Haemolytic Disease of the Fetus and Newborn

Haemolytic Disease of the Fetus and Newborn (HDFN) - Detection and Treatment

• HDFN is a condition where maternal antibodies attack fetal red blood cells
• All pregnant women are screened for ABO and RhD blood groups and red blood cell antibodies during early and late pregnancy
• Antibody specificity is identified
• Antibody levels are monitored to detect sudden changes indicating fetal concerns
• Antibody levels are measured by quantification (anti-D, -c) and antibody titration for other antibodies
• Paternal phenotype and zygosity testing is done when appropriate

Diagnostic Testing - Laboratory Based

• Pregnant women are screened for red blood cell antibodies
• Antibody specificity is determined
• Antibody levels are monitored; sudden changes signal fetal problems
• Antibody levels are measured by quantitation and titration

Alternative Methods

• Fetal blood type:
  • Chorionic villus sampling (CVS)
  • Maternal blood cell-free fetal DNA (cffDNA)
• Amniotic fluid sampling: used for rising bilirubin levels in the amniotic fluid
• Ultrasound: used to assess hydrops and mid-cerebral velocity (MCV)

Anti-D in HDFN

• Anti-D continues to be the main cause of HDNF, due to high immunogenicity
• Even with anti-D prophylaxis introduced in 1969, maternal sensitization still happens annually in roughly 1000 Rh-negative pregnancies
• Effects on first pregnancies are rare

Anti-K in HDFN

• Anti-K is the second most common cause of severe HDNF
• Characterised by severe HDN at low antibody levels
• Affects haemolysis of red blood cells and erythroblasts affecting compensatory erythropoiesis
• Over 50% of antibodies are produced due to multiple transfusions &/or previous pregnancies

Anti-c in HDFN

• Anti-c is the third most common cause of severe HDNF
• A policy is in place to provide R1R1 blood to women of childbearing age with C-negative blood groups

How to Predict HDFN Risk - Antibody Levels

• Quantitation:
  • Anti-D: Mild (<4 IU/mL), Severe (>15 IU/mL)
  • Anti-c: Mild (<7 IU/mL), Severe (>20 IU/mL)
• Titration:
  • Anti-K: No specific cut-off but increasing titres are important
  • Other antibodies: No issues if titres are <32; scores above that may need further investigation

NHSBT HDFN Database Data (12-month period)

• Data on antibody types, frequency of occurrence, and number of cases treated (table of data)

Invasive Procedures for Detection

• Amniocentesis: Measure OD450 (a measure of bilirubin in amniotic fluid) to detect fetal bilirubin levels, but carries a risk of miscarriage, premature labour, and fetal demise
• Fetal blood sampling: Direct measurement of fetal anemia, but associated with a risk of fetal loss, or higher risk with hydropic fetuses

Non-invasive Procedures for Detection

• Ultrasonography: Early signs of hydrops (excess fluid buildup), pleural/pericardial effusions, etc
• Velocimetry: to measure blood flow in fetal arteries and detect signs of anemia

Treatment

• Transfusion:
  • Inter-uterine transfusion: corrects severe anaemia in the womb
  • Exchange transfusion: Reduce bilirubin levels rapidly
  • Top-up transfusion: corrects anaemia if bilirubin levels are not high

Alternate Treatments

• Intravenous immunoglobulin (IVIg): Treatment for severe cases of RhD incompatibility
• Early delivery: Potentially administering antenatal steroids for lung maturity in the fetus
• UV light: Breakdown of unconjugated bilirubin deposited in the skin for less severe cases

Prevention

• Anti-D prophylaxis: Pre-1969 introduction has greatly reduced the incidence of HDFN, along with improved cause of death percentages (per 2,200 births)
• Blood provision: Antigen-negative blood to women of childbearing age, particularly RhD-negative or K-negative blood

Non-invasive Prenatal Testing (NIPT)

• CffDNA detection: Maternal plasma/serum testing began in 1997
• cffDNA analysis: Cells in maternal blood
• Characteristics of cffDNA: Fragmented, derived from apoptosis, removed after delivery

Application of NIPT

• Sequencing and genotyping of fetal DNA in maternal plasma
• Fetal DNA levels: 3% in early pregnancy, and rising to 6% in the third trimester

NICE Approved NIPT Testing

• Individual tests for fetal genotyping (many RH genotypes, RHD, Kell), fetal gender, aneuploidy, hemoglobinopathies, single or gene disorders
• High-throughput NIPT for fetal RHD genotyping to guide antenatal prophylaxis with anti-D immunoglobulin for RhD-negative women

RhD Fetal Genotyping from Maternal Plasma

• Manage sensitized pregnant women, avoids invasive procedures (and reduced risk of miscarriage), less need for RhD-negative blood products, and thus cost savings