Objectives As postnatal identification of accelerated idioventricular rhythm (AIVR) relies on specific electrocardiographic patterns, prenatal diagnosis of this condition is challenging and its true incidence is unknown. The objectives of this study were to evaluate the performance of prenatal ultrasonography in identifying intrauterine cardiocirculatory events linked to specific electrocardiographic signs of postnatal AIVR, including left or right ventricular origin, and to assess the prenatal prognosis of this arrhythmia. Methods We reviewed Doppler tracings from the superior vena cava/ascending aorta (SVC/Ao), ductus venosus (DV), ductus arteriosus (DA) and aortic isthmus (AoI), as well as simultaneous M-mode recordings of septal and left ventricular wall motions of fetuses diagnosed with AIVR from January 2004 to December 2014. Results Three cases of AIVR were identified among 27 912 fetuses. SVC/Ao Doppler flow recordings revealed atrioventricular dissociation (ventricular rates within 20% of atrial rates) in all three fetuses and episodes of isorhythmic atrioventricular dissociation in one, while M-mode confirmed normal left ventricular shortening fraction in all cases. Fusion beats were observed on AoI tracing in one fetus, while simultaneous recordings of AoI and DA revealed signs of right bundle branch block in one case and left bundle branch block in the other two. On DV Doppler recordings, retrograde a-waves in the presence of simultaneous atrial and ventricular contractions were observed in all three fetuses, leading to an increase in central venous pressure in all and hydrops fetalis in two cases without evidence of ventricular dysfunction. Conclusions Echocardiographic criteria required for postnatal diagnosis of AIVR can be documented in utero using specific ultrasonographic approaches. During fetal life, AIVR may not be a benign entity. Hydrops fetalis is frequently associated with AIVR because of increase in central venous pressure related to simultaneous atrioventricular contractions; thus, the ultrasonographic investigation protocol of fetuses with unexplained hydrops fetalis should aim at ruling out AIVR and include Doppler flow recordings in SVC/Ao, DV, AoI, DA and umbilical vein. Copyright (C) 2016 ISUOG. Published by John Wiley & Sons Ltd.

To determine the prognostic value of fetal Doppler and echocardiographic parameters for neonatal survival up to 30 days after laser coagulation in monochorionic pregnancies complicated by twin–twin transfusion syndrome (TTTS).

To determine the factors responsible for the onset of the retrograde telesystolic flow normally observed at the level of the aortic isthmus (AoI) during the second half of gestation. Doppler recordings on normal fetuses aged 18 to 37 weeks of gestation were retrospectively selected in the database of the Fetal Cardiology Unit at CHU St-Justine. The following variables were measured: peak systolic velocities (PSV) and systolic nadir (Ns) of the AoI Doppler waveforms allowing calculation of the systolic index (ISI = Ns ÷ PSV); the total duration of systole (Ttotal) and the duration of the telesystolic retrograde flow (Tretro) for the calculation of the reverse isthmic telesystolic index (RITSI = Tretro ÷ Ttotal). The pulsality index of the umbilical artery (UAPI) and the ductus venosus (DVPI) are routinely measured in our Unit. Descriptive and correlational analyses have been performed. A total of 226 fetuses are included in this study. The systolic AoI flow is entirely antegrade from 18 to 28 weeks of gestation. The RTSF in the AoI appears at the gestational age of 29 weeks and shows a linear increase up to 37 w of gestation (F = 21.92, p < 0.001); ISI and RITSI are inversely correlated (r = −0.79, p < 0.001). No correlation was found between ISI nor RITSI and the PIs in UA and DV. The onset of RTSF occurs when the PIs in the UA and the DV are relatively stable explaining the lack of correlation observed. On the other hand, the appearance of the RTSF corresponds clearly to the start of the fall of the pulsatility index in the MCA as described by Mari. This physiological decline in the MCA resistances during the third trimester is known to cause an increase in superior vena cava flow returning to the right ventricle (RV) and a secondary rise in its stroke volume. Since the RV ejection has a retrograde effect on the flow in the AoI, the physiological change observed in the cerebral vascular network seems to be the principal factor determining the onset of the RTSF.

To determine the prognostic value of fetal Doppler and echocardiographic parameters in early fetal death after laser coagulation in monochorionic pregnancies complicated by Twin–twin transfusion syndrome (TTTS). To evaluate whether hemodynamic changes, pre and post laser photocoagulation, predict the intrauterine fetal demise (IUFD) within 24 hours and 1 week after laser. Fetal echocardiography and outcome data of consecutive cases of TTTS treated by laser photocoagulation were retrospectively reviewed. Hemodynamic and cardiac function parameters were collected pre and post treatment with photocoagulation of placental vascular anastomoses. Between February 2006 and January 2015, 105 laser coagulations were performed. Quintero staging was divided between stage 1 (12%), 2 (40%), 3 (46%) and 4 (2%). Due to the retrospective nature of this study, fetal echocardiography results pre and post laser were available in only 68 cases. Overall rates of early IUFD within 24 h or one week after laser were 15% and 18% for one, 3% and 4% for two fetuses, respectively. Donor was concerned in 59% and 61% of cases respectively. The predictors of early IUFD, within 24 hours and one week after laser, were recipient preoperative right ventricular myocardic performance index (RV MPI) (p = 0.003 and p = 0.004) and postoperative ventricular shortening fraction (SF) (p = 0.009 and p = 0.029). The predictor or recipient IUFD was the postoperative CHOP cardiovascular score (p = 0.045 and p = 0.032, respectively). The predictors or donor IUFD were the ratio of cerebral to umbilical pulsatility index (PI) (p = 0.026 and p = 0.014, respectively) and the ventricular SF (p = 0.006 and p = 0.006, respectively). The hemodynamic predictors of early IUFD after laser were the recipient preoperative RV MPI and postoperative ventricular SF. The postoperative CHOP score was hemodynamic predictors of recipient IUFD. The preoperative ratio of PI and postoperative SF were related to donor IUFD.

