Anti-D (Rho) Immunoglobulin

The development of anti-D antibodies generally results from feto-maternal haemorrhages (FMH) occurring in RhD negative women who carry an RhD positive fetus.
In later pregnancies anti-D antibodies can cross the placenta, causing worsening rhesus haemolytic disease with each successive Rh positive pregnancy.¹

• About 10% of RhD positive babies are born each year in England and Wales (62,000) to RhD negative mothers. The frequency of haemolytic disease of the newborn (HDN) before immunoprophylaxis became available in 1969, was one baby in every 2200 births.
• Anti-D prophylaxis (mostly administered postnatally) and advances in neonatal care have dramatically reduced the frequency of HDN to 1 in 21,000 births. Deaths attributed to RhD alloimmunisation have fallen from 46/100,000 births before 1969, to 1.6/100,000 in 1990.
  This may not be entirely attributable to immunoglobulin; changes in abortion rates and racial composition may also play a part.

Risk factors¹

• Immunisation during first pregnancy
• Immunisation during second or subsequent pregnancy
• Failed prophylaxis

Over 99% of women have a fetomaternal haemorrhage (FMH) of less than 4ml at delivery. 50% of women who have larger feto-maternal haemorrhages occur after normal deliveries.
The following clinical circumstances are more likely to be associated with large FMH:

• Traumatic deliveries including caesarean section
• Manual removal of the placenta
• Stillbirths and intrauterine deaths
• Abdominal trauma during the third trimester
• Multiple pregnancies (at delivery)
• Unexplained hydrops fetalis

• All rhesus negative women should have a test to assess the size of FMH
• Standard test is the Kleihauer acid elution test which detects fetal haemoglobin (HbF). If FMH greater than 15ml (up to 0.3% of women) give more than the standard dose of 1500 iu of immunoglobulin.
• Flow cytometry: an alternative technique for quantifying the size of feto-maternal haemorrhage. Results are more accurate and more reproducible than those from the Kleihauer test.
• The rosetting technique: serological method which offers another alternative for quantifying feto-maternal haemorrhage of RhD positive red cells greater than 4ml.³

• Intramuscular anti-D Ig is given into the deltoid muscle as injections into the gluteal region often only reach the subcutaneous tissues and absorption may be delayed
• Try to give as soon as possible and always within 72 hours. Giving a dose up to 10 days after the sensitising event may however provide some protection.
• Women who are already sensitised should not be given anti-D Ig.
• Women who have a weak expression of the RhD blood group as detected by agglutination tests do not form anti-D and do not therefore require prophylaxis.
• Anti-D Ig does not protect against the development of other antibodies which can cause haemolytic disease of the newborn.

Prophylaxis following abortion¹

250iu should be given before 20 weeks' gestation and 500iu thereafter. A test for the size of FMH should be performed when anti-D Ig is given after 20 weeks.

Therapeutic termination of pregnancy⁵

Give anti-D to all non-sensitised RhD negative women having a medical or surgical therapeutic termination of pregnancy, regardless of gestational age.

Ectopic pregnancy

Give anti-D Ig to all non-sensitised RhD negative women.

Spontaneous miscarriage

• Give anti-D Ig to all non-sensitised RhD negative women who have a spontaneous complete or incomplete abortion after 12 weeks of pregnancy
• 250iu before at 20 weeks' gestation and 500iu thereafter. A test for the size of FMH should be performed when anti-D Ig is given after 20 weeks.
• No clear evidence for management in the case of earlier miscarriages. Anti-D Ig should be given when there has been an intervention to evacuate the uterus, but is currently not recommended in the case of spontaneous miscarriage before 12 weeks' gestation when there has been no instrumentation to evacuate the products of conception.

Threatened miscarriage⁶

• Give anti-D Ig to all non-sensitised RhD negative women with a threatened miscarriage after 12 weeks of pregnancy.
• When bleeding continues intermittently after 12 weeks' gestation, anti-D Ig should be given at 6-weekly intervals.
• Evidence for immunisation in first twelve weeks is scant, and routine administration of anti-D Ig not currently recommended where the fetus is viable and the pregnancy continues. However, consider giving if bleeding is heavy or repeated or if there is associated abdominal pain, especially if the gestation is close to 12 weeks.

