Original papers Med Ultrason 2015, Vol. 17, no. 4,

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1 Original papers Med Ultrason 2015, Vol. 17, no. 4, DOI: /mu rvd The role of ventricular disproportion, aortic, and ductal isthmus ultrasound measurements for the diagnosis of fetal aortic coarctation, in the third trimester of pregnancy. Claudiu Mărginean 1, Cristina Oana Mărginean 2, Iolanda Muntean 3, Rodica Togănel 3, Septimiu Voidăzan 4, Liliana Gozar 3 1 Department of Obstetrics and Gynecology, 2 Pediatrics Clinic I, 3 Pediatric Cardiology Clinic, 4 Department of Epidemiology, University of Medicine and Pharmacy Târgu Mureș, Romania Abstract: Aim: To analyze the role of ventricular disproportion, aortic, and ductal isthmus ultrasound measurements for the diagnosis of fetal aortic coarctation (AoCo) and to evaluate the prediction of a needed neonatal surgical intervention in the presence of a diagnosis of AoCo. Material and methods: We performed a prospective study on 41 fetuses (pregnancy age- 32 to 39 weeks, median 36 weeks) evaluated for left ventricle (LV) < right ventricle (RV) disproportion. Four fetuses were lost from evidence and five fetuses with complex cardiac malformations were excluded. The remaining group of 32 fetuses and newborns were evaluated. Results: AoCo was confirmed in 9 neonates (28.12%), all requiring surgical treatment in the neonatal period. Significant statistical differences were found in Z-score (p=0.0023) and dimensions (p=0.0029) of the aortic isthmus between the neonates with normal aorta and those with AoCo. If the values of RV/LV>1.5, Ductus/Ao isthmus >1.4, and Ao isthmus <4.2 mm are concomitantly accomplished, 83.3% of the fetuses (20 of 23) did not necessitate neonatal surgical intervention. Five of the 9 operated newborns had all three parameters with values over the threshold. The probability for required surgery is times higher when the Ao isthmus is <4.2 mm (OR = [95% CI = ]). Conclusions: The use of the combination between the three studied parameters with their cut-off score prediction decreases the false positive diagnosis of AoCo. The fetuses with ventricular disproportion developed only in the last trimester, had reduced chances for AoCo. Keywords: fetal ultrasound, aortic coarctation, ventricular disproportion Introduction The cardiac ventricular disproportion (the apparent larger right ventricle RV compared with the left ventricle LV) seen in fetal ultrasound is most of the time a subjective finding. In the last trimester of pregnancy this ventricular disproportion can be physiological, due to the Received Accepted Med Ultrason 2015, Vol. 17, No 4, Corresponding author: Septimiu Voidăzan, MD, PhD Departament of Epidemiology, University of Medicine and Pharmacy Târgu Mureş, 38 Gh. Marinescu Street, , Tirgu Mures, Romania Phone: septi_26_07@yahoo.com predominance of the fetal RV [1]. The actual guidelines of echocardiographic screening for the diagnosis of the congenital cardiac malformations include the four chambers, five chambers, and three vessels sections. The evaluation of these sections is recommended to be performed with color Doppler [2]. During the third trimester of pregnancy signs of cardiac chambers disproportion can also be determined by the abnormal caliber of the vessels, as can be encountered in aortic coarctation (AoCo) [3]. The difficulty of positive and differential diagnosis of AoCo has been described in several published papers [3,4-10]. Diagnosis of an aortic isthmus coarctation is possible in 45% of the cases during the fetal life using gray scale ultrasonography [7] and the aortic arch < 3 mm could be considered a good predictor for the need of neonatal surgical intervention [11]. By underlining the turbulent

2 476 Claudiu Mărginean et al The role of ventricular disproportion, aortic, and ductal isthmus ultrasound measurements flow through the aortic arch and the bidirectional flow through the foramen ovale [3,6,10,12], color Doppler ultrasonography can diagnose 65% of AoCo cases [7]. The pulmonary artery/ascending aorta ratio >1.6 [13] and the decreased of LV outflow [14] are other ultrasonographic criteria used for AoCo diagnosis. Pasquini et al developed a Z-score (using the aortic isthmal and ductal diameters) to be used in the prenatal prediction for AoCo [15], especially after 26 weeks of pregnancy [7]. Matsui et al considered predictive for AoCo and requiring surveillance or surgery cases with Z score -2 [7]. All the aforementioned studies underline the limits of echocardiography in AoCo