Early fetal echocardiography: congenital heart disease detection and diagnostic accuracy in the hands of an experienced fetal cardiology program

DOI: 10.1002/pd.4372 ORIGINAL ARTICLE Early fetal echocardiography: congenital heart disease detection and diagnostic accuracy in the hands of an experienced fetal cardiology program Jodi I. Pike, Anita Krishnan and Mary T. Donofrio* Children s National Heart Institute, Children s National Medical Center, Washington, DC 20010, USA *Correspondence to: Mary Donofrio. E-mail: mdonofri@cnmc.org ABSTRACT Objective Evaluate the utility of early fetal echocardiography in the hands of an experienced fetal cardiology program for detection of congenital heart disease (CHD) in high-risk pregnancies. Methods Review of fetal echocardiograms 12 to 16 weeks of gestation. Results There were 151 studies in 142 fetuses (mean age 14.5 weeks). Transabdominal imaging was sufficient for 104; transvaginal imaging was used in 38. CHD was found in 32(22.5%). High yield indications were suspected cardiac anomaly (91.7%) and extracardiac anomaly (50%). Lower yield indications were increased nuchal translucency (13.8%) and family history (6.1%). No fetuses referred for advanced maternal age, maternal lupus, or diabetes had CHD. Mid-gestation follow-up was possible in 128 (ten terminated/four lost to follow-up). Three of 19 initially diagnosed with CHD had normal hearts; none diagnosed as normal had CHD (sensitivity 100%/specificity 97.3%). Seven had modification of original diagnoses: three initially diagnosed with possible septal defects had no defect, two had diagnoses that changed, and two had progression different than predicted. Conclusion Early fetal echocardiography performed in an experienced fetal cardiology program accurately identifies significant CHD. Appropriate referral indications to fetal cardiac specialists include suspected CHD, extracardiac anomaly, increased nuchal translucency, and significant family history. Lesions that may not be diagnosed with accuracy include septal defects and diseases that progress. Funding sources: None Conflicts of interest: None declared INTRODUCTION Prenatal diagnosis of congenital heart disease (CHD) has been shown to have a significant effect on prenatal and postnatal management and outcomes. 1 5 In addition to the potential medical benefits, fetal diagnosis allows for valuable parental counseling, which allows families to make informed decisions regarding the pregnancy, and to prepare emotionally for the birth of the child with significant CHD. Accurate prenatal diagnosis can also lead to additional testing of the fetus, including genetic evaluation and other anatomic imaging, which can yield valuable informationinoverallassessmentofthefetus. Referral for fetal echocardiogram typically occurs between 18 and 22 weeks gestational age. With advances in ultrasound technology, which has allowed for the significant improvements in high-resolution imaging necessary to visualize the developing fetal heart, fetal echocardiography can now be performed in the late first trimester and early second trimester of pregnancy. 6 9 In addition, with the wide availability and practice of nuchal translucency (NT) measurements, which typically occurs between 11 and 14 weeks gestational age, the demand for early fetal cardiac imaging has increased. Increased NT has been shown to be associated with CHD, even in the presence of normal karyotype, 10,11 and early and accurate cardiac diagnosis is an essential part of the evaluation of these fetuses. Despite the potential benefits of early cardiac imaging, it is not the standard of practice in most institutions in the United States. In addition, practice patterns tend to be variable regarding who does the imaging, the imaging protocol, the indications for referral, and the timing of consultation. Given that the utility and accuracy of early fetal cardiac imaging in the hands of experienced fetal cardiologists is undefined, the objective of this study was to evaluate the experience of diagnosing cardiac anomalies using early fetal echocardiography at a large fetal cardiac referral center. METHODS We conducted a retrospective review of all early fetal echocardiograms performed between July 2007 and December 2010 in the Fetal Heart Program at Children s National Medical

