Red cell isoimmunisation

Published on 09/03/2015 by admin

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Chapter 31 Red cell isoimmunisation

Michael Flynn

Perinatal mortality rate

Perinatal mortality due to Rhesus D (RhD) isoimmunisation before the use of prophylaxis was 15 in 1000, or 4% of perinatal deaths. Today, the perinatal mortality rate from RhD isoimmunisation is 0.54 in 10,000, or 0.3%. The reduced perinatal mortality is due to anti-D immunoglobulin prophylaxis and the fall in numbers of large families.

A third of women who become isoimmunised have no demonstrable antibodies at the first antenatal visit, so investigations for antibodies must be repeated during pregnancy in RhD-negative women.

There is a correlation between the time of first antibody detection and the severity of haemolytic disease of the newborn. The earlier the antibodies are present during the pregnancy, the higher the risk of fetal/neonatal problems. If an antibody is present in pregnancy, serial monitoring of antibody levels is required.

Prevention of RhD isoimmunisation

The aim is to provide passive immunisation at times of risk of fetomaternal transfusion. If no prophylaxis is given, 1% of RhD-negative women will develop anti-D antibodies by the end of the first pregnancy and a further 3%–5% have detectable antibodies 6 months after delivery. About 90% of sensitisations can be prevented. 100 IU anti-D immunoglobulin is able to neutralise 2 mL fetal blood. This is given within 72 hours of fetomaternal transfusion for maximum effect. In an RhD-negative woman with no anti-D antibodies present, anti-D prophylaxis is indicated in the following cases:

• Sensitising events in the first trimester (including miscarriage, ectopic pregnancy, termination of pregnancy, chorionic villus sampling) require 250 IU intramuscular RhD immunoglobulin for single pregnancy and 625 IU for multiple pregnancy.
• Events in the second and third trimester (e.g. amniocentesis, cordocentesis, abdominal trauma sufficient to cause fetomaternal haemorrhage, external cephalic version or antepartum haemorrhage) require 625 IU injection of anti-D.
• There is routine administration of 625 IU at 28 and 34 weeks gestation in addition to doses given for sensitising events.
• Postpartum administration of 600 IU is necessary within 72 hours.
• With this prophylaxis regimen, antibody formation rate is reduced to 0.2%.

Contraindications for anti-D prophylaxis

• RhD-positive or Du-positive individual
• RhD-negative or Du-negative individual previously sensitised to RhD

Prevention of postpartum isoimmunisation

• With anti-D prophylaxis, only 0.2% are sensitised.
• In 0.5% of deliveries, a fetomaternal haemorrhage of over 30 mL occurs.
• There is an increased risk with manual removal of the placenta and caesarean sections.

Screening

• All pregnant women have a red cell antibody screen in the first trimester and, when negative, again at around 28–30 weeks gestation.
• When RhD antibody is present, screen the partner’s blood to detect the likelihood of the fetus carrying D antigen. If the partner is RhD-negative, the fetus will be unaffected.

Antenatal management of Rhesus isoimmunisation

Aims

• Identify the severely affected fetus.
• Correct anaemia by transfusion.
• Deliver the fetus when mature.

Determination of fetal Rhesus type

• If the fetal Rhesus type is RhD-negative, then there is no antenatal risk and fetal and maternal monitoring is not required.
• Determine paternal Rhesus type and zygosity, as if homozygous RhD-positive then 100% of babies are at risk, but if heterozygous only 50% are affected.
• Amniocentesis: polymerase chain reaction (PCR) testing on amniocytes to determine fetal blood group is used, although there is up to 1.5% false-negative rate.
• Free fetal DNA: flow cytometry of maternal blood for fetal cells, which are then blood typed, is used. Meta-analysis is reporting 99% accuracy.

Antibody levels

• The first investigation is an assessment of the amount of antibody in maternal circulation.
• Levels may be given as a titre or quantitative value.
• Further investigations are required when the antibody titre is 1:64 or at any time when titres are increased by two dilutions (e.g. a rise from a titre of 1:4 to 1:32).

