Early fetal echocardiography: Experience of a tertiary diagnostic service

Australian and New Zealand Journal of Obstetrics and Gynaecology 2015; 55: 552 558 DOI: 10.1111/ajo.12379 Original Article Early fetal echocardiography: Experience of a tertiary diagnostic service Ritu MOGRA, 1,2,3 Rahmah SAAID, 1 Greg KESBY, 1,3 Janette HAYWARD, 3 Jessica MALKOUN 3 and Jon HYETT 1,2 1 Department of High Risk Obstetrics, RPA Women and Babies, Royal Prince Alfred Hospital, 2 Discipline of Obstetrics, Gynaecology and Neonatology, Faculty of Medicine, University of Sydney, and 3 Sydney Ultrasound for Women, Sydney, New South Wales, Australia Background: There is a growing body of evidence that most of the major cardiac abnormalities can be diagnosed at 14 15 weeks of gestation. We present our experience of early fetal echocardiography. Materials and Methods: This is a retrospective cohort study of women referred for early fetal echocardiography at 13 16 weeks of gestation at Royal Prince Alfred Hospital and Sydney Ultrasound for Women between August 2011 and March 2014. Findings of early fetal echocardiography, details of subsequent ultrasound examinations and pregnancy outcome were recorded. Results: Early fetal echocardiography was performed in 400 euploid fetuses at a mean gestational age of 15 +2 weeks. 85% of women were referred for increased nuchal translucency. 383/400 (96%) women had both normal early and late fetal echocardiograms 15/400 (3.7%) were found to have a cardiac defect at early fetal echocardiography, including 14 major and one minor abnormality. Two additional minor cardiac defects were diagnosed at later antenatal ultrasounds. One case, defined as being normal antenatally, was found to have a minor cardiac abnormality post-natally. Eight (57%) women whose fetus had a major cardiac defect chose to terminate the pregnancy. In the pregnancies that continued, the sensitivity and specificity for major cardiac defects was 100%, 95% CI (0.98 1.00). Conclusion: Early fetal echocardiography is feasible and highly sensitive and specific in experienced hands. The high specificity facilitates early reassurance of those women assessed at increased risk for fetal cardiac malformations. Key words: congenital heart disease, echocardiography, fetus, prenatal diagnosis, ultrasound. Introduction Congenital heart disease (CHD) is a significant contributor to infant mortality and morbidity. Major abnormalities that are potentially lethal or require surgical repair within the first year of life affect approximately 4 per 1000 live births. 1,2 This is similar to the prenatal prevalence of chromosomal abnormality, but the development of highly sensitive screening programs for aneuploidy means that CHD is effectively six times more common in the post-natal period. 3,4 Antenatal screening for CHD has proven to be difficult. Policies defining a high-risk cohort based on maternal demographics are of limited value as the majority (>90%) of affected infants have no significant historical identifier. 5,6 Routine anatomical assessment at the 20-week morphology ultrasound scan, imaging the four-chamber view and Correspondence: Dr Ritu Mogra, Staff Specialist in Obstetric and Gynaecological Ultrasound, RPA Women and Babies, Royal Prince Alfred Hospital, Missenden Road, Camperdown, NSW 2050, Australia. Email: ritu.mogra@sswahs.nsw.gov.au Received 14 January 2015; accepted 18 June 2015. outflow tracts, has had varying success 7,8 with reliance on this mid-trimester assessment also meaning that abnormalities are identified relatively late in pregnancy, increasing the social, psychological and medical risks associated with decisions around termination of pregnancy. 9 The ability to detect fetal cardiac malformations in the 1st trimester is desirable but limited by fetal size and other imaging considerations. Nevertheless, markers for cardiac abnormality can be ascertained at 11 13 +6 weeks of gestation, including increased nuchal translucency and changes in the haemodynamic patterns of flow through the tricuspid valve and ductus venosus, which are known to identify a group of women at increased risk for fetal cardiac malformations. 