diagnosis during the third trimester of pregnancy and the difficulties in prediction of neonatal surgical intervention. A correct prenatal diagnosis is mandatory, because in fetal cases with AoCo the delivery should be performed in specialized centers, equipped with neonatal intensive care units and cardiac surgery. The main objective of this study was to determine a combination of echocardiographic parameters that can contribute to exclude/confirm AoCo in fetal life. The secondary objective was to determine the prediction of a needed neonatal surgical intervention in the presence of a diagnosis of AoCo. Material and methods This prospective study was conducted between the 1 st of February 2010 and 15 th May 2015, in a tertiary center of Obstetrics-Gynecology and Pediatric Cardiology. In this period a number of 41 fetuses, singleton pregnancies, were evaluated for LV<RV disproportion, being referred to our service by specialists from the entire country, with the suspicion of AoCo or/and other cardiac malformation. Four fetuses were lost from evidence. Other 5 fetuses with transposition of the great arteries (two cases), or atrioventricular canal (three cases) were excluded. The remaining group of 32 fetuses and newborns were evaluated in utero and postpartum until the closure of the ductus arteriosus and for 6 months afterwards. Age of pregnancy for these 32 fetuses was between weeks, with median of 36 weeks. Echocardiographic examination The fetal echocardiographic examination was performed by a mixed team composed of an obstetrician and a pediatric cardiologist, both with a fetal cardiac malformation experience of about 2 years. The examinations were performed using a Voluson 730 Pro (General Electric) ultrasound machine with a RAB 4-8 MHz abdominal transducer. Each examination lasted min. If the necessary conditions for the measurements were not achieved, the ultrasound examination was repeated 24 hours later. The difficulties were related to the fetal position and the inferior vena cava syndrome of pregnancy. Ascending aorta (Ao), pulmonary artery (PA) in 3 vessel section, ductus arteriosus and Ao isthmus near to their confluence in 3 vessel sections, and transverse diameters of the RV and LV in 4 chamber view were measured in utero. We measured the transversal diameter of RV under the level of atrioventricular valves, at the end of the diastole. Three measurements (from separate frames) were performed for every item and the mean was used in analysis. Femur length (FL) was used to calculate Z scores [7,15]. The subjective appearance of the aortic arch, the color Doppler assessment of the flow at the aortic arch and the foramen ovale were recorded. Taking in consideration the normal values already established in normal fetuses ( for RV/LV ratio, for pulmonary artery to aorta ratio [16], maximum 1.36 for ratio between Ductus/Ao isthmus [17], and minimum 4.2 mm for Ao isthmus after 32 gestational weeks [18]) we intended to determine a combination of echocardiographic parameters which was able to exclude the AoCo in fetal life. Consequently for this analysis we associated the three variables: RV/LV >1.5, Ductus/ Ao isthmus >1.4, and Ao isthmus <4.2 mm in cases enrolled in our study. Newborns postnatal evaluation was made by a pediatric cardiologist in the first 4 hours after delivery, using a Philips ultrasound machine ie 33 with a S8-3 transducer. The diagnosis of AoCo on newborns relies on the presence of a posterior shelf of the descending aorta, beyond the origin of the left subclavicular artery, with a high velocity and turbulent flow in the aortic isthmus. Prostaglandin E 2 was administered after postnatal diagnosis of ductus arteriosus-dependent AoCo, this treatment being maintained until the surgical intervention. Inconclusive newborn cases were monitored and serial ultrasound examinations were performed, until the final diagnosis was established or after ductus arteriosus closure (days of life). Newborns without ductal dependent AoCo, but with small isthmus in terms of Z score, were followed-up by the cardiologist until minimum the age of 6 months. The fetuses were divided into two groups depending on the presence or absence of the AoCo as was established in postpartum examination: group 1 fetuses without AoCo and group 2 fetuses with AoCo. The pregnant women signed written informed consent before inclusion and the study was performed according to the Helsinki Declaration with the approval of the local Ethics Comitee. Statistical analysis Statistical analysis was performed using the Graph Pad Prisma Software and the MedCalc Software, Version

