Nuchal translucency assessment combined with maternal serum markers is an excellent screening tool for fetal Down syndrome in the general population, with detection rates as high as 87% at a 5% false-positive rate.7,10,11 Studies from Europe have suggested that nuchal translucency may also be a good screening test for major CHD, with one reporting a sensitivity of over 50%.4,5,12 This detection rate exceeds that expected from second-trimester cardiac screening in low-risk populations.13 If reproducible, universal first-trimester nuchal translucency assessment could surpass the traditional four-chamber view for routine CHD screening.
Our data confirm that first-trimester nuchal translucency measurement is associated with major CHD and that the risk increases with increasing nuchal translucency thickness. However, first-trimester nuchal translucency assessment does not perform well as a screening test for major CHD. In our large study of unselected patients, nuchal translucency measurement had a sensitivity of only 9.6% for major CHD and positive predictive value of 5.0% using a cutoff of 3.0 MoM or more, with only marginal improvement when lowering the threshold to 2.0 MoM or more. The landmark study by Hyett and colleagues4 reported that nuchal translucency measurement at the 99th percentile or greater had a sensitivity of 40% for the detection of major CHD. Subsequent studies have been unable to replicate these results, including our own (Table 8).4–6,12 Explanations for the promising findings of Hyett's initial study include its retrospective nature, high-risk population with a median maternal age of 34, inclusion of cystic hygromas, and the lack of extended follow-up.4 In our study, the mean maternal age was 30, septated cystic hygromas were excluded and reported separately, and most of the follow-up data on live births were obtained at 6–12 months of age. The exclusion of septated cystic hygromas may explain in part the smaller nuchal translucency measurements observed in our study and the lower screening performance of nuchal translucency for major CHD. However, in clinical practice, it is anticipated that cases of septated cystic hygroma will be evaluated and managed differently because the risks of aneuploidy and associated anomalies are considerably higher.8 The smaller nuchal translucency measurements may also reflect the large unselected population participating in this study in contrast to referral populations reported in earlier studies that are expected to be at increased risk.4,14 Over the past few years with extension of such screening to low-risk populations, the reported sensitivities of nuchal translucency for major CHD detection have steadily declined, with the lowest detection rate observed in our study.5,6 Based on low sensitivities and positive predictive values with correspondingly high false-positive rates, our findings suggest nuchal translucency measurement is not a good screening tool for major CHD in the general population.
Despite its poor performance for widespread detection of CHD, nuchal translucency assessment in the first trimester is likely to become universal in the United States for aneuploidy screening. Currently, standard recommendations for evaluating cases of enlarged nuchal translucency in which aneuploidy has been excluded are lacking. A meta-analysis of eight studies comprising primarily high-risk referral populations reported that 37% of CHD could be diagnosed by using a nuchal translucency threshold of the 95th percentile.14 However, at this threshold, 5% of the population would require fetal echocardiography, which would necessitate a substantial increase in dedicated resources. In our study of primarily low-risk patients, nuchal translucency measurement cutoffs of 2.0 MoM or more, 2.5 MoM or more, and 3.0 MoM or more detected approximately 15%, 14%, and 10% of major CHD, which supports the concept that increased nuchal translucency is a risk factor for heart anomalies even in the absence of aneuploidy. Nuchal translucency at or above the 99th percentile for gestational age increased the likelihood of major CHD by a factor of 22.5. At this cutoff, 1% of the general population would require a specialized cardiac evaluation to detect nearly 15% of major heart anomalies. This approach may be reasonable based on the screening performance of nuchal translucency and currently available resources for fetal echocardiography. Overall, screening based on traditional risk factors for CHD, such as maternal diabetes, family history, and teratogen exposure, results in only about 10% of heart anomalies being diagnosed prenatally.1 Given that nuchal translucency screening alone performed as well as these accepted indications for fetal echocardiography, specialized cardiac assessment should be recommended as part of the standard evaluation for all ongoing pregnancies with nuchal translucency of 2.5 MoM or more (99th percentile), and increased nuchal translucency should be added to the list of accepted indications for fetal echocardiography.
Early studies observed a strong association between left-sided obstructive lesions such as coarctation, severe aortic stenosis, and hypoplastic left heart syndrome and enlarged nuchal translucency.4,15,16 Coarctation was the most common major defect observed in our unselected population, but all cases had unremarkable nuchal translucency thickness. Recent studies have failed to identify obvious relationships between enlarged nuchal translucency and particular types of cardiac anomaly.17,18 A pooled analysis of major fetal echocardiography centers also found that increased nuchal translucency was not confined to specific types of major CHD.19 Although nuchal translucency of 2.0 MoM or more was observed in 4 of 5 (80%) cases of hypoplastic left heart syndrome, the number of defects in each category were small, and no firm conclusions can be made about the specific spectrum of CHD associated with increased nuchal translucency in the current study.
