Diagnosing Foetal Atrioventricular Heart Blocks

Transcription

1 REVIEW ARTICLE doi: /j x Diagnosing Foetal Atrioventricular Heart Blocks S.-E. Sonesson Department of Women s and Children s Health, Karolinska Institutet, Stockholm, Sweden Received 10 May 2010; Accepted 3 June 2010 Correspondence to: S.-E. Sonesson, Pediatric Cardiology Q1:03, Astrid Lindgren Children s Hospital, SE Stockholm, Sweden. sven-erik.sonesson@karolinska.se Abstract Foetal echocardiograpic ultrasound techniques still remain the dominating modality for diagnosing foetal atrioventricular block (AVB). Foetal electrocardiography might become a valuable tool to measure time intervals, but magnetocardiograpy is unlikely to get a place in clinical practice. Assuming that AVB is a gradually progressing and preventable disease, starting during a critical period in mid-gestation with a less abnormal atrioventricular conduction before progressing to a complete irreversible AVB (CAVB), echocardiographic methods to detect first-degree AVB have been developed. The time intervals obtained with these techniques are all based on the identification of mechanical or hemodynamic events as markers of atrial (A) and ventricular (V) depolarizations and will accordingly include both electrical and mechanical components. Prospective observational studies have demonstrated a transient prolongation of AV time intervals in anti-ro SSA antibody-exposed foetuses, but it has not succeeded to identify a degree of AV time prolongation predicting irreversible cardiac damage and progression to CAVB. Causes of sustained bradycardia include CAVB, 2:1 AVB, sinus bradycardia and blocked atrial bigeminy (BAB). Using foetal echocardiographic techniques and a systematic approach, a correct diagnosis can be made in almost every case. Sinus bradycardia and CAVB are usually easy to diagnose, but BAB has a tendency to be sustained and shows a high degree of resemblance with 2:1 AVB when diagnosed during mid-gestational. As BAB resolves without treatment and 2:1 AVB may respond to treatment with fluorinated steroids, a correct diagnosis becomes an issue of major importance to avoid unnecessary treatment of harmless and spontaneously reversing conditions. Introduction Roughly half of all foetuses with complete atrioventricular block (CAVB) have an associated cardiac malformation, usually left atrial isomerism or discordant atrioventricular connections [1, 2], and a poor neonatal survival of 15 25% [1 3]. In the absence of congenital heart disease, CAVB is most likely the result of transplacental passage of maternal autoantibodies to Ro SSA and La SSB proteins. With circulating Ro SSA and or La SSB antibodies in maternal sera, there is a 2 5% risk of giving birth to a child with CAVB [4], and a 12 25% risk with a previously affected child [5, 6]. Isolated foetal CAVB has a less significant but still substantial peri-neonatal mortality ranging between 10% and 30% [1, 2, 5, 7] and, although transplacental treatment with fluorinated steroids and betamimetics has been suggested to improve outcome [8], further studies are needed to answer this issue [2, 8, 9]. The use of fluorinated steroids might be more justified in incomplete AVB as it has been observed to inhibit progression or even reverse a few cases of first-degree [10 12] and second-degree AVB [13 15]. Foetal treatment with fluorinated steroids does, however, also have risks for both the mother and the foetus [16, 17], making a correct diagnosis an issue of major importance to avoid unnecessary treatment of harmless and spontaneously reversing conditions. Assuming that AVB is a gradually progressing and preventable disease, starting during a critical period in mid-gestation with a less abnormal atrioventricular conduction, before progressing to a CAVB, methods to detect first-degree AVB have been developed. This review will focus on the currently most used diagnostic modalities to classify the degree of AVB and identify other mechanisms causing foetal bradycardia, including some ideas of improvement from our own laboratory. 205

