OBJECTIVE: To estimate the potential value of fetal assessment for tricuspid regurgitation at 11–13 weeks of gestation in the prediction of major cardiac defects.
METHODS: We screened for aneuploidies by measuring fetal nuchal translucency thickness as well as assessing blood flow across the tricuspid valve for evidence of tricuspid regurgitation and in the ductus venosus for evidence of reversed A-wave at 11 0/7 to13 6/7 weeks of gestation. The estimated performance of different combinations of increased fetal nuchal translucency, tricuspid regurgitation, and ductus venosus reversed A-wave in screening for major cardiac defects was examined.
RESULTS: The study population of euploid fetuses included 85 cases with major cardiac defects and 40,905 with no cardiac defects. Fetal nuchal translucency above the 95th percentile, tricuspid regurgitation, or ductus venosus reversed A-wave was observed in 30 (35.3%), 28 (32.9%), and 24 (28.2%) of the fetuses with cardiac defects, respectively, and in 1,956 (4.8%), 516 (1.3%), and 856 (2.1%) of those without cardiac defects. Any one of the three markers was found in 49 of the fetuses with cardiac defects (57.6%, 95% confidence interval [CI] 47.0–67.6%) and in 3,265 of those without cardiac defects (8.0%, 95% CI 7.7–8.2%).
CONCLUSION: Assessment of flow across the tricuspid valve improves the performance of screening for major cardiac defects by fetal nuchal translucency and ductus venosus flow.
LEVEL OF EVIDENCE: II
Doppler blood flow assessment across the fetal tricuspid valve at 11 weeks to 13 6/7 weeks of gestation improves the detection of major cardiac defects.
From the Harris Birthright Research Centre of Fetal Medicine, King's College Hospital, London, United Kingdom; the Department of Fetal Medicine, Medway Maritime Hospital, Gillingham, United Kingdom; Unidad Medicina Fetal, Centro Sanitario Virgen del Pilar, San Sebastián, Spain; and the Department of Fetal Medicine, University College Hospital, London, United Kingdom.
Supported by a grant from The Fetal Medicine Foundation (UK charity number 1037116).
Corresponding author: Kypros H. Nicolaides, Harris Birthright Research Centre for Fetal Medicine, King's College Hospital, Denmark Hill, London SE5 9RS, UK; e-mail: firstname.lastname@example.org.
Financial Disclosure The authors did not report any potential conflicts of interest.
Most major cardiac defects are amenable to prenatal diagnosis by specialist fetal echocardiography.1 However, routine ultrasonographic screening in pregnancy fails to identify the majority of affected fetuses and therefore, effective population-based prenatal diagnosis necessitates improved methods of identifying the high-risk group for referral to specialists.2–4 The traditional method of screening for cardiac defects, which relies on family history of such defects, maternal history of diabetes mellitus, and maternal exposure to teratogens, identifies only approximately 10% of affected fetuses.5 Improved early identification of the high-risk group is provided by increased fetal nuchal translucency thickness and abnormal flow in the ductus venosus manifested as reversed A-wave.6–12 A study of more than 40,000 singleton pregnancies at 11–13 weeks, excluding aneuploidies, reported that screening for major cardiac defects by a combination of fetal nuchal translucency above the 95th percentile and ductus venosus reversed A-wave could detect 47.1% of major cardiac defects at an overall false-positive rate of 6.7%.12
Another potentially useful early ultrasonographic marker of major cardiac defects is tricuspid regurgitation. Assessment of tricuspid flow improves the performance of first-trimester screening for aneuploidies, but tricuspid regurgitation in both euploid and aneuploid fetuses is associated with an increased risk for major cardiac defects.13–16 The aim of this study is to investigate further the association between tricuspid regurgitation and fetal major cardiac defects and estimate whether assessment of flow across the tricuspid valve at 11–13 weeks of gestation improves the overall detection rate of cardiac defects achieved by screening with nuchal translucency thickness and ductus venosus flow.