To assess the prognostic value of the systolic flow through the aortic isthmus, reflecting the relative performances of the left (LV) and right (RV) ventricles in the recipient twin of monochorionic pregnancies complicated by Twin–twin transfusion syndrome (TTTS) treated by laser coagulation. Fetal echocardiography and outcome data of consecutive cases of TTTS treated by laser photocoagulation were retrospectively reviewed. Hemodynamic and cardiac function parameters were collected pre and post treatment with photocoagulation of placental vascular anastomoses. The isthmic systolic index (ISI) was calculated by dividing the end-systolic velocity by the peak systolic velocity, before and after treatment. Results were compared using Kruskal-Wallis and Mann–Whitney statistical tests. Between February 2006 and January 2015, 105 laser coagulations were performed. Quintero staging was divided between stage 1 (12%), 2 (40%), 3 (46%) and 4 (2%). Survival rates in the entire cohort were 17%, 22% and 61% for zero, one or two twins respectively. At least one twin was delivered alive in 83% of the pregnancies. The neonatal suvival rate was 72% for the recipient twin. Due to the retrospective nature of this study, ISI values were available for 43 recipients pre and 33 post laser. Before laser, the median recipient ISI was 0.19 (range −0.23; 0.36) before laser and 0.18 (range −0.43; 0.32) after laser. The recipient's ISI before laser was related to the occurrence of intrauterine fetal demise (p = 0.047) and survival at birth (p = 0.058). We found significant prognostic value of preoperative recipient ISI in TTTS treated by laser photocoagulation.

To determine the prognostic value of fetal Doppler and echocardiographic parameters in neonatal outcome after laser coagulation in monochorionic pregnancies complicated by Twin–twin transfusion syndrome (TTTS). To evaluate whether hemodynamic changes, pre and post laser photocoagulation, predict the neonatal survival. Fetal echocardiography and outcome data of consecutive cases of TTTS treated by laser photocoagulation were retrospectively reviewed. Hemodynamic and cardiac function parameters were collected pre and post treatment. Between February 2006 and January 2015, 105 laser coagulations were performed. Due to the retrospective nature of this study, fetal echocardiography pre and post laser intervention were available in only 68 cases. Survival rates were 17%, 22% and 61% for zero, one or two twins respectively. At least one twin was delivered alive in 83% of the pregnancies. The mean gestational age at surgery was 21 weeks (range 16–26). The mean age at birth in cases with at least one live fetus was 32 weeks (range 23–41). This study found than preoperative predictors for survival rate at birth and after neonatal period, recipient peak systolic velocity of middle cerebral arteria (PSV-MCA) (p = 0.025 and p = 0.023), especially for recipient (p = 0.017 and p = 0.002) and recipient right ventricular myocardial performance index (MPI) (p = 0.004 and p = 0.007), especially for recipient (p = 0.041 and p = 0.02). The preoperative CHOP cardiovascular score was related to survival recipient at birth (p = 0.045) and to neonatal survival (p = 0.046). Donor survival was related to preoperative donor PSV-MCA (p = 0.011). The postoperative predictor for survival rate at birth and after neonatal period were pulsatility index of recipient Ductus Venosus (PIDV) (p = 0.008 and p = 0.001), especially for recipient (p = 0.008 and p = 0.003). The major hemodynamic predictors of neonatal survival found in this study were preoperative recipient PSV-MCA, recipient right ventricular MPI and postoperative recipient PIDV.

Fetal ventricular arrhythmia is rare and accounts for 1% of tachycardias. Prenatal diagnosis is challenging and little is known on the management and prognosis. We sought to report our institution's experience on fetal ventricular arrhythmia from 1995 to 2015 with focus on SVC-Aorta Doppler method. Retrospective, descriptive study. Using our institution's cardiac ultrasound database, we identified patients with a ventricular rhythm disturbance of any kind from 1995 to 2015. We identified 23 patients with ventricular arrhythmia (table1). 6 had sustained VT, one of which had torsades de pointe related to long QT syndrome (figure 1A), 3 with VT and 2 with junctional ectopic tachycardia (JET). 1 subject with VT (figure 1B)and another with JET had hydrops and were treated with antiarrhythmics. 17 had isolated PVCs (figure 1C) with no hydrops and normal anatomies except for 2 cases. All were in sinus rhythm postnatally and none progressed to VT during gestation. Our experience over the last 20 years shows few cases of ventricular arrhythmia. The SVC-Aorta Doppler allows diagnosis in all cases and should be the preferred diagnostic technique. Antiarrhythmic drugs seem to be efficient even in fetuses with hydrops. Postnatal courses are favorable in our cohort. Supporting information can be found in the online version of this abstract Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Knowledge of size and growth of cardiac structures is crucial for fetal screening of congenital heart disease.