10 12 Improvements in the resolution of 2D grey scale and colour Doppler ultrasound imaging, and increasing confidence with regard to fetal echocardiography, mean that it is becoming easier to interrogate the fetal heart at earlier points in gestation. 13,14 Many major cardiac defects can be effectively diagnosed at an earlier stage of pregnancy, with high levels of sensitivity and specificity, allowing clinicians to have confidence in managing these findings. 15 21 We report our experience in offering an early fetal echocardiography service to women identified at increased 552 2015 The Royal Australian and New Zealand College of Obstetricians and Gynaecologists The Australian and New Zealand Journal of Obstetrics and Gynaecology

Early fetal ECHO risk for fetal cardiac malformation in Sydney, New South Wales (NSW), Australia. Materials and Methods This was a retrospective review of a cohort of pregnancies that had early fetal echocardiography performed at one tertiary obstetric hospital and one private practice in central Sydney, NSW. The data represent a consecutive cohort of women seen between August 2011 and March 2014. Early fetal echocardiography was performed between 13 and 16 weeks gestation. Pregnancies that were affected by chromosomal abnormality are excluded from this data set. Analysis was performed in accordance with ethics approval granted by Sydney Local Health District. The early fetal echocardiography service accepted referrals from multiple disciplines, including general practitioners, obstetricians, maternal fetal medicine specialists and clinical geneticists. Appointments were scheduled after and separate to screening for chromosomal abnormality (typically performed at 11 13 +6 weeks gestation). Women who had a high risk for aneuploidy calculated by combined first trimester screening were offered invasive testing (chorionic villus sampling), and these results were normally available at the time of echocardiographic assessment. All early fetal echocardiograms were performed by one sonologist (RM) who has received training and has a special interest in this area. Two-dimensional sonography and colour flow mapping (E8, General Electric Company, Cincinnati, OH, USA with RAB 4 8 Mhz transabdominal and 5 9 Mhz transvaginal probes) were used to assess abdominal situs, the four-chamber view, the right and left ventricular outflow tracts, including crossover of the great arteries, the three-vessel and tracheal views. 22 Systemic and pulmonary venous drainage was also assessed. In most cases, all views could be obtained using a transabdominal approach. In cases where these views were not satisfactory, transvaginal assessment was also performed (5% of total cases). In addition to the cardiac assessment, a systematic sequential anatomical survey was performed. Women were counselled about any abnormality and those that chose to continue the pregnancy had further detailed echocardiography at 20 weeks gestation and were managed by a multidisciplinary paediatric cardiology service through to delivery and infancy. Details describing the indication for referral were prospectively recorded at the time of the examination together with maternal demographic history and the findings at each ultrasound examination. In circumstances where an infant was born with a cardiac defect, details of the nature of the anomaly were obtained from post-natal echocardiogram and/or surgical records. Results Early fetal echocardiography was successfully performed in all 400 cases. The mean gestation at examination was 15 +2 (range: 12 +5 15 +6 ) weeks. The majority (85%) of patients were referred for a finding of increased nuchal translucency at the time of combined first trimester screening (Table 1). Smaller numbers were referred on the basis of traditional factors for defining a high-risk cohort, including maternal medical history (5%), a family history of congenital heart disease (5%) and maternal ingestion of recognised teratogens (2%). Ten (2.5%) women were referred because the heart appeared abnormal, or haemodynamic flow across the heart valves having been assessed as abnormal at the time of the 12- week scan. A total of 15 (3.7%) fetuses were found to have a cardiac defect at the time of the early echocardiogram: this included 14 major and one minor cardiac abnormality (Table 