By Ahizechukwu C. Eke, MD, MPH
Assistant Professor in Maternal Fetal Medicine, Division of Maternal Fetal Medicine, Department of Gynecology & Obstetrics, Johns Hopkins University School of Medicine, Baltimore
Dr. Eke has no relevant financial relationships with ineligible companies to disclose.
SYNOPSIS: In this retrospective cohort study of 1,901 pregnant women between 11 weeks and 13 weeks six days of gestation who had a nuchal translucency (NT) screening for fetal aneuploidies and demonstrated NT measurements > 95th percentile, 47% of fetuses (894/1,901) had an NT between the 95th and 99th percentile and 53% (1,007/1,901) had an NT ≥ the 99th percentile. In addition, of the 43% of fetuses (814/1,901) with at least one abnormality (structural or genetic), 34% (279/814) would have been missed in the first trimester if only cell-free deoxyribonucleic acid was used for prenatal genetic screening. First trimester NT screening still has a role in current day aneuploidy and early fetal anatomy screening.
SOURCE: Bardi F, Bosschieter P, Verheij J, et al. Is there still a role for nuchal translucency measurement in the changing paradigm of first trimester screening? Prenat Diagn 2020;40:197-205.
Fetal chromosomal and structural defects are a major cause of neonatal morbidity and mortality.1,2 The incidence of fetal aneuploidy has been demonstrated to increase with maternal age, with Down syndrome being the most common fetal aneuploidy.2 Although there are several fetal screening procedure technologies available, first trimester combined screening and cell-free fetal deoxyribonucleic acid (DNA) assays are the two most commonly used methods to screen for fetal aneuploidies and structural defects.2
A first-trimester combined screening, offered between 11 and 14 weeks of gestation, uses an ultrasound assessment of fetal nuchal translucency (NT) combined with maternal serum concentrations of beta human chorionic gonadotropin (β-hCG) and pregnancy-associated plasma protein-A (PAPP-A) measurements to determine the risk of fetal aneuploidies.2 Unlike cell-free fetal DNA assessment for fetal aneuploidies, fetal nuchal translucency, when combined with maternal age, is a universally acceptable first-trimester screening test for aneuploidies in both singleton and multiple pregnancies.2 Although there is not a strict cut-off for normal or abnormal nuchal translucency, the 95th and 99th percentiles for gestational age measurements commonly are used, with an NT in the 99th percentile having a greater risk of fetal aneuploidy compared to the 95th percentile.3 With the introduction and increasing use of cell-free fetal DNA testing, the utility of first-trimester combined screening has been increasingly questioned.4
In this retrospective cohort study from the Netherlands, Bardi and colleagues reported their findings in pregnant women between 11 weeks and 13 weeks six days of gestation who had an NT screening for fetal aneuploidies within the six-year period between January 2010 and January 2016.5 Women were eligible for inclusion if their NT measurement was greater than or equal to the 95th percentile at seven tertiary centers in the Netherlands: Erasmus Medical Center Rotterdam, Leiden University Medical Center, Maastricht University Medical Center, Radboud University Medical Center Nijmegen, University Medical Center Groningen, VU University Medical Center Amsterdam, and Academic Medical Center (AMC), University of Amsterdam. Chromosomal microarray (CMA) was offered to women with an NT ≥ 99th percentile (≥ 3.5 mm) and/or fetal structural abnormalities. All seven centers used a cut-off of 5 megabytes for CMA, except for one center using a cut-off of 0.15 megabytes. Pregnant women were excluded if they had NT measurements < 95th percentile. Descriptive analyses were performed to describe the study sample, specifically describing NT, maternal serum screening, and CMA characteristics. Categorical variables were reported as proportions, and continuous measures were reported as means. Differences between groups were assessed with Fisher’s exact tests and Chi-square test for categorical variables (where applicable), and Student’s t-tests for continuous variables.
In the six-year period, 23,494 NT measurements were evaluated. After excluding cases that did not meet inclusion criteria, 1,901 pregnancies with NT measurements ≥ 95th percentile were included for analysis. The median NT measurement was 3.6 mm (interquartile range [IQR]: 2.8-5.1 mm), while the mean maternal age at the time of NT measurement was 34 years (range, 18-48 years). Of all fetuses with an NT ≥ 95th percentile, 894 (47%) had an NT between the 95th and 99th percentile and 1,007 (53%) had an NT ≥ the 99th percentile.
