Abstract
Objectives
To examine the utility of measuring fetal nuchal translucency thickness in screening for major defects of the heart and great arteries at 10-14 weeks of gestation.
Design
Population based cohort study.
Subjects
29 154 singleton pregnancies with chromosomally normal fetuses at 10-14 weeks of gestation.
Setting
Fetal medicine centre in London.
Main outcome measure
Prevalence of major defects of the heart and great arteries.
Results
Of 50 cases with major defects of the heart and great arteries (prevalence 1.7 per 1000 pregnancies) 28 (56%, 95% confidence interval 42% to 70%) were in the subgroup of 1822 pregnancies with fetal nuchal translucency thicknesses above the 95th centile of the normal range. The positive and negative predictive values for this cut off point of nuchal translucency thickness were 1.5% and 99.9% respectively.
Conclusions
Measurement of fetal nuchal translucency thickness—traditionally used to identify fetuses at high risk of aneuploidy—at 10-14 weeks of gestation can identify a large proportion of fetuses with major defects of the heart and great arteries.
Key messages
The majority of congenital abnormalities of the heart and great arteries are associated with subcutaneous oedema in the neck region at 10-14 weeks of gestation
Subcutaneous oedema in the neck region can be visualised by ultrasonography as increased nuchal translucency thickness
The prevalence of major defects of the heart and great arteries increases with increasing fetal nuchal translucency thickness at 10-14 weeks of gestation
Measurement of fetal nuchal translucency thickness at 10-14 weeks of gestation is a sensitive method of screening for major defects of the heart and great arteries
Introduction
Cardiac defects are the most common congenital abnormalities. The prevalence is 3-8 per 1000 pregnancies.1,2 In the United Kingdom, studies on screening women with low risk pregnancies by ultrasonography showed a prevalence of congenital abnormalities of 1.3-3.2 per 1000 pregnancies.3,4 About half of these defects are asymptomatic, and the other half are classed as major because they are either lethal or require surgery. Specialist fetal echocardiography at around 20 weeks of gestation can identify most of the major cardiac defects,5,6 but the main challenge in prenatal diagnosis is to identify those pregnancies at high risk that need referral to specialist centres. Currently, screening is based on examination of the four chamber view of the heart during routine ultrasonography at 16-22 weeks of gestation, but a recent study of 7459 pregnancies showed that an abnormal four chamber view can identify only 26% of major cardiac defects.7
A more sensitive method of screening may potentially be the ultrasonographic measurement of fetal nuchal translucency thickness at 10-14 weeks of gestation.8 Extensive studies have recently shown a strong association between cardiac defects and increased nuchal translucency thickness, which is thought to be the result of subcutaneous oedema in the nuchal region.9–11 In four studies reporting on a total of 21 fetuses with major cardiac defects diagnosed at 10-14 weeks of gestation, 17 (81%) had increased nuchal translucency thickness.12–15 In addition, pathological studies of both chromosomally abnormal and normal fetuses with increased nuchal translucency thickness have shown a high prevalence of abnormalities of the heart and great arteries.16,17 Furthermore, a study of 1389 chromosomally normal fetuses with increased nuchal translucency thickness reported that the prevalence of major cardiac defects increased exponentially with nuchal translucency thickness.18
Our study of 29 154 singleton pregnancies, presumed to be chromosomally normal, examined the utility of measuring fetal nuchal translucency thickness at 10-14 weeks of gestation as a method of screening for major abnormalities of the heart and great arteries.
Subjects and methods
We undertook a retrospective study to examine the prevalence of major cardiac defects in a population of 31 162 singleton pregnancies. The pregnancies were screened for chromosomal abnormalities by a combination of maternal age and fetal nuchal translucency thickness at 10-14 weeks of gestation.
The fetal crown-rump length and nuchal translucency thickness (fig 1) were measured as previously described by transabdominal ultrasonography, unless visualisation was poor in which case vaginal ultrasonography was carried out.8 Demographic details and ultrasound findings including number of fetuses, crown-rump length, and nuchal translucency thickness were entered into a computer database at the time of scanning. Karyotype results and details on pregnancy outcome were added as soon as these became available. Pregnancy outcome was obtained from maternity units, general practitioners, or the patients; the patients were given a questionnaire at the time of the initial scan. If no outcome data were received within two months of the expected date of delivery, we contacted the patients by telephone.
Figure 1.
Ultrasonogram of 11 week old fetus showing measurement of crown-rump length and fetal nuchal translucency thickness
A computer search identified all singleton pregnancies with live fetuses at 10-14 weeks of gestation with a crown-rump length of 38-84 mm and an estimated date of delivery before 1 June 1997. The database was then searched for major abnormalities of the heart and great arteries, diagnosed before or after birth, in the group with a normal fetal karyotype or the birth of a baby with no dysmorphic features suggestive of a chromosomal abnormality.