Early fetal echocardiography 791 Center. Early fetal echocardiograms were defined as studies completed between 12 and 16 weeks estimated gestational age (EGA). Qualifying studies were identified by a database search of all echocardiograms performed during the study period with the summary codes First trimester fetal echocardiogram, Fetal echocardiogram <18 weeks gestational age, and Transvaginal fetal echocardiogram. These codes were then cross-referenced with a database of all fetal echocardiograms performed during the same period to ensure completion. Those performed at a gestational age between 17 and 18 weeks were removed from the dataset given the criteria for entry in this study was 12 to 16 weeks of gestation. The study was approved by the institutional review board of Children s National Medical Center. Participants were referred for early fetal echocardiograms for a variety of reasons; in our early experience, no specific indications for fetal echocardiogram were excluded. However, given practice patterns in the area, those referred for early fetal echocardiograms were considered by obstetricians or maternal fetal specialists to be at higher risk of cardiac defects than the general population. As part of our general practice, all early fetal echocardiograms were first attempted with transabdominal imaging, with transvaginal imaging added when a complete study could not be obtained. The protocol for a complete fetal echocardiogram followed recommendations for heart imaging according to the American Society of Echocardiography Guidelines for Fetal Echocardiography. 12 A complete study included imaging of the four-chamber view, left and right outflow tracts noting crossing, and identification of both the ductal and aortic arches. Twodimensional images of cardiac structures, and color and pulse wave Doppler of all four valves and both great arteries were obtained. Video clips were obtained of two-dimensional and color imaging sweeping inferior to superior from the four-chamber view through the outflow tracts and threevessel views. Video clips were also obtained of both the aortic and ductal arches. Flow acceleration or regurgitation across any valve, and/or reversal of flow in the aorta or ductal arch was noted. Left and right ventricular function was assessed qualitatively. Heart rate, rhythm, and PR interval were determined by analysis of mitral inflow/aortic outflow Doppler. Gestational age was determined by last menstrual period or by ultrasound measurements of fetal biometrics. All women who underwent early fetal echocardiograms were counseled regarding the limitations of early imaging and were recommended to return for comprehensive fetal echocardiogram at greater than 20 weeks of gestation. Maternal medical records were reviewed for genetic and other anatomic diagnoses of the fetus, and indication for fetal echocardiogram referral. Initial and all subsequent fetal echocardiograms were reviewed for accuracy and consistency of diagnoses. For all abnormal fetal echocardiograms, postnatal diagnoses were confirmed. Characteristics of those diagnoses that differed at follow-up evaluation were analyzed. Descriptive statistics and a two-tailed t-test were used to evaluate this data. p < 0.05 was considered significant. RESULTS Demographics During the study period, 151 early fetal studies were performed on 142 fetuses. The mean EGA at initial echocardiogram was 14.5 weeks (range 12.4 16.1 weeks). Transabdominal imaging was sufficient for 104 of 142 fetuses on initial echocardiogram: 38 required transvaginal imaging; in 26, the additional images obtained by transvaginal exam were sufficient to complete the exam. All of those who underwent transvaginal imaging due to limited transabdominal views had an initial fetal echocardiogram at less than 15 weeks EGA with a mean EGA of 13.1 weeks (range 12.4 14.7 weeks). A complete study was obtained in 130 of 142 fetuses. Six women had two studies performed (initial study at 12 weeks in two and 13 weeks in one). In five of the six, repeat early imaging was performed because of family request given the desire to terminate if an abnormality was found. In one, repeat imaging was done to assess fetal heart rate and AV conduction due to positive maternal SSA antibodies. Table 1 Indications for early fetal echocardiography Indication Fetuses imaged Fetuses with disease Percentage abnormal (%) Suspected heart disease 12 11 91.7 Extracardiac abnormality 12 6 50.0 Aneuploidy 9 3 33.3 Arrhythmia 9 2 22.2 Increase nuchal translucency 58 8 13.8 Family history 33 2 6.1 Advanced maternal age 1 0 0.0 Maternal lupus 6 0 0.0 Maternal diabetes mellitus 2 0 0.0 Total 142 32 22.5 Table 2 Termination of pregnancy following early fetal echocardiogram Gestational age at evaluation Indication Early result 13 Arrhythmia CHB, AVSD, heterotaxy 13 Extracardiac anomaly Suspected CHD 14 Suspected heart disease Ectopia cordis 14 Suspected heart disease Ebstein s anomaly 14 Suspected heart disease Single ventricle 14 Increased NT Single ventricle 15 Suspected heart disease AVSD, (+trisomy 21) 16 Suspected heart disease Single ventricle, heterotaxy 16 Family history HLHS 16 Suspected heart disease TOF, (+trisomy 21) CHB, complete heart block; AVSD, atrioventricular septal defect; CHD, congenital heart disease; NT, nuchal translucency; HLHS, hypoplastic left heart syndrome; TOF, tetralogy of Fallot.

