Late first-trimester ultrasound findings can alter management after high-risk NIPT result

Late first-trimester ultrasound findings can alter management after high-risk NIPT result

REVIEWED BY Nayana Parange, FASA | ASA SIG: Women’s Health

REFERENCE | Authors: F Scott, M-E Smet, J Elhindi, R Mogra, L Sunderland, A Ferreira, M Menezes, S Meagher, A McLennan

WHY THE STUDY WAS PERFORMED

Non-invasive prenatal testing (NIPT) is a screening test in pregnancy performed typically around 10–11 weeks of pregnancy to determine the risk of genetic abnormalities in the fetus. This test analyses cell-free DNA (cfDNA), which is principally from the maternal haemopoietic cells and the cytotrophoblast. NIPT sensitivity and specificity are the highest for Trisomy 21. The detection rates are also high for Trisomy 18 and Trisomy 14; however, positive predictive values (PPV) for these are lower as these anomalies are less prevalent and have a greater degree of placental mosaicism. The false positive cfDNA is most often due to placental mosaicism although other contributing factors include maternal factors such as malignancy, fibroids, and mosaicism.

Late first-trimester ultrasound (LFTU) scan for the assessment of fetal anatomy and nuchal translucency (NT) is performed closer to 13 weeks’ gestation and is useful for characterising structural anomalies in keeping with the specific genetic abnormality identified by the high-risk NIPT, thus potentially increasing the PPV of NIPT. Conversely, an unremarkable ultrasound may decrease the NIPT’s PPV.

This study aimed to evaluate the impact of a detailed LFTU on the PPV of a high-risk NIPT for various aneuploidies.

HOW THE STUDY WAS PERFORMED

This was a retrospective study of data for all women with a singleton pregnancy undergoing prenatal invasive diagnostic testing from 3 tertiary providers of obstetric ultrasound from 2 major cities in Australia over 4 years, each using NIPT as a first-line screening test. Data collection included pre-NIPT ultrasound, NIPT results, LFTU findings, placental serology, and later, ultrasound findings.

Pre-NIPT ultrasound information included fetal, number, viability, and gestation. Where structural abnormalities or enlarged NT were identified, genetic counselling ensued to help determine if NIPT was undertaken or bypassed in favour of chorionic villus sampling (CVS).

All LFTUs were performed by Fetal Medicine Foundation-accredited sonographers. LFTU was classified as normal when the fetus displayed appropriate growth and appeared structurally normal with no sonographic aneuploidy markers evident. When structural abnormalities and/or enlarged NT (> 3.00 mm) were identified, invasive testing was offered, even with a low-risk NIPT result.

Statistical analysis was completed in Stata SE Version 14.2. Hypotheses were conducted at a significance level of 0.05 with a two-sided alternative.

WHAT THE STUDY FOUND

Amniocentesis and chorionic villus sampling (CVS) were performed on 2657 patients, 51% of whom had prior NIPT, with 612 (45%) returning a high-risk result. The LTFU findings significantly altered the PPV of the NIPT result for trisomies 13, 18 and 21, monosomy X (MX) and rare autosomal trisomies (RATs), but not for the other sex chromosomal abnormalities or segmental imbalances (> 7 Mb). An abnormal LFTU increased the PPV close to 100% for trisomies 13, 18 and 21, MX and RATs. The magnitude of the PPV alteration was highest for the lethal chromosomal abnormalities. If the LTFU was normal, the incidence of confined placental mosaicism (CPM) was highest for those with an original high-risk T13 result, followed by T18, then T21. After a normal LFTU, the PPV for trisomies 21, 18, 13 and MX decreased to 68%, 57%, 5% and 25% respectively.

A more accurate PPV of a high-risk NIPT result after a late first-trimester scan may facilitate counselling regarding invasive testing and can be reassuring for those with normal late first-trimester ultrasound who opt to wait for amniocentesis to avoid a mosaic result on chorionic villus sampling.

STRENGTHS AND LIMITATIONS OF THE STUDY

The strengths of this study include its broad representation from multiple centres, the large population screened with NIPT, mostly as a first-line screening method, the large number undertaking Genome-wide NIPT, the use of microarray analysis in all cases, the quality of the ultrasound equipment and the sonographers in a specialised obstetric ultrasound service.

Weaknesses of the study include the older maternal age seen in a private ultrasound service, which may not be representative of the general obstetric population, the limited numbers of certain chromosomal abnormalities and the absence of ultrasound information from later gestations, as many confirmed genetic abnormalities resulted in termination of pregnancy. Most of the pregnancies had a pre-NIPT ultrasound, which could be considered as both a strength and a weakness of the study, as ideally an ultrasound should be performed before collecting blood for a NIPT but some cases with anomalies identified on the pretest ultrasound elected to bypass NIPT in favour of CVS, which could cause some inadvertent selection bias in the study.

RELEVANCE TO CLINICAL PRACTICE

Late first-trimester ultrasound in the setting of a high-risk NIPT result when performed by well trained sonographers provides valuable information altering the PPV for many chromosomal abnormalities. This information helps guide pregnancy management and prenatal diagnostic testing decisions.