Objectives To evaluate the performance of three different centers with respect to their ability to identify the fetal aortic isthmus (AoI) adequately and place a Doppler sample volume in the AoI correctly, and to address the reproducibility of the isthmic flow index (IFI) calculated from Doppler waveforms recorded in the three centers.Methods The three collaborating centers sent several ultrasonographic recordings taken at random over a 6-week period to the Saint-Justine Fetal Cardiology Unit (StJ-FCU). A performance quotient ((number of total readings - number of unsatisfactory results)/number of total readings) was calculated for each center by each of three judges, who were experienced fetal cardiologists, to assess the ability of each center to identify the isthmus and to place the Doppler sample volume (DSV) adequately. Intraclass correlation coefficients (ICC) were computed to quantify the variability of IFI measurements ((systolic + diastolic)/systolic flow velocity integrals).Results Fifty-five recordings were available for this study. Concerning isthmus identification, there was 100% agreement between the three judges from StJ-FCU and the performance quotients of Centers A, B and C were: 0.90, 0.95 and 1.00, respectively. For DSV positioning, agreement between the judges varied; for Judge 1 vs. Judge 2, kappa = 0.836 (95% CI, 0.651 -1.000); for Judge I vs. judge 3, kappa = 0.773 (95% Cl, 0.557-1.000); for Judge 2 vs. judge 3, kappa = 0.941 (95% CI, 0.805-1.000). The Performance quotients of the three centers for DSV positioning were consistently lower than were those for identification of the isthmus, being 0.85, 0.76 and 0.92, respectively. The ICC between the first and second measurements of the IFI by Rater 1 was 0.96 (95% CI, 0.93-0.98, P < 0.001) and that between Raters 1 and 2 was 0.97 (95% CI, 0.95-0.99, P < 0.001).Conclusion Adequate imaging of the fetal AoI can be achieved easily by a trained sonographer, while DSV positioning is challenging. The intra- and interrater variability of the IFI are low. Copyright (c) 2009 ISUOG. Published by John Wiley & Sons, Ltd.

To describe early changes in fetal cardiac function after laser treatment in severe twin–twin transfusion syndrome (TTTS). A prospective study was conducted over a five-month period. Cardiac function was assessed in 49 consecutive monochorionic pregnancies presenting with severe TTTS and referred for fetoscopic selective laser coagulation (FSLC) of placental anastomoses as first-line treatment. Echocardiography was performed on admission and after laser treatment (median = 1 day, IQR = 1–3). The studied parameters included cardiac output, myocardial performance index, shortening fraction (SF), and heart dimensions. Median gestational age was 21 weeks (IQR = 19–23). Distribution across Quintero stages was as follow: 32.7%, 18.4%, 46.9% and 2.0% for stages 1, 2, 3 and 4 respectively. Cardiac output significantly increased after laser treatment in both donor (+33%) and recipient twins (+24%). In the recipient twin, a significant increase in LV SF was also found. The increase in cardiac output was not significantly correlated with Quintero stage, the volume of amniotic fluid drained, or gestational age. As early as 24 h after laser treatment, a significant increase in systolic function was found in both twins. These changes seem to be unrelated to initial severity of the syndrome.

For many days after the surprising news that I was selected for the 2005 Ian Donald Gold Medal Award, I could not help but turn the same question over and over in my mind: ‘What was the likelihood of a graduate from the poorest country of the Americas being selected as recipient of the highest award from this prestigious international society?’ In anybody’s opinion, the answer to this question would be very simple: his chances would be very slim indeed! The first reaction might be that this individual must be very lucky; he must have been at the right place at the right time by chance. Another explanation could be that this selection was the result of hard work, plain hard work. In my case, I’m happy to acknowledge that sometimes I have been lucky in my life. As for being a hard worker, I must confess to having some reservations, since my relationship with work has been constantly tinted by a certain relativity of things, sometimes referred to as ‘the Caribbean approach to work’. There is, however, a third dimension that could explain my presence on this podium, a dimension which, I hope, is the most influential. I am referring to my profound conviction that I am an extremely privileged member of the human community. I can only hope that this awareness was and will remain a basic motivation in my professional life, because, in my case, the list of privileges is long indeed. It started way back on my native island when I had the privilege of having access to school in a society in which 60–70% of the population was then illiterate. In the following years, the list kept getting longer and longer: the privileges of being among the happy few to attend medical school at the State University of Haı̈ti; of completing my pediatric training in Montreal, among remarkable and devoted pediatricians at the Sainte-Justine Hospital; of moving to the United States for my pediatric cardiology training and working 2 years with two outstanding scientists – Professor Abraham Rudolph, the father of fetal cardiovascular physiology and Julian Hoffman, an authentic humanist; of starting my fetal cardiology career with a sabbatical leave during which I had the privilege of