792 J. I. Pike et al. Table 3 Cardiac disease detected at early fetal echocardiogram Gestational age at evaluation Indication Early fetal echocardiogram Mid-gestation fetal echocardiogram 12 Increased NT?VSD Normal 12 Increased NT?VSD,?ASD Echogenic focus, thick right ventricle 12 Increased NT AVSD AVSD, Trisomy 21 13 Increased NT?VSD Normal 13 Arrhythmia CHB, AVSD, heterotaxy N/A 13 Increased NT HLHS Aortic and mitral stenosis/ coarctation/ borderline LV 13 Extracardiac anomaly Large mass Large Mass 13 Extracardiac anomaly Likely CHD N/A 13 Suspected CHD VSD VSD 13 Suspected CHD VSD, only one great vessel Pulmonary atresia, VSD, criss-cross heart 14 Extracardiac anomaly?multiple cardiac tumors Echogenic focus,?vsd 14 Extracardiac anomaly?vsd N/A 14 Increased NT AVSD AVSD, Trisomy 21 14 Suspected CHD Ebstein s anomaly N/A 14 Suspected CHD Ectopia cordis N/A 14 Suspected CHD Single ventricle N/A 14 Increased NT Single ventricle N/A 15 Increased NT?VSD Normal 15 Suspected CHD AVSD N/A (Trisomy 21) 15 Family History of CHD Unbalanced AVSD Unbalanced AVSD 16 Suspected CHD AVSD AVSD 16 Suspected CHD AVSD AVSD 16 Aneuploidy AVSD AVSD 16 Aneuploidy AVSD AVSD 16 Aneuploidy Coarctation of the aorta Coarctation of the aorta 16 Arrhythmia Echogenic focus N/A 16 Family History of CHD HLHS N/A 16 Suspected CHD Single ventricle Single ventricle 16 Suspected CHD Single ventricle, heterotaxy N/A 16 Suspected CHD TOF N/A (Trisomy 21) 16 Extracardiac anomaly Tricuspid valve regurgitation N/A 16 Extracardiac anomaly?avsd VSD Italicized fetuses were terminated or lost to follow-up. Fetuses in bold had diagnoses which differed at mid-gestation follow-up. NT, nuchal translucency; VSD, ventricular septal defect; ASD, atrial septal defect; CHB, complete heart block; AVSD, atrioventricular septal defect; CHD, congenital heart disease; HLHS, hypoplastic left heart syndrome; LV, left ventricle; TOF, tetralogy of Fallot; N/A, not applicable;? denotes a suspected finding. Indication for referral By far, the indications for early fetal echocardiogram that were most likely to yield structural cardiac disease were suspected heart disease (91.7%) and extracardiac anatomic anomalies on an early obstetrical ultrasound (50%). Increased NT (>3 mm), an increasingly common indication for early fetal echocardiography, yielded a finding of structural cardiac disease in 13.8% of such referrals. (Table 1) No fetuses referred for advanced maternal age, maternal lupus, or maternal diabetes mellitus had cardiac disease. All those referred for maternal lupus had a normal PR interval. Mid-gestation follow-up Routine fetal echocardiography follow-up at greater than 20 weeks EGA was available in 128 of 142 fetuses. Of the fetuses that did not return, ten pregnancies were known to have been terminated, and four were lost to follow-up (one normal was lost to follow-up; the remaining three had an abnormal initial early fetal echocardiograms). All of those known to have terminated were diagnosed with significant heart disease and/or notable extracardiac or genetic abnormalities. In those with isolated CHD, the result of the early fetal echocardiogram was the primary reason for termination. In those with additional findings, it could not be ascertained as to the primary reason for termination (Table 2).

