First Trimester Screening for Aneuploidy
First trimester screening for aneuploidy, or as it is commonly referred to as ‘combined first trimester risk assessment,’ has gained widespread acceptance in other developed nations over the past decade, and is slowly coming into its own here in the U.S over the past couple of years as well. This screening test uses a combination of fetal measurements, maternal blood pregnancy ‘markers,’ maternal characteristics (age, weight, race, family/pregnancy history, and certain medical problems, such as diabetes) and a large, and continuously expanding, data repository to generate risk numbers for trisomy 21 (Down syndrome) and trisomies 13 and 18. The primary measurements of the baby include the ‘crown-rump length (CRL)’ (top of head to bottom of butt) and the ‘nuchal translucency (NT)’ (clear space between the skin and underlying soft tissues of the back of the neck, head, or upper trunk). The wider the nuchal translucency, the greater is the likelihood that the baby has aneuploidy. A special certification process has been developed for performing NT measurements and completion of this in an acceptable fashion is required before access to the database for combined risk assessment can be obtained. The presence or absence of a fetal nasal bone can also be factored into the risk assessment, since the absence of the same (or the presence of one that is smaller than usual) has also been associated with aneuploidy, especially trisomy 21. Separate certification is required for this to be used in the risk assessment process.
The maternal blood samples assess levels of free ?-hCG (the ‘pregnancy hormone’ secreted by placental tissues, the trophoblasts) and pregnancy-associated plasma protein A (PAPP-A) (associated with differentiation of the placental trophoblasts). Free ?-hCG levels usually decrease after 10 weeks’ gestation in normal pregnancies, whereas they often remain elevated or increase in cases of trisomy 21. Indeed, the difference between these and normal pregnancies increases with gestational age. In contrast, babies with trisomy 21 tend to have lower levels of PAPP-A than normals, but the difference between these and normal babies tends to decrease with gestational age.
For combined risk assessment, the fetal crown-rump length must be between 45 and 84 mm, roughly corresponding to 11-14 weeks’ gestation. The maternal blood screening can be done at the same time the fetal measurements are obtained, or as early as 8-9 weeks,’ and then combined with the fetal measurements when these are performed. The advantage of this latter approach is that a ‘final result’ can be obtained the same day, whereas about a week is required for the former because that is the time required for processing of the maternal blood samples. The test is most reliable (has the greatest combined sensitivity of the NT and blood screens) at the gestational ages between 11 and 12 weeks and this is also the time when it is easiest to obtain the most accurate NT and CRL measurements.
The ‘sensitivity’ of the test relates to the probability if the disease (in this case aneuploidy) is present, the test will be positive. Neither the NT measurement nor the blood tests by themselves have sufficient sensitivity to stand alone as a good ‘screening test’ that would be widely acceptable. At the risk of great over-simplification, combined risk assessment has been shown to have the capability of detecting trisomies 21, 13, and 18 in 85-95% of cases with false positive rates (probability that the test is abnormal, but the baby is not aneuploid) in the range of 5% or less. In our own experience over the past two years, we have not missed a case of one of these trisomies in ‘at risk’ women (women expected to be 35 years or older at delivery), younger women at increased risk for aneuploidy, or who simply wanted reassurance and had this screening performed.
There are distinct advantages to combined first trimester screening. In most instances, it provides early reassurance to ‘at risk’ and even low risk women who undergo the screening process. It also offers the opportunity for early detection of babies with the chromosomal abnormalities noted above, and for detection of other chromosomal abnormalities (and congenital heart defects as a side benefit in babies that may or may not have a chromosomal abnormality) that might also be accompanied by abnormalities of the NT. This allows patients more time to consider their diagnostic and therapeutic options at a time in the pregnancy where privacy and confidentiality are much easier to preserve. At the same time, the cost, sensitivity, and false positive rates are comparable to, if not better than, that of midtrimester screening.
There are also some limitations of first trimester screening that must be conveyed to all women considering this procedure. The test is still just a ‘screening’ test and therefore cannot replace an invasive diagnostic test such as chorionic villus sampling, amniocentesis, or umbilical cord blood sampling for the definitive diagnosis (or not) of aneuploidy. Although ‘false positive rates’ are low, a “positive result” does not mean that a baby definitely has a genetic abnormality. Indeed, many will not. By the same token, a “negative result” does not guarantee the absence of a chromosomal abnormality, other heritable or syndromic problems, or fetal birth defects that are not clearly related to a specific genetic cause. For that reason, even to women who have had ‘reassuring first trimester screening, we offer both maternal serum alpha-fetoprotein (MSAFP) screening at 16 weeks’ and a ‘targeted’ genetic sonogram at 18-20 weeks’ gestation.
In the next (or some time in the near future) post, we will discuss what it means to have an “abnormal” first trimester screen as well as the options for follow-up of the same…