Congenital heart disease is the most common congenital abnormality in the human fetus and accounts for more than half of the deaths from birth defects in childhood.1 To improve the early prenatal detection of congenital heart disease, several indirect ultrasonographic markers have been proposed for screening between 11 0/7 and 13 6/7 weeks of gestation including increased nuchal translucency, abnormal blood flow in ductus venosus, and tricuspid regurgitation.2–7 High-frequency ultrasound probes along with substantial improvements in signal processing have dramatically increased our ability to visualize the developing fetus during the first trimester of pregnancy, allowing detailed investigation of fetal anatomy and diagnosis of major congenital anomalies in this period.8 Assessment of the transverse view of the fetal chest at the level of the four-chamber view is currently required by the International Society of Ultrasound in Obstetrics and Gynecology practice guidelines for performance of first-trimester fetal ultrasound scan to document the normal position of the heart (levocardia).9 The four-chamber view allows for the assessment of the fetal cardiac axis. Studies were performed to establish normal values and the feasibility of cardiac axis measurement in early gestation using either the transabdominal or transvaginal approach.10,11 It was shown that successful cardiac axis measurement rates increased with increasing gestational age and can be achieved in 80–100% of cases.10,11
The purpose of this study was to investigate the association between abnormal cardiac axis and fetal congenital heart disease to demonstrate the potential clinical applicability of cardiac axis measurement for detection of congenital heart disease in early gestation.
MATERIALS AND METHODS
This multicenter case–control study was undertaken at three tertiary centers with expertise in early fetal imaging in the United States, Germany, and the Russian Federation. Permission was obtained from each local institutional review board or independent ethics committee to retrospectively examine the medical records of all pregnant women who presented for first-trimester screening between January 2005 and June 30, 2011. In all three institutions an assessment of fetal basic anatomy including transverse plane of the fetal chest at the level of the four-chamber view was performed routinely in early gestation (11 0/7 and 14 6/7 weeks of gestation) since January 1, 2005, using the same ultrasound protocol. Cases of confirmed fetal congenital heart disease diagnosed prenatally with well-documented four-chamber views between 11 0/7 and 14 6/7 weeks of gestation were identified from the prenatal database in each study center and comprised the study group. Confirmation of congenital heart disease was based on the second- to third-trimester fetal, postnatal imaging or autopsy, or all of these. The term “major congenital heart disease” was used to describe cardiac malformations in which surgery or an intervention procedure is usually necessary during the first year of life. Cases of pregnancy terminations, miscarriages, or lost of follow-up at less than 18 weeks of gestation were excluded. A control group was selected from respective center population by matching each case of congenital heart disease with two fetuses in a control group with similar crown-rump length (±5 mm) and date of study (±2 months). Only cases without preexisting risk factors for fetal congenital heart disease with normal ultrasound findings and known uncomplicated pregnancy outcome were included in the control group. One ultrasound image per case demonstrating the four-chamber view in two-dimensional or in two-dimensional+color Doppler was retrieved from the database. Images for study and control groups were selected if the following criteria were met: 1) obtained at gestational age between 11 0/7 and 14 6/7 weeks, 2) vaginal or transabdominal ultrasonography was used, and 3) demonstrated anatomic markers including one complete rib on each side of the fetal lateral chest wall and clear visualization of the cardiac chambers. All images were deidentified before review (contained no personal health information). The Information Technology Department of the research center created center-specific directories on its FTP server designed to facilitate the uploading of images. A research coordinator who was not involved in the assessment of the data coordinated the reception of the images and randomly assigned a number to each image. A linking tool to crossreference the images to the clinical data was created. All images were placed in a standardized position (the spine at the 6 o'clock position and the apex of the heart in the left upper chest). Cardiac axis was measured by one investigator (E.S.S.) as the angle between the line that traces the long axis of the heart and the line that bisects the thorax in an anteroposterior direction (Fig. 1). In patients with isolated major fetal congenital heart disease, other first-trimester ultrasound findings, including nuchal translucency measurement, presence of tricuspid regurgitation, and blood flow in ductus venosus, were recorded. The investigator performing cardiac axis measurements was blinded to the source of the image, the clinical data, and pregnancy outcomes.
All ultrasound examinations were performed on Voluson 730 Expert and Voluson E8 ultrasound equipment with transabdominal transducer 4–8 MHz and transvaginal transducer 5–9 MHz or 6–12 MHz.
Statistical analysis was performed using the SAS 9.1.3 software. Normal distribution of continuous variables was assessed with the Kolmogorov-Smirnov test. Continuous variables are reported as mean±standard deviation or median (range) depending on the data distribution. Categorical data were expressed by frequencies and percentages. A P value of <.05 was considered significant. The effect of fetal crown-rump length and gestational age on the cardiac axis was evaluated using regression analysis. The prevalence of abnormal cardiac axis, enlarged nuchal translucency (above 95th percentile or greater then 3.5 mm), presence of tricuspid regurgitation, and reversed A-wave in ductus venosus waveform was calculated and compared using the χ2 test and Fisher exact test.