2 206 AVB Diagnosis S.-E. Sonesson Diagnostic methods Foetal electrocardiography Classification of foetal cardiac rhythm and conduction is based on the chronology of atrial and ventricular depolarizations. Recent advances in signal processing have improved the acquisition of transabdominal foetal ECG making it possible to identify individual ventricular depolarizations (QRS complexes). Still, this technique does not allow identification of individual atrial depolarizations (P waves), and despite signal averaging over many heart beats P waves are not detected in 15 40% of examinations [18 20]. Reference ranges for cardiac time intervals have been established [18, 19] and single studies report a higher success rate, suggesting that foetal ECG should be the diagnostic tool of choice to detect prolonged PR intervals, i.e. first-degree AVB [21]. Foetal magnetocardiography Foetal magnetocardiography provides significantly better signal quality than ECG, making it easy to identify both atrial and ventricular depolarizations in averaged magnetocardiagrams [22, 23], and under optimal condition also possible to recognize individual QRS complexes as well as P waves [24]. Truly, this technique has provided important information regarding electrocardiographic time intervals, repolarization abnormalities [25] and complex rhythms in association with AVB [23], but it is expensive, requires a magnetically shielded room and is only available in very few centres. Foetal echocardiography Foetal echocardiography with m-mode and Doppler techniques remains the dominating modality for prenatal diagnosis of foetal cardiac rhythm and conduction. Using standard ultrasound echocardiographic equipment, atrial and ventricular depolarizations are identified indirectly by their mechanical [M-mode, Doppler tissue velocity imaging (DTI)] or hemodynamic [Doppler flow velocity (Doppler)] consequences. In M-mode, the line of interrogation is directed to simultaneously demonstrate systolic movements of an atrial wall and a ventricular free wall or the aortic valve. A limitation with M-mode recordings is that the onset and maximum of atrial and ventricular contraction is often not clearly defined, making it less suitable to diagnose first-degree AVB and in my personal experience also second-degree AVB. In accordance, both experimental [26] and clinical [27] studies have demonstrated the superiority of the Doppler technique compared with the m-mode approach for measuring atrioventricular (AV) time intervals as a substitute for the electric PR interval in ECG. With pulsed wave Doppler, signals can be recorded simultaneously from the mitral valve left ventricular aortic outflow (MV-Ao) [28], the superior vena cava ascending aorta (SVC-Ao) [29, 30] as well as a pulmonary vein and peripheral pulmonary artery [31]. In these recordings, the mitral A waves and the a waves seen in the systemic and pulmonary veins represent atrial depolarization, and the start of the arterial profiles in the aorta and the peripheral pulmonary artery are used as markers of ventricular activation (Fig. 1). Some investigators use the outflow profile in the left ventricle for MV- Ao recordings, but in my personal opinion measurements will be more reproducible by also including aortic valveclicks. MV-Ao recordings are usually the easiest to obtain but have the disadvantage of not showing what goes on in the atria during ventricular systole when the MV is closed. Still, as all these Doppler techniques are angle dependent, foetal position frequently decides which technique will give the best result. Recognizing foetal position as a limitation to get the high-quality recordings needed to clarify the underlying electrophysiological mechanisms, we have at our laboratory also included A B Figure 1 Doppler flow velocity recordings from a foetus with indirect signs of first-degree atrioventricular block (AVB) at 19 weeks of gestation. (A) A recording from the mitral valve (upward) and left ventricular outflow to the aorta (downward). The first vertical line denotes the intersection of the mitral early filling wave (e) and the later wave attributed to atrial contraction (a*), and the second line the onset of ventricular ejection (v), between which the AV time interval is measured. (B) A recording from superior vena cava (upward) and ascending aorta (downward). In this recordings, AV time intervals are measured from the beginning of retrograde venous flow in the SVC owing to atrial contraction (first line), to the beginning of the aortic ejection wave (second line). Both AV time intervals are more than four z-scores above normal mean.