MATERIALS AND METHODS
The data for this study were derived from first-trimester screening for aneuploidies at King's College Hospital, London, UK, and Medway Maritime Hospital, Gillingham, UK, between March 2006 and September 2009. In this visit, which was held at 11 to 13 6/7 weeks of gestation, maternal characteristics and medical history were recorded and an ultrasonographic scan was performed transabdominally (using 3- to 7.5-MHz curvilinear transducers) to first determine gestational age from the measurement of the fetal crown–rump length; second measure fetal nuchal translucency thickness; third, diagnose any major fetal abnormalities; and fourth, assess blood flow across the tricuspid valve and in the ductus venosus.9,15–18 At King's College Hospital, assessment of risk for aneuploidies included measurement of maternal serum free β-human chorionic gonadotropin and pregnancy-associated plasma protein-A.19 This study constitutes analysis of data derived from a routine clinical examination and did not require ethics committee approval.
Presence or absence of tricuspid regurgitation was determined by pulsed-wave Doppler during fetal quiescence.15 A sample volume of 3.0 mm was positioned across the tricuspid valve in an apical four-chamber view of the fetal heart such that the angle to the direction of flow was less than 30°. A minimum of three attempts were made because the regurgitation jet, when present, may vary its direction toward the right atrium. The diagnosis of tricuspid regurgitation was made if it was found during at least half of the systole and with a velocity of more than 60 cm/s, because aortic or pulmonary arterial blood flow at this gestation can produce a maximum velocity of 50 cm/s.
The policy in our hospitals was to offer routinely a second ultrasound examination at 20 to 23 6/7 weeks. This scan was also performed transabdominally and involved systematic detailed examination of the fetus, including a sweep through the heart in the transverse plane to include the four-chamber view, outflow tracts, and a three-vessel view of the heart and great vessels. All cases of suspected fetal abnormalities were examined by a fetal medicine specialist. Likewise, all cases of suspected fetal cardiac defect were examined by a fetal cardiologist. In addition, the cardiologists carried out fetal echocardiography at 11–14 weeks in those with nuchal translucency above the 99th centile and at 20 weeks in those with nuchal translucency between the 95th and 99th centiles.
All neonates were examined by a pediatrician. Prenatal and neonatal findings were recorded in computerized databases. Data on pregnancy outcome from women who booked for obstetric care in our hospitals but delivered in other hospitals were obtained either from the maternity computerized records in these hospitals or the general medical practitioners of the women.
In a previous study in the same population, we reported on the relation between fetal nuchal translucency and ductus venosus blood flow at 11–13 weeks with major fetal cardiac defects.12 In this study, we present the data on tricuspid flow in pregnancies with major fetal cardiac defects and those resulting in live birth of phenotypically normal neonates. We excluded all aneuploidies and noncardiac defects diagnosed prenatally or in the neonatal period. We also excluded pregnancies with no abnormal fetal findings at the 11–13 weeks scan, the 20–23 weeks scan, or both, which resulted in termination, miscarriage, or stillbirth and those lost to follow-up.
Cardiac defects are considered to be major if they require surgery or interventional cardiac catheterization within the first year of life. We included all cases with major cardiac defects diagnosed by pediatric cardiologists antenatally, in the neonatal period, or both. Abnormalities suspected antenatally but not confirmed in the neonates were not included. In contrast, the prenatal diagnosis in cases of terminations and miscarriages at less than 24 weeks or stillbirths at or after 24 weeks was assumed to be correct because in these cases, postmortem examination was not performed systematically. The following fetal cardiac defects were not included: first, ventricular septal defects because they are generally not considered to be major defects; second, right aortic arch, persistent left superior vena cava, and aberrant right subclavian artery because these are variants of normal rather than true defects; and third, cardiac tumors developing during the second and third trimesters of pregnancy because these defects would not be expected to have any manifestations during the 11–13 weeks scan.
The prevalence of tricuspid regurgitation, ductus venosus reversed A-wave, and nuchal translucency above the 95th and 99th percentiles in fetuses with and without major cardiac defects was calculated and comparisons were performed by chi-square test or Fisher's exact test. Logistic regression analysis was used to determine the significant contributors in the prediction of cardiac defects. The performance of screening was estimated by receiver operating characteristic curves and the performance of different methods of screening was compared using the areas under the receiver operating characteristic curves.20
The statistical software packages PASW statistics 18.0 and Medcalc were used for the data analyses.
During the study period, we carried out an ultrasonographic examination at 11–13 weeks in 45,191 singleton pregnancies with a live fetus and crown–rump length of 45–84 mm. The median maternal age was 31 years (range, 14–51 years) and the median weight was 66 kg (range, 35–167 kg).