In total, 197 fetuses met the inclusion criteria and comprised the study group. Three hundred ninety-four fetuses were selected for the control group. The demographic and clinical characteristics of fetuses with congenital heart disease and fetuses in the control group are shown in Table 1.
In the study group, preexisting risk factors for fetal cardiac anomalies were found in 29 of 197 (14.7%) patients including personal (4/29) or family history (6/29) of congenital heart disease, pregestational diabetes (8/29), exposure to medication with a possible teratogenic effect (2/29), and use of assisted reproductive technology for the current pregnancy (9/29). Nearly 40% of the fetuses in the study group had normal karyotype based on prenatal invasive testing or postnatal studies. Chromosomal and extracardiac abnormalities identified in fetuses with congenital heart disease are presented in Figure 2.
In total 407 patient charts were reviewed to select 394 patients for the control group. Thirteen cases (3.3%) did not meet the inclusion criteria secondary to poor resolution of the images between 11 0/7 and 11 6/7 weeks of gestation (six cases), presence of fetal anomalies including enlarged nuchal translucency (four cases), and maternal pregestational diabetes (two cases). In the control group, the cardiac axis ranged from 24 to 68° (mean 44.5±7.4°; 95% confidence interval 29.8–59.2). Cardiac axis did not appear to differ significantly with gestational age (r=−0.07; P=.19). Using 1.96 standard deviations, range, and mean for in the entire control group, cardiac axis was defined as abnormal when the measurement was found to be above the 97.5th percentile (left deviation) or below the 2.5th percentile (right deviation). In case of an absent or nonvisualized interventicular septum, measurement was impossible to perform and cardiac axis was considered nonidentifiable (Fig. 3). A normal cardiac axis was defined as being at least 30° but less than 60°.
The mean cardiac axis in the entire congenital heart disease group of 197 fetuses was 62.0±21.7° (range 0–114°). Individual measurements of cardiac axis in fetuses with congenital heart disease and normal fetuses in the control group are plotted on the reference range for crown-rump length (median, 5th and 95th percentiles), shown in Figure 4. In the congenital heart disease group, 51 of 197 (25.9%) fetuses had cardiac axis measurements within normal limits and ranged from 33 to 59°. In 146 of 197 (74.1%), the cardiac axis was abnormal including 110 cases with left deviation, 19 cases with right deviation, and 17 cases with nonidentifiable cardiac axis (Table 2).
The types of cardiac anomalies and their relation to increased nuchal translucency thickness and cardiac axis between 11 0/7 and 14 6/7 weeks of gestation are summarized in Table 3. In fetuses with congenital heart disease, nuchal translucency above 95th percentile, nuchal translucency above 3.5 mm, or abnormal cardiac axis was observed in 51.7%, 43.1%, and 74.1%, respectively. Prevalence of enlarged nuchal translucency and abnormal cardiac axis was similar for septal defects (69.1% compared with 63.2%; P=.59). However, abnormal cardiac axis was found more commonly in conotruncal anomalies (81.6% compared with 30.6%; P<.01) and complex congenital heart disease including univentricular hearts (96.6% compared with 37.9%; P<.01).
When the 119 fetuses with chromosomal abnormalities were excluded, in the reminding 78 fetuses, the mean cardiac axis was 61.7±20.1° (range 0–97°). Table 4 presents the incidence of enlarged nuchal translucency and abnormal cardiac axis in the subgroup of 78 fetuses with congenital heart disease and normal karyotype. In this subgroup an abnormal cardiac axis was present more commonly than an enlarged nuchal translucency (71.8% compared with 19.2%; P<.01). The incidence of abnormal cardiac axis in the fetuses with normal and abnormal karyotype did not differ significantly (71.8% compared with 75.6%; P=.81).
In 58 fetuses with normal karyotype and major isolated congenital heart disease, data regarding presence or absence of tricuspid regurgitation as well as pattern of blood flow in ductus venosus were available for review. Prevalence of enlarged nuchal translucency, abnormal cardiac axis, tricuspid regurgitation, and reversed A-wave in ductus venosus in fetuses with isolated major congenital heart disease is shown in Table 5. The estimated performance of cardiac axis measurement in screening for major congenital heart disease was significantly better than enlarged nuchal translucency, tricuspid regurgitation, or reversed A-wave in ductus venosus used alone or in combination.
