Haemolytic Disease of the Fetus and Newborn

Haemolytic disease of the fetus and newborn is an immune-mediated condition. Maternal alloimmunisation against a fetal red cell antigen, inherited from the father and absent in the mother, leads to transplacental transfer of maternal IgG antibody and destruction of fetal red blood cells.

It is most classically associated with Rhesus D alloimmunisation, though other red cell antigens, including Kell and other Rhesus system antigens, can also cause it. Severity ranges from mild, subclinical disease to severe fetal anaemia with hydrops fetalis and, in the most severe untreated cases, fetal death.

Widespread, systematic anti-D immunoglobulin prophylaxis has dramatically reduced its incidence and severity over recent decades, a significant public health success.

Pathophysiology

• Maternal alloimmunisation occurs when fetal red blood cells expressing a paternally inherited antigen, absent from the maternal red cell surface, enter the maternal circulation. This is most common at delivery. It can also follow antepartum sensitising events, including miscarriage, invasive prenatal testing, or significant abdominal trauma. The maternal immune system recognises the cells as foreign and produces IgG antibody against the antigen.
• Unlike the initial IgM response typical of many sensitisation events, this IgG antibody crosses the placenta.
• The sensitising pregnancy itself is generally unaffected, because of the typically brief interval between fetomaternal haemorrhage (most commonly at delivery) and the antibody response.
• Any subsequent pregnancy with a fetus carrying the antigen is at risk of significant fetal red cell destruction. Pre-formed maternal IgG is readily available and crosses the placenta from early in that pregnancy.
• Fetal red cell destruction produces progressive fetal anaemia. Compensatory extramedullary erythropoiesis contributes to fetal hepatosplenomegaly. In severe cases, high-output cardiac failure and generalised fetal oedema (hydrops fetalis) follow, reflecting the severity of the anaemia and its haemodynamic consequences.
• Postnatally, ongoing haemolysis in the affected, undelivered infant, combined with the immaturity of neonatal hepatic bilirubin conjugation, produces significant, potentially severe neonatal jaundice (see neonatal jaundice).
• Kernicterus (bilirubin-induced neurological injury) is a serious potential complication requiring prompt, effective postnatal management.

• The great majority of at-risk pregnancies are identified through structured, proactive antenatal screening in an otherwise asymptomatic mother. The condition affects the fetus and then the newborn, and produces no specific maternal symptom.
• Fetal manifestations, identified through structured antenatal surveillance in an alloimmunised pregnancy, range from mild, subclinical anaemia to progressively more severe anaemia.
• The most severe manifestation is hydrops fetalis: generalised fetal subcutaneous oedema with pleural and pericardial effusion and ascites. It carries substantial mortality risk if not promptly and effectively treated.
• Postnatal manifestations in an affected infant include significant, often early-onset neonatal jaundice (ongoing haemolysis and elevated bilirubin production) and anaemia.
• Where significant in utero disease has occurred, hepatosplenomegaly reflects the compensatory extramedullary erythropoiesis of fetal life.
• Severity in a given pregnancy is influenced by the antibody titre and the antigen involved (some antigens are associated with more consistently severe disease than others).
• Severity tends to worsen with each successive affected pregnancy in an alloimmunised woman, reflecting progressive, cumulative maternal immune sensitisation.

• Antenatal blood group and antibody screening is a routine part of antenatal booking assessment (see pregnancy) and is repeated at defined intervals during pregnancy. It identifies maternal red cell alloantibodies. Any clinically significant antibody prompts structured, specific surveillance of the pregnancy for fetal involvement.
• Paternal blood typing supports assessment of whether the fetus carries the relevant antigen and is therefore at risk. Where available and appropriate, non-invasive fetal antigen genotyping using cell-free fetal DNA from a maternal blood sample can be used instead.
• A fetus confirmed or predicted to be antigen-negative does not need the intensive surveillance otherwise indicated for an alloimmunised pregnancy.
• Where the fetus is at risk, monitor maternal antibody titres serially. Once titres reach a defined threshold, add middle cerebral artery peak systolic velocity Doppler ultrasound. This is the standard, essential surveillance approach for an at-risk, alloimmunised pregnancy.
• Doppler has substantially superseded the historical, invasive approach of serial amniocentesis for bilirubin assessment. It detects fetal anaemia non-invasively through the compensatory increase in cerebral blood flow velocity that accompanies significant anaemia.
• Postnatal diagnosis in an affected infant is supported by a positive direct Coombs test (demonstrating antibody-coated fetal red cells) and by haemoglobin and bilirubin levels. These are an essential part of neonatal evaluation in any infant born to a known alloimmunised mother.

• Prevention through systematic anti-D immunoglobulin prophylaxis for Rhesus D negative women is the single most effective strategy for reducing incidence (see anti-D immunoglobulin). It prevents initial maternal sensitisation to this historically dominant antigen.
• Structured, ongoing antenatal surveillance of an alloimmunised at-risk pregnancy informs the timing and need for in utero intervention.
• Intrauterine fetal blood transfusion, delivered via ultrasound-guided umbilical cord puncture, is the definitive treatment for significant, confirmed fetal anaemia. It is performed by an experienced specialist fetal medicine team and repeated at structured intervals through the rest of the pregnancy according to surveillance findings.
• Delivery timing is individualised to the severity of disease and the response to any in utero treatment. It balances the risks of prematurity against the risks of continued in utero disease progression.
• Plan delivery at a centre with neonatal intensive care facilities, given the anticipated need for full postnatal management.
• Postnatal management of an affected infant addresses the hyperbilirubinaemia and anaemia. Phototherapy is first-line treatment for hyperbilirubinaemia (see neonatal jaundice).
• Reserve exchange transfusion for the most severe cases, with bilirubin levels approaching or exceeding the established thresholds that carry significant kernicterus risk. Give top-up red cell transfusion as clinically indicated where significant anaemia is present.
• Follow affected infants up over the long term, including monitoring for late anaemia. This can develop some weeks after birth, as residual maternal antibody is gradually cleared and its diminishing effect on the infant's own red cell production and survival continues.
• Counsel the mother about the implications for future pregnancies, given the pattern of worsening severity with successive affected pregnancies.