2). A further two additional minor cardiac Table 1 Findings of cardiac abnormality in cases referred for early fetal echocardiography Indication for referral Total N (% all cases) Major CHD (n; %) Minor CHD (n; %) Yield (major or minor CHD) Family history of cardiac abnormality 18 (4.5) 1 (5.5) 1 in 18 Maternal illness (eg diabetes) 19 (4.75) 1 (5) 1in19 Ingestion of teratogen (eg Lithium) 6 (1.5) Abnormal 12-week scan Abnormal cardiac views (with normal NT) 4 (1.0) 1 (25) 1 in 4 Tricuspid regurgitation (with normal NT) 5 (1.25) 1 (20) 1in5 Abnormal ductus venosus flow (with normal NT) 1 (0.25) NT between 95th centile and 3.0 mm 182 (45.5) 2 (1.1) 1 (0.5) 1 in 60 NT between 3.0 mm and 3.5 mm 81 (20.0) 4 (4.9) 1in20 NT > 3.5 mm 81 (20.0) 6 (7.4) 1in14 Others 3 (0.75) Total 400 14 (3.5) 3 (0.75) 1 in 24 CHD, congenital heart disease; NT, nuchal translucency. Maternal age n = 1; High risk T21 n = 1; High risk T13 n = 1. 2015 The Royal Australian and New Zealand College of Obstetricians and Gynaecologists 553

R. Mogra et al. Table 2 Clinical course of the cardiac abnormalities seen in this series Case no. Cardiac anomaly Clinical course Abnormal 4-chamber view at 12 weeks 1 Hypoplastic left heart syndrome (HLHS) 2 Hypoplastic left heart syndrome (HLHS) 3 Hypoplastic left heart syndrome (HLHS) 4 Pulmonary atresia with intact septum 5 Pulmonary atresia with intact septum 6 Atrioventricular septal defect (AVSD) 12-week scan NT 2.7 mm, High risk for T21, 4-chamber view not examined 15-week findings mitral atresia and aortic atresia (HLHS). Outcome surgical termination of pregnancy (TOP) at 14 weeks gestation 12-week scan NT 2.7 mm, High risk for T21, 12-week scan performed elsewhere 15-week findings mitral atresia and aortic atresia (HLHS). 12-week scan NT 3.1 mm, High risk for T21, 4-chamber view not examined 15-week findings mitral atresia and aortic atresia (HLHS). 12-week scan NT 4.7 mm, High risk for T21, 4-chamber view appeared abnormal 15-week findings hypoplastic right ventricle, No flow across tricuspid valve, Pulmonary atresia with reverse flow in the pulmonary artery through ductus arteriosus. 12-week scan NT 5.6 mm, High risk for T21, 4-chamber view not examined 15-week findings hypoplastic right ventricle, No colour flow across tricuspid valve, Pulmonary atresia with reverse flow in the pulmonary artery through ductus arteriosus. 12-week scan NT 3.2 mm, low risk for T21, 4-chamber view not examined 15-week findings AVSD, amniocentesis revealed normal karyotype 20-week findings AVSD was confirmed at 20 weeks and post-natal scan Counselling: included surgical repair at age of three to six months with excellent results Outcome AVSD repaired at age of three months Normal 4-chamber view 7 Aortic stenosis 12-week scan NT 3.6 mm, High risk for T21, 4-chamber view not examined 15-week findings increased aortic velocity, mitral regurgitation and structurally normal heart 20 weeks aortic stenosis with no ventricular disproportion Counselling: initial counselling was difficult due to uncertainty regarding progression of the disease in utero; however, later on as the left ventricle remained normal size, it was apparent that this baby would not require staged surgery and univentricular palliation Outcome balloon valvuloplasty at birth 8 Transposition of great arteries (TGA) with pulmonary atresia 9 Transposition of great arteries (TGA) 12-week scan NT 1.4 mm, low risk for T21, heart not examined 15-week findings TGA with pulmonary atresia Counselling: included potential for neonatal shunt procedure followed by corrective surgery. 12-week scan NT 3.5 mm twin 1, low risk for T21, 4-chamber view appeared normal 15-week findings transposition of great arteries (TGA) 19 20-week findings TGA, ventricular septal defect (VSD) Counselling: included corrective surgery in neonatal period with excellent surgical results. Outcome neonatal switch procedure 554 2015 The Royal Australian and New Zealand College of Obstetricians and Gynaecologists