3 S.-E. Sonesson AVB Diagnosis 207 Figure 2 A systematic approach to foetal bradycardia primarily based on the chronology of atrial (A) and ventricular (V) depolarizations, indirectly identified by their mechanical or hemodynamic consequences. Please see text; diagnosing second- and third-degree atrioventricular block, for explanation. recordings from the pulmonary trunk and ductus venosus when diagnosing foetuses with bradyarrhythmias. Recordings from the pulmonary trunk are obtained from any view with a narrow angle of insonation and the sampling volume adjusted to the flow in, or just above, the pulmonary valve. Besides typical systolic outflow profiles, these recordings also comprise very sharp diastolic flow profiles, in the same direction, corresponding to atrial contractions (Figs. 3C and 4C). Doppler recordings of the ductus venosus are obtained in a midsagittal or transverse section as previously described [32]. In the absence of foetal body or breathing movements, these records frequently demonstrate distinct troughs or sharp spikes of reversed flow corresponding to atrial contractions (Fig. 5B). DTI is usually performed using an apical view of the atria and ventricles (4-chamber view) to obtain atrial and ventricular wall motion velocities for later off line analysis [12, 20, 33]. Most frequently, data recorded from the right ventricular free wall at the level of the tricuspid valve is used to identify the A wave as marker of atrial depolarization, and a point corresponding to the start of right ventricular isovolumetric contraction to denote ventricular activation [12, 20]. Recordings from the ventricular myocardium will not detect atrial activity during ventricular systole, a problem that can be reduced by a more complex technique, simultaneously analysing the much slower velocities in the atrial wall [33]. Classification of AV conduction disturbances In first-degree AVB, all impulses are conducted from the atria to the ventricles, but the AV conduction time is prolonged beyond the upper limit of normal. Seconddegree AVB refers to a failure to conduct some, but not all, atrial impulses to the ventricles. In Mobitz type I (Wenckebach) second-degree AVB, there is a progressive lengthening of the AV conduction, until an isolated impulse is blocked. Mobitz type II second-degree AVB is characterized by a sudden block of an isolated impulse without prior lengthening of the AV conduction time. In 2:1 second-degree AVB, only every second atrial impulse is conducted to the ventricles. Third-degree AVB or CAVB denotes a situation where there is no AV conduction at all, and the atria and ventricles beat independently. A B C D Figure 3 Recordings from foetuses with complete heart block and atrioventricular dissociation, demonstrating the regular slow ventricular rhythm (v) and the faster atrial rhythm (a) without any constant relationship. (A) M-mode recording through an atrial and ventricular wall. (B) A Doppler flow velocity recording from the mitral valve (downward) left ventricular outflow (upward). (C) A recording from the pulmonary trunk, and (D) a recording from a pulmonary artery (upward) and vein (downward) with retrograde flow during atrial contraction. a and v; indirect markers of atrial and ventricular activation and contraction.

4 208 AVB Diagnosis S.-E. Sonesson A B C D Figure 4 A case of 2:1 second-degree atrioventricular block owing to long QT syndrome (A D). The absolutely regular chronology of conducted (a*) and blocked (a) atrial beats is clearly observed in recordings from the pulmonary trunk (C) and superior vena cava ascending aorta (D) but more difficult to recognize in the m-mode recording (A) and impossible to identify in the mitral valve left ventricular outflow tracing (B) with fusion of mitral E and A waves. Diagnosing first-degree AVB At present, Doppler flow velocimetry from the MV-Ao or SVC-Ao are the most widely used modalities for detecting prolonged AV conduction. The methods have been validated [20, 34 36], and reference values established [20, 34, 37 39]. AV time intervals are systematically longer than the PR interval in an ECG, which is well explained by the fact that these Doppler-derived measurements include the first systolic phase of isovolumetric contraction. Interestingly, this mechanical component of the AV time interval has been demonstrated to contribute to the prolongation of AV time intervals seen in some Ro SSA antibody-exposed foetuses, in turn, suggesting that these foetal hearts have not only disturbed electrical conduction but also decreased cardiac performance [40]. AV time intervals increase with gestation and decrease with increased heart rate [20, 37, 39]. Increased heart rate and prolongation of the AV interval also result in difficulties to correctly identify the starting point of the MV-Ao measurement, making the SVC-Ao method superior in these foetuses [30]. A Our experience of using these techniques for surveillance of Ro52 SSA antibody-exposed foetuses at risk for CAVB is that one-third had abnormal AV conduction, but <5% developed second- or third-degree AVB [41, 42]. The remaining 28% had AV time intervals exceeding our 95% reference range, on at least two weekly examinations performed during weeks of gestation, subsequently normalizing before or shortly after birth. We also observed that mid-trimester Doppler had the potential to identify almost all foetuses with firstdegree AVB at birth, with a positive predictive value of approximately 45%, and to exclude conduction disturbances in the newborn period, with a negative predictive value close to 100% [42]. From a basic science perspective, this observation of a transient, spontaneously reversible, prolongation of AV conduction, also observed by other investigators [11], is very interesting. However, from a clinical perspective there is a clear need to identify an early marker of irreversible cardiac damage and progression to CAVB, but to date, no prospective controlled studies have been performed to answer this issue. In the multicenter PRIDE study [11] comprising 98 B Figure 5 A case of blocked atrial bigeminy, with a shorter time interval between the conducted (a*) and following blocked ectopic (a ) beats. Although this atrial rhythm can be recognized in the pulmonary vein and artery recording (A), it is more clearly observed in the tracing from the ductus venosus (B). Vertical lines denote the positions used when AA time intervals are measured.