In 735 (1.6%) of the 45,191 cases, there was prenatal or postnatal diagnosis of aneuploidy, noncardiac abnormalities, ventricular septal defect, or cardiac tumors and these were excluded from further analysis (Fig. 1). A total of 85 major cardiac defects were diagnosed, including 28 at 11–13 weeks, 56 at 20–23 weeks, and one postnatally. The maternal characteristics of those with and without fetal major cardiac defects are described in Table 1.
The types of major cardiac defects and their relation to increased fetal nuchal translucency thickness, ductus venosus reversed A-wave, and tricuspid regurgitation at the 11–13 weeks scan are summarized in Table 2. Fetal nuchal translucency above the 95th percentile and above the 99th percentile, ductus venosus reversed A-wave, or tricuspid regurgitation was observed in 35.3%, 21.2%, 28.2%, and 32.9, respectively, of the fetuses with cardiac defects and in 4.8%, 0.7%, 2.1%, and 1.3%, respectively, of those without cardiac defects (Table 3).
The incidence of tricuspid regurgitation and ductus venosus reversed A-wave was significantly higher in fetuses with nuchal translucency above the 95th percentile than in those with nuchal translucency at or below the 95th percentile both in cases with and those without major cardiac defects (Table 4).
The estimated performance of different combinations of increased fetal nuchal translucency in screening for major cardiac defects is summarized in Table 3. In these calculations it was assumed that all major cardiac defects can be detected antenatally by specialist fetal echocardiography.
The estimated detection rate of major cardiac defects is essentially dependent on the availability of specialist fetal cardiac services. If all cases with fetal nuchal translucency above the 95th centile, those with ductus venosus reversed A-wave, tricuspid regurgitation, or all of these have fetal echocardiography, 57.6% (95% confidence interval [CI] 47.0–67.6%) of the major cardiac defects would be detected but the false-positive rate would be 8.0% (95% CI 7.7–8.2%). Echocardiography for cases with nuchal translucency above the 99th centile, those with ductus venosus reversed A-wave, tricuspid regurgitation, or all of these would detect 51.8% (95% CI 41.3–62.1%) of major cardiac defects at an overall false-positive rate of 4.1% (95% CI 3.9–4.3%).
Multivariable logistic regression analysis showed that significant prediction of cardiac defects was provided by delta nuchal translucency in millimeters (odds ratio [OR] 2.3, 95% CI 1.9–2.8, P<.001), ductus venosus reversed A-wave (OR 7.7, 95% CI 4.4–13.4, P<.001), and tricuspid regurgitation (OR 17.1, 95% CI 10.0–29.2).
The patient-specific risk for major cardiac defects can be calculated from the formula: odds/(1+odds), where odds=eY. The Y for the relation between cardiac defects and delta nuchal translucency was derived by univariable logistic regression analysis (Y=−6.546+1.104×delta nuchal translucency in millimeters). The Y for a combination of delta nuchal translucency, ductus venosus reversed A-wave, and tricuspid regurgitation was derived by multivariable logistic regression (Y=−6.924+0.833×delta nuchal translucency in millimeters+2.039 if ductus venosus reversed A-wave and 0 if normal flow+2.841 if tricuspid regurgitation, and 0 if normal tricuspid flow). The relation between the patient-specific risk for major cardiac defect and fetal delta nuchal translucency with and without ductus venosus reversed A-wave or tricuspid regurgitation is illustrated in Figure 2.
The areas under the curve for the prediction of cardiac defects by nuchal translucency alone and in combination of nuchal translucency with ductus venosus flow and tricuspid flow are shown in Table 5 and Figure 3. The area under the curve of screening by nuchal translucency alone was improved by the addition of ductus venosus flow (P<.001) and further improved by the addition of tricuspid flow (P<.001). For fixed false-positive rates of 1%, 3%, and 5%, the detection rates of major cardiac defects by a combination of nuchal translucency, ductus venosus flow, and tricuspid flow were 36.5%, 48.2%, and 54.1%, respectively (Table 5).
The findings of this study demonstrate that tricuspid regurgitation at 11–13 weeks of gestation is observed in approximately 1% of normal fetuses and in one-third of those with major cardiac defects. The incidence of tricuspid regurgitation and ductus venosus reversed A-wave increases with nuchal translucency thickness both in fetuses with and those without major cardiac defects. However, the presence of tricuspid regurgitation is not confined to cases with increased nuchal translucency and ductus venosus reversed A-wave and consequently measurement of nuchal translucency and assessment of flow in the ductus venosus and across the tricuspid valve can be combined to provide an effective early method of screening for major cardiac defects.
