Isolated Increased Nuchal Translucency in First Trimester Ultrasound Scan: Diagnostic Yield of Prenatal Microarray and Outcome of Pregnancy

Abstract

Background: Increased nuchal translucency (NT) is associated with aneuploidy. When the karyotype is normal, fetuses are still at risk for structural anomalies and genetic syndromes. Our study researched the diagnostic yield of prenatal microarray in a cohort of fetuses with isolated increased NT (defined as NT ≥ 3.5 mm) and questioned whether prenatal microarray is a useful tool in determining the adverse outcomes of the pregnancy.Materials and Methods: A prospective study was performed, in which 166 women, pregnant with a fetus with isolated increased NT (ranging from 3.5 to 14.3 mm with a mean of 5.4 mm) were offered karyotyping and subsequent prenatal microarray when karyotype was normal. Additionally, all ongoing pregnancies of fetuses with normal karyotype were followed up with regard to postnatal outcome. The follow-up time after birth was maximally 4 years.Results: Totally, 149 of 166 women opted for prenatal testing. Seventy-seven fetuses showed normal karyotype (52%). Totally, 73 of 77 fetuses with normal karyotype did not show additional anomalies on an early first trimester ultrasound. Totally, 40 of 73 fetuses received prenatal microarray of whom 3 fetuses had an abnormal microarray result: two pathogenic findings (2/40) and one incidental carrier finding. In 73 fetuses with an isolated increased NT, 21 pregnancies showed abnormal postnatal outcome (21/73, 28.8%), 29 had a normal outcome (29/73, 40%), and 23 were lost to follow-up (23/73, 31.5%). Seven out of 73 live-born children showed an adverse outcome (9.6%).Conclusions: Prenatal microarray in fetuses with isolated increased NT had a 5% (2/40) increased diagnostic yield compared to conventional karyotyping. Even with a normal microarray, fetuses with an isolated increased NT had a 28.8% risk of either pregnancy loss or an affected child.

Application of chromosome microarray analysis and karyotyping in diagnostic assessment of abnormal Down syndrome screening results

“…The positive rate was lower than previous reports because the NT cut-off for invasive testing in our department is 2.5 mm vs. 3.0-3.5 mm in most previous studies. Consist with these studies, aneuploidy and gross deletion/duplication accounted for more than 80% chromosomal abnormalities (NT cut-off 2.5 ~ 3.0 mm: 80% ~ 90%, NT cut-off 3.5 mm: > 90%) [16][17][18][19][20][21]. CMA could detect 1.9% more CNVs than karyotyping in serum screening group, which is consistent with previous reports [22,23].…”

“…The American College of Obstetrics and Gynecology (ACOG) and the American Maternal-Fetal Medicine Association's 2016 guidelines clearly suggest CMA as a first-line prenatal diagnostic method in pregnant women with ultrasounds structural abnormalities [12,28]. However, only a few reports had mentioned the effectiveness of CMA in pregnant women with DS screening abnormities [17][18][19][20][21][22]. In this study, CMA idenitified 1.9% more P/LP CNVs which is the first cause of congenital abnormities than karyotyping.…”

Fetal left ventricular myocardial performance index measured at 11–14 weeks of gestation in fetuses with an increased nuchal translucency

“…Also, the frequency of adverse pregnancy outcomes is closely connected with the increase in NT severity and the existence of additional anomalies on first-or second-trimester US examination. 5,6 Evidence indicates that nuchal fluid collection from first-trimester fetuses might show heart defects, lymphatic system disorders, and abnormalities regarding the levels of extracellular matrix components of the nuchal skin. 7 The close connection of the unchallenged skin with abnormal ductus venosus blood flow and consequently with impaired atrial contraction of the fetal heart suggests that cardiac dysfunction rather than cardiac structural defects is an important cause of an increase in NT.…”

“…Fetuses with increased NT thickness with normal karyotypes are still at risk for genetic syndromes and structural abnormalities. Also, the frequency of adverse pregnancy outcomes is closely connected with the increase in NT severity and the existence of additional anomalies on first‐ or second‐trimester US examination 5,6 . Evidence indicates that nuchal fluid collection from first‐trimester fetuses might show heart defects, lymphatic system disorders, and abnormalities regarding the levels of extracellular matrix components of the nuchal skin 7 .…”

Prenatal whole‐exome sequencing in fetuses with increased nuchal translucency

“…Identification of the etiology of increased NT is essential to assist in genetic counseling, inform prognosis, establish recurrence risk, and direct clinical care. Chromosomal abnormalities can be identified in approximately 30% of increased NT by combining karyotype and CMA (Bardi et al, 2020; Bilardo et al, 2007; Stuurman et al, 2021). However, fetuses with negative results on karyotype analysis and CMA are still at high risk for adverse pregnancy outcomes, which indicates some as‐yet‐undiscovered underlying causes (Bilardo et al, 2007; Ghi et al, 2001).…”