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Erythroblastosis Fetalis

para>Any Rh-positive pregnancy in an Rh-negative woman can cause alloimmunization (~9% of pregnancies have an Rh-negative mother with an Rh-positive fetus).
  • Without prophylactic immunotherapy (RhIG), risk of Rh sensitization is up to 16% during or after term pregnancy, ~3% for spontaneous abortion, and 5-6% for surgical abortion.

  • Prophylaxis with RhIG drastically reduces risk of sensitization to <1% of susceptible pregnancies.

  • Universal screening for Rh sensitization and widespread use of RhIG in 3rd trimester and/or at birth have made this disease relatively rare.


  • Genetics
    55% of the population are heterozygous for the RhD locus and 50% of their offspring will be Rh positive (2)[C]. The RhD antigen is most frequently implicated but other antibodies may be the source of alloimmunization. DNA techniques now make it possible to diagnose the fetal blood type through free fetal DNA in maternal plasma as early as 12 weeks gestational age. †

    GENERAL PREVENTION


    • For pregnant patients:
      • Administer anti-D immunoglobulin (i.e., RhoGAM) to Rh-negative pregnant women at increased risk of fetomaternal hemorrhage, at 28 weeks' gestational age and within 72 hours of birth of an Rh-positive infant.
    • For nonpregnant patients who are of childbearing age:
      • Crossmatching of all transfused blood products is standard of care in developed countries. Rh-negative women should be treated with anti-D immunoglobulin if they receive Rh-positive RBCs in error or in emergency transfusions.
      • Platelets can contain small amounts of RBCs. Prophylactic anti-D immunoglobulin should be considered in Rh-negative women of childbearing age who are receiving Rh-positive platelets.

    DIAGNOSIS


    PHYSICAL EXAM


    • Antenatal (the fetus)
      • Hepatomegaly
      • Splenomegaly
      • Hydrops (two or more of the following US findings: ascites, pericardial effusion, pleural effusion, skin edema, polyhydramnios)
      • Death
    • Postpartum (the infant, in addition to the above)
      • Pallor
      • Respiratory distress
      • Jaundice, icterus
      • Purpura
      • Coagulopathies
      • Hypotension/shock

    DIFFERENTIAL DIAGNOSIS


    • Fetal blood loss anemia
    • Twin-to-twin transfusion
    • Arteriovenous or cardiac malformations
    • Hereditary hemolytic anemias: G6PD deficiency, pyruvate kinase deficiency, hereditary spherocytosis
    • Hemoglobinopathy
    • Drug-induced hemolytic anemia
    • Nonimmune fetal hydrops from intrauterine infection (syphilis, toxoplasmosis, cytomegalovirus, others)
    • Congenital cardiac anomalies
    • Noncardiac congenital anomalies
    • Cardiac arrhythmia
    • Chromosomal anomalies

    DIAGNOSTIC TESTS & INTERPRETATION


    Initial Tests (lab, imaging)
    DURING PREGNANCY: †
    • Maternal antibody screen. A positive indirect Coombs test implies IgG antibodies.
    • CBC to evaluate for anemia, thrombocytopenia, or nucleated RBCs on differential
    • Screen for reticulocytosis and hyperbilirubinemia.
    • Measure maternal antibody titer as soon as alloimmunization is identified. If it remains below the critical titer of 1:16, continue to monitor this every 4 weeks (2,3)[C].
    • If the titer reaches ≥1:16, further evaluation of the fetus with Doppler velocimetry middle cerebral artery (MCA) peak systolic velocity (PSV), ultrasonography, growth measurements, and antepartum testing is indicated.
    • US to evaluate for presence of fetal hepatomegaly, splenomegaly, ascites, pericardial effusion, pleural effusion, subcutaneous edema