A total of 814 (43%) pregnancies had at least one abnormality (structural or genetic), with 23.3% of these fetuses (n = 190) having an NT between the 95th and 99th percentile, and 76.7% of the fetuses (n = 624) having an NT ≥ 99th percentile. Of 636 fetuses (33.3%) with genetic abnormalities, 560 (29.4%) were chromosomal in nature, with trisomy 21, 18, and 13 observed in 272/560 (45.5%), 134/560 (22.4%), and 50/560 (8.4%) cases, respectively. Of the 178 (9.3%) fetuses with structural anomalies but normal chromosomal analyses, cardiac, urogenital, and central nervous system defects were the most common anomalies, and were detected in 74 (3.9%), 20 (1%), and 11 (0.6%) fetuses, respectively. Multiple congenital abnormalities were diagnosed in 29 fetuses (1.6%). Of the 814 congenital structural abnormalities, 34% would have remained undiagnosed in the first trimester if cell-free DNA testing had been offered as the only screening test. These include sex chromosome abnormalities (n = 81), triploidy (n = 7), single gene disorders (n = 38), submicroscopic aberrations < 5 Mb (n = 38), and structural abnormalities diagnosed in the first trimester (n = 115).
In many developed countries, prenatal genetic screening has become a standard of care in all pregnancies. The introduction and increasing use of genome-wide-based testing, such as cell-free fetal DNA screening, into obstetric practice has revolutionized the strategies used for prenatal testing, and has raised important questions about the continued use and utility of first-trimester NT assessment in aneuploidy screening.4 Although cell-free fetal DNA testing has better positive and negative predictive values in detecting common fetal trisomies such as 21, 18, and 13, as well as some sex chromosome aneuploidies, cell-free fetal DNA screening does not provide as much information on fetal structural anomalies that can be readily diagnosed in the first trimester using combined first-trimester ultrasound and serum screening, making first-trimester NT screening a relevant and essential component of prenatal genetic screening.4
This study by Bardi et al demonstrated that, although genome-wide-based cell-free fetal DNA tests aimed at accurate prenatal identification of fetal aneuploidies are superior to first-trimester NT screening, first-trimester NT screening has an advantage over cell-free DNA testing methods in the identification of common structural anomalies, especially cardiac, urogenital, and central nervous system structural anomalies in fetuses with normal chromosomal analyses.5 In addition, there is an association between an increased NT measurement and the risk of aneuploidies, with an NT detection rate of 75% with a 5% false-positive rate and a combined first-trimester screening (NT plus hCG and PAPP-A) detection rate of 95% and a 5% false-positive rate for Down syndrome, but a lower detection rate for either trisomy 18 or 13. More importantly, in addition to nuchal enlargement, the first-trimester ultrasound assessment can detect other anomalies, including central nervous system anomalies (anencephaly and ventriculomegaly), cardiac anomalies (common atrioventricular canal defect and hypoplastic left heart), and many other structural anomalies not detectable with cell-free fetal DNA testing.
In conclusion, despite the increasing use of cell-free DNA for prenatal genetic screening because of its high positive and negative predictive values in detecting common chromosomal aneuploidies, the combined first-trimester NT and maternal serum screening can detect very lethal structural anomalies not detectable by cell-free DNA. Therefore, it still is recommended in current day obstetric practice.
- Almli LM, Alter CC, Russell RB, et al. Association between infant mortality attributable to birth defects and payment source for delivery – United States, 2011-2013. MMWR Morb Mortal Wkly Rep 2017;66:84-87.
- Dey M, Sharma S, Aggarwal S. Prenatal screening methods for aneuploidies. N Am J Med Sci 2013;5:182-190.
- Nicolaides KH, Heath V, Cicero S. Increased fetal nuchal translucency at 11-14 weeks. Prenat Diagn 2002;22:308-315.
- Soceity for Maternal-Fetal Medicine; Norton ME, Biggio JR, et al. The role of ultrasound in women who undergo cell-free DNA screening. Am J Obstet Gynecol 2017;216:B2-B7.
- Bardi F, Bosschieter P, Verheij J, et al. Is there still a role for nuchal translucency measurement in the changing paradigm of first trimester screening? Prenat Diagn 2020;40:197-205.