Diagnostic Accuracy of Routine Antenatal Determination of Fetal RHD Status Across Gestation

The RhD (RH1) antigen of the rhesus system is the most commonly implicated antigen for hemolytic disease of the fetus. Postnatal prophylaxis with anti-RhD immunoglobulin in RhD− women with an RhD+ child has been shown to reduce the risk of becoming alloimmunized. Subsequent introduction of routine antenatal prophylaxis with anti-RhD immunoglobulin in the third trimester for all RhD− women is now standard in many countries. Cell-free fetal DNA in maternal plasma can be tested for the presence or absence of the RHD gene, essentially screening for fetal Rh status. This prospective, multicenter cohort study was performed to determine the diagnostic accuracy of RHD genotyping in RhD− parturients and the optimal gestation for implementation into practice. From 2009 to 2012, consenting parturients had blood samples obtained at their initial appointment, at Down syndrome screening (11–21 weeks’ gestation), and at routine anomaly scanning (18–23 weeks’ gestation). At the third trimester visit (∼28 weeks), women were given the results of molecular testing, and an additional blood sample was obtained to confirm fetal RHD status. When this testing confirmed that the fetus was RHD−, women were allowed to opt out of receiving anti-RhD immunoglobulin. All women predicted to be carrying an RhD+ baby, or if the genotyping result was inconclusive, were offered anti-RhD immunoglobulin. All women who had a sensitizing event at less than 28 weeks were also offered anti-RhD immunoglobulin. RhD typing on cord blood samples was performed using routine serologic methods. Genotyping results were interpreted as RHD+, RHD−, or inconclusive. The final analysis included 2288 women and 4913 fetal genotype results with 4 analyses or less per parturient. Genotyping results were inconclusive for 393 samples (8.0%; 95% confidence interval, 7.3%–8.8%). Based on cord blood analyses, 2023 samples were from RhD− babies, of which 18 had been falsely predicted antenatally to be genotypically RHD+, and 85 were inconclusive; 2890 were RhD+, of which 308 were inconclusive on fetal RHD genotyping, and 19 were falsely predicted to be genotypically RHD−. The odds of correctly identifying RHD+ and RHD− fetuses increased significantly with gestational age, with low levels of false-negative results after 11 weeks’ gestation. At less than 11, 11 to 13, 14 to 17, 18 to 23, and more than 23 weeks, the sensitivities for detecting fetal RHD positivity were 96.85% (94.95%–98.05%), 99.83% (99.06%–99.97%), 99.67% (98.17%–99.94%), 99.82% (98.96%–99.97%), and 100% (99.59%–100%). At less than 11 weeks, 16 (1.9%) of 865 babies tested were falsely predicted to be RHD−. Massive throughput fetal RHD genotyping can be performed as soon as possible at 11 weeks or more. After 11 weeks, the incidence of false-negative results was considerably lower and did not decrease between 11 and 24 weeks, in agreement with evidence that concentrations of cell-free fetal DNA increase only minimally at 10 to 20 weeks’ gestation. The small number of false RHD− results after 11 weeks would lead to a small increase in the risk of alloimmunization. The tradeoffs between treating fewer women with antepartum immunoglobulin versus a few women becoming alloimmunized need to be considered carefully.

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