The prenatal detection of major cardiac malformations has the potential to influence pregnancy management and impact pregnancy outcomes. Although there is no accepted definition of major CHD, most studies include defects that are lethal, require surgical correction in infancy, or are ductal-dependent at birth.5,6,9 Ductal-dependent lesions require maintenance of fetal vascular communications for adequate oxygenation postnatally and, therefore, are quite likely to benefit from prenatal diagnosis.20–22 Minor defects, such as atrial septal defects, small ventricular defects, and mild valvular stenoses, are expected to have favorable perinatal outcomes and are not commonly detected prenatally. The lack of any fetal or neonatal deaths in the ongoing pregnancies with minor CHD, along with 99.6% live births compared with only 91% live births with major CHD (after excluding terminations), support our classification of major and minor defects. Overall, slightly less than 25% of all cardiac anomalies were categorized as major, which is less than the commonly cited 30–50%.9,13 The most likely explanation for this difference is the classification of ventricular septal defects as major CHD in previously published studies.4,14 Ventricular septal defect was the most common heart anomaly observed in our population, but all had favorable outcomes and thus were classified as minor CHD. In our study, about 14% of major defects had enlarged nuchal translucency using the 99th percentile cutoff, which is also considerably lower than that reported in earlier studies and below the expected detection rate of cardiac screening in the second trimester.13 In a prospective observational study, increased nuchal translucency identified only 26.5% of major CHD compared with a 75% overall detection rate of CHD using the four-chamber view and outflow tracts.23 Abnormal views of the fetal heart during second-trimester sonographic evaluation of the fetus have become the most common indication for fetal echocardiography, yielding more cases of CHD that all other traditional risk factors combined.24,25 Based on our findings, first-trimester nuchal translucency assessment will miss about 85% of major CHD and, therefore, cannot replace screening with the four-chamber and ventricular outflow tract views later in pregnancy.
One potential limitation of our study is incomplete ascertainment. Despite a rigorous study design and review of all medical records of cases in which the parents, medical record, or outcome data suggested a possible fetal or neonatal problem, three of the 52 (5.8%) major heart defects were identified through a random review of 10% of the medical records of the remaining study participants. However, the finding of a small number of major cardiac anomalies in this group with no other abnormal indicators further supports our conclusion that nuchal translucency is not a good screening test for major CHD.
This is a large cohort study of nuchal translucency as a screening tool for CHD and is notable for being performed in an unselected population. Although nuchal translucency assessment lacks the characteristics of a good screening tool for major CHD, a nuchal translucency measurement of 2.5 MoM or more (99th percentile) in a fetus without aneuploidy is a marker for CHD and warrants referral for fetal echocardiography. Ultimately, nuchal translucency sonography is a complementary tool for screening for congenital heart defects and should contribute to an increase in prenatal diagnosis of these common malformations.
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The authors thank the members of the FASTER Research Consortium: K. Welch, MS, R. Denchy, MS (Columbia University, New York, NY); F. Porter, MD, M. Belfort, MD, B. Oshiro, MD, L. Cannon, BS, K. Nelson, BSN, C. Loucks, RNC, A. Yoshimura (University of Utah, and IHC Perinatal Centers, Salt Lake City, Provo, and Ogden, UT); D. Luthy, MD, S. Coe, MS (Swedish Medical Center, Seattle, WA); J. Esler, BS (William Beaumont Medical Center, Royal Oak, MI); G. Hankins, MD, R. Bukowski, MD, J. Lee MS, (UTMB Galveston, TX); R. Berkowitz, MD, Y. Kharbutli MS (Mount Sinai Medical Center, New York, NY); I. Merkatz, MD, S. Carter, MS (Montefiore Medical Center, Bronx, NY); J. Hobbins, MD, L. Schultz, RN (University of Colorado Health Science Center, Denver, CO); M. Paidas, MD, J. Borsuk, MS (NYU Medical Center, New York, NY); B. Isquith, MS, B. Berlin, MS (Tufts University, Boston, MA); J. Canick, PhD, G. Messerlian, PhD, C. Duquette, RDMS (Brown University, Providence, RI); R. Baughman, MS (University of North Carolina, Chapel Hill, NC); J. Hanson, MD, F. de la Cruz, MD (National Institute of Child Health and Human Development); and K. Dukes, PhD, L. Sullivan, PhD, D. Emig, MPH, J. Vidaver, MA, Jamie Collins (DM-STAT Inc, Medford, MA).