Anti-D Ig should be given to all non-sensitised RhD negative women after the following events during pregnancy:

• Invasive prenatal diagnosis (amniocentesis, chorionic villus sampling, fetal blood sampling) other intrauterine procedures (e.g. insertion of shunts, embryo reduction)
• Antepartum haemorrhage
• External cephalic version of the fetus
• Closed abdominal injury
• Intrauterine death

A dose of 250iu is recommended for prophylaxis following sensitising events up to 20 weeks of pregnancy. After 20 weeks, at least 500iu anti-D Ig should be given followed by a test to identify FMH greater than 4ml; additional anti-D Ig should be given as required.

Routine antenatal prophylaxis^1,7

Routine antenatal anti-D prophylaxis (RAADP) should be discussed with all pregnant women who are RhD-negative, so the patient can make an informed choice about whether to have the injection. Such a discussion should include the following issues:

• The difference between RAADP and prophylactic anti-D given where there is a high risk that sensitisation has taken place
• Ante-natal anti-D given in early pregnancy (AADP) does not obviate the need to give it again later on
• RAADP becomes less clinically and cost-effective with each successive pregnancy. Circumstances cited by NICE include:
  • The woman has opted to be sterilised after birth.
  • The father is RhD-negative, where this is known.
  • The woman is most unlikely to have another child.
• Each year about 25-30 babies in England and Wales still die from HDN and additional fetal loss is thought to occur from spontaneous abortions. About 15 children each year will have major permanent developmental problems .
• Adverse effects - possible interference with the baby's immune system, possible problems in later life when RhD negative girl babies want to reproduce (so far theoretical concerns, no hard evidence despite many babies given anti-D now reaching adulthood).
• Risk of transmission of an unknown pathogen is extremely small (3 women in every 100 years).
• The option of having anti-D after the baby is born.

NICE emphasise that, having been giving all the relevant information, the decision whether or not to have RAADP should rest with the patient, not the clinician.

Postnatal prophylaxis¹

• Give at least 500iu of anti-D Ig to every non-sensitised RhD negative woman within 72 hours following the delivery of a RhD positive infant. This includes women with alloantibodies other than anti-D. 500iu (100mcg) of anti-D Ig given intramuscularly is as effective as both 1500iu and 1000iu.
• A test to detect feto-maternal haemorrhage greater than 4ml must also be undertaken, so that additional anti-D can be given as appropriate. Protocols vary, but one study suggested that 10mcg additional anti-D should be given for every additional 0.5 ml of fetal red blood cells.
• Some women who have received anti-D Ig during pregnancy may have detectable anti-D in their blood at delivery. It may be difficult or impossible to distinguish between passive anti-D Ig and weak anti-D resulting from early immunisation, and so anti-D Ig should be given to any woman with weak anti-D antibody at delivery unless it has been confirmed that she is already sensitised.

Transfusion of RhD positive blood components¹

• RhD negative women requiring platelet transfusion can normally be transfused with RhD negative platelets. However, if these are not available, RhD positive platelets may need to be used. In such circumstances, prophylaxis against possible Rh alloimmunisation by red cells contaminating the platelet product should be given.
• 250iu (50mcg) anti-D Ig should be given following every three adult doses (i.e. derived from up to 18 routine donations) of platelets. Patients who have marked thrombocytopenia should be given the anti-D Ig subcutaneously to avoid the possibility of a haematoma following intramuscular injection.
• Inadvertent transfusion of RhD positive blood: if less than 15ml of RhD positive blood has been transfused to a RhD negative woman capable of childbearing, the appropriate dose of anti-D Ig should be given. When more than 15ml have been transfused, a larger dose of anti-D Ig should be given (2500iu or 5000iu).
• When more than 2 units of RhD positive blood have been transfused, an exchange transfusion and anti-D may be required but the patient should be counselled regarding the implications of both non-intervention (for future pregnancies) and the potential hazards from receiving donated blood.