La cardiologie foetale est aujourd'hui une discipline bien etablie de la cardiologie pediatrique. Elle n'est plus un simple exercice de depistage prenatal de malformations cardiaques. Elle englobe egalement l'investigation et le traitement des arythmies et l'evaluation cardiocirculatoire, fonctionnelle et dynamique, de foetus qui ne sont pas tous atteints d'une pathologie cardiaque organique primaire. C'est de ce dernier aspect dont il sera question dans cette presentation. L'ensemble des interactions coeur gauche/hemodynamique foetale sera regroupe sous deux titres principaux selon que la dysfonction myocardique gauche est primaire ou secondaire a des alterations de la pre- ou de la post-charge. Les singularites hemodynamiques de la circulation foetale normale restent tout au long de ce texte une toile de fond indispensable a la comprehension des phenomenes observes.

Objective To review the pattern of presentation, management and outcome of fetal complete atrioventricular block (CAVB) associated with major structural congenital heart disease (CHD), when compared to isolated CAVB.Methods Retrospective analysis of the medical records and echocardiograms of all CAVB cases, diagnosed prenatally at two tertiary care centers between the years 1990 and 2002.Results Of a total of 59 consecutive fetal cases of CAVB, 24 (41%) had underlying major CHD, mainly left isomerism (n = 18) and congenitally corrected transposition of the great arteries (cc-TGA) (n = 3). When compared to isolated CAVB (n = 35), cases with CHD were detected earlier (21 +/- 6 vs. 26 +/- 6 weeks; P < 0.02) and - despite comparable heart rates - more often had fetal hydrops (38% vs. 9%; P < 0.02), while pregnancy continuation (66% vs. 94%; P < 0.02) or prenatal treatment (19% vs. 64%; P < 0.001) was less likely. Of 16 CHD cases with pregnancy continuation, P-inotropic treatment of fetal bradycardia was attempted in three cases: all had left isomerism and died early postnatally. Livebirth and 1-year survival rates of CAVB with CHD were 56% and 19%, respectively, when compared to isolated CAVB with 88% and 75%, respectively (P < 0.0001). The four neonatal survivors (one left isomerism, three cc-TGA) had heart rates persistently > 60 bpm throughout gestation and 3/4 underwent a biventricular repair.Conclusions Fetal CAVB with CHD continues to be associated with a poor outcome, in particular in the presence of left isomerism and fetal heart rates < 60 bpm. Copyright (c) 2005 ISUOG.

BACKGROUND:In the preterm newborn, a patent ductus arteriosus is in large part a result of the increased sensitivity of the immature ductus to prostaglandin E2 (PGE2). PGE2 acts through 3 G protein-coupled receptors (EP2, EP3, and EP4) that activate both adenyl cyclase and K(ATP) channels. We explored these pathways to identify the mechanisms responsible for the increased sensitivity of the immature ductus to PGE2. METHODS AND RESULTS:We measured EP receptor content (mRNA and protein), receptor binding, cAMP production, and isometric tension in rings of ductus taken from immature (65% gestation) and mature (95% gestation) sheep and baboon fetuses. Ductus relaxation and cAMP generation were augmented in response to selective EP receptor agonists in the immature ductus. 8-Br-cAMP, a stable cAMP analogue, produced greater relaxation in the immature ductus. In the presence of a selective protein kinase A inhibitor, Rp-8-CPT cAMPS, the developmental differences in sensitivity to PGE2 could no longer be demonstrated. EP2, EP3, and EP4 receptor densities were higher in immature ductus, despite similar receptor mRNA and protein contents at the 2 gestational ages. In contrast, forskolin and NaF, direct activators of adenyl cyclase and Gs, respectively, elicited comparable increases in cAMP in both age groups. KATP channel inhibition also had similar effects on PGE2-induced relaxation in both age groups. CONCLUSIONS:Two mechanisms explain the increased sensitivity of the immature ductus to PGE2: (1) increased cAMP production because of increased binding of PGE2 to the individual EP receptors and (2) increased potency of cAMP on protein kinase A-regulated pathways.

Background - Untreated isolated fetal complete atrioventricular block ( CAVB) has a significant mortality rate. A standardized treatment approach, including maternal dexamethasone at CAVB diagnosis and beta-stimulation for fetal heart rates < 55 bpm, has been used at our institutions since 1997. The study presents the impact of this approach.Methods and Results - Thirty-seven consecutive cases of fetal CAVB since 1990 were studied. Mean age at diagnosis was 25.6 +/- 5.2 gestational weeks. In 33 patients (92%), CAVB was associated with maternal anti-Ro/La autoantibodies. Patients were separated into those diagnosed between 1990 and 1996 ( group 1; n = 16) and those diagnosed between 1997 and 2003 ( group 2; n = 21). The 2 study groups were comparable in the clinical presentation at CAVB diagnosis but did differ in prenatal management ( treated patients: group 1, 4/16; group 2, 18/21; P < 0.0001). Overall, 22 fetuses were treated, 21 with dexamethasone and 9 with beta-stimulation for a mean of 7.5 +/- 4.5 weeks. Live-birth and 1-year survival rates of group 1 were 80% and 47%, and these improved to 95% for group 2 patients ( P < 0.01). The 21 patients treated with dexamethasone had a 1-year survival rate of 90%, compared with 46% without glucocorticoid therapy ( P < 0.02). Immune-mediated conditions ( myocarditis, hepatitis, cardiomyopathy) resulting in postnatal death or heart transplantation were significantly more common in untreated anti- Ro/La antibody - associated pregnancies compared with patients treated with steroids (0/18 versus 4/9 live births; P = 0.007).Conclusions - A standardized treatment approach, including transplacental fetal administration of dexamethasone and beta-stimulation at heart rates <55 bpm, reduced the morbidity and improved the outcome of isolated fetal CAVB.