Early fetal echocardiography 793 A structural cardiac anomaly was found in 32 out of 142 fetuses (22.5%) (Table 3). One hundred twenty-eight fetuses, 19 with a cardiac anomaly at the initial early study, had a follow-up fetal echocardiograms at greater than 20 weeks EGA. At follow-up evaluation, three of the 19 fetuses initially diagnosed with a cardiac anomaly had a normal heart; conversely, no fetuses initially diagnosed with a normal heart were subsequently found to have cardiac disease. This yielded a sensitivity of 100%, a specificity of 97.3%, a positive predictive value of 84.2%, and a negative predictive value of 100% for major structural heart disease. In total, seven fetuses (5%) had some modification of the initial cardiac diagnosis at follow-up (Table 3; bolded subjects). As stated, three had a structurally normal heart at the followup comprehensive mid-gestation echocardiogram. All three were described as having a suspected or possible ventricular septal defect at the early fetal echocardiogram. It is unclear whether these ventricular septal defects were inaccurately diagnosed at initial echocardiogram, or the defect closed and early imaging reveals the potential natural history of small septal defects closing during gestation. Of the remaining fetuses with modified diagnoses, another with a possible ventricular septal defect was later found to have an intact ventricular septum, but a thickened right ventricle. One fetus was described as having a possible atrioventricular canal at initial early fetal echocardiogram; the diagnosis was changed to a moderate ventricular septal defect at follow-up. Another, referred for significant extracardiac anomalies was thought to have multiple cardiac tumors at initial exam but found to have an echogenic focus and ventricular septal defect at subsequent follow-up examination. Finally, a fetus referred at 13 weeks for increased NT was initially diagnosed with hypoplastic left heart syndrome but was ultimately determined at follow-up scan to have Shone s syndrome including aortic and mitral stenosis, coarctation of the aorta, and a borderline left ventricle (Figure 1). Figure 1 Early scans (12 and 16 weeks) and mid-gestation scan (28 weeks) in a fetus originally diagnosed with a hypoplastic left heart syndrome variant, later noted to be Shone s with mitral and aortic stenosis, coarctation, and borderline left ventricle. RA = right atrium, RV = right ventricle, LA = left atrium, LV = left ventricle. (A) Two-dimensional (2D) four-chamber view at 12 weeks. (B) Color four-chamber view at 12 weeks using transvaginal imaging, note the color difference filling the RV and LV. (C) 2D four-chamber view at 16 weeks. (D) Color four-chamber view at 16 weeks, note the color difference filling the RV and LV. (E) 2D four-chamber view at 28 weeks. (F) Color four-chamber view at 28 weeks

794 J. I. Pike et al. There was no difference between the EGA at initial study of those with a modification of diagnosis at follow-up and those with no change in diagnosis (13.6 vs 14.5 weeks, p = 0.07), though there was a trend towards improved accuracy with no change in diagnosis if the initial early fetal echocardiogram was performed later in gestation. As expected, image quality improved throughout gestation (Figure 2). Postnatal follow-up In no subjects with an abnormal scan was there a significant change in diagnosis between the mid-gestation fetal echocardiogram and the initial postnatal study, though this information was only available for 14 of the 16 with abnormal fetal echocardiograms at mid-gestation, as there were two subsequent in utero demises. Of the 109 with normal fetal echocardiograms at both initial early study and subsequent mid-gestation study, there were postnatal echocardiograms available in 26; 78 had no postnatal follow-up and 5 were known to have terminated. Normal echocardiograms were found in 24 of the 26 at initial postnatal study. In the remaining two subjects, a small muscular ventricular septal defect was found on postnatal exam. No unexpected severe CHD was identified postnatally (Figure 3). DISCUSSION Our study shows that early fetal echocardiography, performed between 12 and 16 weeks gestational age, is technically feasible and can identify a wide variety of significant cardiac anomalies in the hands of experienced providers specializing in cardiac imaging. Such evaluation can be an important part of early prenatal counseling, especially in those fetuses with known genetic abnormalities or other extracardiac defects. In addition, it allows for the assessment of the progression of disease throughout gestation and as in utero interventions become more widespread, this may allow for earlier and more effective intervention. 13 In our hands, the detection rate of CHD was high in the group of patients referred for early fetal cardiac exam, specifically those in which a cardiac defect was already suspected, or those in which an extracardiac anomaly had been previously diagnosed. Low yield indications were those referred due to maternal risk profile such as maternal diabetes or lupus, though this may be secondary to small sample size, as the number of those referred for these indications was limited. However, as these indications for referral are typically used for screening in mid-gestation, it is not surprising that the vast majority had no cardiac disease, as opposed to those in which the indication is an already suspected abnormality. Given that referral to a fetal cardiac specialist early in gestation for a fetal echocardiogram is not for screening purposes, these indications with low yield of diagnosis may not warrant referral unless an abnormality is suspected. Another common referral for early fetal echocardiogram is in women with a significant family history of CHD, often in a prior pregnancy. While the yield of heart disease detection was lower (6.1%) than other indications in which abnormalities Figure 2 Four chamber view of the heart through early gestation. Note improvement in resolution and better delineation of structures from 12 to 17 weeks of gestation. RA = right atrium, RV = right ventricle, LA = left atrium, LV = left ventricle. (A) 12 weeks. (B) 13 weeks. (C) 14 weeks. (D) 15 weeks. (E) 16 weeks. (F) 17 weeks

