Let's Incorporate First-Trimester Screening Into Obstetric Practice

The addition of human chorionic gonadotropin and sometimes unconjugated estriol levels measured at 15–18 weeks (the double- and triple-screening protocols) raised the detection rate to approximately 50% in women younger than 35. Yet another measurement—inhibin A—later raised it even more, although we know now that the detection rate is still not as high as that achieved with the first-trimester screening protocol.

These were second-trimester screening tests, however, so women faced the often difficult choice of either having a first-trimester diagnosis by CVS or waiting for screening.

Biochemists experimented with first-trimester measurements and found that AFP and estriol were useless when measured this early. Free β-HCG, however, showed promise, as did measurement of another analyte, pregnancy-associated plasma protein-A (PAPP-A).

(There are two ways of measuring HCG, however, and it is important to understand that virtually all studies done on first-trimester biochemistry have used the so-called free β subunit of HCG—the dissociated part of HCG's β chain. Despite the fact that measurement of the intact β chain is not nearly as useful or accurate, some laboratories still market total β-HCG measurements. It is free β-HCG that we need to measure.)

Meanwhile, ultrasound had become more sophisticated, and it also became apparent that nuchal translucency (the thickness of the back of the fetal neck) in the late first trimester was the strongest indicator of fetal abnormalities identified thus far. It was clear that the bigger the NT measurement, the larger the risk of major chromosomal anomalies.

Because ultrasound and biochemistry are independent markers, a consensus quickly developed that first-trimester screening should utilize both.

It is interesting to note that biochemistry alone is problematic because it does not work as well with multiples and because values are commonly dependent upon gestational age, the determination of which really requires ultrasound. In fact, the late first-trimester ultrasound is the most accurate indicator of gestational age, and in this sense, it offers tremendous obstetric advantages.

We also now know that if NT values are increased and there is not a chromosomal etiology, there may be other congenital problems, principally cardiac anomalies. Early detection of such problems allows not only for reproductive choice but also for planned delivery in appropriate facilities with the best subspecialists.

The Evidence

The person who deserves the lion's share of credit for our shift to first-trimester screening is Dr. Kypros Nicolaides of Kings' College London. Through the second half of the 1990s and continuing on to this point, his group has repeatedly shown that when ultrasound is done correctly and is combined with the proper biochemistry, about 90% of fetuses with trisomy 21 syndrome and other major chromosomal abnormalities can be identified with a 5% false-positive rate.

Investigators of the main American trial on first-trimester screening, called the BUN (Biochemistry, Ultrasound, Nuchal Translucency) study, reported an 83% detection rate with an 8% false-positive rate. Detection rates were similar—even higher—in the FASTER (First- and Second-Trimester Evaluation of Risk) trial published late last year.

In addition to examining first-trimester screening, the FASTER trial addressed the idea of integrating first- and second-trimester screening results. Everyone agrees that the FASTER trial results showed that first-trimester screening works far better than second-trimester screening, and that some patients can modify their first-trimester risk by adding second-trimester protocols. My interpretation, however, is that the vast majority of patients do not need to wait for additional screening. They can have superb results in the first trimester.

Biochemistry can be done anytime between 9 and 13 weeks, but it is best done at weeks 9 or 10. Nuchal translucency, on the other hand, is only interpretable during weeks 11, 12, or 13. Before week 11 or after week 13, we cannot use the data.

Some experts have pointed to the possible added value of the fetal nasal bone measurement, but it is a much harder measurement to perform, and I believe it is unlikely that a large percentage of physicians will be able to do it competently. When it can be correctly obtained, however, it can be a good adjunct to the risk calculation. I consider it a second-line screening test that can be used if there is confusion or ambiguity about the first round of tests.

Ultrasound Quality

Successful first-trimester screening is contingent upon accurate nuchal translucency measurement. There are a number of ways to do the measurement, and frankly, the way in which a standard method was chosen was, in essence, arbitrary. Standardization is necessary, however. NT measurement is not an art.

If we're going to use ultrasound numbers in an algorithm—as we are in our new screening protocols—we must employ the same quality control we expect of any other laboratory measurement. Although the issue of ultrasound certification as a prerequisite of the performance of NT measurement has been debated, several organizations perform quality review.