5 S.-E. Sonesson AVB Diagnosis 209 Ro SSA antibody-positive pregnancies, two foetuses developed AV time prolongation exceeding 150 ms (three z-scores above normal mean), reverting to normal conduction during transplacental dexamethasone treatment. In our single-centre study of 95 foetuses, three with MV-Ao time intervals exceeding 150 ms spontaneously normalized their AV conduction before birth in one case and after birth in two cases [42]. Combining data from these two studies [11, 42], there was only one of seven cases, where an abnormal AV time interval was documented before progression to second- or third-degree AVB. Two cases had normal AV time intervals 1 week before the block was diagnosed, and in four more time had elapsed from a previous normal examination, suggesting that weekly examinations are insufficient to identify a marker of irreversible progression to CAVB. DTI has also been suggested as a technique to detect foetuses with first-degree AVB. The technique has been validated [43, 44] and reference values published [12, 20]. Using the start of isovolumetric contraction as the marker of ventricular activation, these measurements will systematically be shorter than flow Doppler measurements including the isovolumetric contraction time, and more closely related to the PR interval in ECG [20]. In accordance, a prospective multicenter study using DTI for surveillance of Ro SSA- and or La SSB antibodypositive pregnancies, found an AV time interval exceeding two z-scores above normal mean in <10% (6 70) of their cases [12]. All six cases were transplacentally treated with dexamethasone and normalized AV conduction within 3 14 days. This relative small proportion of affected foetuses, compared to the 30% observed by us when using the flow Doppler technique [42], may in part be attributed to that DTI measurements are not including the first systolic phase of isovolumetric contraction, which might contribute to prolongation of flow Doppler derived AV time measurements [40]. That the DTI technique offers a measurement more closely related to the start of ventricular depolarization do, however, not necessarily make it superior to the flow Doppler technique as a method of foetal surveillance, as signs of myocardial involvement might also at a point predict irreversible damage and risk of progression to CAVB. In agreement with this concept, we could not demonstrate any improvement in precision of detecting foetuses with firstdegree AVB in ECG at birth, by excluding the isovolumetric contraction time from our MV-Ao AV time measurements [42]. Diagnosing second- and third-degree AVB Second-degree AVB (Mobitz type I II) results in a regular rhythm with a normal rate and isolated missed beats showing a close resemblance to blocked atrial ectopic beats. Diagnosing these types of AVB requires high-quality recordings over several heart beats, best obtained by Doppler techniques simultaneously recording both venous and arterial flow velocity profiles [14, 30, 31]. Both CAVB and 2:1 AVB, as well as sinus bradycardia and blocked atrial ectopic beats in bigeminy, result in a slow, regular ventricular rhythm [30, 45, 46]. Sustained sinus bradycardia has been observed in foetuses with sinus node dysfunction and impending foetal demise from cardiac as well as extracardiac causes [30, 46]. Moderate sinus bradycardia and rare cases of 2:1 AVB have also been described in foetuses with long QT syndrome [46, 47]. In approximately 30% of cases with sustained foetal bradycardia the mechanism is blocked atrial bigeminy, resulting in a well-tolerated reduction in the ventricular rate, which usually converts spontaneously to normal sinus rhythm before delivery [30, 45, 46]. Our experience of foetal bradycardia from a tertiary foetal cardiology unit setting is that intermittent AVB is extremely rare, patients with blocked atrial bigeminy have a heart rate of beats min, and is frequently intermittent, 2:1 AVB results in a heart rate of beats min, and a heart rate below 60 beats min is strongly suggestive for a CAVB [48]. A