The prevalence of major cardiac defects in our population of approximately two per 1,000 is lower than the reported four per 1,000 prevalence of cardiac defects in live births (three to eight per 1,000).21 The most likely explanations for this apparent difference is that first, we selected only major defects; second, we excluded fetuses with aneuploidies and extracardiac malformations; and third, we did not undertake detailed cardiologic assessment, including echocardiography, of all neonates and inevitably some of the asymptomatic defects would have been missed.
The underlying mechanism for the association between cardiac defects and both increased nuchal translucency and abnormal flow across the tricuspid valve, in the ductus venosus, or both is uncertain. However, they may be mediated by impairment in cardiac function that is manifested only during the first trimester because at this gestation, the compliance of the fetal heart is low and cardiac afterload resulting from placental resistance is high.
We developed an algorithm combining fetal nuchal translucency with flow in the ductus venosus and across the tricuspid valve to estimate the patient-specific risk for major cardiac defects. Ultimately, the detection of major cardiac defects will depend on the proportion of the population that can be offered specialist fetal echocardiography and our algorithm could be used to define the risk cutoff that selects the patients requiring referral for such an examination. The risk increases exponentially with nuchal translucency thickness from one per 1,000 in those with nuchal translucency at or below the 95th percentile to seven per 1,000 for nuchal translucency between the 95th and 99th percentile and 58 per 1,000 for nuchal translucency above the 99th centile. The risk is further increased if there is ductus venosus reversed A-wave, tricuspid regurgitation, or both and decreased if flow in the ductus venosus and across the tricuspid valve is normal. For fixed false-positive rates of 1%, 3%, and 5%, the estimated detection rates of major cardiac defects in screening by fetal nuchal translucency alone were 25.9%, 30.6%, and 35.3%, respectively, and these were increased to 36.5%, 48.2%, and 54.1%, respectively, in screening by a combination of nuchal translucency and both ductus venosus and tricuspid flow.
An alternative approach to using a combined risk cutoff for referral to specialist fetal echocardiography is to define as high risk all cases with tricuspid regurgitation, ductus venosus reversed A-wave, or both, which constitute approximately 3% of the population and contain 48% of those with major cardiac defects. If cases with nuchal translucency above the 99th percentile are also included, the screen-positive rate would increase to approximately 4% and the estimated detection rate would be 52%. If there are available resources for performing fetal echocardiography in 8% of the population, then the nuchal translucency cutoff for defining the high-risk group could be reduced to the 95th percentile with an increase in the estimated detection rate to 58%.
This was a population-based study of singleton pregnancies undergoing routine screening in a research center of fetal medicine with extensive experience in ultrasonographic examination at both 11–13 weeks and 20–24 weeks of gestation. In all pregnancies, the ultrasonographic scan at 11–13 weeks included measurement of fetal nuchal translucency and Doppler assessment of blood flow in the ductus venosus and across the tricuspid valve. The limitation of the study is the method of ascertainment of major cardiac defects. In the live births, exclusion of cardiac defects was based on clinical examination in the immediate neonatal period. It is therefore likely that in some defects such as coarctation of the aorta and transposition of the great arteries, the diagnosis may have been missed. In cases of pregnancy termination or fetal death, the antenatal findings were not validated by postmortem examination. In these cases, the method of diagnosing or excluding a cardiac defect was based on the pragmatic end point of ultrasonographically detectable defect by a pediatric cardiologist specialist in fetal echocardiography.
There is now widespread acceptance of first-trimester screening for aneuploidies by measurement of fetal nuchal translucency and maternal serum free β-human chorionic gonadotropin and pregnancy- associated plasma protein-A, because the detection rate, at a false-positive rate of 5%, of approximately 90% is superior to the 30% achieved with screening by maternal age or 55–70% with second-trimester biochemical testing.18,22–30 The performance of first-trimester combined screening can be improved further if, in addition to measurement of nuchal translucency, the ultrasonographic examination includes assessment of flow across the tricuspid valve and in the ductus venosus.28 The detection rate would increase to 93–96% and the false-positive rate would decrease to 2.5%.16,31 The findings of this study demonstrate that an additional advantage of including Doppler studies in the first trimester is that including this improves the detection rate of major cardiac defects in euploid fetuses.
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