Hemolytic Disease of the Fetus and Newborn
- Hemolytic disease of a fetus or newborn (HDFN) occurs due to the destruction of fetal and newborn red blood cells (RBCs) by maternal antibodies passively transferred across the placenta.
- Primarily related to rhesus (Rh) and less often ABO blood group isoimmunization
- Rh incompatibility
- Incidence of Rh hemolytic disease: 6 to 7/1,000 live births
- Prevalence of RhD-positive (RhD+) fetus in RhD-negative (RhD−) mother: 15%
- RhD− status in 15% of white, 7–8% of black and Hispanic, and 2% of Asian persons
- 48–55% are heterozygous (Dd)
- 35–45% are homozygous (DD)
- Of all Rh-sensitized pregnancies:
- 9% require intrauterine transfusion
- 10% are delivered early and require newborn exchange transfusion
- 31% require treatment after a full-term delivery
- 50% require no treatment
- ABO incompatibility
- Occurs in 12% of first pregnancies
- Only 10–20% become significantly jaundiced, requiring phototherapy.
- RhD− mother becomes pregnant with an RhD+ fetus; D-antigen is inherited from the father.
- Omitted or failed RhIG (anti-D) prophylaxis
- Type O mother pregnant with a type A, type B, or type AB fetus
- Only a fraction of women at risk develop antibodies.
- Rh incompatibility: RhIG is given to an RhD− woman after any exposure to RhD+ blood.
- Given at 28 weeks, 34 weeks (prophylaxis), and within 72 hours of birth, or following maternal event, for example, amniocentesis, abortion, antepartum bleeds
- No prophylaxis for HDFN caused by other blood group incompatibilities
- Isoimmunization—general principles:
- Passage of fetal RBCs into maternal circulation occurs as a result of asymptomatic transplacental hemorrhage.
- Initial sensitization of mother from fetomaternal hemorrhage can occur with placental abruption, abortion, ectopic pregnancy, or procedures (chorionic villus sampling, amniocentesis, or cordocentesis).
- Exposure triggers maternal immune response (anti-D antibodies).
- Maternal IgG antibodies cross the placenta and bind to fetal RBCs. Coated RBCs are then destroyed in the reticuloendothelial system, primarily the spleen.
- Isoimmunization may lead to hyperbilirubinemia, severe anemia, and potentially hydrops.
- Extramedullary hematopoiesis in the fetal liver and spleen is a response to severe fetal anemia, leading to hepatosplenomegaly.
- Rh isoimmunization
- Passage of RhD+ fetal RBCs which cross the placenta into the circulation of an Rh− mother
- RhD− state is the absence of D antigens on RBCs.
- Decreased risk of RhD sensitization of mother if fetus is also ABO incompatible (<2%) versus ABO compatible (~16% risk).
- Rh isoimmunization rarely occurs in first pregnancy.
- ABO isoimmunization
- Occurs in type O mothers with a type A or B fetus; clinically a milder hemolysis compared to Rh incompatibility and rarely requires intervention
- 1% of type O mothers have high titers of IgG antibodies against both A and B that cross the placenta and cause HDFN.
- Hemolysis due to anti-A is more common.
- Hemolysis due to anti-B can be more severe and may require exchange transfusion in the newborn.
- Fetomaternal hemorrhage, usually asymptomatic, with maternal immune response to foreign fetal RBC antigens
- Most common systems involved: RhD antigens, with more severe HDFN, and ABO blood group antigens, with milder anemia, jaundice
- 1% of cases involve other RBC antigens, such as Kell, Kidd, Duffy, or MNS blood groups.