The synthesis of PGE(2), the major vasodilator prostanoid of the ductus arteriosus (DA), is catalyzed by PGE(2) synthases (PGES). The factors implicated in increased PGE(2) synthesis in the perinatal DA are not known. We studied the developmental changes of PGES along with that of cyclooxygenase (COX)-2 and cytosolic phospholipase A(2) (cPLA(2)) in the DA of fetal (75-90% gestation) and immediately postnatal newborn (NB) piglets. Levels of microsomal PGES (mPGES), COX-2, and PGE(2) in the DA of NB were approximately 7-fold higher than in fetus; activities of cytosolic PGES (cPGES) and cPLA(2) in DA of the fetus and NB did not differ. Because platelet-activating factor (PAF) could regulate COX-2 expression, the former was measured and found to be more abundant in the DA of the NB than of fetus. PAF elicited an increase in mPGES, COX-2, and PGE(2) in fetal DA to levels approaching those of the NB; cPGES, cPLA(2), and COX-1 were unaffected. In perinatal NB DA, PAF receptor antagonists BN-52021 and THG-315 reduced mPGES, COX-2, and PGE(2) levels and were associated with increased DA tone. It is concluded that PAF contributes in regulating DA tone by governing mPGES, COX-2, and ensuing PGE(2) levels in the perinate.

OBJECTIVE:To evaluate a management protocol of fetal supraventricular tachycardia (SVT) based on prior identification of the underlying mechanism.DESIGN AND SETTING:Prospective study in a mother-child tertiary university centre.PATIENTS:During a consecutive 36 month period, 18 fetuses with sustained SVT underwent a superior vena cava/ascending aorta (SVC/AA) Doppler investigation in an attempt to determine the atrioventricular (AV) relation and to treat the arrhythmia according to a pre-established management protocol.MAIN OUTCOME MEASURE:Rate of conversion to sinus rhythm.RESULTS:Seven fetuses had short ventriculoatrial tachycardia, five of these with a 1:1 AV conduction suggesting re-entrant tachycardia. The first choice drug was digoxin and all were converted. One fetus had AV dissociation leading to the diagnosis of junctional ectopic tachycardia, which was resistant to digoxin and sotalol; amiodarone achieved postnatal conversion. One fetus had SVT and first or second AV block; the diagnosis was atrial ectopic tachycardia (AET), which responded to sotalol given as a drug of first choice. Seven fetuses had long ventriculoatrial tachycardia: one with sinus tachycardia (no treatment), one with permanent junctional reciprocating tachycardia (PJRT), and three with AET. The first choice drug was sotalol and all were converted. One AET was classified postnatally as PJRT. Six fetuses had intra-atrial re-entrant tachycardia: five with 2:1 AV conduction and one with variable block. The first choice drug was digoxin. Conversion was achieved in all but one, who died after birth from advanced cardiomyopathy.CONCLUSION:The electrophysiological mechanisms of fetal SVT can be clarified with SVC/AA Doppler. The proposed management protocol has so far yielded a good rate of conversion to sinus rhythm.