3 , using a significance threshold alpha of Descriptive statistics for central tendency and spread of quantitative variables have been performed. The normality of the quantitative variables was tested using a Kolmogorov-Smirnov test followed by Q-Q plots. Differences between groups were tested using the two-tailed Student s t test (data expressed as mean ± SD) for the two-group comparisons. Multivariate analysis was carried out using linear regressions. We used as dependent variables: the group of children who did not undergo a surgical intervention which were codified with 1, and those who underwent a surgical intervention, codified with 0. The independent variables were the RV/LV ratio, the Z score of the ascending aorta, the Ductus/Ao isth- Med Ultrason 2015; 17(4): mus ratio, the PA/ascending aorta ratio, the length of the femur, the Z score of the aortic isthmus, and the value of the aortic isthmus (expressed in millimeters). Results AoCo was confirmed in 9 of the 32 neonates (28.12%), all the cases requiring surgical treatment in the neonatal period. The associations between the prenatal and postnatal diagnosis in group 2 (9 cases) are shown in Table I and the postnatal echocardiographic diagnosis in group 1 (23 cases) in Table II. The comparative analysis between newborns with and without AoCo is detailed in Table III. Table I. Comparison between lesions associated with aortic coarctation dectected during the prenatal and postnatal ecocardiography (n=9 cases). Prenatal echocardiography Postnatal echocardiography 3 cases of aortic arch hypoplasia one associated with aortic valve anomaly and persistent superior left vena cava 3 cases of aortic arch hypoplasia one associated with aortic valve anomaly, persistent superior left vena cava and agenesis of biliary duct (a newborn with surgical intervention for AoCo, who died 3 weeks after surgery) one with superior left vena cava one with persistent superior left vena cava one with ventricular septal one with ventricular septal defect defect 2 cases of ventricular septal defect 3 cases of pulmonary hypertension (associated with persistent foramen ovale) 1 case of a newborn small for gestational age 2 cases of bicuspid aortic valve 3 cases without diagnostic associations 1 case of atrial septal defect Table II. Postnatal diagnosis in neonates without aortic coarctation (n = 23 cases). Number of cases Echocardiographic diagnosis 3 pulmonary hypertension (one associated with persistent foramen ovale) 1 suspicion of a genetic syndrome (genetic molecular results are not yet available) 2 atrial septal defect 1 ventricular septal defect 16 no pathology Table III. Comparisons between the newborns with confirmed postnatal aortic coarctation (AoCo) versus newborns without AoCo. Parameters Postnatal normal aorta (n= 23) Postnatal AoCo ( n=9) p value Mean ± SD Mean ± SD (Student test) Weeks of gestation ± ± RV/LV 1.66 ± ± Z isthmus ± ± Z Ao (ascending) ± ± Duct/ Ao isthmus 1.47 ± ± PA/Ao 1.49 ± ± Ao (ascending)- mm 7.03 ± ± Ao isthmus- mm 4.46 ± ± FL- cm 6.77 ± ± n- number of cases, SD standard deviation, RV right ventricle, LV left ventricle, Z isthmus Z score of aortic isthmus Z Ao ascending Z score of ascending aorta, PA main pulmonary artery, Ao aorta, FL femural length

4 478 Claudiu Mărginean et al The role of ventricular disproportion, aortic, and ductal isthmus ultrasound measurements Table IV. Multivariate logistic regression, in which the dependent variables are the cases with surgical interventions versus the cases without surgical interventions and the independent variables are the Ao ishtmus, ductal isthmus, and RV/LV Dependent Y Groups Variable OR [95% CI] P Ao isthmus OR = [95% CI = ] Ductus/ Ao isthmus OR = 5.73 [95% CI = ] 0.40 RV/LV OR = 0.21 [95% CI = ] 0.14 OR: odds ratio, CI: confidence interval, Ao: aorta, RV: right ventricle, LV: left ventricle Table V. Cut-off prediction of the three variables (RV/LV > 1.5, Ductus/ Ao isthmus > 1.4, Ao isthmus < 4.2 mm) for the indication of neonatal surgical intervention The presence/absence of the three cut-off parameters (RV/LV > 1.5, Ductus/ Ao isthmus > 1.4, Ao With surgery Whithout surgery Groups Total (32 cases) isthmus < 4.2 mm) after birth (9 cases) after birth (23 cases) Parameters no Count without parameters % within parameters 16.7% 83.3% % within groups 44.4% 87.0% yes Count with parameters % within parameters 62.5% 37.5% % within groups 55.6% 13.0% Total Count % within parameters 28.1% 