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Prenatal Diagnosis Society Recommends cfDNA Screening for Autosomal Trisomies in Twin Pregnancies

NEW YORK – The International Society for Prenatal Diagnosis (ISPD) on Wednesday published a set of recommendations on the use of cell-free DNA testing to screen multifetal pregnancies for Down syndrome and other autosomal trisomies, noting that the literature shows such testing to be appropriate for screening twin pregnancies and may also be a viable option for screening triplet pregnancies.

In a position statement published in the journal Prenatal Diagnosis, ISPD researchers said they addressed the choices faced by women carrying multifetal pregnancies: whether to undergo invasive diagnostic testing to receive the most comprehensive and actionable information, to undergo screening tests for common aneuploidies and/or additional disorders such as microdeletion/duplication syndromes, or to choose to have no testing at all. Although they focused on Down syndrome, they also addressed trisomies 13 and 18. The evidence they looked at included screening performance in multifetal pregnancies for combinations of serum and ultrasound markers, as well as by cfDNA testing methodologies. And although current professional guidelines compare the performance of cfDNA in twin pregnancies to that reported for cfDNA screening in singleton pregnancies, the ISPD compared cfDNA testing to other screening methods available for multifetal pregnancies, focusing on test characteristics such as sensitivity, specificity, and the test failure rate.

Overall, the researchers concluded, the use of cfDNA screening in the first trimester for common autosomal trisomies is appropriate for twin pregnancies "due to sufficient evidence showing high detection and low false-positive rates with high predictive values." If such testing reveals an increased risk, then it should be followed by counseling and an offer of diagnostic testing to confirm the results, the ISPD also said.

Further, the society recommended, laboratories performing cfDNA testing in multifetal pregnancies should take evidence of zygosity into account when interpreting both test results and fetal fractions. And when a cfDNA test failure occurs, they should consider ultrasound and diagnostic testing, or a second blood draw and retesting if there is sufficient time.

The ISPD said that while screening options for triplet pregnancies are lacking, cfDNA may be a potential option. However, diagnostic testing should always be offered and the limitations of screening tests should be stressed to expecting parents.

In their review, the ISPD researchers noted that while the use of cfDNA screening for Down syndrome in multifetal pregnancies has received increasing attention in recent years, only three out of 10 statements from professional societies that they reviewed actually allowed or recommended cfDNA screening in twin pregnancies. Others did not address the issue, suggesting that the data were too sparse to make a recommendation or recommended against its use. The earliest recommendation, published in 2015, implied screening was acceptable for all three disorders by stating that the performance of cfDNA screening in twins was similar to that in singleton pregnancies. Only two recommendations directly addressed triplet pregnancies. Both recommended the use of first trimester ultrasound markers at 11 to 13 weeks' gestation and did not address cfDNA testing. Ultimately, none of the professional societies recommend for, or suggested the use of, cfDNA screening in triplet pregnancies.

Since the ISPD drafted its own recommendations, prepublication of a new ACOG Practice Bulletin was released, making a level B recommendation that "cell-free DNA screening can be performed in twin pregnancies." In addition, England's National Health Service recently released a plan to employ cfDNA testing in both singleton and twin pregnancies, the ISPD said.

The researchers also analyzed results from a formal review of the literature regarding the performance of cfDNA testing in twin pregnancies. The results showed that in a total of 3,780 twin pregnancies, there were 56 that had at least one fetus with Down syndrome. Among the 56, there was one false-negative and two false-positive results. In another analysis, which included additional studies, a total of 117 twin pregnancies had at least one fetus with a common autosomal trisomy (84 with Down syndrome, 29 with trisomy 18, and four with trisomy 13), with detection rates for cfDNA screening of 98.8 percent, 93.1 percent, and 75 percent, respectively. The overall false-positive rate among unaffected pregnancies was 0.29 percent.

Finally, the ISPD said, two studies reported cfDNA test results in more than 10 triplet pregnancies, but none were reported to be positive or from a known trisomic pregnancy. Therefore, observed detection rates for Down syndrome and other common trisomies were absent. Test failure rates are likely to be higher for triplets than for twins, the researchers noted, especially when fetus-specific fetal fraction estimates are not available. However, there are data showing that cfDNA testing can correctly identify the fetal sex in all triplet combinations.

"Based on our current knowledge of how cfDNA testing distinguishes the underlying genetics between mother and fetus, one could extrapolate this knowledge from screening singletons and twins to a theoretical performance [of detecting autosomal trisomies] in triplet pregnancies," the authors wrote.

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