Key Facts

Rhesus disease (haemolytic disease of the fetus and newborn, HDFN) results from maternal alloimmunisation against the RhD antigen on fetal red blood cells. Prevention with anti-D immunoglobulin prophylaxis has dramatically reduced the incidence.

Epidemiology

• RhD-negative women: approximately 15% of Caucasians in the UK, lower in other ethnic groups
• Prior to routine prophylaxis, HDFN affected 1% of pregnancies
• With current prophylaxis, clinically significant HDFN is rare (<0.4 per 1,000 births)
• Other antibodies (anti-c, anti-Kell) can also cause HDFN but are less common

Aetiology

• Fetomaternal haemorrhage (FMH): transfer of fetal RhD-positive red cells into maternal circulation
• Sensitising events: delivery, miscarriage, TOP, ectopic, APH, amniocentesis, CVS, ECV, abdominal trauma
• Primary exposure produces IgM (does not cross placenta); subsequent exposure produces IgG (crosses placenta)

Pathophysiology

• Maternal anti-D IgG antibodies cross the placenta and bind to RhD-positive fetal red cells
• Opsonised fetal red cells are destroyed in the fetal reticuloendothelial system (extravascular haemolysis)
• Results in fetal anaemia, compensatory extramedullary haematopoiesis (hepatosplenomegaly), and eventually hydrops fetalis
• Hydrops fetalis: generalised oedema, ascites, pleural effusions, pericardial effusions due to cardiac failure
• After birth: neonatal jaundice from unconjugated hyperbilirubinaemia (risk of kernicterus)

Maternal Presentation

• Usually asymptomatic
• Detected by routine antibody screening at booking and 28 weeks
• History of sensitising events

Fetal Presentation

• Fetal anaemia detected by MCA Doppler (non-invasive)
• Fetal hydrops on ultrasound: subcutaneous oedema, ascites, pleural/pericardial effusions, polyhydramnios, placentomegaly
• Reduced fetal movements
• Intrauterine fetal death in severe untreated cases

Neonatal Presentation

• Jaundice within 24 hours of birth (pathological)
• Anaemia (pallor)
• Hepatosplenomegaly
• Hydrops fetalis (severe)

Red Flags

• Anti-D titre rising rapidly (>4 IU/mL or rising by ≥2 dilutions)
• MCA PSV >1.5 MoM
• Features of hydrops fetalis on USS
• Reduced fetal movements

Bedside

• Blood group and antibody screen at booking and 28 weeks
• Kleihauer test after sensitising events (>20 weeks)

Bloods

• Maternal blood group and antibody screen: identify anti-D or other clinically significant antibodies
• Quantify anti-D titre: monitored 4-weekly; referral to fetal medicine if >4 IU/mL
• Cell-free fetal DNA (cffDNA): from 16 weeks, determines fetal RhD status non-invasively from maternal blood
• Kleihauer test: quantifies FMH to guide additional anti-D doses (1 fetal cell per 50 LPF = ~4 mL FMH)

Imaging

• MCA Doppler: peak systolic velocity (PSV) >1.5 MoM indicates moderate-severe fetal anaemia
• Serial USS: fetal growth, liquor volume, signs of hydrops (ascites, oedema, effusions, placentomegaly)

Special Tests

• Fetal blood sampling (cordocentesis): direct measurement of fetal haemoglobin if MCA Doppler abnormal
• Amniocentesis (historical; largely replaced by MCA Doppler and cffDNA)
• Neonatal: DAT (Coombs test), bilirubin, FBC, reticulocyte count, blood film

Non-pharmacological

• Education of RhD-negative women about the importance of anti-D prophylaxis
• Inform about sensitising events and when to seek anti-D
• Early booking and regular antenatal care

Pharmacological

• Routine antenatal anti-D prophylaxis (RAADP): single dose of 1,500 IU IM at 28 weeks (NICE NG156) or two doses of 500 IU at 28 and 34 weeks
• Anti-D for sensitising events: minimum 250 IU before 20 weeks; minimum 500 IU after 20 weeks; within 72 hours
• Postnatal anti-D: 500 IU IM within 72 hours of delivery if baby is RhD-positive; Kleihauer to guide additional doses
• Intrauterine transfusion (IUT): O-negative, irradiated, CMV-negative packed red cells via cordocentesis for severe fetal anaemia before 34 weeks

Surgical/Interventional

• Intrauterine transfusion: performed by fetal medicine specialist under USS guidance
• Early delivery: planned from 34-37 weeks depending on severity and response to IUT
• Neonatal exchange transfusion or phototherapy for hyperbilirubinaemia

Referral Criteria

• Anti-D titre >4 IU/mL: refer to fetal medicine for MCA Doppler monitoring
• Rising antibody levels: 2-4 weekly monitoring in fetal medicine unit
• cffDNA positive for RhD: continue prophylaxis and monitoring
• cffDNA negative for RhD: no further anti-D required (confirmed RhD-negative fetus)

• With routine prophylaxis, incidence of RhD alloimmunisation has fallen from 13% to <1%
• Mild HDFN: excellent prognosis with phototherapy
• Moderate-severe HDFN: good outcomes with intrauterine transfusion (survival >90% in experienced centres)
• Hydrops fetalis without treatment: high mortality (>50%)
• With IUT: survival rates 85-95% in non-hydropic fetuses
• Long-term neurodevelopmental outcomes generally good with appropriate management

Anti-D Dosing Guide

MCA Doppler Interpretation