71.9% % within groups 100.0% 100.0% RV right ventrincle, LV left ventricle, Ao- aorta No statistically significant differences between the RV/LV disproportion, Z score of the ascending aorta, Ductus/Ao isthmus ratio, PA/ascending aorta ratio, and FL between the two groups were found. We obtained statistically significant higher values for the Z score of the aortic isthmus in group 1 in comparison with group 2 (p=0.0023) and also statistically significant higher values for the aortic isthmus in group 1 versus group 2 (p=0.0029). The statistical differences between the values of the Z score of the isthmus in group 1 (normal aorta in newborns) and the group 2 with AoCo and postnatal surgical intervention are represented in figure 1a. In multivariate logistic regression analysis, considering the cases with surgical interventions versus the cases without surgical interventions as dependent variables and the Ao isthmus, ductal isthmus, and RV/LV ratio as independent variables, we obtained a statistically significant correlation for the Ao isthmus. So, the probability (odds ratio) of a newborn undergoing surgical intervention in the neonatal period for AoCo was 13.7 times higher when the fetal aortic isthmus was <4.2 mm (table IV). The aortic isthmus dimensions in group 1 (with normal aorta in newborns) versus group 2 with AoCo and postnatal surgical intervention are represented in figure 1b. When the three variables (RV/LV > 1.5, Ductus/ Ao isthmus > 1.4, Ao isthmus < 4.2 mm) were applied to the study group, we found 8 of the 32 fetuses concomitant Fig 1. Box plots of the a) Z score for isthmus in study groups and b) dimensions of the isthmus (in mm) in study groups Fig 2. The 4 chamber view ventricular disproportion. AS left atrium, AD right atrium, VS left ventricle, VD right ventricle.

5 Fig 3. Fetal AoCo image in parasagittal view of the aortic arch and the descending aorta: a) gray scale: b) color Doppler. fulfilling these values. Five of these newborns (62.5%) had AoCo and needed surgical intervention. Concerning the rest of the 24 fetuses which did not accomplish all the three variables, 20 (83.3%) newborns did not undergo surgical intervention. Applying the same variables association in the group 2 with AoCo and postnatal surgical intervention, only 5 of the 9 cases accomplished these cut-off values (table V). In figures 2-4 we exemplified 3 cases with AoCo. Discussions Fig 4. The three vessels trachea view with the aortic arch smaller than the ductal isthmus and the suspicion of fetal AoCo Ductal-dependent AoCo is a complex pathology that requires prenatal diagnosis in order to refer the cases to hospitals with the facilities of an intensive care unit and cardiac surgery. The majority of the cases are confirmed by echocardiography performed in the first two weeks after delivery but there are cases with in utero suspicion confirmed with AoCo even at 12 weeks after ductus arteriosus closure [5]. This fact implies the necessity to follow up these cases for a longer time. In our study the newborns without ductal dependent AoCo, but with small isthmus in terms of Z score cases were followed up until the age of 6 months. The explainable mechanism Med Ultrason 2015; 17(4): seems to be represented by the ductal tissue which expands in the distal aortic arch [5]. In our study we found all the AoCo cases in the isthmus area (between the origin of the last branch subclavian artery and the confluence with ductus arteriosus) similar to the majority of the predicted locations of AoCo from the literature [5], although sometimes the AoCo can be found in the other part of the aortic arch [5]. Various diagnostic ultrasound applications have been described as helpful in the diagnosis of AoCo. The continuous flow in diastole, outlined by the off-line analysis with M mode on STIC volume storage with B flow at this level, was considered a sign of aortic coarctation by Paladini et al [19,20] but Woolcock et al [21] does not confirm these results. The long axis views of the aortic arch is misleading as the arch can appear quite normal in this view in the presence of coarctation or alternatively a normal arch can be made to appear abnormal [22]. The aortic isthmus remains relatively small in comparison with the descending aorta after 30 weeks of pregnancy, representing the source of false AoCo diagnosis [13]. Sharland et al [3] showed that the mild forms of AoCo are impossible to be excluded in the third trimester of pregnancy. The measurement of the aortic isthmus during fetal ultrasound is one