The development of anti-D antibodies generally results from feto-maternal haemorrhage (FMH) occurring in rhesus D (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 rhesus positive pregnancy.¹

For further information on the aetiology, epidemiology, presentation, investigation and differential diagnosis, see separate article Haemolytic Disease of the Newborn.

Preparations licensed for use in the UK are:

• D-GAM® (Bio Products Laboratory): available as 250, 500 and 2500 IU vials, for intramuscular use only.²
• Partobulin SDF® (Baxter Bioscience): available as 1250 IU prefilled syringe, for intramuscular use only.
• Rhophylac® (ZLB Behring): available as 1500 IU prefilled syringe, for intramuscular or intravenous use.³
• WinRho SDF® (Cangene Corporation): available as 1500 IU and 5000 IU vials, for intramuscular or intravenous use.

The European Agency for the Evaluation of Medical Products has produced a core anti-D Summary of Product Characteristics (SPC).⁴ Licensed use and dosage regime vary between products so see individual SPCs or the manufacturer's information where available. The National Institute for Health and Clinical Excellence (NICE) recommend that the product with the lowest acquisition cost should be used.¹

What dose is required?⁵

In the UK, testing is recommended to quantify the size of the feto-maternal haemorrhage (FMH).⁶ An anticoagulated blood sample is taken from the susceptible mother as soon as possible (within two hours) after delivery and Kleihauer screening is performed. If the Kleihauer result indicates a very large FHM, flow cytometry may also be used to quantify the amount accurately:

• 500 IU anti-D immunoglobulin (anti-D Ig) intramuscularly will neutralise an FMH of up to 4 ml (99% of women).
• For each millilitre above 4 ml, 125 micrograms of extra anti-D Ig are required.
• Minimum recommended dose of anti-D at less than 20⁺⁰ weeks of gestation is 250 IU.
• The minimum dose at 20⁺⁰ weeks of gestation and above is 500 IU.

Indications⁵

Miscarriage, ectopic pregnancy or termination of pregnancy

250 IU anti-D Ig is given up to 19⁺⁶ weeks of gestation and 500 IU thereafter. A test for the size of feto-maternal haemorrhage (FMH) should be performed when anti-D Ig is given at or after 20⁺⁰ weeks of gestation:

• Anti-D Ig is not required for spontaneous miscarriage before 12⁺⁰ weeks of gestation, unless there is instrumentation or medical evacuation of the uterus. It should be considered in women if there is heavy, repeated bleeding with abdominal pain as she approaches 12⁺⁰ weeks of gestation.
• Anti-D Ig should be given to all non-sensitised RhD-negative women who have a threatened, spontaneous complete or incomplete miscarriage at or after 12⁺⁰ weeks of gestation. If the woman continues to bleed intermittently after 12⁺⁰ weeks of gestation, anti-D Ig should be given at 6-weekly intervals.
• Anti-D Ig should be given to all women who have an ectopic pregnancy or termination of pregnancy, regardless of method of management.

Potential antenatal sensitising events

Potential sensitising events include invasive prenatal diagnosis, other intrauterine procedures (e.g. insertion of shunts, embryo reduction), antepartum haemorrhage, external cephalic version of the fetus (including attempted), any abdominal trauma or fetal death.

A minimum dose of 250 IU is recommended up to 19⁺⁶ weeks of gestation and 500 IU anti-D Ig thereafter. Women at 20⁺ weeks of gestation should be given a test to identify FMH greater than 4 ml red cells and additional anti-D Ig given as required.

If there is recurrent vaginal bleeding after 20⁺⁰ weeks of gestation, anti-D Ig should be given at a minimum of 6-weekly intervals.

Routine antenatal anti-D prophylaxis (RAADP) programme

RAADP is not used uniformly throughout the NHS.¹ In 2005 a survey reported that 75% of obstetric units offered it, usually administered by community midwives or at antenatal clinics. Routine prophylaxis is separate from that given after potentially sensitising events, as above, or threats to the pregnancy. It is not offered to women who have already been sensitised. It is designed to protect women when sensitisation is 'silent'. This occurs more frequently as gestation advances and is thought to be around 45% in the third trimester. There are two regimens, of similar efficacy; two doses of 500 IU anti-D Ig at 28 and 34 weeks of gestation (offered by 81% units) or a single dose of 1500 IU at 28 weeks of gestation.

If the routine programme is declined (maybe on religious grounds or because the woman intends to be sterilised after this pregnancy) antibody screening should be performed at booking and at 28 weeks of gestation, to identify sensitisation. The woman can be reassured that sensitisation occurring in the third trimester, is unlikely to cause significant fetal problems in that pregnancy.

Postnatal prophylaxis

After a Kleihauer test, at least 500 IU of anti-D should be given to every non-sensitised RhD-negative woman, within 72 hours of delivering a rhesus positive infant.
If the pregnancy is stillborn (and no sample can be obtained from the baby), anti-D should be given.

There is no universally accepted postnatal dose; it varies from country to country. 1500 IU is the standard dose in the USA, 500-600 IU in Canada and 1000-1250 IU in many European countries except the UK.

Contra-indications⁴

Hypersensitivity to any of the components.

Special precautions⁴

The patient should be observed for twenty minutes after the injection, to exclude the development of an anaphylactic reaction. The name and batch number should always be recorded. In the unlikely event of a subsequent identification of an infected batch of this blood product, the patient can be checked.

Interactions

• Active immunisation with live virus vaccines (e.g. measles, mumps or rubella) should be deferred until three months after the last administration of anti-D Ig, as the efficacy of the live virus may be affected. If anti-D Ig needs to be administered within 2-4 weeks of a live virus vaccination, then the efficacy of such a vaccination may be impaired.
• After injection of immunoglobulin the transitory rise of the various passively transferred antibodies in the patient's blood may result in misleading positive results in serological testing.
• The results of blood typing and antibody testing including the Coombs' or antiglobulin test, are significantly affected by the administration of anti-D immunoglobulin.

Adverse effects⁴

• Local pain and tenderness can occur. This can be limited by dividing larger doses over several injection sites.
• Fever, malaise, headaches, cutaneous reactions and chills can occur.
• Rarely, nausea, vomiting, hypotension and tachycardia have been reported.
• Allergic or anaphylactic reactions can include dyspnoea and shock. There may be no history of hypersensitivity to a previous injection.

Document references

1. Pregnancy (rhesus negative women) - routine anti-D (review); Pregnancy (rhesus negative women) - routine anti-D, NICE Technology Appraisal (August 2008)
2. Summary of Product Characteristics, D-GAM Solution for Injection®, BPL (Bio Products Laboratory), electronic Medicines Compendium. September 2011
3. Summary of Product Characteristics, Rhophylac®, 300 (1500 IU), CSL Behring UK Limited, electronic Medicines Compendium. August 2011
4. Guideline on the Core SPC for human Anti-D immunoglobulin for intramuscular use - Revision 1, European Medicines Agency, September 2007
5. The Use of Anti-D Immunoglobulin for Rhesus D Prophylaxis, Royal College of Obstetricians and Gynaecologists (April 2011)
6. Guidelines for the Estimation of Fetomaternal Haemorrhage, British Committee for Standards in Haematology (April 2009)