The prevalence of major cardiac defects was determined and the utility of screening for nuchal translucency thickness including sensitivity, specificity, and positive and negative predictive values were calculated for the nuchal translucency thickness cut off points of the 95th and 99th centiles for crown-rump length. Nuchal translucency thickness normally increases with crown-rump length, and the 95th centile is 2.2 mm for a crown-rump length of 38 mm and 2.8 mm for a crown-rump length of 84 mm; the 99th centile does not change significantly with crown-rump length and is about 3.5 mm.9
Results
Our study group comprised 31 162 pregnancies. We excluded from further analysis 323 pregnancies with chromosomal abnormalities, 317 pregnancies with spontaneous miscarriages, and 1368 pregnancies where the women had changed address and despite repeated attempts through their general practitioners and maternity hospitals, it was impossible to obtain information on pregnancy outcome. In the remaining 29 154 pregnancies the median gestation at the time of screening was 12 weeks (range 10-14 weeks) and the median maternal age was 34 years (range 15-48 years). The fetal nuchal translucency thickness was above the 95th centile for crown-rump length in 1822 (6.3%) pregnancies and above the 99th centile in 315 (1.1%) pregnancies.
Major defects of the heart and great arteries were identified in 50 of the pregnancies. These included 18 pregnancies that were diagnosed antenatally by ultrasonography at 16-31 weeks of gestation (table 1), 13 that were diagnosed at pathological examination after intrauterine death or termination of pregnancy for conditions other than cardiac defects (table 2), and 19 that were diagnosed in live births (table 3).
Table 1.
Major defects of heart and great arteries that were diagnosed antenatally
| Case | Nuchal translucency thickness (mm) | Diagnosis (weeks) | Outcome | Major abnormality of heart and great arteries |
|---|---|---|---|---|
| 1 | 1.0 | 18 | Termination | Ventricular septal defect, presented with congenital heart block |
| 2 | 1.2 | 31 | Termination | Ebstein’s anomaly with pulmonary stenosis |
| 3 | 4.0* | 12 | Termination | Exocardia |
| 4 | 1.8 | 20 | Termination | Tetralogy of Fallot |
| 5 | 2.1 | 20 | Termination | Hypoplastic left heart with double outlet right ventricle, asymmetrical pulmonary valve |
| 6 | 2.3† | 20 | Termination | Atrioventricular septal defect |
| 7 | 2.7† | 16 | Termination | Hypoplastic left heart syndrome |
| 8 | 3.5* | 19 | Termination | Tetralogy of Fallot |
| 9 | 4.0* | 18 | Termination | Mitral atresia, ventricular septal defect, double outlet right ventricle |
| 10 | 3.6* | 21 | Termination | Hypoplastic left heart syndrome |
| 11 | 5.0* | 24 | Termination | Hypoplastic right ventricle, atresia of tricuspid valve, ventricular septal defect, hypoplastic ductus arteriosus, right subclavian arterial ring |
| 12 | 5.5* | 18 | Termination | Aortic atresia and atrioventricular septal defect to dominant right ventricle |
| 13 | 1.8 | 25 | Postnatal death‡ | Atrioventricular septal defect |
| 14 | 2.2 | 30 | Postnatal death‡ | Ventricular septal defect requiring surgery |
| 15 | 2.7† | 20 | Live birth | Ventricular septal defect requiring surgery |
| 16 | 2.8† | 20 | Live birth | Coarctation of the aorta, ventricular septal defect; arch repaired surgically |
| 17 | 4.5* | 18 | Live birth | Transposition of great arteries |
| 18 | 4.0* | 21 | Live birth | Transposition of great arteries, pulmonary stenosis, dextrocardia |
Thickness greater than 99th centile for gestational age. †Thickness greater than 95th centile for gestational age.
Death occurred after surgery for cardiac abnormality.
Table 2.