of the most important criteria for the diagnosis of AoCo. Therefore, Achiron et al [18] describes normal values of more than 3 mm of this lumen after 28 weeks, and more than 4.2 mm after 32 weeks, and concluded that lower values than the above can raise the suspicion of AoCo. In our study, the median value of the Ao isthmus was 3.63±0.62 mm, associated with the presence of real AoCo. Regarding the comparison between the transversal diameter of the RV and the LV, one study underlined that the normal value is 1.19, increasing to 1.69 when AoCo is present [23]. In our study, we found that the mean RV/ LV is 1.77 if AoCo is present, but without a statistical significance when compared with fetuses without AoCo, where the mean value was In our study, the newborns that benefit from surgical intervention for AoCo had a statistically significant smaller Z score comparing with newborns without AoCo, a higher score that the value obtained by Matsui et al [7]. The fetal aortic root increases with gestational age, but the AP/Ao ratio remains constant in normal conditions [1]. We obtained no statistically significant difference regarding AP/Ao ratio when comparing the 2 groups. The diagnosis of AoCo in the last period of pregnancy is difficult, due to the right heart predominance [24]. Gomez et al considered that the ventricular and great arteries disproportion were indirect

6 480 Claudiu Mărginean et al The role of ventricular disproportion, aortic, and ductal isthmus ultrasound measurements signs of AoCo [4]. The authors composed a multiparametric score for AoCo prognosis, the best combination for AoCo prediction being the pregnancy age of diagnosis, Z score of the ascending aorta, ratio between the size of the pulmonary and aortic valves, respectively the Z score of the aortic isthmus, measured in the three vessels section. Using this score the diagnosis accuracy was enhanced from 20% to 51% after the age of 28 weeks [4]. Our study, conducted only for the third trimester fetuses, found similar results for the Z score of the aortic isthmus and the dimension of the isthmus in the three vessels section, which were predictive for AoCo. However, in our study there were also fetuses with a Z score between -1 and -2 who developed AoCo in the neonatal period. Different studies revealed that the frequency of postpartum confirmation of fetal AoCo suspicion, after LV<RV disproportion, in correlation with the gestational age, was between % depending on the gestational age of diagnosis [3-5,17,25]. All these data are consistent with the frequency identified in our study: 9 cases with AoCo out of the 32 studied cases (28.12%) in the third trimester. According to our results, the combination between RV/LV < 1.5, Ductus/ Ao isthmus < 1.4, Ao isthmus > 4.2 mm during the third trimester of pregnancy, can affirm the absence of AoCo in 83.3% cases with cardiac ventricular disproportion. The LV<RV disproportion found at the ultrasound performed in the third trimester of pregnancy should be followed by: exclusion of other cardiac anomalies (the complex ones, but also the persistence of superior left vena cava [4,5,7], venous pulmonary anomalies [5], different degrees of aortic arch hypoplasia [4], bicuspid aortic valve [8], ventricular septum defect [6,8], anomalies of the mitral valve [6,8]) and evaluation of the aortic arch with measurement of the ascending aorta and of the isthmus part with 2 D and Doppler ultrasound [1,2]. The fetuses with ventricular disproportion that were identified only in the last trimester, have statistically reduced chances of AoCo in our study (28.12 %), results that are in line with the results from several published studies [3-5,17,25]. The main limitation of our study consisted of a reduced number of fetuses. This was caused on one hand by the relatively low incidence of this pathology, and on the other hand by the lack of evaluation in our center of pregnancies in the second trimester. Another limitation of the study was the lack of serial assessment of the fetal valves. Other limitations of the study included: the lack of interobserver agreement in the pre- and postnatal evaluation, the usage of normal values from the literature applied on our own groups of healthy fetuses, and the insufficient knowledge regarding the geographical, ethnical, and other differences between the fetuses. The small group does not allow us to draw general conclusions, which is why the study is worth being extended on a larger fetuses group. 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