- Maternal exposure to incompatible blood products
- Previous stillbirths and/or abortions
- Neonatal hyperbilirubinemia requiring exchange transfusion in previous pregnancy
- RhIG not given after previous pregnancy or abortion
- Milder cases—hyperbilirubinemia only
- Minimal jaundice at birth but rapidly develops within 24 hours
- Pallor, tachycardia, tachypnea due to congestive heart failure (CHF) secondary to severe anemia
- Generalized edema and massive hepatosplenomegaly in cases with severe anemia and hydrops
- Hematologic: α-thalassemia, severe G6PD deficiency, twin-to-twin transfusion
- Cardiac: hypoplastic left heart syndrome, myocarditis, endocardial fibroelastosis, heart block
- Congenital infections: parvovirus, syphilis, cytomegalovirus (CMV), rubella
- Renal: renal vein thrombosis, urinary tract obstruction, nephrosis
- Placental: umbilical vein thrombosis, true knot of umbilical cord
- Genetic: trisomy 13, 18, 21; triploidy; aneuploidy
- Other: diaphragmatic hernia
Diagnostic Tests and Interpretation
- ABO and Rh blood typing of all mothers at first prenatal visit
- Indirect Coombs test: detects anti-D antibodies in maternal serum
- Father’s ABO and Rh type and zygosity (DD or Dd)
- Fetal blood group typing from amniotic fluid or fetal cord blood
- Fetal serial Doppler ultrasounds of the peak systolic velocity in the middle cerebral artery to detect fetal anemia
- Cord blood or neonate’s RBCs for ABO and Rh types
- Hemoglobin (Hgb), hematocrit (Hct), bilirubin (direct and indirect), reticulocyte count
- Direct Coombs test: detects maternal anti-D antibodies already bound to fetal/newborn RBCs
- Kleihauer-Betke test or flow cytometry: estimates proportion of fetal RBCs in maternal circulation
- Peripheral smear: nucleated RBCs (spherocytes in ABO disease)
- Fetal ultrasound (estimate fetal size, weight, and organomegaly)
- Doppler ultrasonography of fetal middle cerebral artery: peak systolic velocity
- Fetal cordocentesis (for fetal anemia)
- Quantitative polymerase chain reaction, for paternal RhD zygosity
- Pathologic findings
- Extramedullary hematopoiesis
- Serial fetal monitoring
- Intrauterine RBC transfusion: for severely affected fetuses (fetal Hct <25–30%) where early delivery is not possible; usually performed after 20 weeks’ gestation
- Early delivery and neonatal resuscitation may be required if with severe HDFN.
- For high-risk fetus after amniocentesis or history of a prior stillbirth or hydrops
- Phototherapy, IV hydration, and serial bilirubin monitoring begins immediately.
- Exchange transfusion: removes sensitized fetal RBCs and circulating bilirubin, and also
- Corrects anemia in severely anemic infants
- Removes circulating antibodies
- Indications for early exchange transfusion:
- Cord blood bilirubin >3 mg/dL and Hgb <13 g/dL
- Bilirubin rising at rate >1 mg/dL/h despite optimal phototherapy
- Indirect bilirubin ≥20 to 25 mg/dL or rising to reach that level
- Hgb 11 to 13 g/dL and bilirubin rising at rate >0.5 mg/dL/h despite optimal phototherapy
- Lower indirect bilirubin triggers are used in preterm or high-risk infants.
- In hydropic infants, immediate partial exchange may be needed to correct anemia and CHF.
- Double-volume exchanges may be needed for hyperbilirubinemia.
- Selection of blood for exchange transfusion:
- Fresh, washed, CMV-safe, and irradiated, Hgb S negative
- For Rh disease: type O, Rh− cross-matched against mother’s blood
- For ABO disease: type O, Rh− or Rh compatible cross-matched against mother or infant’s serum
- For other antibodies: antigen-negative RBCs selected to avoid the clinically significant antibody. ABO type–specific blood can be used if baby’s type confirmed.
- Risks of exchange transfusion include prolonged neutropenia, thrombocytopenia, hypocalcemia, arrhythmias, thrombosis, late anemia, and death.
- Some infants with milder Rh isoimmunization may have only exaggerated late physiologic anemia at 8 to 12 weeks.
- Most infants with ABO incompatibility require either no treatment or phototherapy only.
- Avoid drugs that interfere with bilirubin metabolism or its binding to albumin (e.g., sulfonamides, caffeine, and sodium benzoate).
Issue for Referral
Late anemia: Infants who had significant HDFN are at risk due to reticulocytopenia related to persistent high titers of circulating maternal antibody. Small-volume RBC transfusion may be required.
- Intravenous immunoglobulin (IVIG): in some studies shown to diminish hemolysis and may prevent the need for exchange transfusion
- Oral iron supplementation
- Erythropoietin, with iron, may be used to support infants at high risk for late anemia.