(a) Diagram of the fetal circulation, illustrating the unique position of the aortic isthmus, between the aortic and pulmonary arches. (b) During systole the left and right ventricular stroke volumes have opposite effects on the direction of flow through the isthmus. (c) During diastole the two downstream vascular impedances are the only determinants of the direction of the isthmic flow. Due to the disposition of the two arterial circuits on each side of the aortic isthmus, blood ejected by the fetal LV and RV has opposite effects on the direction of flow through the isthmus. Left ventricular stroke volume will cause forward flow while right ventricular ejection will have the opposite effect (Figure 1b). The final systolic pattern of isthmic flow will be determined by the relative contributions of left and right ventricular stroke volumes as well as the balance between vascular impedances of the upper and lower body. In diastole (Figure 1c), when the two semilunar valves are closed, the direction of isthmic blood flow will be influenced only by the two downstream vascular impedances, especially in the brain for the upper body, and in the placenta for the subdiaphragmatic vascular system. Doppler flow velocity studies have confirmed that in the normal fetus, forward flow is present through the isthmus, both in systole and diastole, because of the low placental vascular impedance (Figure 2a). A number of elements should cause a progressive decrease of forward flow through the isthmus as gestation progresses; among them the right ventricular preponderance which increases during the second half of gestation2 and placental vascular resistance which reaches a plateau in the last months of gestation, while cerebral vascular resistance follows a curvilinear pattern, peaking at mid-gestation and declining progressively at the end4. This reduction in flow could explain the relative narrowing of the isthmus observed in term fetuses. Systematic recordings of the isthmic flow velocity profile throughout gestation have shown that starting at approximately 25 weeks, a brief reversal of flow occurs toward the end of systole, and increases steadily with the progression of gestation5 (Figure 2b). In term ovine fetuses this phenomenon has been found to be caused by a delayed onset and longer acceleration time of ductus flow velocity at the isthmus–ductus junction6. The same dynamic events can also be observed in the human fetus (Figure 2c). Doppler flow velocity patterns in the fetal aortic isthmus throughout gestation. (a) During the first half of pregnancy, forward flow is present both in systole and diastole. (b) During the second half of pregnancy, a brief reversal of flow appears at the end of systole as illustrated in this 32-week fetus. (c) In the same fetus a delayed onset and longer acceleration time of the ductal wave are observed at the isthmus–ductus junction, explaining the late systolic reversal of flow in the isthmus. To objectively monitor the flow pattern through the fetal aortic isthmus we developed an isthmic flow index (IFI), which reflects both the amount and direction of blood through this vascular segment. The proposed index was obtained by dividing the sum of the systolic (S) and diastole (D) Doppler flow velocity integrals by the systolic flow integrals: IFI = S + D/S. Positive and negative signs are assigned to antegrade and retrograde velocity values, respectively. The normal reference ranges of the IFI have been published recently7. For clinical purposes, five types of IFI are possible (Figure 3). In Type I the index is higher than 1, meaning that antegrade flow is present both in systole and diastole. Normal fetuses have a Type I flow pattern in their aortic isthmus. However, because of the physiological hemodynamic changes mentioned above, a progressive decrease of the IFI is observed throughout the second half of pregnancy7. Type II corresponds to an absence of diastolic flow. The IFI is then equal to 1, below the normal range. In Type III, the IFI is between 1 and 0, expressing some diastolic flow reversal but with predominant antegrade flow. The closer the index is to 0, the greater is the retrograde flow. Type IV is observed when the retrograde and antegrade flows are equal and the IFI reaches 0. Finally, in Type V the index becomes negative, below 0, meaning that forward flow is decreased and retrograde flow increased to the point that net flow to the isthmus is retrograde. Illustrations of the five possible types (I–V) of the isthmic flow index. The Doppler flow waveforms at the bottom of the figure are taken from fetuses with placental circulatory insufficiency. The normal direction of the isthmic shunt towards the subdiaphragmatic circulation can be altered by abnormal fetal conditions involving either the ventricles or the peripheral circulation. A functional impairment or any stenotic lesion along one of the two parallel pathways of the fetal heart induces a redistribution of flow toward the unaffected side. For this reason, trans-stenotic gradients are unreliable for the assessment of fetal cardiac obstructive lesions8. By contrast, individual ventricular dysfunction will always influence fetal isthmic flow, and the changes observed will be different, depending on whether the left or the right side is affected. Left ventricular dysfunction or stenosis is associated with a decrease of LV output and of normal forward flow through the isthmus. If the reduced isthmic flow remains antegrade (IFI > 1) this would mean that despite the stenosis, left ventricular stroke volume is still sufficient to maintain perfusion of both the upper body and part of the subdiaphragmatic circulation (Figure 4a). One can then safely predict that, after birth, the systemic circulation will not be dependent on a patent DA. Inversely, reverse isthmic flow (IFI < 1) associated with LV functional impairment indicates a significant fall in LV output, causing compensatory perfusion of at least part of the upper body circulation by blood coming from the RV (Figure 4b). In this instance, the LV will be unable to take charge of the postnatal systemic circulation, which will be dependent on the patency of the DA. In Figure 4b, since the hemodynamic problem concerns essentially the ejection phase of the cardiac cycle, retrograde flow occurs only in systole while normal forward diastolic flow towards the low resistance placental circulation is still recorded in the isthmus. The extreme of this condition is the hypoplastic left heart syndrome where the functioning RV perfuses not only the isthmus but also the entire aortic