2 Clinical need and practice

The problem addressed

2.1 NICE technology appraisal guidance on routine antenatal anti-D prophylaxis for women who are rhesus D negative recommends anti‑D immunoglobulin for all rhesus‑D (D) negative pregnant women who are not known to be sensitised to the D antigen, to reduce the risk of sensitisation. The British Committee for Standards in Haematology's guideline on the use of anti-D immunoglobulin for the prevention of haemolytic disease of the fetus and newborn also recommends that all D‑negative pregnant women who are not known to be sensitised to D antigen have anti‑D immunoglobulin after:

  • potentially sensitising events

  • birth, if the baby is confirmed to be D positive by cord blood typing.

2.2 Anti‑D immunoglobulin is produced from the pooled plasma donated by large numbers of D‑negative people who have had a transfusion of D‑positive red cells to stimulate the production of D antibodies. It is a finite resource and, because there have been shortages in the past, it needs to be used carefully to maintain stocks. Anti‑D immunoglobulin is a blood product and may also carry the risks common to all blood products, including physiological reactions, processing errors and the potential future risk of unknown blood-borne viruses or prion diseases. Physiological reactions must be reported to the Medicines and Healthcare products Regulatory Agency and processing errors to the Serious Hazards of Transfusion Scheme.

2.3 High-throughput non‑invasive prenatal testing (NIPT) for fetal RHD genotype involves analysing cell-free fetal DNA in maternal blood and is intended for use in pregnant women who are D negative and are not sensitised to D antigen. It is a laboratory-developed test offered by the International Blood Group Reference Laboratory, Bristol. This laboratory is an accredited NHS Blood and Transplant Laboratory that is currently providing NIPT for RHD genotype for some NHS patients.

2.4 High-throughput NIPT for fetal RHD genotype would allow D‑negative women who are carrying a D‑negative fetus to avoid unnecessary treatment with anti‑D immunoglobulin.

2.5 High-throughput NIPT for fetal RHD genotype would allow D‑negative women to make an informed choice about whether to have treatment with anti‑D immunoglobulin. This may improve adherence to anti‑D immunoglobulin treatment, reduce the number of sensitisations and so reduce haemolytic disease of the fetus and newborn in later pregnancies.

The condition

2.6 During pregnancy, small amounts of fetal blood can enter the maternal circulation (an event called fetomaternal haemorrhage). The presence of fetal D‑positive cells in the maternal circulation, after fetomaternal haemorrhage, can cause a mother who is D negative to produce antibodies against the D antigen on the fetal blood cells (anti‑D) – a process called sensitisation. Sensitisation can happen at any time during pregnancy, but is most common during the third trimester and delivery. It can follow events in pregnancy known to be associated with fetomaternal haemorrhage, such as medical interventions, terminations, late miscarriages, antepartum haemorrhage and abdominal trauma. These are called potentially sensitising events.

2.7 The process of sensitisation has no adverse health effects for the mother and usually does not affect the pregnancy during which it occurs. However, if the mother is exposed to the D antigen from a D‑positive fetus during a later pregnancy, the immune response is quicker and much greater. The anti‑D produced by the mother can cross the placenta and cause haemolytic disease of the fetus and newborn. This can cause severe fetal anaemia, leading to fetal heart failure, fluid retention and swelling (hydrops), and intrauterine death.

2.8 The risk of sensitisation can be reduced if D‑negative pregnant women have anti‑D immunoglobulin. Before anti‑D immunoglobulin was available, the incidence of sensitisation in D‑negative women after the birth of 2 D‑positive babies was about 16%. Haemolytic disease of the fetus and newborn, which occurred in about 1% of all births, was a significant cause of morbidity and mortality. After routine postpartum anti‑D prophylaxis was introduced, the incidence of D sensitisation dropped to about 2%. The sensitisation rate has further reduced since the introduction of routine antenatal anti‑D prophylaxis.

2.9 In England, there were 646,904 births from April 2013 to March 2014, of which about 15% (97,036 births) were to D‑negative women. About 40% of these women carry a D‑negative fetus (around 39,000 per year) and so do not need to have anti‑D immunoglobulin. D‑negative status occurs in about 15% of people of white European family origin, about 3% to 5% of people of black African family origin, and is very rare in people of eastern Asian origin. Most D‑negative people of white European family origin have an RHD gene deletion; less than 1% have RHD gene variants. However, in D‑negative people of black African family origin, 66% have an inactive RHD gene (the RHD pseudogene), which mostly results from genes that contain D sequences but do not produce D antigen.