The transverse plane of the fetal chest at the level of the cardiac four-chamber view is routinely used in screening for congenital heart disease in the second trimester of pregnancy and has been recently proposed as a potential screening tool in the first trimester.9,12 This view allows evaluation of cardiac axis and position. Cardiac axis is defined as the angle made by the interventricular septum of the heart and the anteroposterior axis of the chest. In normal fetuses, cardiac axis was reported to be approximately 45±20° in the second and third trimesters.13 It has been demonstrated that cardiac axis measurement in early gestation is feasible using either the transabdominal or transvaginal approach (or both).10,11 There has been some discrepancy in the reported data on the normal values of the cardiac axis in early gestation. This discrepancy may be explained by the relatively small number of cases in earlier studies, the technical difficulties or limited resolution of cardiac imaging before 12 weeks of gestation, and differences in grouping of patients by gestational age. In the present study, reference values of the cardiac axis between 11 0/7 and 14 6/7 weeks of gestation were determined using a large cohort of normal fetuses. We have demonstrated that mean values of the cardiac axis did not change significantly between 11 0/7 and 14 6/7 weeks of gestation; however, the highest variation of the cardiac axis measurements was noted at 11 0/7–11 6/7 weeks of gestation. Our results of cardiac axis measurement in early gestation were similar to those reported in the middle of the second and third trimesters.14–16 This observation supports the earlier proposed theory that fetal cardiac axis establishes its position by the 12th week of gestation and remains unchanged during pregnancy.17,18
Studies performed in the second and third trimesters have differed slightly with regard to the definition of an abnormal cardiac axis. The very first study by Comstock13 suggested an abnormal cardiac axis as greater than 65° or less than 25°. Another study considered a small cardiac axis as less than 28° and cardiac axis greater than 59°, consistent with left axis deviation.14 Similar criteria were used to define abnormal axis in small series of 10 fetuses diagnosed with congenital heart disease between 12 and 15 weeks of gestation.11 In our study, we defined normal cardiac axis as at least 30° but less than 60°. In addition, three types of cardiac axis abnormalities were suggested including left axis deviation, right axis deviation, and nonidentifiable cardiac axis. The findings of this study demonstrated that between 11 0/7 and 14 6/7 weeks of gestation, abnormal cardiac axis is present in 74% of fetuses with congenital cardiac anomalies. Our results are in agreement with the findings of a previous study, in which the sensitivity of the abnormal cardiac axis in congenital heart disease between 16 and 40 weeks of gestation was found to be 75%.14 Cardiac anomalies occurred in fetuses with small and large cardiac axes. However, left deviation of the cardiac axis in fetuses with congenital heart disease is the most common and in our study was found in 55.8% cases. Similar results were previously reported by in the second trimester.15 Defining left axis deviation as greater than 57° allowed the detection of congenital heart disease in 44% of fetuses between 17 and 40 weeks of gestation.15
Incidence of abnormal cardiac axis has been reported to be dependent on type of congenital heart disease.15 Our results demonstrated that an abnormal cardiac axis is more likely to be found in fetuses with conotruncal anomalies and complex congenital heart disease including univentricular hearts. Assessment of the cardiac axis can be particularly helpful in early detection of conotruncual anomalies such as Tetralogy of Fallot and common arterial trunk, because these are commonly characterized by a normal four-chamber view.
In the last 15 years, several ultrasonographic markers including increased nuchal translucency, abnormal flow in the ductus venosus, and tricuspid regurgitation have been proposed for cardiac screening between 11 0/7 and 13 6/7 weeks of gestation. In addition, diagnostic algorithms using different combinations of these markers were developed to estimate patient-specific risk for major congenital heart disease, allowing a detection rate of cardiac anomalies up to 54%.6 An important observation of this study is that in contrast to nuchal translucency, cardiac axis performs equally well in detecting congenital heart disease in fetuses with normal and abnormal karyotype. Furthermore, performance of cardiac axis measurement in detection of major congenital heart disease in fetuses with normal karyotype seems to be significantly better than enlarged nuchal translucency, tricuspid regurgitation, or reversed A-wave in ductus venosus used alone or in combination. This observation, however, should be further substantiated in a larger population-based study.
There are several limitations to this study that should be mentioned. First, measurement of the cardiac axis was performed retrospectively. We do not believe that this has a significant effect on the results, because standard four-chamber planes for cardiac axis assessment were retrieved from prospectively collected imaging databases. Second, a case–control study design did not allow estimating diagnostic value of the cardiac axis measurement for the general population. Despite the fact that all cardiac axis measurements were performed by one observer, we do not feel that the accuracy of the results was affected. Excellent interobserver and intraobserver reproducibility of cardiac axis measurement between 11 0/7 and 14 6/7 weeks of gestation was previously reported by our group.10 Finally, every effort was made to keep the observer blinded to the diagnosis; however, evident abnormal appearance of the four-chamber view in certain congenital heart diseases could have contributed to potential bias.
This study validates the potential clinical applicability of the cardiac axis measurement as a screening tool for cardiac anomalies in late first and early second trimester of pregnancy. The findings of the study demonstrated that addition of cardiac axis assessment to the nuchal translucency measurement is helpful in defining a population at risk for fetal congenital heart disease. Identification of abnormal cardiac axis during routine ultrasound evaluation in early gestation should be considered an indication for fetal echocardiogram.
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