Noninvasive prenatal testing for chromosome aneuploidies and subchromosomal microdeletions/microduplications in a cohort of 42,910 single pregnancies with different clinical features.

BACKGROUND: Since the discovery of cell-free DNA (cfDNA) in maternal plasma, it has opened up new approaches for non-invasive prenatal testing. With the development of whole-genome sequencing, small subchromosomal deletions and duplications could be found by NIPT. This study is to review the efficacy of NIPT as a screening test for aneuploidies and CNVs in 42,910 single pregnancies. METHODS: A total of 42,910 single pregnancies with different clinical features were recruited. The cell-free fetal DNA was directly sequenced. Each of the chromosome aneuploidies and the subchromosomal microdeletions/microduplications of PPV were analyzed. RESULTS: A total of 534 pregnancies (1.24%) were abnormal results detected by NIPT, and 403 pregnancies had underwent prenatal diagnosis. The positive predictive value (PPV) for trisomy 21(T21), trisomy 18 (T18), trisomy 13 (T13), sex chromosome aneuploidies (SCAs), and other chromosome aneuploidy was 79.23%, 54.84%, 13.79%, 33.04%, and 9.38% respectively. The PPV for CNVs was 28.99%. The PPV for CNVs ≤ 5 Mb is 20.83%, for within 5-10 Mb 50.00%, for > 10 Mb 27.27% respectively. PPVs of NIPT according to pregnancies characteristics are also different. CONCLUSION: Our data have potential significance in demonstrating the usefulness of NIPT profiling not only for common whole chromosome aneuploidies but also for CNVs. However, this newest method is still in its infancy for CNVs. There is still a need for clinical validation studies with accurate detection rates and false positive rates in clinical practice.

Evidence of compliance with and effectiveness of guidelines for noninvasive prenatal testing in China: a retrospective study of 189,809 cases.

In China, the medical guidelines recommend performing noninvasive prenatal testing (NIPT) with caution for pregnant women aged 35 years or older. However, the Mother and Child Health Care Law suggests that all primiparous women whose age is older than 35 years undergo prenatal diagnosis. These two inconsistent suggestions/recommendations have made obstetricians confused about whether to offer NIPT to these older pregnant women. To face this issue and find out the solution we performed a retrospective study of 189,809 NIPT samples collected from 28 provincial-leveled administrative units in China. Of 1,564 women with high-risk pregnancies who underwent NIPT, 459 (29.3%) did not participate in follow-up. The compound sensitivity and specificity of NIPT for trisomies 21, 18 and 13 detection was 99.1% (95% CI, 98.0%-99.6%) and 99.9% (95% CI, 98.8%-99.9%), respectively. In secundiparous women, NIPT showed high sensitivity and specificity similar to that in primiparous women. The observed risk for trisomies 21 and 18 significantly increased when the maternal age was 39 and older. After the publication of the current NIPT policy, the follow-up rate at our center was 91.9%; however, a large number of women are not in maternal and infant care networks nationwide, and that makes the follow-up rate outside our center relatively low. Our study shows that to balance the prevention of major aneuploidies and the limited resources for prenatal diagnosis, the cut-off age of 35 for invasive prenatal diagnosis might be unnecessary. Although the NIPT guidelines are well written, how to practice it effectively, especially in less industrialized areas, is worth discussing.

Non-invasive prenatal testing reveals copy number variations related to pregnancy complications.

BACKGROUND: Pregnancy complications could lead to maternal and fetal morbidity and mortality. Early diagnosing and managing complications have been associated with good outcomes. The placenta was an important organ for development of pregnancy complications. Thus, non-invasive prenatal testing technologies could detect genetic variations, such as aneuploidies and sub-chromosomal copy number variations, reflecting defective placenta by maternal plasma cffDNAs. Maternal cffDNAs had been proved to derive from trophoblast cells of placenta. RESULTS: In order to find out the relationship between genetic variations and pregnancy complications, we reviewed NIPT results for subchromosomal copy number variations in a cohort of 3890 pregnancies without complications and 441 pregnancies with pregnancy complications including gestational diabetes mellitus (GDM), pregnancy-induced hypertension (PIH), preterm prelabor rupture of membranes (PPROM) and placenta implantation abnormalities (PIA). For GDMs, we identified three CNV regions containing some members of alpha- and beta-defensins, such as DEFA1, DEFA3, DEFB1. For PIHs, we found three duplication and one deletion region including Pcdhα, Pcdhß, and Pcdhγ, known as protocadherins, which were complicated by hypertensive disorders. For PPROMs and PIAs, we identified one and two CNV regions, respectively. SFTPA2, SFTPD and SFTPA1, belonging to surfactant protein, was considered to moderated the inflammatory activation within the fetal extra-embryonic compartment, associated to duration of preterm prelabor rupture of fetal membranes, while MEF2C and TM6SF1 could be involved in trophoblast invasion and differentiation. CONCLUSIONS: Our findings gave a clue to correlation between genetic variations of maternal cell-free DNAs and pregnancy complications.