Antibody quantification

• When levels are lower than 4 IU/mL, the fetus is minimally affected, and fewer than 5% then require an exchange transfusion.
• Levels of 4–8 IU/mL indicate moderate disease, and delivery is advised by 38 weeks gestation.
• Levels >10 IU/mL suggest the risk of severe disease in the fetus. Management is by further assessment of the fetus and delivery by 36 weeks gestation.
• Repeat maternal serum testing every 2 weeks.
• This is for first affected pregnancies. Pregnancies after this involve a greater severity of fetal neonatal haemolytic disease.

Assessment of the fetal anaemia

• Severe anaemia seen as hydrops is not seen until fetal haemoglobin is <40 g/L.
• Middle cerebral artery peak systolic velocity is used as the best non-invasive tool to predict fetal anaemia.
• The anaemic fetus preserves brain oxygenation by increasing cerebral flow.
• Sensitivity if use >1.5 multiples of the median for gestational age of measurement of flow for prediction of moderate to severe anaemia was 100%.
• Screening interval appears to be 1–2 weeks.
• Amniocentesis and measurement of amniotic fluid bilirubin as indirect assessment of severity of fetal anaemia was previously first-choice investigation; however, similar sensitivity and specificity to middle cerebral artery flows has led to decreased use of this invasive procedure.

Fetal blood sampling

• Information available includes fetal blood group, haemoglobin, total bilirubin, platelet count and haematocrit. These are the only direct assessments of the severity of disease.
• Fetal loss rate from the procedure is 1%–2%.
• The procedure can provoke marked rises in maternal antibody levels, as there is a 50%–70% risk of fetomaternal haemorrhage.
• Intrauterine transfusion with O negative is indicated if haematocrit is <2 standard deviations for gestational age and the fetus is immature.
• The second transfusion takes place 2 weeks after the first, as the rate of decrease in haematocrit after the first transfusion is unpredictable. The rate of fall in haematocrit is 0.5%–2% per day.
• Donor blood is not susceptible to destruction; thus, the time interval between transfusions tends to increase.
• Suppression of fetal erythropoiesis occurs after two to three transfusions.

Neonatal management

• Arrange delivery at appropriate time (after 34 weeks gestation if requiring intervention).
• At delivery, collect cord blood for fetal haemoglobin, blood group, direct Coombs’ test and bilirubin concentration.
• Exchange transfusion is required if the fetal haemoglobin is <100 g/L.
• Measure bilirubin concentration every 6 hours for the first 48 hours. Be aware of the risk of chronic hypoplastic anaemia.

Other red cell antibodies

There are about 700 red cell antibodies, but only a few cause severe haemolytic disease of the newborn. Many antibodies (A, P(I), Le(a), M, I) produce an immunoglobulin M (IgM) response only, which cannot cross the placenta, so they are of no significance in pregnancy. Some red cell antigens are poorly developed on fetal red cells, so antibodies (Lu(b), Y+(a)), even if IgG produced and crosses the placenta, have no adverse affect. Antibodies known to stimulate haemolytic disease of the newborn include:

• anti-Kell
• anti-c (less commonly anti-C)
• anti-E (less commonly anti-e)
• anti-Fya and anti-Fyb
• anti-Ra and anti-Rb

In Western countries, these have a higher frequency than D alloimmunisation and may be due to unmatched blood transfusions.

Anti-Kell

Over 90% of the population is Kell-negative. Most Kell antibodies develop because of incompatible transfusion. There appears to be a poor correlation between the antibody titre and the effect on the fetus or neonate. Anti-Kell severity can change rapidly due to the antibodies’ ability to suppress erythropoiesis. Ultrasound assessment of fetal liver size is useful.

Management

The management of all red cell antibodies is similar in principle to Rhesus disease, including paternal genotype, serial titres, assessment of fetal anaemia and early delivery.

ABO incompatibility

• This mostly occurs when the mother is group O and the baby A or B. It occurs in 15% of pregnancies, but only 1 in 30 show mild jaundice, 1 in 150 mild anaemia, and 1 in 3000 require exchange transfusion.
• ABO incompatibility can occur in the first pregnancy, with no tendency to increase in severity with subsequent pregnancies.

Further reading

Moise K.J. The usefulness of middle cerebral artery Doppler assessment in the treatment of the fetus at risk for anemia. American Journal of Obstetrics and Gynecology. 2008;198:161.

Oepekes D., Seaward P.G., Frank P.H.A., et al. Doppler ultrasonography versus amniocentesis to predict fetal anemia. New England Journal of Medicine. 2006;355:156-164.

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