arch, including the coronary arteries. Serial recordings of flow patterns through the isthmus should, therefore, help the fetal sonographer in the important task of assessing the progression of a left-sided obstruction in prenatal life. (a) Moderate aortic stenosis. The flow velocity patterns through the aortic valve (upper trace) and isthmus (lower trace) are illustrated. A peak systolic velocity of 2.2 m/s is recorded through the aortic valve. Flow through the isthmus is decreased but remains antegrade both in systole and diastole. (b) Severe aortic stenosis. The peak velocity of the transvalvular jet is 4 m/s (upper trace) and a reverse systolic flow is recorded through the isthmus (lower trace). IFI, isthmic flow index. Right ventricular dysfunction or outlet stenosis increases forward flow through the isthmus since, in this condition, a greater portion of the combined cardiac output is made up of blood coming from the LV. The rise in volume flow through the isthmus explains the similarity in size between the isthmus and the adjacent aorta, as observed in term fetuses with prenatal pulmonary stenosis or tetralogy of Fallot (Figure 5). In our experience, the changes in IFI in these circumstances are variable. Further studies are needed to establish if this index can be used to predict the need for a shunt in the postnatal period to maintain perfusion of the lungs. For the time being the appearance of systolic flow reversal in the pulmonary arch during fetal life remains the most reliable predictive criterion of postnatal ductal dependency to maintain an adequate pulmonary circulation. (a) Aortic arch of a normal 37-week fetus. Note the narrowing of the aortic isthmus. (b) Aortic arch of a 36-week fetus with tetralogy of Fallot. Note the absence of reduction of the isthmus diameter. Since the fetal aortic isthmus is the sole link between the two arterial systems organized in parallel fashion, any change of flow or resistance affecting one of these arterial networks should influence flow patterns within the isthmus. In the upper body, cerebral arteriovenous (AV) fistulae represent typical examples of an abnormal decline in vascular impedance associated with a tremendous increase in flow. Doppler investigations of fetuses with cerebral AV fistula have demonstrated the presence of reverse diastolic flow in their aortic isthmus9 (Figure 6). A unique circulatory dynamic is then established: the lower to upper body isthmic shunt joins LV output to perfuse the fistula while the markedly increased venous return comes back to the RV through the superior vena cava. This pattern explains the marked increase of flow through the pulmonary arch in prenatal life and the right ventricular hypertrophy classically observed in the postnatal electrocardiograms. It is worth mentioning that, as in critical left ventricular dysfunction, normal forward diastolic flow is still recorded in the aortic isthmus of fetuses with cerebral AV fistulae since their placental vascular impedance is normal. The same pattern of flow has been found in aorto-atrial fistulae (Sven-Erik Sonesson, pers. comm.). It can be speculated that the association of 'leaks' created by both the fistula and the normal diastolic isthmic shunt towards the placenta should cause a marked fall in systemic diastolic pressure. This low diastolic perfusion pressure could have, among other consequences, deleterious effects on placental blood flow and function. (a) Doppler flow pattern in the aortic isthmus of a 35-week fetus with cerebral arteriovenous fistulae. Note the retrograde flow after a brief systolic forward ejection wave. (b) A simultaneous recording of the velocity waveforms of both the ductus arteriosus and aortic isthmus of the same fetus demonstrates that, because of the marked increase in volume flow through the pulmonary arch, flow reversal through the isthmus occurs as early as mid-systole. In the lower body, intrauterine growth restriction (IUGR) due to placental circulatory insufficiency is one of the most frequent conditions where alteration of peripheral vascular impedance causes major changes in the isthmic shunt. In this condition, placental resistance, which is normally the lowest in the whole fetal circulation, increases. This alone could be responsible for at least a decrease in forward diastolic flow or in more severe cases a reversal of this flow through the isthmus. Another major element in the hemodynamic picture of IUGR fetuses is the reduction in O2 delivery. Both experimental10, 11 and clinical12-14 investigations have demonstrated that placental circulatory insufficiency causes fetal hypoxemia by reducing umbilical blood flow. The hypoxemia, by eliciting cerebral vasodilatation, potentiates the reversal effect of elevated placental resistance on the direction of the isthmic flow. The arterial hypoxemia is also responsible for vasoconstriction of the mesenteric, renal and musculoskeletal arteries, further increasing vascular impedance in the lower body. It is now well established that, depending on the degree of severity of the increase in placental vascular resistance, Doppler flow velocity waveforms of the umbilical artery will show decreased, absent or reverse diastolic velocities15, 16. The same changes in diastolic velocities described in the umbilical artery also occur in the isthmus17, 18 (Figure 3). More interestingly, quantitative assessment of isthmic flow during a stepwise increase in resistance to placental flow in fetal lambs demonstrated a strong positive correlation between actual umbilical blood flow and the amount of blood shunted through the isthmus19 (Figure 7). In IUGR, therefore, the amount of flow going through the fetal aortic isthmus can be considered to be a good indicator of placental flow. Because O2 delivery to the fetus is closely related to placental flow, one can extrapolate and consider that fetal O2 delivery is also closely related to aortic isthmus blood flow. Linear regression analysis correlating aortic isthmic blood flow with placental blood flow19. Figure reproduced, with permission, from Bonnin P, Fouron JC, Teyssier G, Sonesson SE, Skoll A, Quantitative assessment of circulatory changes in the fetal aortic isthmus during progressive increase of resistance to umbilical blood flow, Circulation 1993; 88: 216–222. © American Heart Association. Monitoring the flow pattern through the isthmus in IUGR fetuses could potentially play a major role in the prevention of postnatal sequelae of prenatal hypoxic brain injury. It is known that, despite the hypoxemia, the IUGR fetus can still maintain adequate cerebral