Early fetal ECHO Table 2 (Continued ) Case no. Cardiac anomaly Clinical course 10 Ebstein s anomaly with pulmonary atresia 11 Left atrial isomerism- interrupted IVC 12 DORV with pulmonary atresia, Probable right atrial isomerism 12-week scan NT 3.1 mm, low risk for T21, 4-chamber view not examined 15-week findings severe tricuspid regurgitation, tricuspid valve dysplasia, Pulmonary atresia 19 20-week findings Ebstein s anomaly with pulmonary atresia Counselling: included neonatal shunt procedure followed by corrective surgery later. Outcome neonatal death at 3 weeks due to sepsis after shunt procedure 12-week scan NT 1.2 mm, low risk for T21, Stomach was noted to be positioned on the right side of abdomen and heart correctly positioned on left side 15-week findings interrupted IVC, Normal intracardiac anatomy, left atrial isomerism 19 20-week findings interrupted IVC, Normal intracardiac anatomy, left atrial isomerism Counselling: included risk of cardiac arrhythmia, malrotation of gut requiring surgery and biliary atresia Outcome diagnosis confirmed after birth, neonatal surgery for malrotated gut 12-week scan NT 1.4 mm, low risk for T21, stomach was noted to be positioned on the right side of abdomen and heart correctly positioned on left side 15-week findings hypoplastic left ventricle, ventricular septal defect (VSD), double outlet right ventricle with pulmonary atresia, probable right isomerism and univentricular palliation and significant morbidity associated with right isomerism. Outcome surgical TOP at 15 + 4 weeks gestation 13 Tricuspid valve dysplasia 12-week scan NT 1.2 mm, low risk for T21, tricuspid regurgitation noted at 12 weeks 15-week findings moderate to severe tricuspid regurgitation, no ventricular or arterial disproportion 19 20-week findings tricuspid dysplasia, right atrial dilatation which progressed as pregnancy advanced Counselling: included good outcome at 19 20 weeks; however, there was significant progression of the pathology alter in the pregnancy. Outcome univentricular Fontan s palliation 14 Fallot s tetralogy 12-week scan NT 4.7 mm, High risk for T21, NT scan was performed elsewhere 15-week findings pulmonary stenosis, VSD 19 20-week findings Fallot s tetralogy, Bilateral cystic hygromata, normal CGH array Counselling: Included corrective surgery for Fallot s tetralogy with good surgical results. 10 15% risk of genetic syndrome was also discussed. Outcome: medical TOP at 20 weeks gestation, autopsy declined 15 Coarctation of aorta (COA) 12-week scan NT 4.5 mm, High risk for T21, NT scan was performed elsewhere 15-week findings Coarctation of aorta (COA) 19 20-week findings COA, small perimembranous VSD Counselling: included surgical repair after birth with good prognosis. Outcome: COA repaired at birth abnormalities (small ventricular septal defects that have not required surgical repair) were identified on follow-up ultrasound at 19 weeks gestation. A total of 12/14 (85.7%) of the major cardiac defects had increased nuchal translucency at the time of the routine 11 13 +6 -week scan: six had a NT between the 95th centile and 3.5 mm (which equates to the 99th centile) and six had a NT >3.5 mm. The two remaining major defects were suspected for differing reasons: a maternal history of type 1 diabetes and the finding of tricuspid regurgitation at the 12-week scan. A total of 180/400 cases had a high adjusted risk for aneuploidy through combined first trimester screening. In the high-risk group, 165 had an invasive test, six had NIPT, and nine declined any further investigation. All pregnancies that resulted in termination were karyotyped. In the liveborn cohort, no abnormal phenotypic features suggestive of chromosomal abnormalities were identified. A total of seven of the 14 (50%) women who had a fetus affected by a major cardiac defect chose to terminate the pregnancy <16 weeks gestation, and another had a termination of pregnancy after a second echocardiographic assessment at 20 weeks gestation. Ultrasound-based cardiac findings were checked by a second experienced sonologist prior to termination of pregnancy in all cases. Four women had fetal hypoplastic left heart, and two fetal 2015 The Royal Australian and New Zealand College of Obstetricians and Gynaecologists 555

