Cell-free DNA screening for trisomy 21 in twin pregnancy: a large multicenter cohort study

Abstract

OBJECTIVE: Somatic abnormalities involving chromosome 21, 18, and 13 are found in cancers and are detectable in circulating cfDNA. Previous publications have suggested increased risks of maternal neoplasm when multiple aneuploidies are detected on non-SNPbased NIPTs with normal fetal karyotypes. SNP-based NIPT distinguishes maternal/fetal cfDNA, allowing for CNV origin identification. This study reviewed maternal/fetal outcome SNP-based NIPT data to determine if multiple maternal copy number variants (CNVs) can predict increased risk of maternal neoplasms. STUDY DESIGN: Fetal/maternal outcomes were retrospectively collected for SNP-based NIPT cases accessioned from 7/1/2017 to 3/ 30/2021. Cases reported as unspecified atypical findings with data suggesting multiple maternal CNVs were included. RESULTS: Of 2,004,428 cases with results, 38 (0.002%) had unspecified atypical results with internal data consistent with maternal CNVs. Fetal/maternal health outcomes were obtained in 26/38 (68.4%) cases. A malignancy was diagnosed before, during, or after delivery in 14/26 cases. Positive predictive values (PPVs) for maternal neoplasm ranged from 39% (15/38 all cases) to 58% (15/26 known outcomes). One case of leiomyoma (1/26, 3.8%), and one case of lymphadenopathy (1/26, 3.8%) were observed. Fetal triploidy without reported maternal health issues was seen in 2 cases (2/26; 7.7%). 8/26 (30.8%) cases had no reported fetal/maternal health issues, including one with a family history of a BRCA mutation with patient mutation status unknown. (Table 1) CONCLUSION: SNP-based NIPT can incidentally identify maternal neoplasm presence/recurrence. When maternal CNVs are identified on SNP-based NIPT, our data suggests an increased risk of maternal neoplasm with PPVs ranging from 39-59%. Neoplasms in this cohort could be underdiagnosed due to limited follow-up time post NIPT (2-48 months). Reporting this incidental finding allows for better informed maternal clinical management, with possible earlier neoplasm detection.

Prenatal Genetic Screening in Twin Pregnancy

“…15 A recent multicenter retrospective cohort study of 1764 twin pregnancies from 17 US centers including 42 pregnancies with T21 reported a 97.6% (95% CI 83.8-99.7) detection rate. 16 The median gestational age at cfDNA screening was 12.3 weeks. Thirty-eight of the 42 cases of T21 were from dichorionic pregnancies including the one false-negative case.…”

“…17 It is likely that the non-reportable rates for cfDNA screening twins will decrease with advances technology as evidenced by the 2023 multicenter US study of 1764 twin pregnancies in which 3.9% of twin pregnancies had a non-reportable result, with 58% of cases with second draw receiving a result. 16 There are several risk factors for non-reportable results that may be more common in twin pregnancies including conception with in vitro fertilization, advanced maternal age, and abnormal placentation. 17 Another consideration of multiples is that of "vanishing twins," or the early miscarriage of one fetus after a twin pregnancy has been confirmed or suspected on ultrasound.…”

First Trimester Ultrasound and Aneuploidy Screening in Twins

“…In addition, although limited by low overall number of cases, screening performance for T18 and T13 was good, with all 10 cases of T18 detected (with one false-positive), and 4 out of 5 cases of T13 detected. 20 The recent ACOG and SMFM Practice Bulletin states that cfDNA is an appropriate test for aneuploidy screening in twin pregnancies 1 . The document acknowledges that further research is needed to evaluate the performance of cfDNA detection of T13 and T18 in twins.…”

“…The sensitivity for the detection of T21 in a total of 42 pregnancies with at least one twin affected with T21 was 97.6% (95% CI: 83.8-99.7), with one false-negative case and a specificity of 100% (95% CI: 99.7-100). In addition, although limited by low overall number of cases, screening performance for T18 and T13 was good, with all 10 cases of T18 detected (with one false-positive), and 4 out of 5 cases of T13 detected 20 …”

Cell-free DNA Screening for Aneuploidy

“…As twins are less common than singletons, there are more limited data on cfDNA screening for aneuploidy in multifetal gestations. However, available data indicate that the sensitivity and specificity of cfDNA for aneuploidy in multiple gestations is also high, although somewhat lower than with singleton gestations [54][55][56] (see Chapter 7).…”