A new protocol for RhD-negative pregnant women?

University of Colorado Family Medicine Residency Program, Denver, Colo

James J. Stevermer, MD, MSPH

Department of Family and Community Medicine, University of Missouri-Columbia

Can cell-free DNA testing reduce unnecessary use of anti-D immunoglobulin in RhD-negative women and still prevent harm to their RhD-positive infants?


Employ cell-free DNA testing at 27 weeks’ gestation in your RhD-negative obstetric patients to reduce unnecessary use of anti-D immunoglobulin.1


B: Based on a single, prospective, cohort study.

de Haas M, Thurik FF, van der Ploeg CP, et al. Sensitivity of fetal RHD screening for safe guidance of targeted anti-D immunoglobulin prophylaxis: prospective cohort study of a nationwide programme in the Netherlands. BMJ. 2016;355:i5789.




A 30-year-old G1P0 woman presents to your office for routine obstetric care at 18 weeks’ gestation. Her pregnancy has been uncomplicated, but her prenatal lab evaluation is notable for blood type A-negative. She wants to know if she really needs the anti-D immune globulin injection.

Rhesus (Rh)D-negative women carrying an RhD-positive fetus are at risk of developing anti-D antibodies, placing the fetus at risk for HDFN (hemolytic disease of the fetus and newborn). If undiagnosed and/or untreated, HDFN carries significant risk of perinatal morbidity and mortality.2

With routine postnatal anti-D immunoglobulin prophylaxis of RhD-negative women who delivered an RhD-positive child (which began around 1970), the risk of maternal alloimmunization was reduced from 16% to 1.12%-1.3%.3-5 The risk was further reduced to approximately 0.28% with the addition of consistent prophylaxis at 28 weeks’ gestation.4 As a result, the current standard of care is to administer anti-D immunoglobulin at 28 weeks’ gestation, within 72 hours of delivery of an RhD-positive fetus, and after events with risk of fetal-to-maternal transfusion (eg, spontaneous, threatened, or induced abortion; invasive prenatal diagnostic procedures such as amniocentesis; blunt abdominal trauma; external cephalic version; second or third trimester antepartum bleeding).6

The problem of unnecessary Tx. However, under this current practice, many RhD-negative women are receiving anti-D immunoglobulin unnecessarily. This is because the fetus’s RhD status is not routinely known during the prenatal period.

Enter cell-free DNA testing. Cell-free DNA testing analyzes fragments of fetal DNA found in maternal blood. The use of cell-free DNA testing at 10 to 13 weeks’ gestation to screen for fetal chromosomal abnormalities is reliable (91%-99% sensitivity for trisomies 21, 18, and 137) and becoming increasingly more common.

A notable meta-analysis. A 2017 meta-analysis of 30 studies of cell-free DNA testing of RhD status in the first and second trimester calculated a sensitivity of 99.3% (95% confidence interval [CI], 98.2-99.7) and a specificity of 98.4% (95% CI, 96.4-99.3).7 Denmark, the Netherlands, Sweden, France, and Finland are using this method routinely. As of this writing, the American College of Obstetricians and Gynecologists (ACOG) has not recommended the use of cell-free DNA RhD testing in the United States, but they do note that as the cost of the assay declines, this method may become preferred.8 The National Institute for Health and Care Excellence in England recommends its use as long as its cost remains below a set threshold.9

This study evaluated the accuracy of using cell-free DNA testing at 27 weeks’ gestation to determine fetal RhD status compared with serologic typing of cord blood at delivery.

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