    Follow-Up Tests & Special Considerations
    • DURING PREGNANCY
      • Serial MCA-PSV via Doppler US are used to assess for fetal anemia; measure fetal hemoglobin/hematocrit if > 1.5 multiples of the mean (MOM).
      • MCA-PSV is performed weekly after 20 weeks' gestational age or from time of diagnosis. MCA-PSV is not continued after 34 to 35 weeks due to the high false positive-rate at this gestational age.
      • Ultrasonography and fetal growth measurements are performed every 3 to 4 weeks until delivery.
      • Antepartum testing with a biophysical profile (BPP) is performed weekly after 28 to 32 weeks and continues until delivery.
      • A mother with a previously affected infant or a history of alloimmunization to Kell antigen should have further fetal evaluation in current and subsequent pregnancies regardless of antibody titers.
    • AFTER DELIVERY
      • Screening for all infants: A positive direct Coombs test of infant implies "foreign"Ě antibodies are present that can cause hemolytic anemia.
      • If there is a positive screen or known maternal alloimmunization: CBC, peripheral blood smear, reticulocyte count, bilirubin measurement
      • As indicated: EKG, echo, chest x-ray, abdominal x-ray or US, cultures to evaluate for infection, chromosomal analysis, newborn screening

    TREATMENT


    GENERAL MEASURES


    • Intrauterine transfusion is indicated when the hematocrit is ‚ȧ30 OR is 2 standard deviations below the mean value for gestational age.
    • The intravascular approach for transfusion via the umbilical vein is becoming preferred over the intraperitoneal approach and appears to be more effective.
    • Delivery by 37 to 38 weeks' gestational age if testing remains normal
    • If abnormal testing or the fetal condition is worsening despite optimal treatment, may need to consider early delivery
    • Depending on severity of involvement, treatment of the delivered infant may include the following:
      • Phototherapy
      • Transfusion
      • Exchange transfusion
      • Thoracentesis, paracentesis
      • Diuretics
      • Anti-infectives as indicated for infection
      • Addressing cardiac arrhythmias and heart failure

    ISSUES FOR REFERRAL


    • Affected pregnancies are usually managed at the tertiary care level by perinatologists because of the specialized treatment measures involved.
    • Delivery should occur in an institution capable of performing exchange transfusion, even if only mild involvement of the infant is expected.
    • Infants with moderate or severe disease require neonatal intensive care and potential consultation with hematology, cardiology, neurology, surgery, and infectious disease specialists.

    ONGOING CARE


    PROGNOSIS


    • 50% of affected infants have mild disease and require no treatment (or treatment of anemia and jaundice only after delivery). 30% have moderate disease with anemia and hepatomegaly (4)[C].
      • They require close follow-up of the pregnancy for signs of deterioration, which may require early delivery after 32 to 34 weeks or intrauterine transfusion prior to that age.
      • After delivery, exchange transfusion is usually needed to treat anemia and hyperbilirubinemia.
    • 20% have fetal hydrops and require intrauterine transfusion and delivery as early as 32 to 34 weeks.
    • 25% become hydropic and die in utero.
    • Disease severity tends to worsen in subsequent pregnancies (5)[C].
    • Without treatment, overall perinatal mortality is ~50%.
    • With intrauterine treatment, the survival rate can reach 78%.
    • With appropriate monitoring and treatment, most infants do well, even those requiring intrauterine transfusion, and perinatal mortality has been reduced to 2-3% (2)[C].
    • In long-term follow-up of patients requiring transfusion, only 4.8% overall had signs of neurodevelopmental impairment.
    • Severe fetal hydrops substantially increased the risk of long-term impairment, so timely intervention to prevent development or worsening of hydrops is appropriate.

    COMPLICATIONS


    • Fetal distress requiring emergent delivery
    • Fetal death in utero
    • DIC
    • Pregnancy loss from umbilical blood sampling or intrauterine transfusion
    • Neonatal hemolytic anemia, mild to severe
    • Neonatal anemia from hematopoietic suppression after intrauterine transfusion
    • Pulmonary edema
    • Congestive heart failure
    • Cardiogenic or noncardiogenic shock
    • Neonatal jaundice, mild to severe
    • Neurodevelopmental impairment

    REFERENCES


    11 Aitken †SL, Tichy †EM. Rh(O)D immune globulin products for prevention of alloimmunization during pregnancy. Am J Health Syst Pharm.  2015;72(4):267-276.22 Moise †KJJr. Management of rhesus alloimmunization in pregnancy. Obstet Gynecol.  2008;112(1):164-176.33 American College of Obstetricians and Gynecologists. ACOG Practice Bulletin No. 75: management of alloimmunization during pregnancy. Obstet Gynecol.  2006;108(2):457-464.44 Santos †MC, S ° †C, Gomes †SCJr, et al. The efficacy of the use of intravenous human immunoglobulin in Brazilian newborns with rhesus hemolytic disease: a randomized double-blind trial. Transfusion.  2013; 53(4):777-782.55 Moise †KJJr, Argoti †PS. Management and prevention of red cell alloimmunization in pregnancy: a systematic review. Obstet Gynecol.  2012;120(5):1132-1139.