Early fetal echocardiography 795 Figure 3 Summary outcome information for fetal patients having an early fetal echocardiogram were noted, it is a higher detection rate than what is reported at mid-gestation. 14 16 This could be due to different patient characteristics. Though speculative, we believe that it is more likely that a family with a history of severe disease such as heterotaxy syndrome or hypoplastic left heart syndrome would be sent for early imaging, and the recurrence risk for these severe defects may be higher. In these families with significant past experience, the benefit of early fetal cardiac evaluation may actually lie in the reassurance given with a normal study, and the emotional stress that this may ease for the woman and her partner. In these cases, though family history as a reason for referral is considered at mid-gestation to be an indication, the benefits of the early fetal echocardiogram to the family may outweigh the small likelihood of actually identifying significant CHD. For this reason, we believe that family history of significant CHD in a first degree relative is a reasonable indication for referral to a fetal cardiac specialist for early fetal echocardiogram. Even with reassuring accuracy in regards to identifying major CHD as demonstrated by our high sensitivity, specificity, and negative and positive predictive values, it remains vitally important to counsel patients regarding the limitations of early fetal echocardiography. There are technical constraints to image resolution that become particularly important when imaging fetuses in early gestation, and it is for this reason that septal defects may remain difficult to diagnosis with complete accuracy. In addition, there are diseases that progress throughout gestation, and early fetal echocardiography can only describe the structure of the heart at the time point of imaging. Other studies have also looked at the usefulness of evaluation of the fetal heart early in gestation. 17 19 These studies demonstrated that early imaging of the fetal heart is technically feasible and can identify a wide spectrum of significant CHD; however, unlike our study, there was significant cardiac disease that was missed on the initial early evaluation. Of course, it is expected that not all CHD will be identified, though we believe that with increasing experience and fetal cardiac expertise, improvements in technology, and creation of universal guidelines for fetal cardiac imaging, detection rates and accuracy will continue to improve. This study suggests that in the hands of a fetal cardiac specialist acquiring not only two-dimensional still frames of the fetal heart, but real-time imaging with acquisition of video clips with sweeps, and color and pulsed Doppler interrogation of all cardiac structures, most major defects can be detected if images of the heart can be obtained. Of note is that these same criteria for fetal heart imaging in mid-gestation (18-22 weeks) were recently published as Fetal Echocardiography Guidelines by a multidisciplinary writing group for the American Institute of Ultrasound in Medicine. 20 It suffices to say that these same guidelines should apply to early imaging to maximize the likelihood of detection of cardiac abnormalities. In our experience, transabdominal imaging was most often sufficient to acquire all views and sweeps; however, transvaginal imaging

796 J. I. Pike et al. was a useful adjunct particularly 15 weeks. We must caution, however, that limitations in imaging do exist, and we support the recommendation for mid-gestation fetal echocardiograms in all patients. Our study has several important limitations. It is retrospective in nature and therefore follow-up mid-gestation and postnatal echocardiograms were not available in several subjects, most notably the ones with normal first and midtrimester exams. In addition, given the relatively small number of women referred for early fetal echocardiograms, the number of abnormal early fetal echocardiograms available for analysis was limited. The small number of abnormal early studies might especially limit the assessment of the yield of various indications for early fetal echocardiograms. The feasibility of extrapolating these results to a general population without an increased risk for significant disease should not be assumed. CONCLUSION In summary, early fetal cardiac imaging performed by an experienced fetal cardiac specialist is useful in the evaluation of high-risk pregnancies for diagnosis of CHD and reassurance when normal. Regardless of initial result, early fetal echocardiography should be followed by a comprehensive cardiac evaluation at 18 to 22 weeks EGA to maximize detection and accuracy of diagnosis. ACKNOWLEDGEMENT We would like to thank Amanda Fulgium for her expert imaging and Kami Skurow-Todd for her assistance with data management. WHAT S ALREADY KNOWN ABOUT THIS TOPIC? Fetal echocardiography is feasible early in gestation. Reports of experience with early fetal heart imaging in the United States from obstetrics/maternal fetal medicine imaging laboratories suggest that, in most fetuses, imaging of the four chambers and outflow tracts is possible. WHAT DOES THIS STUDY ADD? Report of usefulness of early fetal echocardiography in an experienced fetal cardiac center. 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