Follow-up in Patients With Non-invasive Prenatal Screening Failures: A Reflection on the Choice of Further Prenatal Diagnosis.

Sha Liu,Xiaosha Jing,Xiang Wei,Lingling Xing,Quanfang Zhou,Jianlong Liu,Qian Zhu,Tianyu Xia,Ting Bai,Yuan Luo,Jing Cheng,Hongqian Liu,Cechuan Deng,Yunyun Liu

doi:10.3389/fgene.2021.666648

Abstract

BackgroundOur aim was to provide a theoretical basis for clinicians to conduct genetic counseling and choose further prenatal diagnosis methods for pregnant women who failed non-invasive prenatal screening (NIPS).MethodsA retrospective analysis was performed on pregnant women who had failed NIPS tests.ResultsAmong the 123,291 samples, 394 pregnant women did not obtain valid results due to test failures. A total of 378 pregnant women were available for follow-up, while 16 patients were lost to follow-up. Of these 378, 135 pregnant women chose further prenatal diagnosis through amniocentesis, and one case of dysplasia was recalled for postpartum chromosome testing. The incidence rate of congenital chromosomal abnormalities in those who failed the NIPS was 3.97% (15/378), which was higher than that of the chromosomal abnormalities in the common population (1.8%). Among the pregnant women who received prenatal diagnosis, the positive rates of chromosomal abnormalities in the chromosomal microarray analysis/copy number variation sequencing (CMA/CNV-seq) group and in the karyotyping group were 15.28 and 4.76%, respectively.ConclusionPrenatal diagnosis should be strongly recommended in posttest genetic counseling for pregnant women with NIPS failures. Further, high-resolution detection methods should be recommended for additional prenatal diagnoses.

Highlights

In recent years, non-invasive prenatal screening (NIPS) using cell-free fetal DNA in the peripheral blood of pregnant women has been widely used because of its high specificity, sensitivity, and non-invasive characteristics for screening common fetal chromosomal aneuploidies. Gil et al (2017) conducted a meta-analysis of 35 relevant studiesFollow-up of NIPS Failures and found that screening approximately 220,000 NIPS test samples collected in 2017 in singleton pregnancies could detect up to 99% of trisomy 21, 98% of trisomy 18, and 99% of trisomy 13 at a combined false-positive rate (FPR) of 0.13%.NIPS detection failure always exists in clinical practice
According to the follow-up results, the incidence of chromosomal abnormalities in NIPS test failure cases could reach 3.97%. This was higher than that of chromosomal abnormalities in the common population (1.8%), which was mentioned in previous reports (Evans et al, 2016). These results indicate that pregnant women who fail NIPS need to undergo adequate genetic counseling and focus on invasive prenatal diagnosis
A low fetal fraction was the main reason for the failure of non-invasive prenatal screening (NIPS) testing (79.44%) (Table 1)

Summary

Introduction

Non-invasive prenatal screening (NIPS) using cell-free fetal DNA (cffDNA) in the peripheral blood of pregnant women has been widely used because of its high specificity, sensitivity, and non-invasive characteristics for screening common fetal chromosomal aneuploidies (trisomy 21, trisomy 18, and trisomy 13). Gil et al (2017) conducted a meta-analysis of 35 relevant studiesFollow-up of NIPS Failures and found that screening approximately 220,000 NIPS test samples collected in 2017 in singleton pregnancies could detect up to 99% of trisomy 21, 98% of trisomy 18, and 99% of trisomy 13 at a combined false-positive rate (FPR) of 0.13%.NIPS detection failure always exists in clinical practice. In a study by Norton et al (2015), the detection rate of chromosome aneuploidy was 0.36% (57/15841) in the successful NIPS group and 2.25% (11/488) in the failed NIPS group. In a study by Revello et al (2016), the detection rate of chromosome aneuploidy was 2.1% (218/10382) in the successful NIPS group and 2.53% (8/316) in the failed NIPS group. In actual clinical genetic counseling, doctors recommend invasive prenatal diagnosis for pregnant women who fail NIPS. With the wide clinical application of high-resolution detection methods such as CMA, it is possible to find pathogenic copy number variations beyond the detection range of karyotype analysis (Hay et al, 2018). Our aim was to provide a theoretical basis for clinicians to conduct genetic counseling and choose further prenatal diagnosis methods for pregnant women who failed non-invasive prenatal screening (NIPS)

Objectives

Methods

Results