The diagnostic and care pathways

Care for D‑negative pregnant women who are not sensitised to D antigen

2.10 In current practice, babies born to women who are D negative and not sensitised to D antigen have their Rh blood group determined after birth, using cord blood typing. Testing to find out the RHD genotype of the fetus during pregnancy is not currently done in most centres in the NHS.

2.11 The NICE guideline on antenatal care for uncomplicated pregnancies and the British Committee for Standards in Haematology (BCSH) guideline on blood grouping and antibody testing in pregnancy recommend that women should be offered testing for ABO and Rh blood group in early pregnancy. All women identified as D‑negative would be tested for the presence of D antibodies, regardless of whether they are known to be sensitised or not. To prevent sensitisation in women identified as D‑negative but without D antibodies, anti‑D immunoglobulin is recommended, both as prophylaxis and after potentially sensitising events.

2.12 The NICE technology appraisal guidance on routine antenatal anti-D prophylaxis for women who are rhesus D negative recommends routine antenatal anti‑D prophylaxis (RAADP) as a treatment option for all pregnant women who are D negative and who are not known to be sensitised to the D antigen. RAADP can be given as 2 doses at weeks 28 and 34 of pregnancy, or as a single dose between 28 and 30 weeks.

2.13 The guideline from the BCSH on using anti-D immunoglobulin for the prevention of haemolytic disease of the fetus and newborn recommends that all D‑negative pregnant women, who are not known to be sensitised to D antigen, have anti‑D immunoglobulin after:

  • potentially sensitising events

  • birth, if the baby is confirmed to be D positive by cord blood typing.

    The BCSH guideline also states that RAADP should be given regardless of, and in addition to, any anti-D immunoglobulin that may have been given for a potentially sensitising event.

Care for D‑negative pregnant women who are sensitised to D antigen

2.14 The Royal College of Obstetricians and Gynaecologists' (RCOG) guidance on managing women with red cell antibodies during pregnancy recommends that all women who are D negative and are sensitised to D antigen should:

  • attend pre-pregnancy counselling with a clinician who has knowledge and expertise in managing this condition

  • have their blood group and antibody status determined at the booking appointment (ideally by 10 weeks of gestation) and at 28 weeks of gestation

  • be offered non‑invasive fetal RHD genotyping using maternal blood if maternal anti‑D is present.

    The NIPT offered to D-negative women who are sensitised to D antigen is different to the high-throughput NIPT for fetal RHD genotype assessed in this diagnostics guidance, and has different diagnostic accuracy.

2.15 The RCOG guideline and the BCSH guideline on blood grouping and antibody testing in pregnancy also recommend that if a D‑positive fetus is identified, additional monitoring and treatment are needed during the pregnancy, which should include:

  • measuring D‑antibody levels every 4 weeks up to 28 weeks of gestation and then every 2 weeks until delivery

  • referral to a fetal medicine specialist if D‑antibody levels are rising or are at a level above a specific threshold, or ultrasound features suggest fetal anaemia

  • weekly monitoring by ultrasound if D‑antibody levels rise above a specific threshold

  • fetal blood sampling if ultrasound shows signs of fetal anaemia, and considering intrauterine transfusion

  • considering early delivery of the baby, depending on antibody levels and whether any fetal therapy has been needed

  • using continuous electronic fetal heart monitoring during labour.

2.16 After the baby is born, the RCOG guideline recommends that assessments should include:

  • a direct antiglobulin test to detect maternal antibodies adhering to the baby's red blood cells

  • confirmation of the baby's blood group (using a cord blood sample)

  • haemoglobin level measurement to test for anaemia

  • bilirubin level measurement to test for jaundice

  • clinical assessment of the baby's neurobehavioural state and observations for jaundice and anaemia.

2.17 The NICE guideline on jaundice in newborn babies under 28 days gives recommendations on diagnosing and treating jaundice.

  • National Institute for Health and Care Excellence (NICE)