Anti-D (Rho) immunoglobulin

What is anti-D immunoglobulin?

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.

All RhD-negative pregnant women who do not have immune anti-D, should be offered additional routine prophylaxis with anti-D immunoglobulin (anti-D Ig) during the third trimester of pregnancy¹ .

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

Preparations licensed for use in the UK are:

• D-GAM® (Bio Products Laboratory): available as 250, 500 and 1500 IU vials, for intramuscular use only.

• Rhophylac® (ZLB Behring): available as 1500 IU prefilled syringe, for intramuscular (IM) or intravenous (IV) use.

In the UK, testing is recommended to quantify the size of the FMH after delivery. An anticoagulated blood sample is taken from the susceptible mother after around 30-45 minutes following delivery. If the result indicates a very large FMH, flow cytometry may also be used to quantify the amount accurately:

• 500 IU anti-D immunoglobulin IM will neutralise an FMH of up to 4 ml (99% of women).

• For each millilitre above 4 ml, 125 micrograms of extra anti-D immunoglobulin are usually required.

• In cases of large FMH, and particularly if FMH is in excess of 100 ml, a suitable preparation of IV anti-D immunoglobulin should be considered.

• Minimum recommended dose of anti-D immunoglobulin 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.

Following potentially sensitising events, it is recommended that anti-D immunoglobulin should be administered as soon as possible and always within 72 hours of the event³ . If, exceptionally, this deadline has not been met, some protection may be offered if anti-D immunoglobulin is given up to 10 days after the sensitising event.

Potential sensitising events in pregnancy

Potential sensitising events include:

• Invasive prenatal diagnosis - eg, amniocentesis, chorionic villus biopsy.

• Hemorragia anteparto.

• External cephalic version of the fetus (including attempted).

• Embarazo ectópico.

• Evacuation of molar pregnancy.

• Intrauterine death and muerte fetal.

• Intrauterine procedures (eg, insertion of shunts, embryo reduction).

• Aborto espontáneo or threatened miscarriage after 12 weeks of gestation.

• Therapeutic termination of pregnancy.

• Delivery - normal, instrumental or caesarean section.

Potentially sensitising events in pregnancies of less than 12 weeks of gestation³

• Anti-D immunoglobulin is not required for spontaneous miscarriage before 12⁺⁰ weeks of gestation, unless there is instrumentation or medical evacuation of the uterus.

• In pregnancies <12 weeks of gestation, anti-D immunoglobulin prophylaxis is only indicated following embarazo ectópico, molar pregnancy, therapeutic termination of pregnancy and in cases of uterine bleeding where this is repeated, heavy or associated with abdominal pain.

• 250 IU anti-D Ig is usually given within 72 hours of the event.

• A maternal blood group and antibody screen should be undertaken to determine or confirm the RhD group and check for the presence of immune anti-D in these cases.

• A test for FMH is not required.

• Anti-D immunoglobulin should be given to all women who have an ectopic pregnancy or termination of pregnancy, regardless of method of management.

• NB: National Institute for Health and Care Excellence (NICE) guidance actually recommends against offering anti-D Ig if the ectopic pregnancy is managed medically; however, there is no clear evidence to support this⁴ .

Potentially sensitising events in pregnancies of 12 weeks to less than 20 weeks of gestation³

• For potentially sensitising events between 12 and 20 weeks of gestation, a dose of 250 IU should be administered within 72 hours of the event.

• Women who are RhD-negative presenting with continual uterine bleeding between 12 and 20 weeks of gestation should be given at least 250 IU anti-D Ig, at a minimum of six-weekly intervals.

• A maternal blood group and antibody screen should be undertaken to determine or confirm the RhD group and check for the presence of immune anti-D in these cases.

• If anti-D is identified, further history should be obtained and investigation undertaken to determine if this is immune or passive. If this is not clear then the women should be offered anti-D prophylaxis, as the assumption should be made that it is passive.

• A test for FMH is not required.

Potentially sensitising events in pregnancies of more than 20 weeks of gestation to term³

• For potentially sensitising events between 20 weeks of gestation and term, a dose of 500 IU should be administered within 72 hours of the event.

• A maternal blood group and antibody screen should be undertaken to determine or confirm the RhD group and check for the presence of immune anti-D in these cases.

• If anti-D is identified, further history should be obtained and investigation undertaken to determine if this is immune or passive. If this is not clear then the women should be offered anti-D prophylaxis, as the assumption should be made that it is passive.

• An FMH test is required to detect fetal cells in the maternal circulation and, if present, to estimate the volume of FMH to allow calculation of additional anti-D doses required to clear the fetal cells.

• If FMH >4 ml is detected, follow-up samples are required at 48 hours following an IV dose of anti-D or 72 hours following an IM dose to check for clearance of fetal cells.

• Women who have continual uterine bleeding which is the same sensitising event should be given a minimum dose of 500 IU at six-weekly intervals. Estimation of FMH should be undertaken at two-weekly intervals. Additional anti-D should be given to cover the volume of FMH.

• If new symptoms occur suggestive of an additional sensitising event then an additional dose of 500 IU anti-D immunoglobulin should be given.

Laboratory testing

Routine antenatal anti-D prophylaxis (RAADP) programme
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.

A sample should be taken for the routine 28-week blood group and antibody screen before RAADP is given. If anti-D is identified, further history should be obtained and investigation undertaken to determine if this is immune or passive. If this is not clear then the women should be offered anti-D prophylaxis as the assumption should be made that it is passive.

There are two regimens, of similar efficacy: two doses of 500 IU anti-D immunoglobulin at 28 and 34 weeks of gestation or a single dose of 1500 IU at 28 weeks of gestation. NICE recommends using the preparation with the lowest acquisition cost¹ .

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.

The detection of fetal RhD status by using a non-invasive method from maternal circulation has been found to be possible⁵ . In the future this might be available which will avoid unnecessary testing and anti-D immunoglobulin administration in some women.

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.

FMH testing should be undertaken on all RhD-negative women delivering RhD-positive infants to determine if additional doses of anti-D immunoglobulin are required.

Allergic reactions are very rare but severe hypersensitivity including anaphylaxis can occur⁶ . Hypersensitivity to any of the components in the past is a contra-indication.

• 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.

• Some manufacturers recommend that medication such as adrenaline (epinephrine) should be available for immediate treatment of acute severe hypersensitivity reactions.

• Anti-D immunoglobulin might impair the immune response to the following vaccines:

  • BCG

  • Influenza

  • MMR

  • Poliomyelitis

  • Rotavirus

  • Smallpox

  • Fiebre tifoidea

  • Varicella-zoster

  • Fiebre amarilla

• For these vaccines, it is recommended that the vaccines should be given at least three weeks before or three months after anti-D immunoglobulin administration.

• However, the Vacuna MMR may be given in the postpartum period with anti-D Ig provided that separate syringes are used and the products are administered into different limbs.

• 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.