oxygenation because of many adaptative mechanisms20. The defense system against cerebral hypoxia can, however, be overwhelmed. In clinical practice, IUGR fetuses suffering from placental circulatory insufficiency are being delivered on the basis of signs reflecting decompensation of their defense mechanisms21. The fetuses are then in metabolic acidemia and at significant risk of cerebral hypoxia22, 23. Ideally, to prevent postnatal sequelae of cerebral hypoxia, the decision to deliver should be made just before decompensation. There are presently no signs that could help the attending physician to identify the fetus whose defense mechanisms against hypoxemia are about to fail. Experimentally, a stepwise increase in resistance to placental flow causes a fall in oxygen delivered to the brain only when predominant reverse diastolic flow is observed through the aortic isthmus10. IUGR fetuses with predominant reverse flow through their aortic isthmus also present signs of non-optimal postnatal neurodevelopmental outcome24 as well as impairment of their venous Doppler25, a late sign of fetal compromise. Finally, a good negative correlation has been found between the fetal IFI and postnatal neurodevelopmental outcome in the same group of IUGR fetuses (author's personal data). All these observations can be explained by the unique position of the isthmus. When reverse flows occurs in the aortic isthmus, blood coming from the MPA and DAo is being diverted from its normal destination, mainly the placenta. Because of the placental circulatory insufficiency, this preplacental blood has a lower O2 content than normal. The brain is then partly perfused by blood deprived of substrates, placental and maternal, essential for fetal development and, at the same time, by red cells very poorly saturated in oxygen. Since the IFI is an indicator of the amount and direction of the shunt through the fetal isthmus, it could be used as a clinical marker for the identification of IUGR fetuses who need to be delivered before evidence of cerebral hypoxia. The greater the reverse isthmic flow, the lower is the IFI and the higher should be the risk of prenatal cerebral damage. Our ongoing clinical investigation aims presently at establishing the IFI level corresponding to impending decompensation; at this level, delivery of an IUGR fetus would be rationally indicated before the appearance of signs of central nervous system impairment. The difference between the significance of the DA and the aortic isthmus during prenatal life is well illustrated by the consequences of their obstruction or absence. The fetal aortic isthmus can be hypoplastic or absent. A hypoplastic aortic isthmus is usually associated with obstructive malformations of the LV and represents a secondary event related to decreased left ventricular output with a marked fall in the amount of blood shunting through the isthmus26. Complete absence of the aortic isthmus represents one of the types of interruption in the aortic arch. Both conditions are well tolerated during fetal life. A decrease or absence of shunt through the isthmus can be easily compensated for by a proportional increase in right ventricular flow through the pulmonary arch, maintaining the normally elevated turnover of blood in the umbilical circulation. This explains why marked right ventricular preponderance is classically observed in neonates with obstructions such as coarctation of the aorta. The aortic isthmus, therefore, is not an essential component of the fetal circulation, and its absence does not justify an aggressive approach during intrauterine life. In contrast, the situation is quite different with the DA. Partial compression of the DA in fetal lambs has been reported to cause an immediate elevation of pulmonary pressure, associated with a transient rise in pulmonary flow27. The most intriguing finding was that pulmonary vascular resistance, which fell during the first 30 min of compression, steadily increased thereafter, suggesting the involvement of yet unidentified factors, such as injury to the pulmonary arterial endothelium, and augmented neural, humoral or local vasoconstricting stimuli that could be responsible for deterioration of the pulmonary arterial system. Complete surgical ligation of the DA in the sheep fetus produces structural remodeling of the peripheral pulmonary vascular bed, characterized by an increase in the proportion of muscularized pulmonary arteries at the level of the terminal bronchioles and within the acini28. In the same experimental model, marked changes have been demonstrated in the biochemical and mechanical properties of large capacitance pulmonary arteries as well as smaller resistance units29. In the human fetus, premature closure of the fetal ductus, which is a well-documented complication of maternal therapy with prostaglandin synthetase inhibitors, causes major alterations in right ventricular function leading to hydrops fetalis30 and, in the pulmonary circulation, is responsible for the persistence of pulmonary hypertension after birth31, 32. Primary absence of the DA is also commonly observed in tetralogy of Fallot with a dysplastic or absent pulmonary valve. Here again, this is a major malformation that results in lethal vascular and bronchial disorders33, 34. All these observations support the contention that the DA is an integral element of the fetal circulation. The situation is completely reversed when, after birth, the fall in pulmonary vascular resistance allows the entire cardiac output to go through the lungs. The two ventricles are then disposed in series. The aortic isthmus is no longer a shunt but becomes an integral part of the systemic arterial circuit; its absence creates major circulatory disturbances that require surgical correction. Conversely, the DA, if patent, conforms then with the definition of a shunt with all the well-known clinical consequences. Based on the abovementioned experimental and clinical data, the following concepts regarding the fetal circulation are proposed: Concept I: The aortic isthmus, not the DA, is the only arterial shunt in the fetal circulation. Concept II: A simple recording of the isthmic flow velocity pattern can provide information on global fetal cardio-circulatory dynamics. Concept III: Doppler flow recording in the aortic isthmus is a reliable indicator of fetal individual ventricular performance. Concept IV: (a) In IUGR, flows through the placenta and the aortic isthmus are closely related. (b) In IUGR, monitoring of blood flow through the aortic isthmus allows indirect assessment of cerebral oxygenation.