R. Mogra et al. hypoplastic right heart; these women had been advised that the baby would require staged operations leading to Fontan s circulation One fetus had transposition of the great arteries with pulmonary atresia that would have required a neonatal shunt procedure and corrective surgery later; the mother elected to interrupt the pregnancy at an early stage. One woman asked to terminate the pregnancy at 20 weeks gestation; the fetus had Fallot s tetralogy, and the decision to end the pregnancy was based on the presence of other extracardiac abnormalities. Seven women had a surgical termination <16 completed weeks gestation, and the fetal heart was not available for examination. One woman had a medical termination at 20 weeks gestation but declined autopsy. The outcomes of the six pregnancies that had a major defect and three pregnancies with minor anomalies that continued to term were confirmed post-natally (Table 2). Additional minor cardiac findings (ventricular septal defect) were identified in two of the cases with a major one that had previously been defined as having coarctation of the aorta, the other with transposition of the great arteries. No major cardiac anomalies were reported in the remaining cohort of 383 women who had a normal early fetal echocardiography and a normal scan at 20 weeks, although one infant, affected by Noonan syndrome, was found to have pulmonary stenosis at six months of age this is being managed expectantly. The sensitivity for major cardiac defects for the pregnancies which continued was 100%, 95% CI (0.74 1.00) and specificity was 100%, 95% CI (0.98 1.00). Discussion Early fetal echocardiography provides a valuable opportunity to examine fetal cardiac anatomy in women deemed to have a fetus at high risk of having an affected pregnancy. A total of 3.7% of fetuses referred for assessment at this early gestation had a cardiac abnormality, approximately a tenfold increase on the prevalence seen in a background population. The sensitivity and specificity in detecting major defects was very high (100%) as was the negative predictive value so women deemed to be high risk after their 12-week scan could also benefit from early echocardiographic reassurance. Minor defects were harder to identify at this early gestation. Although the sample size is small (only four fetuses had an isolated minor cardiac defect), only one of these anomalies was detected at 14 15 weeks gestation, whilst two were identified at 19 weeks and one was not defined until six months of age. There are no recognised national or international guidelines describing indications for referral for early fetal echocardiography. Indications typically vary according to resources that are available. We have established indications for referral based on assessment of maternal history, indirect signs of cardiac function (nuchal translucency, ductus venosus and tricuspid valve haemodynamics) and the appearance of the fetal heart at the time of the 12-week scan. Increased nuchal translucency is recognised as being associated with structural cardiac defects, although the sensitivity of this tool in screening for cardiac abnormalities has varied significantly in different studies. 10,23 However, this marker is routinely assessed in all 11 13 +6 -week scans, and this was the commonest indication for referral in our cohort. We chose to define the 95th centile as the point where a risk of a cardiac defect was increased and an early fetal echocardiogram should be offered. Using this cut-off allowed detection of twice as many major cardiac defects although it also led to three times as many scans being performed when compared to a static 3.5 mm cut-off. The other indirect signs of a cardiac defect that can be demonstrated at 11 13 +6 weeks are reversed flow in the A wave of the ductus venosus and reversed flow across the tricuspid valve. These features are not commonly assessed as part of combined first trimester screening in Australia, reflected in the relatively low number of fetuses referred for early fetal echocardiography on the basis of these findings in our series. This may also explain the apparent low prevalence of these markers in the group of major cardiac defects that were reviewed. Fetal heart activity is routinely documented at 11 13 +6 weeks, and if this is carried out using an axial section of the chest, the sonographer can demonstrate the fourchamber view in 90% of cases, which has a high yield for abnormality. 