Introduction
In the era of noninvasive prenatal testing (NIPT) with maternal plasma cell-free DNA, the combined first-trimester screening (CFTS) based on the nuchal translucency (NT) measurement and serum markers is waning in importance as a primary aneuploidy screening test, with many countries reporting NIPT uptake rates of 20% or higher.1,2 Despite the superior performance of NIPT for the detection of the common autosomal aneuploidies (trisomies 21, 18, and 13), professional societies still recommend the retention of the 11- to 13-week NT ultrasound. The International Society of Ultrasound in Obstetrics and Gynecology (ISUOG) recommends that a woman with a negative NIPT test result should still have fetal NT thickness measured and reported but without computing first-trimester risk estimates for trisomies 21, 18, and 13.3 However, no specific ISUOG guidance is given on the management of increased NT with a previous negative NIPT result; members are simply directed to “local guidelines.” Nevertheless, an NT of ≥3.5 mm is well accepted as a strong predictor of aneuploidy or other fetal abnormalities, and diagnostic testing with chromosomal microarray (CMA) is routinely offered in this situation, with an incremental yield of 4% to 7% over G-banded karyotype.4AJOG at a Glance
The nuchal translucency (NT) measurement continues to have importance in the era of noninvasive prenatal testing (NIPT) and chromosomal microarrays (CMAs) for the detection of atypical chromosome abnormalities. The use of a fixed measurement of 3.0 mm to define an enlarged NT rather than a gestational age–adjusted metric is poorly substantiated in the literature. We used a large population-based cohort of women undergoing first-trimester screening to determine the optimal definition of an enlarged NT for detecting atypical chromosome abnormalities.
A gestational age–adjusted NT threshold of 1.9 multiple of the median (MoM) is superior to a threshold of 3.0 mm for the detection of atypical chromosome abnormalities, providing a similar sensitivity rate for 31% fewer “screen positives.” In the era of NIPT and CMAs, NT of >1.9 MoM or NT at the >99th centile seems to be a reasonable NT threshold at which to offer diagnostic testing (1 in 270 risk of an atypical chromosome abnormality). The risk of an atypical chromosome abnormality in a fetus with an enlarged NT was 11% in the presence of a coexisting fetal abnormality compared with 3% for fetuses with isolated enlarged NT.
We examined the diagnostic yield of various NT thresholds using high quality data from a large population-based cohort, overcoming the limitations of the previous studies such as ascertainment bias, small sample size, and low microarray utilization rates. We showed that a gestation-specific NT threshold such as 1.9 MoM or 99th centile is superior to a fixed 3.0 mm millimeter cutoff for offering microarray testing for atypical chromosome abnormalities. The positive predictive value (PPV) of an enlarged NT for any atypical chromosome abnormality is 1 in 32 for an NT of ≥1.9 MoM compared with 1 in 47 for an NT of ≥3.0 mm. The PPV rises to 1 in 9 in the presence of a fetal structural abnormality. A detailed first-trimester ultrasound including NT measurement continues to have importance in the NIPT era.
In the current era of NIPT and CMA, there is little contemporary evidence to define the optimal NT cutoff to recommend invasive prenatal diagnosis. Some recent reports have suggested that the NT threshold should be lowered from a fixed cutoff of 3.5 mm to 3.0 mm.5, 6, 7, 8 The American College of Obstetricians and Gynecologists and the Society for Maternal-Fetal Medicine (SMFM) recently recommended offering genetic counseling and diagnostic testing for enlarged NT at ≥3.0 mm or above the 99th centile.9 Others have argued that pathogenic copy number variants (CNVs) are rare in fetuses with an NT of <3.5 mm in the absence of additional structural abnormalities10,11 and not more frequent than the 1 in 250 to 270 risk estimated for fetuses without structural abnormalities.12,13 Most of the published literature are limited by small sample sizes, selective use of CMA, exclusion of pregnancies that did not undergo prenatal diagnosis, and single-center design. Furthermore, the existing data are limited to prenatal diagnosis cohorts and have not included postnatal samples from live infants, miscarriages, or stillbirths.
Another question that has not been examined in the CMA era is whether NT metrics that account for gestation are superior to fixed millimeter cutoffs for defining an enlarged NT. Previous studies investigating the use of multiples of the median (MoMs) and centile cutoffs14,15 did not find a difference in diagnostic yield compared with millimeter cutoffs, but these studies predated the use of CMA so the benefit for the detection of a full range of atypical abnormalities, including submicroscopic CNVs, is unknown.
Given the limitations of existing literature, we performed a population-based study timed during a period of high uptake of CFTS and CMA in our state. We performed individual record linkage of women undergoing CFTS and prenatal or postnatal diagnosis to calculate the rate of typical and atypical chromosome abnormalities by NT millimeter and MoM categories. In doing so, we aimed to derive an optimal definition of an enlarged NT for the detection of atypical chromosome abnormalities.