Until recently, the moment of birth was a surprise. We anxiously awaited the obstetrician’s announcement: “It’s a boy!” or “It’s a girl!” Then we checked to see if any crucial parts were missing and we counted the fingers and toes. We had to wait for a baby to be born before we could know its sex and whether it was normal. Today, thanks to prenatal testing, we can know the sex of a fetus, diagnose a number of genetic abnormalities and malformations, and we can even operate on the fetus in utero to correct certain problems before birth. I had amniocentesis for my two pregnancies because of the higher risk of Down syndrome at my age (37 and 39). It was reassuring to know the baby didn’t have Down syndrome, and it was fun for my husband to point to my burgeoning belly and introduce it to people as “our daughter Kristin.”
Amniocentesis is invasive, carries risks, and can’t be done until the 15th to 20th week of pregnancy. Now there is a safe, noninvasive, accurate blood test that can be done as early as the 9th week. It analyzes cell-free fetal DNA (cfDNA) circulating in the mother’s blood. It sounds ideal, but there are some caveats. It’s not yet appropriate to recommend it to all pregnant women. An editorial in The New England Journal of Medicine expressed concern that pressures are promoting diffusion of cfDNA testing beyond the boundaries of available evidence.
What tests are available?
- Standard screening tests on maternal blood for serum markers associated with chromosomal abnormalities (like the trisomy of Down syndrome) and neural tube defects (like spina bifida). Indicates elevated risk but doesn’t make a diagnosis. Further invasive testing required.
- Nuchal translucency, measured at end of first trimester
- Nuchal fold, measured at end of second trimester
- Can also visualize gross anatomical abnormalities
- Combining serum marker tests with ultrasound nuchal measurements can decrease the number of false positives to 4-5% with a true positive rate of up to 90%. Not diagnostic: indicates a need for further invasive testing.
- Chorionic villus sampling (CVS) samples placental tissue.
- Can be done at 8-10 weeks gestation
- 2 approaches: through the vagina or the abdomen
- Risks: miscarriage (0.5-1%), infection, amniotic fluid leakage, limb reduction defects
- False positives can occur with mosaicism, where the placental cells are abnormal but the fetus is normal, and false negatives can occur if the sample is contaminated with maternal cells
- If the fetus is Rh positive and the mother is Rh negative, the procedure can introduce fetal cells into the maternal circulation and cause Rh sensitization
- Needle inserted into amniotic fluid
- Done later than CVS, between 15th and 20th week of pregnancy
- Risks similar to those of CVS, but miscarriage rate is lower (estimates vary from 1 in 200 to 1 in 500)
- Can also predict fetal lung maturity
- Percutaneous umbilical cord blood sampling
- Needle inserted through abdomen into baby’s umbilical cord under ultrasound guidance
- Can detect chromosomal abnormalities, infections, blood disorders and some metabolic disorders
- Can detect fetal anemia and treat with blood transfusion
- Done after 17 weeks pregnancy
- Risks: similar risks to amniocentesis but with a higher rate of miscarriage (1-2%)
- cfDNA tests
- Noninvasive: require only drawing blood from the mother
- Can be done as early as 9 weeks
- High sensitivity and specificity
What can prenatal testing diagnose?
All the invasive tests and the new cfDNA tests collect fetal DNA and analyze it. They all require a 1-2 week wait for results. They can detect chromosomal abnormalities include Down syndrome, other trisomies, sex chromosome abnormalities like Turner syndrome, and fragile X syndrome. Specific tests can be done for cystic fibrosis, Tay-Sachs, sickle cell disease, muscular dystrophy, and other inheritable conditions when indicated by family history.
What if results are abnormal?
If a condition like Down syndrome is detected, about 90% of parents choose to terminate the pregnancy. For some conditions like spina bifida, fetal surgery may be an option. Parents who continue the pregnancy can use the information to plan for the care of a child with special needs, anticipate lifestyle changes, and identify support groups and resources.
Some people reject any testing because of religious or moral objections to pregnancy termination, because they are comfortable with the idea of raising the child no matter what handicaps it has, or because they reject any testing that poses any risk to the fetus.
Currently available cfDNA tests in the US are offered by 4 companies (Verinata, Sequenom, Ariosa, and Natera) at a cost of $795 to $2762. They all screen for trisomy 21 (Down syndrome), trisomy 18 (Edwards syndrome), and trisomy 13 (Patau syndrome). Some additionally offer sex determination and screening for sex-chromosome abnormalities like XO, XXX, XXY and XYY. They do not test for anything else. They are being aggressively marketed though channels like Facebook, and consumers may not understand the trade-offs and the limitations.
Patients considering cfDNA testing should be aware that:
- They do not provide all the information available through other tests
- They are generally not covered by insurance
- They are said to be accurate, but the reported sensitivities and specificities of these tests are based on studies with a high proportion of abnormals (with a prevalence as high as 1 in 8 for Down syndrome). They will be less accurate when applied to the whole population of pregnant women.
- If the test is positive, what’s the likelihood that the individual really has the condition? In other words, what is the test’s positive predictive value (PPV)? We don’t know, because the companies have not reported that information. Sensitivity and specificity depend on the prevalence of the condition in the population being tested; we want to know the PPV for an individual in the specific population we are testing. In a low risk population a positive result will have a lower PPV than in a high risk population.
The American Congress of Obstetricians and Gynecologists and other professional organizations recommend cfDNA testing only for high-risk pregnancies, and specify that abnormal results should be confirmed by invasive testing before any action is taken.
Who would have imagined that fetal DNA was circulating in the mother’s blood? Or that it could be separated from her blood to allow analysis of the fetus’s genetic makeup? This is an exciting scientific development. These new cfDNA blood tests have great promise, especially if they can be expanded to include broader screening of DNA for more abnormalities. Meanwhile, the currently available tests are only able to detect a few specific abnormalities and they shouldn’t be used as a screening test for all pregnancies. They are useful in high-risk pregnancies but abnormal results must still be confirmed by invasive testing.