- Recombinant Rh immune globulin is in development.
- Hgb/Hct and reticulocyte count every 1 to 2 weeks for first 2 to 3 months, especially for infants who had exchange transfusion, due to risk of late anemia at 8 to 12 weeks
- Assess for neurodevelopmental delays or neurologic injury.
- ~50% of affected infants have minimal anemia and hyperbilirubinemia and require either no treatment or phototherapy only.
- ~25% with severe HDFN will require exchange transfusions.
- Data suggest normal neurologic outcome in 94% of cases following intrauterine transfusion
- Hydropic infants have a ~30% mortality rate.
- Hydrops fetalis
- Kernicterus—bilirubin encephalopathy
- Garabedian C, Rakza T, Drumez E, et al. Benefits of delayed cord clamping in red blood cell alloimmunization. Pediatrics. 2016;137(3):e20153236. [PMID:26908660]
- Hendrickson JE, Delaney M. Hemolytic disease of the fetus and newborn: modern practice and future investigations. Transfus Med Rev. 2016;30(4):159–164. [PMID:27397673]
- Louis D, More K, Oberoi S, et al. Intravenous immunoglobulin in isoimmune haemolytic disease of newborn: an updated systematic review and meta-analysis. Arch Dis Child Fetal Neonatal Ed. 2014;99(4):F325–F331. [PMID:24514437]
- Moise KJ Jr, Argoti PS. Management and prevention of red cell alloimmunization in pregnancy: a systematic review. Obstet Gynecol. 2012;120(5):1132–1139. [PMID:23090532]
- Ross MB, de Alarcon P. Hemolytic disease of the fetus and newborn. Neoreviews. 2013;14:e83–e88.
- 773.1 Hemolytic disease of fetus or newborn due to ABO isoimmunization
- 773.0 Hemolytic disease of fetus or newborn due to Rh isoimmunization
- 773.2 Hemolytic disease of fetus or newborn due to other and unspecified isoimmunization
- 773.5 Late anemia of fetus or newborn due to isoimmunization
- P55.1 ABO isoimmunization of newborn
- P55.0 Rh isoimmunization of newborn
- P55.8 Other hemolytic diseases of newborn
- P55.9 Hemolytic disease of newborn, unspecified
- 32858009 Hemolytic disease of fetus OR newborn due to ABO immunization
- 86986002 Hemolytic disease of fetus OR newborn due to RhD isoimmunization
- 387705004 Hemolytic disease of fetus OR newborn due to isoimmunization (disorder)
- 206434001 Late anemia of newborn due to isoimmunization (disorder)
- Q: Why does the Rh isoimmunization become worse with each pregnancy?
- A: Most sensitizing fetomaternal hemorrhages occur at delivery. In the first exposure, mother produces IgM antibodies, which does not cross the placenta; IgG antibodies slowly develops. In second or subsequent pregnancies, repeat exposure to even small amounts of fetal RhD causes rapid production of IgG anti-D, which crosses the placenta and attacks fetal RBCs. Other antibodies, such as Kell, may result in severe HDFN even in a first pregnancy.
- Q: Can maternal blood be used to transfuse the affected baby?
- A: Washed maternal blood may be used, but donor infectious disease testing protocols would need to be followed so it would not be routinely available in an emergency situation.
- Q: How does IVIG work, and does it decrease the need of an exchange transfusion?
- A: The mechanism of action for IVIG is not completely clear. HDFN occurs by destruction of RBCs via an antibody-dependent cytotoxic mechanism mediated by Fc receptors of the neonatal reticuloendothelial system. One possibility is that IVIG nonspecifically blocks these Fc receptors, decreasing hemolysis. However, there may be other ways in which IVIG provides immunomodulation as well.
- Q: How might delayed cord clamping (DCC) following delivery impact neonatal RBC alloimmunization?
- A: In a 2016 single-center study of neonates who required in utero transfusions for fetal anemia, Garabedian et al. found that the DCC group had a higher Hgb and less anemia at birth and were less likely to require a postnatal exchange transfusion compared to the immediate cord clamping group.
Maureen M. Gilmore, MD
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