    ADDITIONAL READING


    • Alcock †GS, Liley †H. Immunoglobulin infusion for isoimmune haemolytic jaundice in neonates. Cochrane Database Syst Rev.  2002;(3):CD003313.
    • Bowman †J. Thirty-five years of Rh prophylaxis. Transfusion.  2003;43(12):1661-1666.
    • Branch †DR, Scofield †TL, Moulds †JJ, et al. Unexpected suppression of anti-Fya and prevention of hemolytic disease of the fetus and newborn after administration of Rh immune globulin. Transfusion.  2011;51(4):816-819.
    • Cardo †L, Garc ≠a †BP, Alvarez †FV. Non-invasive fetal RHD genotyping in the first trimester of pregnancy. Clin Chem Lab Med.  2010;48(8):1121-1126.
    • Elalfy †MS, Elbarbary †NS, Abaza †HW. Early intravenous immunoglobin (two-dose regimen) in the management of severe Rh hemolytic disease of the newborn-a prospective randomized controlled trial. Eur J Pediatr.  2011;170(4):461-467.
    • Lindenburg †IT, Smits-Wintjens †VE, van Klink †JM, et al. Long-term neurodevelopmental outcome after intrauterine transfusion of the fetus/newborn: the LOTUS study. Am J Obstet Gynecol.  2012;206(2):141.e1-141.e8.
    • Mikesell †KV, George †MR, Castellani †WJ, et al. Evaluation of different testing methods for identification of RhIG in red blood cell antibody detection. Transfusion.  2015;55(6 Pt 2):1444-1450.
    • Ruma †MS, Moise †KJJr, Kim †E, et al. Combined plasmapheresis and intravenous immune globulin for the treatment of severe maternal red cell alloimmunization. Am J Obstet Gynecol.  2007;196(2):138.e1-138.e6.
    • Smits-Wintjens †VE, Walther †FJ, Rath †ME, et al. Intravenous immunoglobulin in neonates with rhesus hemolytic disease: a randomized controlled trial. Pediatrics.  2011;127(4):680-686.

    SEE ALSO


    • Anemia, Autoimmune Hemolytic
    • Algorithm: Jaundice, Newborn

    CODES


    ICD10


    • P55.9 Hemolytic disease of newborn, unspecified
    • P55.0 Rh isoimmunization of newborn
    • P55.1 ABO isoimmunization of newborn
    • P55.8 Other hemolytic diseases of newborn

    ICD9


    • 773.2 Hemolytic disease of fetus or newborn due to other and unspecified isoimmunization
    • 773.0 Hemolytic disease of fetus or newborn due to Rh isoimmunization
    • 773.1 Hemolytic disease of fetus or newborn due to ABO isoimmunization
    • 773.3 Hydrops fetalis due to isoimmunization

    SNOMED


    • Hemolytic disease of fetus OR newborn due to isoimmunization (disorder)
    • Hemolytic disease of fetus OR newborn due to RhD isoimmunization
    • Hemolytic disease of fetus OR newborn due to ABO immunization
    • Hydrops fetalis due to isoimmunization

    CLINICAL PEARLS


    • Prior to administration of Rho(D) IG during pregnancy may lead to weakly false-positive indirect Coombs test in mother and direct Coombs test in infant.
    • Rh antigen alloimmunization is usually acquired by pregnancy.
    • Kell antigen alloimmunization is usually acquired by transfusion.
    • The fetus may be severely affected without hydrops; the presence or absence of hydrops on US is poor at predicting the need for intervention.
    • IVIG infusions have not been proven to reduce the need for exchange transfusions.
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