24,25 Assessment of flow across the tricuspid valve can also be carried out in the 4-chamber view once the sonographer has identified the right heart chambers, improving recognition of cardiac anatomy at 11 13 +6 weeks. Colour Doppler is also valuable in demonstrating the outflow tracts. Although few fetuses were referred on the basis of an abnormal four-chamber view, these cases have a high yield for abnormality and sonographers should be encouraged to develop these skills. Increased NT is a strong indicator for cardiac abnormality. In this cohort, an NT 95th centile to 3 mm had a prevalence of cardiac abnormality of 1.1%; a 3.6- fold increase from the background population. This increased to a prevalence of 4.9% with NT 3.0 3.5 mm and 7.4% with NT >3.5 mm. These rates are very similar to those reported previously. 26 28 Each cut-off impacts on the specificity and positive predictive value of screening and needs to be tailored to suit local service availability. First trimester echocardiography for the detection of major cardiac malformations has been shown to be highly sensitive and specific in experienced hands. Sensitivity and specificity of major cardiac defects (for the pregnancies which continued) in our study was 100%, which is not different from other studies performed by experienced operators in first trimester. Accuracy of first trimester detection of major cardiac abnormalities was demonstrated in a systematic review of studies where verification was possible either by post-natal echocardiography or by postmortem; specificity reached nearly 100% in pooled analysis. 29 Three recent studies evaluated diagnostic 556 2015 The Royal Australian and New Zealand College of Obstetricians and Gynaecologists

Early fetal ECHO accuracy of early fetal echocardiography by post-natal follow-up and have demonstrated that most major cardiac abnormalities were correctly diagnosed in the first trimester with few false positives. 19 21 It is encouraging to see that all false positives were minor defects for which intervention in the pregnancy would not have been considered at earlier stage. The high sensitivity and specificity of early fetal echocardiography, including the high negative predictive value, demonstrates the value of extending the skill sets of fetal medicine specialists and paediatric cardiologists to provide this service. The limitations of this study include that the prenatal sonographic findings were not confirmed through a process of autopsy in 57% of the pregnancies where the pregnancy was interrupted. These data reflect a referred population, so we are unable to comment on the prevalence of cardiac disease in a wider population although there are other series that have reported the prevalence and detection rates of cardiac defects in relation to first trimester markers. In conclusion, we have demonstrated that early fetal echocardiography is feasible and is highly sensitive, specific and accurate in the diagnosis of major cardiac abnormality in experienced hands. Detailed fetal echocardiography at 14 16 weeks gestation also provides early reassurance when cardiac anatomy is normal. References 1 Campbell M. Incidence of cardiac malformations at birth and later, and neonatal mortality. Br Heart J 1973; 35: 189 200. 2 Hoffmann JIE, Christianson R. Congenital heart disease in a cohort 19,502 births with long-term follow up. Am J Cardiol 1978; 42: 641 647. 3 Van der Linde D, Konings EE, Slager MA. Birth prevalence of congenital heart disease worldwide: a systematic review and meta-analysis. J Am Coll Cardiol 2011; 58: 2241 2247. 4 Morris JK, Alberman E. Trends in Down s syndrome live births and antenatal diagnoses in England and Wales from 1989 to 2008: analysis of data from the National Down Syndrome Cytogenetic Register. BMJ 2009; 339: b3794. 5 Wilson NJ, Allen BC, Clarkson PM et al. One-year audit of a referral fetal echocardiography service. N Z Med J 1994; 107: 258 260. 6 Maher JE, Colvin EV, Samdarshi TE et al. Fetal echocardiography in gravidas with historic risk factors for congenital heart disease. Am J Perinatol 1994; 11: 334 336. 7 Tegnander E, Eik-Nes SH. The examiner s ultrasound experience has a significant impact on the detection rate of congenital heart defects at the second-trimester fetal examination. Ultrasound Obstet Gynecol 2006; 28: 8 14. 