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Research Demonstrates Potential for High-Throughput Fetal RhD Typing From Maternal Blood

NEW YORK (GenomeWeb News) – High-throughput testing of fetal DNA in a Rhesus-D negative, pregnant woman’s blood can detect the vast majority of cases in which her fetus has an RhD positive blood group, new research suggests.
In a study of nearly 2,000 pregnant women, British researchers used real-time quantitative PCR to determine fetal RhD genotypes from maternal blood samples, which contain fetal DNA. They found that the test accurately predicted a newborn’s RhD blood group almost 96 percent of the time. The work, which appeared online yesterday in the British Medical Journal, is promising, the researchers said, because it demonstrates a non-invasive test that could decrease unnecessary prophylactic treatments.
“The introduction of fetal genotyping followed by the withholding of antenatal anti-RhD prophylaxis from mothers with an RhD negative fetus would result in about 36 percent of women being saved from unnecessary exposure to human blood products, inconvenience, and discomfort,” the authors wrote.
Roughly 60 percent of RhD negative Caucasian women give birth to RhD positive children. In some cases, this incompatibility between maternal and fetal blood leads to so-called maternal alloimmunization during pregnancy, in which a mother’s body produces antibodies against fetal RhD antigens. This can cause RhD disease and conditions such as jaundice, anemia, brain damage, heart failure, and even death in newborns.
In most cases, this can be prevented by giving pregnant RhD negative women anti-RhD immunoglobulin — antibodies against RhD — in their seventh month of pregnancy. But nearly 40 percent of RhD negative women receive the treatment unnecessarily. This could be avoided by finding a reliable and non-invasive way to know for sure whether the fetus is RhD positive or negative.
In this study, senior author Geoff Daniels, the head of molecular diagnostics at the International Blood Group Reference Laboratory in Bristol, and his colleagues used an Applied Biosystems Prism 7900 HT instrument to do real-time quantitative PCR on maternal and fetal DNA extracted from pregnant women’s blood.
For each of the 1,997 blood samples, which were taken for routine blood testing at about their 28th week of pregnancy, they amplified parts of the RHD and RHDE genes and determined the fetal genotypes. They then compared these genotypes with the actual RhD phenotype, determined after birth by serologically typing 1,869 cord blood samples.
The genotyping tests predicted the correct fetal RhD phenotype 95.7 percent of the time. And when they didn’t, the results were most often inconclusive or false-positive RhD tests.
Only 0.16 percent of the cases showed false-negative results — which are of greatest concern because they could lead to anti-RhD treatment being withheld when it’s actually necessary. And many of the false negative and inconclusive tests occurred when the total DNA concentration in maternal blood was high or when the samples were more than two weeks old.
The team also compared different models for applying the DNA genotyping test for RhD. The researchers found that if they classified all those who tested positive for RhD as well as those who were RhD variant or had inconclusive test results, they could detect 99.7 percent of RhD positive cases. 
Using this approach, the authors noted, only two percent of women would have received anti-RhD unnecessarily as opposed to the 38 percent who get it unnecessarily under the current standard of care.
In an accompanying editorial in the same issue of BMJ, Sailesh Kumar, a consultant in fetal medicine at the Queen Charlotte’s and Chelsea Hospital in London, lauded the research for its potential to decrease unnecessary anti-RhD treatments during pregnancy.
“The benefits of wider implementation of antenatal fetal genotyping are obvious. Antenatal prophylaxis can be given to those women who actually need it,” Kumar wrote. “The costs of testing everyone need to be balanced against the costs of giving immunoglobulin to everyone, but again mass testing is likely to result in a net saving by reducing pharmacy and manpower costs.”
But, he noted, such tests could potentially be even more beneficial earlier in pregnancy. Similarly, Daniels and his team suggest that such testing should be done after about 26 weeks of gestation. They intend to do feasibility trials on maternal blood testing for fetal RhD after eight to 16 and 20 weeks gestation.
This is not the only research being conducted on fetal RhD tests done on a mother’s blood, though. For instance, research from a similar trial in Amsterdam was published in 2006. And this January, Sequenom announced that it is testing its own MassARRAY and SEQureDx technology for determining fetal RhD status from maternal blood in a multi-center trial involving the North American Fetal Therapy Network.

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