Non-Invasive Prenatal Diagnosis Screening

Abstract & Commentary

Synopsis: This study demonstrates that a sequential screening program that provides patients with first-trimester results and offers the option for early invasive testing or additional serum screening in the second trimester can detect 98% of trisomy 21-affected pregnancies. However, such an approach will result in 17% of patients being considered at risk and, hence, potentially having an invasive test.

Source: Platt LD, et al. Obstet Gynecol. 2004;104(4): 661-666.

Non-invasive prenatal diagnostic screening has become a hot topic of late. Large studies from England, Europe, and now 2 from the United States have borne out the efficacy of first trimester ultrasound determined nuchal translucency (NT) testing, with or without additional information provided by first trimester biochemical analysis (beta-hCG and PAPP-A). Now the data from one of these NICHD-funded studies (First Trimester Maternal Serum Biochemistry and Fetal Nuchal Translucency Screening [BUN]) have been published regarding the usefulness of adding a second trimester triple screen to the diagnostic mix.

Platt and colleagues tracked 4325 patients of the original 7392 patients having first trimester NT and biochemical screening who elected to have second trimester testing through triple screening (total hCG, unconjugated estriol, and alpha-fetoprotein). In this study, 4145 patients had a negative first-trimester screen and 180 had a positive first-trimester screen (> 1:270).

In the 4325 first-trimester screen-negative sample, there were seven fetuses with trisomy 21, 6 of whom were picked up by the second trimester biochemistry. All 7 cases of trisomy 21 that were in the screen positive group were also identified with the second trimester biochemistry, but there was a screen positive rate of 38% in this group. Platt et al found that by using both first and second trimester testing together in this way (the sequential method) a sensitivity of 98% could be attained with a cut-off for trisomy 21 of 1:270 at an overall false-positive rate of 17%.

Comment by John C. Hobbins, MD

Over the past 5 years various combinations of prenatal testing for Down syndrome have emerged: 1) ultrasound assessment of NT alone (with or without evaluation of the fetal nasal bone); 2) combined—NT and first trimester biochemistry; 3) integrated—NT, first trimester biochemistry and second trimester quad screen (hCG, E3, MSAFP, and Inhibin-A); and now 4) sequential—as described above. The difference between the integrated method and the sequential method is simply that with the former only one risk figure is generated which is only available to the patient after the results of the second trimester biochemistry are in. With the sequential approach each patient will get 2 sets of results: one at the end of the first trimester and another a short time after the second trimester blood is drawn. The advantage of the sequential method is that the patient can weigh her options at least 2½ weeks earlier than the patient enrolling in the integrated program. The theoretical advantage of the integrated screen is that it is more sensitive than the sequential while generating fewer false positives.

It is interesting that some individuals initially challenged the ethics of the soon to be published First and Second Trimester Evaluation of Risk Trial (FASTER) trial in which information about the thickness of the NT and the biochemistry was withheld until the second trimester data had been folded into the results. In fairness, however, if cystic hygromas or large NT’s were found in the FASTER study, the patient was immediately notified at the time of the ultrasound scan. Also, when the study was initiated the compelling data from Britain was not matched by results from the only United States study at the time which had a sensitivity of 33%, compared with the NT data from the Landmark British Trial, suggesting a sensitivity > 75%. The FASTER study represented a way to independently assess in an American population the true sensitivity of NT testing with well-trained operators using compulsively standardized methods. Fortunately, this study and the BUN investigation have yielded information that is very similar to the British group’s data.

Now patients have a variety of options available to them, which, hopefully, can be laid out in a way that is reasonably easy to understand (despite the nuances involved). We have not even touched upon the role a genetic sonogram might play as either an additional diagnostic adjunct or as a substitute for, let’s say, second trimester biochemistry. The obvious benefit would be to identify non-chromosomal anomalies and those forms of aneuploidy, such as trisomy 13, which might not be screened in by the above testing regimens. Data from patients in the FASTER trial suggest that the genetic sonogram also will pick up the remaining trisomy 21’s not screened in with NT and first and second trimester biochemistry testing.

The goal of all non-invasive testing, which seems to be close to being met, is to limit the need for chorionic villus sampling and amniocentesis to a minimum while re-assuring with reasonable accuracy the overwhelming majority of patients that their risk of having a fetus with trisomy 21 is substantially lower than the risk of invasive testing.

Additional Reading

  • Wapner R, et al. N Engl J Med. 2003;349:1405-1413.
  • Snijders RJ, et al. Lancet. 1998;352:343-346.
  • Pandya PP, et al. Br J Obstet Gynaceol. 1995;102: 957-962.
  • Krantz DA, et al. Am J Obstet Gynecol. 1996;174: 612-616.
  • Wald NJ, et al. Lancet. 2003;361:835-836.
  • Hobbins JC, et al. J Ultrasound Med. 2003;22:33-38.

John C. Hobbins, MD, Professor and Chief of Obstetrics, University of Colorado Health Sciences Center, Denver, is Associate Editor for OB/GYN Clinical Alert.