8 Ogge G, Gaglioti P, Maccanti S et al. Prenatal screening for congenital heart disease with four-chamber and outflow-tract views: a multicenter study. Ultrasound Obstet Gynecol 2006; 28: 779 784. 9 Rauch ER, Smulian JC, De Prince K et al. Pregnancy interruption after second trimester diagnosis of fetal structural anomalies: the New Jersey Fetal Abnormalities Registry. Am J Obstet Gynecol 2005; 193: 1492 1497. 10 Hyett JA, Perdu M, Sharland GK et al. Increased nuchal translucency at 10 14 weeks of gestation as a marker for major cardiac defects. Ultrasound Obstet Gynecol 1997; 10: 242 246. 11 Chelemen T, Syngelaki A, Maiz N et al. Contribution of ductus venosus Doppler in first trimester screening for major cardiac defects. Fetal Diagn Ther 2011; 29: 127 134. 12 Pereira S, Ganapathy R, Syngelaki A et al. Contribution of fetal tricuspid regurgitation in first trimester screening for major cardiac defects. Obstet Gynecol 2011; 117: 1384 1391. 13 Sairam S, Carvalho JS. Early fetal echocardiography and anomaly scan in fetuses with increased nuchal translucency. Early Hum Dev 2012; 88: 269 272. 14 Comas Gabriel C, Galindo A, Martınez JM et al. Early prenatal diagnosis of major cardiac anomalies in a high-risk population. Prenat Diagn 2002; 22: 586 593. 15 Huggon IC, Ghi T, Cook AC et al. Fetal cardiac abnormalities identified prior to 14 weeks gestation. Ultrasound Obstet Gynecol 2002; 20: 22 29. 16 Simpson JM, Jones A, Callaghan N et al. Accuracy and limitations of transabdominal fetal echocardiography at 12-15 weeks of gestation in a population at high risk for congenital heart disease. BJOG 2000; 107: 1492 1497. 17 Zosmer N, Souter VL, Chan CS et al. Early diagnosis of major cardiac defects in chromosomally normal fetuses with increased nuchal translucency. Br J Obstet Gynaecol 1999; 106: 829 833. 18 Rustico MA, Benettoni A, D Ottavio G et al. Early screening for fetal cardiac anomalies by transvaginal echocardiography in an unselected population: the role of operator experience. Ultrasound Obstet Gynecol 2000; 16: 614 619. 19 Vita Zidere MD, Bellsham-Revell H, Nicola Persico MD et al. A comparison of the echocardiographic findings in fetuses less than 15 weeks gestation with later cardiac evaluation. Ultrasound Obstet Gynecol 2013; 42: 679 686. 20 Mirza FG, Bauer ST, Williams IA et al. Early fetal echocardiography: ready for prime time? Am J Perinatol 2012; 29: 313 318. 21 Volpe P, De Robertis V, Campobasso G et al. Diagnosis of congenital heart disease by early and second-trimester fetal echocardiography. J Ultrasound Med 2012; 31: 563 568. 22 Carvalho JS, Allan LD, Chaoui R et al. International Society of Ultrasound in Obstetrics and Gynecology. Ultrasound Obstet Gynecol 2013; 41: 348 359. 23 Westin M, Saltvedt S, Bergman G et al. Is measurement of nuchal translucency thickness a useful screening tool for heart defects? A study of 16,383 fetuses. Ultrasound Obstet Gynecol 2006; 27: 632 639. 24 Haak MC, Twisk JWR, Van Vugt JMG et al. How successful is fetal echocardiographic examination in the first trimester of pregnancy? Ultrasound Obstet Gynecol 2002; 20: 9 13. 25 Gembruch U, Shi C, Smrcek JM et al. Biometry of the fetal heart between 10 and 17 weeks gestation. Fetal Diagn Ther 2000; 15:20 31. 26 Mogra R, Alabbad N, Hyett J. Increased nuchal translucency and congenital heart disease. Early Hum Dev 2012; 88: 261 267. 27 Atzei A, Gajewska K, Huggon IC et al. Relationship between nuchal translucency thickness and prevalence of major cardiac 2015 The Royal Australian and New Zealand College of Obstetricians and Gynaecologists 557

R. Mogra et al. defects in fetuses with normal karyotype. Ultrasound Obstet Gynecol 2005; 26: 154 157. 28 Clur SA, Mathijssen IB, Pajkrt E et al. Structural heart defects associated with an increased nuchal translucency: 9 years experience in a referral centre. Prenat Diagn 2008; 28: 347 354. 29 Rasiah SV, Publicover M, Ewer AK et al. A systematic review of the accuracy of first-trimester ultrasound examination for detecting major congenital heart disease. Ultrasound Obstet Gynecol 2006; 28: 110 116. 558 2015 The Royal Australian and New Zealand College of Obstetricians and Gynaecologists