Major defects of heart and great arteries diagnosed at postmortem examination after termination of pregnancy for extracardiac defects or intrauterine death
| Case | Nuchal translucency thickness (mm) | Outcome | Pathological findings |
|---|---|---|---|
| 19 | 3.0* | Termination at 13 weeks for limb abnormalities | Coarctation of the aorta, ventricular septal defect, bicuspid aortic valve |
| 20 | 4.7† | Termination at 23 weeks for Smith Lemli Opitz syndrome | Hypoplastic right ventricle |
| 21 | 9.0† | Termination at 13 weeks for exomphalos | Hypoplastic pulmonary trunk |
| 22 | 14.0† | Termination at 15 weeks for hydrops | Interrupted aortic arch, ventricular septal defect |
| 23 | 1.7 | Intrauterine death at 37 weeks | Premature closure of foramen ovale with associated left heart hypoplasia |
| 24 | 1.7 | Intrauterine death at 20 weeks | Univentricular heart, absent tricuspid valve, pulmonary trunk arising from right atrium |
| 25 | 1.9 | Intrauterine death at 28 weeks | Truncus arteriosus |
| 26 | 4.9† | Intrauterine death at 13 weeks | Coarctation of aorta |
| 27 | 6.0† | Intrauterine death at 13 weeks | Coarctation of aorta, perimembranous ventricular septal defect |
| 28 | 8.0† | Intrauterine death at 13 weeks | Narrow ascending aorta and aortic isthmus, imperforate aortic valve, dilated pulmonary trunk, ductus arteriosus |
| 29 | 8.2† | Intrauterine death at 14 weeks | Coarctation of aorta, ventricular septal defect |
| 30 | 9.4† | Intrauterine death at 16 weeks | Coarctation of aorta |
| 31 | 11.0† | Intrauterine death at 15 weeks | Coarctation of aorta |
Thickness greater than 95th centile for gestational age. †Thickness greater than 99th centile for gestational age.
Table 3.
Major defects of heart and great arteries diagnosed postnatally
| Case | Nuchal translucency thickness (mm) | Major abnormality of heart and great vessels |
|---|---|---|
| 32 | 1.0 | Tetralogy of Fallot |
| 33 | 1.5 | Large ventricular septal defect |
| 34 | 1.5 | Total anomalous pulmonary drainage |
| 35 | 1.6 | Tetralogy of Fallot |
| 36 | 1.7 | Tetralogy of Fallot |
| 37 | 1.7 | Transposition of great arteries |
| 38 | 1.8 | Transposition of great arteries, ventricular septal defect |
| 39 | 1.9 | Tetralogy of Fallot |
| 40 | 1.9 | Transposition of great arteries |
| 41 | 2.0 | Transposition of great arteries, ventricular septal defect |
| 42 | 2.2 | Tetralogy of Fallot |
| 43 | 2.2 | Tetralogy of Fallot |
| 44 | 2.3 | Ebstein’s anomaly |
| 45 | 2.3* | Transposition of great arteries |
| 46 | 3.0* | Large ventricular and atrial septal defect |
| 47 | 3.0* | Ventricular septal defect, double outlet right ventricle, pulmonary stenosis |
| 48 | 3.5† | Tetralogy of Fallot |
| 49 | 3.8† | Large ventricular septal defect |
| 50 | 4.5† | Transposition of great arteries |
Thickness greater than 95th centile for gestational age.
Thickness greater than 99th centile for gestational age.
The prevalence of major cardiac defects was 1.7 per 1000 pregnancies (50/29 154), which increased with nuchal translucency thickness from 0.8 per 1000 for those pregnancies with nuchal translucency thickness below the 95th centile to 63.5 per 1000 for those pregnancies with nuchal translucency thickness above the 99th centile (table 4). There were essentially six groups of cardiac defects; tetralogy of Fallot, hypoplastic left heart, transposition of the great arteries, coarctation of the aorta and aortic stenosis or atresia, ventricular and atrioventricular septal defects, and a sixth group of other complex defects (table 5). Table 6 shows the sensitivity, specificity, and positive and negative predictive values of nuchal translucency thickness cut off points of the 95th and 99th centiles in the detection of major cardiac defects, and figure 2 shows a receiver-operator characteristic curve.
Table 4.
Prevalence of major defects of heart and great arteries in fetuses that were chromosomally normal
| Nuchal translucency thickness | No of fetuses | No of major cardiac defects | Prevalence per 1000 fetuses |
|---|---|---|---|
| <95th centile | 27 332 | 22 | 0.8 |
| ⩾95th centile-3.4 mm | 1 507 | 8 | 5.3 |
| 3.5-4.4 mm | 208 | 6 | 28.9 |
| 4.5-5.4 mm | 66 | 6 | 90.9 |
| ⩾5.5 mm | 41 | 8 | 195.1 |
| Total | 29 154 | 50 | 1.7 |
Table 5.
Detection of specific cardiac defects using increased fetal nuchal translucency thickness
| Cardiac defect | No (%) of fetuses | Nuchal translucency
|
|
|---|---|---|---|
| No (%) >95th centile | No (%) >99th centile | ||
| Tetralogy of Fallot | 9 (18) | 2 (22) | 2 (22) |
| Hypoplastic left heart | 3 (6) | 2 (67) | 1 (33) |
| Transposition of great arteries | 8 (16) | 4 (50) | 3 (38) |
| Coarctation of aorta, aortic stenosis, or atresia | 10 (20) | 10 (100) | 8 (80) |
| Ventricular and atrioventricular septal defects | 8 (16) | 4 (50) | 1 (13) |
| Other defects | 12 (24) | 6 (50) | 5 (42) |
| Total | 50 (100) | 28 (56) | 20 (40) |
Table 6.
