Noninvasive antenatal testing using cell free fetal DNA

Today's post is by a guest author, Joshua Cook, M.D.  Dr. Cook is a pathology resident at the University of Utah.

Fetal cells, largely of placental origin, circulate freely in the mother’s bloodstream during gestation.  In some cases fetal cells are detectible in maternal blood for years post delivery.  Cell free fetal DNA (cffDNA) is also present in the peripheral blood of pregnant women, though it disappears rapidly at delivery.  cffDNA appears early in the first trimester and tends to increase in concentration as gestation progresses.  A number of studies over the last decade have shown this naked fetal DNA provides a noninvasive method for rendering prenatal diagnoses without risk to the fetus or mother.

Consider hemolytic disease of the newborn (HDN).  About 10% of pregnancies in Caucasian RBCs populations involve a rhesus Rh(D)- negative mother carrying an Rh(D)-positive fetus.  Such a mother is at risk of becoming sensitized, or isoimmunized, to Rh(D)-positive red blood cells following exposure to fetal blood. 

Small physiologic fetal-maternal hemorrhages commonly occur at delivery or during miscarriage.  Exposure of the mother’s immune system to fetal red blood cells may result in the generation of maternal antibodies to fetal antigens (sensitization or isoimmunization).  These antibodies may then cross the placenta in subsequent pregnancies and harm a future baby.  In pregnancies with Rh(D) incompatibility [Rh(D)-negative mom with Rh(D)-positive fetus] the mother has historically had about a 10% risk of becoming sensitized. 

Knowledge of the fetal RHD genotype in Rh(D) negative women greatly simplifies antenatal management.  Modern medical practice requires that immunoprophylaxis (anti-D IgG immunoglobulin; aka RhoGAM) routinely be given to all non-sensitized RhD-negative woman in pregnancy to prevent isoimmunization.  This had led to a dramatic decrease in HDN since the 1960’s.  When administered, the anti-Rh(D) antibodies circulate in the mother’s bloodstream and prevent her immune system from reacting to Rh(D)-positive fetal blood.  The standard of care is to provide anti-Rh(D) administration at 26 to 28 weeks of gestation, and after suspected antepartum fetal-maternal hemorrhage (i.e. amniocentesis, chorionic villous sampling, pregnancy loss, ectopic pregnancy).  Anti-D IgG is also given with within 72 hours of delivery if the baby is found to be Rh(D)-positive.

Because the Rh(D) status of the fetus is usually not known prior to birth, about 40% of immunoprophylaxis is given unnecessarily to Rh(D)-negative mothers who are carrying Rh(D)-negative fetuses.  cffDNA testing restricts immuneprophylaxis to the 60% of pregnancies with a true Rh(D)-positive fetus.  Fetal RHD genotyping using maternal plasma is about 95% accurate at 11 -13 weeks gestation and is nearly 99.8% accurate by 26 weeks (when the first dose of immuneprophlyaxis is administered).  Accuracy improves throughout gestation because the amount of cffDNA in maternal peripheral blood increases with gestational age. 

cffDNA testing is currently used in Europe to identify high risk pregnancies [i.e. Rh(D)-positive fetus  in a previously sensitized mother] which benefit from intensive antenatal monitoring.  cffDNA RHD genotyping is used to determine the risk of chorionic villous sampling (CVS) in sensitized women.  CVS is a technique used in the prenatal diagnosis of fetal aneuploidies (such as Down syndrome) and other inherited genetic disorders; however it is relatively contraindicated in isoimmunized women since procedure related fetal-maternal hemorrhage exacerbates pre-existing sensitization.  If the fetus lacks Rh(D) then boosting the maternal amnestic response is not an issue.

Cost and outcome studies for noninvasive cffDNA prenatal screening are in progress, but obstetricians may soon have a powerful new tool in their armamentarium.

 

 

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