Obstetrics & Gynecology:
Nuchal Translucency and the Risk of Congenital Heart Disease
Simpson, Lynn L. MD1; Malone, Fergal D. MD1; Bianchi, Diana W. MD2; Ball, Robert H. MD3; Nyberg, David A. MD4; Comstock, Christine H. MD5; Saade, George MD6; Eddleman, Keith MD7; Gross, Susan J. MD8; Dugoff, Lorraine MD9; Craigo, Sabrina D. MD2; Timor-Tritsch, Ilan E. MD10; Carr, Stephen R. MD11; Wolfe, Honor M. MD12; Tripp, Tara MA13; D'Alton, Mary E. MD1; for the First and Second Trimester Evaluation of Risk (FASTER) Research Consortium
From 1Columbia University Medical Center, New York, New York, 2Tufts University, Boston, Massachusetts, 3University of Utah, Salt Lake City, Utah, 4Swedish Medical Center, Seattle, Washington, 5William Beaumont Hospital, Royal Oak, Michigan, 6University of Texas Medical Branch, Galveston, Texas, 7Mount Sinai Medical Center, New York, New York, 8Albert Einstein College of Medicine, New York, New York, 9University of Colorado Health Sciences Center, Denver, Colorado, 10New York University, New York, New York, 11Brown University, Providence, Rhode Island, 12University of North Carolina Medical Center, Chapel Hill, North Carolina, and 13DM-STAT, Boston, Massachusetts
* For members of the FASTER Research Consortium, see the Appendix.
Funded by the National Institute of Child Health and Human Development, Supplemental Grant to Number RO1 HD 38652.
Presented at the 25th Annual Meeting of the Society for Maternal–Fetal Medicine, Reno, Nevada, February 7–12, 2005.
Corresponding author: Lynn L. Simpson, MD, Columbia University Medical Center, Department of Obstetrics and Gynecology, 622 West 168th Street, PH 16-66, New York, NY 10032; e-mail: firstname.lastname@example.org.
OBJECTIVE: To estimate whether nuchal translucency assessment is a useful screening tool for major congenital heart disease (CHD) in the absence of aneuploidy.
METHODS: Unselected patients with singleton pregnancies at 103/7 to 136/7 weeks of gestation were recruited at 15 U.S. centers to undergo nuchal translucency sonography. Screening characteristics of nuchal translucency in the detection of major CHD were determined using different cutoffs (2.0 or more multiples of the median [MoM], 2.5 or more MoM, 3.0 or more MoM).
RESULTS: A total of 34,266 euploid fetuses with cardiac outcome data were available for analysis. There were 224 cases of CHD (incidence 6.5 per 1,000), of which 52 (23.2%) were major (incidence 1.5 per 1,000). The incidence of major CHD increased with increasing nuchal translucency: 14.1 per 1,000, 33.5 per 1,000, and 49.5 per 1,000 at 2.0 or more MoM, 2.5 or more MoM, and 3.0 or more MoM cutoffs, respectively. Sensitivity, specificity, and positive predictive values were 15.4%, 98.4%, and 1.4% at 2.0 or more MoM; 13.5%, 99.4%, and 3.3% at 2.5 or more MoM; and 9.6%, 99.7%, and 5.0% at 3.0 or more MoM. Nuchal translucency of 2.5 or more MoM (99th percentile) had a likelihood ratio (95% confidence interval) of 22.5 (11.4–45.5) for major CHD. Based on our data, for every 100 patients referred for fetal echocardiography with a nuchal translucency of 99th percentile or more, three will have a major cardiac anomaly.
CONCLUSION: Nuchal translucency sonography in the first trimester lacks the characteristics of a good screening tool for major CHD in a large unselected population. However, nuchal translucency of 2.5 or more MoM (99th percentile or more) should be considered an indication for fetal echocardiography.
LEVEL OF EVIDENCE: II
Congenital heart disease (CHD) remains one of the most significant malformations to threaten the health of infants, particularly those born when the malformation has not been prenatally diagnosed. Currently, only 15–30% of newborns with structural heart anomalies are detected prenatally.1,2 There are different strategies to increase the prenatal detection of cardiac anomalies. Unfortunately, the most common approach of performing fetal echocardiography, based on pre-existing risk factors, has not performed as well as expected in routine clinical practice.1,3 Recent studies have found a relationship between increased nuchal translucency in the first trimester and CHD.4–6 It has been suggested that nuchal translucency screening may be a useful method to identify cardiac anomalies in chromosomally normal fetuses.4 The objective of this study was to estimate whether first-trimester nuchal translucency measurement is a useful screening tool for major CHD in a large unselected population in the absence of aneuploidy.
MATERIALS AND METHODS
This was an observational cohort study carried out at 15 clinical centers in the United States. Institutional review board approval was obtained at all sites, and all participants gave written informed consent. Patients were eligible for inclusion if they were aged 16 years or older and had a singleton live pregnancy, with a crown-rump length of 36–79 mm (10 weeks, 3 days, to 13 weeks, 6 days) obtained at the time of nuchal translucency screening. Cases of fetal aneuploidy were excluded from the analysis. Patients were enrolled from October 1999 to December 2002.
Nuchal translucency ultrasonography was performed according to a standardized protocol by specially trained ultrasonographers.7 Transvaginal ultrasonography was used if optimal views could not be obtained using a transabdominal approach. A formal sonographic quality assurance program was in place for the duration of the trial as described previously.7 Nuchal translucency was interpreted by using multiples of the median (MoM) values, and the mean of three separate measurements was used for risk calculation. Cases of septated cystic hygroma were followed and reported separately.8 Comprehensive ultrasonography with cardiac screening was recommended for all patients with first-trimester nuchal translucency measurements of 2.0 MoM or more.