Sensitivity and specificity of screening for major defects of heart and great arteries using fetal nuchal translucency thickness. Values are percentages (95% confidence intervals)
| Using 95th centile | Using 99th centile | |
|---|---|---|
| Sensitivity | 56.0 (42.0 to 70.0) | 40.0 (26.0 to 54.0) |
| Specificity | 93.8 (93.6 to 94.1) | 99.0 (98.9 to 99.1) |
| Positive predictive value | 1.5 (1.0 to 2.1) | 6.3 (3.7 to 9.0) |
| Negative predictive value | 99.9 (99.8 to 100.0) | 99.9 (99.8 to 100.0) |
Figure 2.
Receiver-operator characteristic curve showing detection rate for major cardiac defects at various false positive rates with increased nuchal translucency thickness
Discussion
Our study shows that 55% of major abnormalities of the heart and great arteries are associated with increased fetal nuchal translucency thickness at 10-14 weeks of gestation. This method of screening compares favourably with the reported sensitivity of 26% using the four chamber view of the heart at 16-22 weeks of gestation. The clinical implication of our findings is that increased nuchal translucency thickness constitutes an indication for specialist fetal echocardiography. Certainly the overall prevalence of major cardiac defects in such a group of fetuses (about 2%) is similar to that found in pregnancies affected by maternal diabetes mellitus or with a history of a previously affected offspring, which are well accepted indications for fetal echocardiography.19,20
At present there may be insufficient facilities for specialist fetal echocardiography to accommodate the potential increase in demand if the 95th centile of nuchal translucency thickness is used as the cut off point for referral. In contrast, a cut off point of the 99th centile would result in only a small increase in workload, and in this population the prevalence of major cardiac defects would be very high.
The consequence of combining data from terminations of pregnancy and intrauterine deaths with data from live births would be an overestimate of the true prevalence of cardiac defects in live births from a non-selected population; a proportion of cardiac defects diagnosed antenatally would have resulted in intrauterine death. However, the opportunity to determine such prevalence in “undisturbed” populations was lost in the early 1970s with the advent of prenatal diagnosis. In any case, as shown in the group of patients where the parents chose to continue with the pregnancy after the prenatal diagnosis of major cardiac defects, although the defect obviously persists throughout pregnancy, increased nuchal translucency thickness observed at 10-14 weeks of gestation often resolves by the second trimester and the babies are born alive. Similarly, information on intrauterine deaths is important both for offering a possible explanation for the death and in defining the risk of recurrence. This risk rises from 2% to 10% if there are two rather than one previously affected offspring, and the recurrence is frequently of the same severity or greater severity as the index case.20
The prevalence of major cardiac defects in our population (1.8 per 1000 pregnancies) of presumed chromosomally normal fetuses is compatible with the previously reported prevalence for all cardiac defects in live births (3-8 per 1000 pregnancies); the higher prevalence was reported in studies using echocardiography for diagnosing lesions that are asymptomatic, minor, and even without murmurs. Our study did not include detailed cardiological assessment of all neonates, and since many of the asymptomatic defects would inevitably have been missed, we used major defects as the outcome measure. In contrast to previous studies, our population was confined to those pregnancies presumed to be chromosomally normal; about 25% of affected individuals are chromosomally abnormal. Another factor that may have underestimated our birth prevalence of cardiac defects is the short interval between delivery and obtaining outcome data (in most cases within one month); previous studies have reported that only about 60% of congenital cardiac defects are diagnosed by one month after birth.4
The distribution of different types of cardiac defects in our study (table 6) is similar to that described in previous prenatal and postnatal series.3,4,7,21,22 Although increased nuchal translucency thickness was observed with all types of major abnormalities of the heart and great arteries, there was a stronger association with left sided defects such as hypoplastic left heart and coarctation of the aorta.
Pregnancies identified by nuchal translucency scanning as being at high risk of cardiac defects need not wait until 20 weeks for specialist echocardiography. Improvements in the resolution of ultrasound machines have made it possible to undertake detailed cardiac scanning in the first trimester of pregnancy.13,23–25 Furthermore there are several case reports or small series on the ultrasonographic diagnosis of cardiac defects at 10-14 weeks of gestation, and it is interesting that in 21 fetuses with major cardiac defects, 17 (81%) had increased nuchal translucency thickness.12–15
Measurement of fetal nuchal translucency thickness at 10-14 weeks of gestation—traditionally used to identify fetuses at high risk of aneuploidy26—also identifies the majority of pregnancies with major defects of the heart and great arteries.
Editorial by Mol
Footnotes
Funding: Fetal Medicine Foundation.
Conflict of interest: None.
References
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