the fetus and newborn (HDN) caused by maternal IgG antibodies directed against the Rhc red blood cell (RBC) antigen. The condition results from maternal alloimmunization to fetal Rhc-positive red cells, leading to fetal or neonatal hemolysis, anemia, and hyperbilirubinemia. Disease severity ranges from mild to severe, and complications can include kernicterus, neutropenia, and thrombocytopenia. The Rhc ("little c") antigen is implicated in only about 7 in 10,000 pregnancies, but roughly 20–30% of affected infants develop severe disease, making anti-Rhc the second most common cause of severe HDN. Diagnosis relies on serological testing of the parents and, where indicated, fetal antigen typing and middle cerebral artery Doppler assessment. Management may involve intrauterine transfusion (IUT), intravenous immunoglobulin (IVIG), plasmapheresis, early delivery, and postnatal phototherapy or exchange transfusion.
Signs and symptoms Affected fetuses and newborns may present with anemia, hyperbilirubinemia, and, in severe cases, hydrops fetalis. Clinical and laboratory findings can include any of the manifestations listed below.
Complications High or rapidly rising bilirubin at birth Prolonged hyperbilirubinemia Bilirubin-induced neurological dysfunction Cerebral palsy Kernicterus Neutropenia Thrombocytopenia Hemolytic anemia (which should not be treated with iron supplementation) Late-onset anemia, which should not be treated with iron and may persist for up to 12 weeks after birth
Transfusion reactions Once a woman has developed alloantibodies, she is at increased risk of a hemolytic transfusion reaction. She is therefore generally advised to carry a medical alert card and to inform treating clinicians of her antibody status. Acute hemolytic transfusion reactions can be either immune-mediated or nonimmune-mediated. Immune-mediated reactions caused by immunoglobulin M (IgM) anti-A, anti-B, or anti-A,B antibodies typically produce severe, potentially fatal, complement-mediated intravascular hemolysis. By contrast, immune-mediated reactions caused by IgG antibodies against Rh, Kell, Duffy, or other non-ABO antigens generally result in extravascular red cell sequestration, shortened survival of transfused cells, and milder clinical effects. Such reactions can occur even when antibodies are not detected by routine laboratory testing.
Causes A Rhc-negative mother can become sensitized to red blood cell Rhc antigens during a first pregnancy with a Rhc-positive fetus or as a result of blood transfusion. The mother may then produce IgG anti-Rhc antibodies, which can cross the placenta into the fetal circulation. If the fetus is Rhc-positive, alloimmune hemolysis may result, producing HDN.
Diagnosis Evaluation for HDN includes blood testing of both parents and may also involve amniocentesis and middle cerebral artery (MCA) Doppler assessment. In anti-C and anti-c HDN, the direct antiglobulin test (DAT) may be negative even when the infant is severely affected. An indirect Coombs test is therefore also performed. In women with anti-c, repeat antibody screening at around 28 weeks is suggested to detect possible co-development of anti-E.
Maternal testing Antibody screening in the mother is performed using the indirect Coombs test (also called the indirect agglutination test, IAT), which detects circulating antibodies in maternal plasma. If a clinically relevant antibody is identified, its titer is determined. Critical titers are associated with significant risk of fetal anemia and hydrops fetalis. A titer of 1:8 or higher is considered critical for Kell, and 1:16 or higher for most other antibodies. Once a critical titer is reached, ongoing care is generally guided by MCA Doppler studies. A sudden rise in titer late in pregnancy, or a fourfold increase in titer, is regarded as significant regardless of whether the critical threshold has been crossed. After a previously affected pregnancy, maternal titers are not reliable predictors of fetal anemia and should not be used to direct management. Titers are generally checked monthly until 24 weeks and every two weeks thereafter. Two situations call for monitoring that differs from standard Rh(D) management. In alloimmunization to the C, c, or E antigens, hemolysis has been reported at titers below 1:16, so MCA Doppler assessment may be reasonable if a stable low titer rises later in pregnancy. In Kell isoimmunization, severe fetal hemolysis can occur even at low titers, so antibody titers alone are not adequate for risk assessment. When the indirect Coombs test is positive, the woman is generally advised to carry a medical alert card or bracelet long-term because of the ongoing risk of a hemolytic transfusion reaction.
Paternal testing The father is generally tested to help establish the likely fetal antigen status. If he is homozygous for the antigen, every offspring of the couple will be antigen-positive and at risk for HDN; if he is heterozygous, each pregnancy carries a 50% chance of an antigen-positive fetus. The result informs management of the current pregnancy and counseling about future pregnancies. For Rh(D), this test is termed the RhD genotype; for RhCE and Kell, it is referred to as antigen phenotyping.
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