Major CHD was defined as structural cardiac anomalies associated with poor perinatal outcome or those with the potential to be ductal-dependent after birth or both. These included heart defects with risk of significant neonatal morbidity and mortality or need for surgical correction in infancy, such as atrioventricular septal defects, hypoplastic left heart syndrome, coarctation of the aorta, Ebstein anomaly, hypoplastic right ventricle, tetralogy of Fallot, double outlet right ventricle, transposition of the great arteries, double inlet ventricle, truncus arteriosus, and severe valvular stenosis. Ductal-dependent lesions were included because their prenatal detection results in changes in postnatal management that may improve survival. Minor CHD was defined as defects expected to have favorable perinatal outcomes, such as atrial septal defects, small ventricular septal defects, and mild valvular stenosis. Patent foramen ovale and patent ductus arteriosus were not classified as CHD because these conditions cannot be diagnosed prenatally in that they are normally patent fetal structures.
Cases of CHD were obtained from pregnancy and pediatric outcome data. Trained research coordinators at each clinical site recorded patient information using case report forms from the patient's first-trimester screening visit through their pregnancy outcome. Completed case report forms were forwarded to the data coordinating center for central processing. Because there were several patient assessments to track throughout the pregnancy and assessment differed by patient characteristics, a computerized tracking system was developed to optimize protocol adherence and data quality. Specifically, the tracking system's reporting feature prompted the site research coordinator of upcoming patient assessments and had preprogrammed quality control checks, at both item and protocol level, to maximize not only quality but efficiency.
Copies of fetal and pediatric medical records, including pathologic examinations, were submitted for review by a single pediatric geneticist in all cases in which parents or the medical record suggested a possible fetal or neonatal medical problem, in all screen-positive cases without karyotype results, and in a 10% random sample of all other enrolled cases. Fetal chromosome status was determined by amniocentesis and from neonatal cord blood in screen-positive cases whose mothers declined amniocentesis, as well as in cases of spontaneous pregnancy loss, pregnancy termination, or stillbirth. All structural heart defects were identified, and each case was classified as major or minor based on above definitions and all available information. At the completion of the pregnancy and pediatric outcome data review, the study population was divided into three groups: major CHD, minor CHD, and no CHD.
Performance characteristics, including the sensitivity, specificity, and positive and negative predictive values, were estimated at different nuchal translucency cutoff values: 2.0 MoM or more, 2.5 MoM or more, and 3.0 MoM or more. Standard statistical methods were used to calculate means, standard deviations (SD), odds ratios (OR), 95% confidence intervals (CI), and P values. Univariable logistic regression analyses were used to compare major CHD with minor CHD and no CHD combined and to compare major and minor CHD combined with no CHD with regard to demographics and pregnancy outcomes. P<.05 was considered statistically significant.
There were 38,033 pregnancies enrolled and cardiac outcome data were available on 34,370 cases (90%). Aneuploidy was found in 104 of these cases, and these were excluded, leaving 34,266 for analysis. Completeness of ascertainment was assessed by calculating the expected number of CHD cases based on the number of women enrolled in the study and recently published birth prevalence data.2,9 This assessment suggested that 171–274 cases of CHD (5–8 per 1,000) should have been present in this study, and we identified 224 cases, suggesting that ascertainment was as expected. Of the 52 major heart defects, three (5.8%) were obtained through the random review of 10% of the medical records of FASTER participants. Demographic characteristics of this population are shown in Table 1. Infants born with major and minor CHD had lower birth weights, which may in part be due to the fact that these infants were born earlier than those without CHD.
Overall, there were 224 cases of CHD (incidence 6.5 per 1,000) with 52 major defects (incidence 1.5 per 1,000). Of the 52 major cardiac anomalies, 18 (35%) were detected prenatally and 34 (65%) were detected after birth. The incidence of major CHD increased with increasing nuchal translucency thickness (Table 2). Table 3 shows the sensitivity, specificity, and positive and negative predictive values of nuchal translucency measurements at different thresholds for the detections of major CHD. Sensitivities and positive predictive values were low at all nuchal translucency cutoffs, but the OR for major CHD increased from 10.9 at 2.0 MoM or more to 37.8 at 3.0 MoM or more. The screening performance of nuchal translucency remained low when minor heart defects were also included (Table 4). The nuchal translucency measurements corresponding to the 98th and 99th percentiles for each gestational age in the study population of 34,266 cases without aneuploidy are shown in Table 5. Overall, measurements at or above the 98th and 99th percentile thresholds had likelihood ratios for major CHD of 9.5 and 22.5, respectively. Based on these data, for every 100 patients referred for fetal echocardiography with a nuchal translucency of 2.5 MoM or more (99th percentile or more), three would be expected to have a major cardiac anomaly. The major and minor cardiac defects are shown in Table 6. Overall, 84.6% (44 of 52) cases of major CHD had nuchal translucency of less than 2.0 MoM, 86.5% (45 of 52) had nuchal translucency less than 2.5 MoM, and 90.4% (47 of 52) had nuchal translucency less than 3.0 MoM.
Pregnancy outcome data are shown in Table 7. Terminations, intrauterine fetal deaths, and neonatal deaths were highest in the major CHD group. In contrast, there were no intrauterine fetal deaths or neonatal deaths in those with minor CHD. Excluding pregnancy terminations, the proportion of live births was lowest in the major CHD group: 91% (41 of 45) compared with 100% (164 of 164) for those with minor CHD and 99.6% (33,634 of 33,754) for those without CHD (P<.001).
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). Cited Here...
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