Feasibility of noninvasive prenatal testing for common fetal aneuploidies in an early gestational window

Abstract

Background: Noninvasive prenatal testing (NIPT) by massively parallel sequencing (MPS) of the circulating cell free fetal (cff) DNA during the second trimester of pregnancy is now a frontline test for detecting common fetal chromosomal abnormalities. However, the availability of an earlier test result in the first trimester would enable better clinical management of high-risk pregnancies. The aim of the study was to determine the feasibility of early gestational NIPT.

Methods: Plasma DNA libraries were subjected to MPS and chromosomal read counts normalized to reference. Chromosomal aneuploidy was determined by z-scores (-3<z<3, normal range). The cff DNA fraction in 96 male pregnancies was calculated by the relative proportion of Y chromosomal reads.

Results: NIPT results were obtained in the first (8-12 weeks) and second (15-18 weeks) trimester for 182 high-risk women. NIPT identified T21, T13 and 45,X in 3 pregnancies that were confirmed by karyotyping, but missed a T15 pregnancy that eventually miscarried. In the remaining 178 pregnancies, results for first and second trimester NIPT were normal. The median fetal fraction in the first trimester was 7.6 ± 4.18% and 15% of samples were identified with a cff fraction below 4%. Different trends of cff DNA fraction change were observed between the first and second trimester, with 59% of pregnancies showing an increase, 17% showing no change and 24% showing a decrease.

Conclusions: Although NIPT was highly reliable and accurate at an earlier gestational age, clinical implementation should proceed with caution due to a small, but significant, number of pregnancies associated with a low cff DNA fraction.

Keywords: Cell free fetal DNA fraction; Early gestation; Fetal aneuploidies; Non-invasive prenatal testing.