Introduction:

• It is a hemolytic anemia caused by transplacentally transmitted IgG antibodies which are produced against paternally inherited antigens, that are present on fetal red cells but absent on maternal red cells.
• 3 main classes
  • Rh related
  • ABO related
  • Other red cell antigens 

Epidemiology:

• With advent of Anti-D prophylaxis incidence has greatly reduced after 1970s 

Pathogenesis:

Antigen negative women develop antibodies as a result of exposure to foreign red cell antigens through blood transfusions/ silent fetomaternal hemorrhage during pregnancy/ delivery/ obstetric procedures such as chorionic villus biopsy/amniocentesis/ abortion.

Antigens frequently associated with severe HDN include- Rh-D and Rh-c, Kell-K

Extent of Rh expression and type of Rh antigen determines the amount of allo immunization.

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Maternal Anti-D, IgG antibodies cross placenta and bind to D antigen on the surface of fetal RBCs

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Adherence of coated RBCs to Fc-gamma receptors of macrophages

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Extravascular non-complemet mediated phagocytosis and lysis of RBCs in spleen leading to severe anemia

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Compensatory extramedullary erythropoiesis in liver spleen, kidney and adrenal glands

Ascites and pleural effusion

Pulmonary hypoplasia

Liver dysfunction with hypoproteinemia

Cardiac failure

• HDN due ABO antigens is extremely rare, as Anti A and Anti B antibodies are IgM type and cannot cross placenta.

Clinical Features: Severity varies depending on extent of hemolysis

• Mild:
  • 50% cases, who do not require any intervention
• Moderate:
  • Hemolytic anemia
  • Hepatosplenomegaly
  • Kernicterus- Lethargy, poor feeding and hypotonia which may later lead to frank opisthotonos and irregular respirations
  • Edema
  • Hypoglycemia and acidosis
• Severe:
  • Hydropsfetalis with intrauterine death

Investigations:

• Maternal ABO and Rh typing at 10 and 16 weeks of gestation.
• If at risk of HDN- Screening for red cell alloantibodies done at 14 and 28 weeks (ICT using reagent cells which express all Rh antigens and other blood group antigens is done) 
• Hemolysis in fetus can be tested through various means, which are not easily available. If severe hemolysis is noted, intrauterine fetal blood transfusion needs to be given.
• After birth, immediately do following tests of neonate: Complete hemogram, reticulocyte count, LFT, ABG, DCT

Treatment of affected child (Hb<11, with features of hemolysis):

• Should be treated under neonatologist
• ET with ventilation
• Drain pleural and ascitic fluid to facilitate gas exchange
• Exchange transfusion after initial stabilization
  • It corrects anemia and removes excess of bilirubin
  • Volume- 80ml/kg- two times- which replaces 85% of infants blood volume 
  • Umbilical vein is vascular access. Exchange is done with push and pull technique with aliquots of 5-10ml each time.
  • It lasts for usually 1-2 hrs
• Phototherapy- To prevent bilirubin neurotoxicity
• High dose IVIg (1gm/Kg)- decreases the need of phototherapy and exchange transfusion.
• Synthetic heme analogues such as Sn-Protoporphyrin- suppress bilirubin production

For mother:

• During 3rd trimester of pregnancy- At 28 weeks- Anti D- 1500 IU single dose
• After delivery if baby is Rh-positive 500 IU has to be repeated.
• Any sensitizing event Anti-D immunoglobulin has to be administered within 72hrs of event
  • <12 weeks- 250 IU
  • >12 weeks- 500 IU
  • Dose and frequency depends on amount of fetomaternal hemorrhage which is done by flow cytometry/ acid elution technique

Recent advances:

Nipocalimab in Early-Onset Severe Hemolytic Disease of the Fetus and Newborn

This phase 2 study evaluated nipocalimab, an anti-neonatal Fc receptor blocker, in 13 pregnancies at high risk for early-onset severe hemolytic disease of the fetus and newborn (HDFN). The treatment resulted in live births at 32 weeks or later without intrauterine transfusions in 54% of cases. No fetal hydrops occurred, and 46% of pregnancies required no antenatal or neonatal transfusions. The treatment showed a reduction in alloantibody titer and IgG levels, with no unusual infections observed. Nipocalimab appears effective in delaying or preventing fetal anemia and transfusions in severe HDFN cases.

https://doi.org/10.1056/NEJMoa2314466