Fetal genotyping to determine Rhesus status

4 April 2008

A new paper in the BMJ reports results from a trial of the new technique for non-invasive prenatal diagnosis, utilizing cell-free fetal DNA present in the maternal blood. The technique has various potential applications including prenatal genetic testing and screening; in this instance, the test is being considered as an alternative to standard procedures for pregnant women with Rhesus-negative blood.

The Rhesus (RhD) factor is one of multiple blood cell surface markers, including the best known A/B/O blood group markers. Around 85% of the UK population are RhD-positive, having these markers; the remainder are RhD-negative, and do not have them. Knowledge of blood-group status is important because transfusion of donor blood with cell surface markers (such as RhD-positive blood) to a recipient who lacks them (RhD-negative) can cause an immune reaction to be mounted against the foreign cells, in a similar manner to rejection of tissue transplants.

The same problem can arise when a RhD-negative mother gives birth to a RhD-positive baby; mixing of the maternal and fetal circulation around birth can ‘alert’ the maternal immune system to the Rhesus antigens, so that any subsequent RhD-negative fetuses are at high risk of developing serious haemolytic disease at or before birth. To avoid this, all RhD-negative pregnant women are offered anti-RhD immunoglobulin (antibodies, effector molecules of immune responses) to effectively block any RhD-positive fetal cells that enter the maternal circulation and prevent the maternal immune system from recognizing them, an intervention that is highly effective in preventing haemolytic disease of the newborn.

However, around 38% of RhD-negative mothers will actually be carrying a RhD-negative fetus and so receive the immunoglobulin treatment unnecessarily. It would be preferable to avoid this, not only on the basis of the cost but also because the administration is uncomfortable and there are concerns associated with the potential for contamination via human blood products. Dr Geoff Daniels of the NHS Blood and Transplant International Blood Group Reference Laboratory, who led the study said: "It's good practice not to give treatment to people who don't need it" (see BBC news). The trial used free fetal DNA analysis (genotyping) to determine the blood group of the fetus during pregnancy, with a reported 95.7% success rate when compared with the actual blood group determined at birth [Finning K et al. BMJ, doi:10.1136/bmj.39518.463206.25 (published 3 April 2008)]. Since this technique is suitable for high-throughput analysis, the authors propose that it is a feasible approach to prevent unnecessary anti-RhD administration for almost all RhD-negative mothers.

Comment: This study contributes further evidence that genotyping using fetal genetic material from the maternal bloodstream has clinical utility, in this instance as a potential alternative to current antenatal care for RhD-negative women. The PHG Foundation is currently undertaking a flagship project on cell-free fetal nucleic acid analysis, to work with stakeholders to produce strategic recommendations for appropriate implementation of the technique into different clinical services, including the outstanding requirements for evidence, and necessary safeguards. For this particular application, one of the key issues is what would constitute an acceptable false-negative rate for the technique; in this study it was found to be below 0.2% (3 out of approaching 1900 cases), representing the number of women from whom immunoglobulin treatment would have been inappropriately withheld, had administration been based on the fetal genotyping results. The cost-efficacy of the technique when compared with blanket administration of immunoglobulin is also a factor that must be considered; the capacity for high throughput testing makes it more likely to be an affordable measure.

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