Antenatal Diagnosis of Fetal RhD Status
Antenatal Diagnosis of Fetal RhD Status
ABSTRACT & COMMENTARY
Synopsis: It is possible to determine the Rhesus (hemolytic) disease (RhD) status of fetuses of RhD-negative women after the first trimester of pregnancy, using a sensitive molecular polymerase chain reaction technique that can detect and characterize minute quantities of fetal DNA in the mother’s plasma.
Source: Lo YMD, et al. Prenatal diagnosis of fetal RhD status by molecular analysis of maternal plasma. N Engl J Med 1998;339:1734-1738.
The rhesus (hemolytic) disease (rhd) gene has been identified and cloned and is absent in RhD-negative individuals. Beginning early in normal pregnancies, small numbers of fetal cells enter the maternal circulation, but these are difficult to detect by usual techniques. Lo and associates from the University of Hong Kong Prince of Wales Hospital used a sensitive fluorescence-based polymerase chain reaction (PCR) test to demonstrate the presence or absence of RhD DNA in the plasma of RhD-negative pregnant women. Among 45 RhD-negative pregnant women studied in the second and third trimesters, the results of the maternal RhD PCR analysis were completely concordant with the fetus’s RhD genotype determined serologically at the time of birth. Of 12 pregnancies studied in the first trimester, two maternal serums contained no RhD DNA, but the fetuses were later found to be RhD positive. In the remaining 10 pregnancies, there was agreement between the PCR test and fetal Rh status (seven were RhD positive and three were RhD negative). Lo et al conclude that noninvasive fetal RhD genotyping can be performed rapidly and reliably using a PCR analytic technique on maternal plasma beginning in the second trimester of pregnancy.
COMMENT BY HOWARD A. PEARSON, MD, FAAP
Despite the widespread use of Rh immune globulin prophylaxis in RhD-negative women, Rh isoimmunization still occurs. In cases when the father is heterozygous for the RhD gene and a sensitized mother is RhD negative, there is a 50% chance that a fetus will be RhD negative and so will not be at risk for hemolytic disease of the newborn. Further studies of such an RhD-negative fetus will not be necessary. However, if the fetus is RhD positive, studies may be indicated to determine the severity of the fetal hemolytic process and the need for therapeutic interventions.
Previous studies of fetal RhD status have examined samples of amniotic fluid or chorionic villi. However, due to the invasive nature by which these samples are obtained, there is always a risk of further sensitizing the mother, to say nothing of a small, but finite, risk of inducing a miscarriage. Lo et al have previously detected fetal DNA in the circulation of pregnant women. In this study, they characterized the fetal DNA for the specific DNA sequence of the RhD gene using a sensitive method based upon the PCR technique. This technique is so sensitive that Lo et al believe that it can detect the DNA from a single RhD-positive cell.
Lo et al studied 57 RhD-negative pregnant women. The results of the DNA test were compared with the RhD status of the infant at the time of birth. In maternal samples obtained in the second and third trimesters of pregnancy, there was complete agreement between the results of DNA and neonatal serologic results. The results in the first trimester were slightly less predictive because two of 10 maternal samples contained no fetal DNA. This technique uses fairly standard molecular technology and should be widely available in the near future.
In an accompanying editorial, John Bowman, MD, characterizes the results of Lo et al as a "major advance in fetal RhD genotyping."1 Bowman also stresses the importance of prevention. RhD immunoglobulin must be give to an RhD-negative woman who has given birth to an RhD-positive infant. Unless the father of the current pregnancy is known with certainty to be RhD negative, or unless the fetus is shown to be RhD negative by the PCR examination of the mother’s plasma, RhD immunoglobulin should be given at 28 weeks of gestation. RhD immunoglobulin should also be administered after abortion or threatened abortion and after amniocentesis, chorionic villus biopsy, or other invasive intrauterine procedure. If all aspects of Rh prophylaxis are implemented, the prevalence of RhD isoimmunization can be reduced by 96%. Finally, Bowman points out that, despite the best of programs, there will always be a small number of RhD-immunized pregnant women, and because there are no practical ways to prevent isoimmunization to other low-frequency blood groups such as c and Kell, there will always be a need to maintain the fetal and neonatal transfusion skills that have been developed in the last 50 years. Not too long ago, exchange transfusion was one of the most common invasive procedures performed by pediatricians. I wonder how many of the present generation of pediatricians would feel competent to perform one today?
Reference
1. Bowman JM. RhD hemolytic disease of the newborn. N Engl J Med 1998;339:1775-1777.
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