By John C. Hobbins, MD

Professor, Department of Obstetrics and Gynecology, University of Colorado School of Medicine, Aurora

Dr. Hobbins reports no financial relationships relevant to this field of study.

SYNOPSIS: Recent studies using data from the California Prenatal Screening Program show that standard screening protocols, which combine first trimester ultrasound and biochemistry with second trimester biochemistry, has a very acceptable detection rate and outperforms NIPT in cost-effectiveness in low-risk patients.

SOURCES: Baer RJ, et al. Detection rates for aneuploidy by first trimester and second trimester screening. Obstet Gynecol 2015;126:753-759.

Kaimal AJ, et al. Prenatal testing in the genomic age: Clinical outcomes, quality of life, and costs. Obstet Gynecol 2015;126:737-746.

Over a short time, noninvasive prenatal testing (NIPT) with cell-free DNA has become the darling of providers when screening for fetal aneuploidy. At first it was recommended for high-risk patients only, targeting mostly those of advanced maternal age. Then, perhaps because of the marketing strategies of companies vying for a gigantic market, the tests began being offered to low-risk populations, with detection rates touted as high as 98-99% for trisomy 21 (T21), in particular. Two studies in Obstetrics and Gynecology were published in September, both dealing with the extensive California Prenatal Screening Program database.1,2 Baer et al mined 3 years’ worth of data (2009 through 2012) from the California Screening Program, during which time it was mandated that all pregnant patients in the state be offered screening for fetal aneuploidy.1 This included first trimester nuchal translucency screening, along with biochemical markers (pregnancy associated plasma protein-A and human chorionic gonadotropin (HCG). To this “combined screen” was added second trimester biochemistry (HCG, estriol, alpha-fetoprotein, inhibin-A) to make it a “sequential screen.” The data registry has complete immediate outcome information on all patients entered.

During the study period 452,901 patients had screening with this method, 73% of whom were < 35 years of age. In the study, 91.1% had first and second trimester screening. The researchers found that 20,446 patients (4.5%) were screen positive for aneuploidy, in general, and 17,435 (3.8%) were positive for T21, in particular. In 1291 cases of T21, the detection rate was 92.9%. For those women who were not advanced maternal age, the detection rate was 88.1%, and for those 35 years the T21 detection rate was 95.6%. Most (72.3%) of those screen-positive patients in the first trimester did not have a second trimester quad screen. In those fetal T21 patients with a first trimester positive screen who chose to have second trimester biochemistry, in only two cases (0.2%) did the second trimester information reclassify them as “negative.”

T21 accounted for about half (49.5%) of all aneuploid fetuses in the study. For the remaining chromosomal abnormalities, the detection rate for trisomy 18 was 93.7%, for trisomy 13 was 80.3%, for Turner syndrome was 80%, and for Kleinfelter syndrome was 50.8%. The detection rate for triploidy was 91%.

COMMENTARY

This study shows in a very large cohort of patients that the standard “old way” of screening is still pretty darn good, with an overall detection rate for T21 of 96% in women  35 years of age and 88% in younger women. With NIPT, most laboratories are quoting a T21 detection rate of 98-99%. However, 50% of the aneuploid fetuses in the overall group were not T21. Published detection rates are 98-99% for T18, but for other forms of aneuploidy detection rates have been substantially lower with NIPT.

In another article addressing the same issue, the authors compared six screening strategies with a decision–analytic model, using the above California database.2 They found that multiple marker (standard) methods had the highest detection rates at the lowest cost for all chromosomal abnormalities lumped together in women ages 20 through 38 years. After that time ( 39 years of age), NIPT was the best first-line screening test. If one used NIPT as a backup in only those who were screen-positive by multiple markers, then there was a reduction for the need of invasive testing. NIPT is a remarkable test that has expanded our screening possibilities, but we need to explain to our patients that:

  1. It does not pick up all types of aneuploidy or other anomalies.
  2. At present, it is still expensive.
  3. The test results need to be explained fully.

Apropos of the last point, a few days ago, a 31-year-old woman whose first trimester NIPT was positive for T21 called. Based on the positive predictive value, the lab estimated that her chance of having a fetus with T21 was 67%. This calculation was predicated on the prevalence of this condition at her age. However, her primary provider told her that this figure was wrong and that, based on the “accuracy” of the test, her risk was almost 100% for T21. Interestingly, there were no clues for T21 at the time of a 14-week ultrasound scan. She is booked for an amniocentesis. Regardless of whether the fetus has T21, what she heard from a well-meaning provider was not correct.

The nuances with all forms of screening can be confusing for patients and providers. Now that some of the newness and glitter of the new test has worn off, it is time for us to step back and reboot by putting this and other screening tests into proper perspective.

REFERENCES

  1. Baer RJ, et al. Detection rates for aneuploidy by first trimester and second trimester screening. Obstet Gynecol 2015;126:753-759.
  2. Kaimal AJ, et al. Prenatal testing in the genomic age: Clinical outcomes, quality of life, and costs. Obstet Gynecol 2015;126:737-746.