correct diagnosis does, however, rest on recognition of the chronological relationships between atrial (A) and ventricular (V) depolarizations, usually identified by their mechanical (M-mode) or hemodynamic (Doppler) consequences. Our algorithm used to diagnose foetuses with a slow, regular ventricular rhythm is presented in Fig. 2. Briefly, a foetus where all atrial depolarizations are conducted to the ventricles (1:1 AV relationship) is considered to be in sinus rhythm, even if it cannot be excluded that the atrial pacemaker is ectopic and not really situated in the sinus node. A slow ventricular rhythm in association with AV dissociation is only seen in CAVB. A situation where every second atrial beat is followed by a ventricular contraction (2:1 AV relationship) can be attributed to an incomplete AVB that might respond to transplacental treatment with fluorinated steroids, or a more benign spontaneously reversible blocked atrial bigeminy. An alternative diagnosis is CAVB with isorhythmic AV dissociation, closely resembling 2:1 AVB [24], where steroid treatment is unlikely to have any effect on AV conduction. Blocked atrial bigeminy frequently has a typical atrial rhythm with a shorter AA time interval, between the conducted and following blocked atrial beats, alternating with a clearly longer AA time interval between the blocked and following conducted beat. In mid-gestation, this pattern is less obvious and high-quality recordings together with careful measurements are needed to differentiate blocked bigeminy from 2:1 AVB [45, 48]. Both CAVB and 2:1 AVB have a regular atrial rhythm, and a repeated recording will usually reveal whether the AV time interval remains the same, suggesting 2:1 AVB or has changed which will indicate CAVB. Long QT

6 210 AVB Diagnosis S.-E. Sonesson syndrome with a prolongation of ventricular repolarization resulting in a pattern where every second atrial beat will not result in ventricular contraction is rare and sometimes impossible to differentiate from true 2:1 AVB. A family history and ECG recordings on the pregnant woman and family members can be helpful. Runs of ventricular tachycardia are suggestive of long QT syndrome [47], but junctional ectopic tachycardia and or ventricular tachycardia has also been described in the acute stage of AVB [23]. Another possible marker of long QT syndrome may be that the extremely long time needed for ventricular repolarization might result in a prolonged time interval between aortic valve closure and MV opening, as observed in one of our cases (Fig. 4B). Using foetal echocardiographic techniques, a correct diagnosis can be made in almost every case. M-mode recordings are usually diagnostic in CAVB with clear AV dissociation (Fig. 3A) but frequently unsuitable for diagnosing cases with a 2:1 AV relationship (Fig. 4A). The disadvantage with recordings techniques not demonstrating atrial activity during ventricular systole is less in cases with bradycardia with long periods of diastolic filling. Still, flow waves representing early passive mitral inflow may fuse with the A waves representing atrial contraction in MV-Ao tracings, making it difficult to diagnose AV dissociation (Fig. 3B) or even impossible to distinguish 2:1 AVB from blocked atrial bigeminy (Fig. 4B). Recordings from the pulmonary trunk do not suffer from this limitation and have in our hands been very handy to diagnose both CAVB (Fig. 4C) and 2:1 AVB (Fig. 3C). Techniques simultaneously recording arterial and venous flow, such as SVC-Ao (Fig. 4D) and pulmonary vein artery (Figs. 3D and 5A), are optimal but not always easy to obtain, especially with the high quality required to make sure whether the atrial rhythm is absolutely regular or not in cases with a 2:1 AV relationship. In this situation, we have found recordings from the ductus venosus very useful to distinguish between 2:1 AVB and blocked atrial bigeminy (Fig. 5B) [48]. Conclusions In spite of recent development in the field of foetal electrocardiography and magnetocardiograpy, foetal echocardiograpic ultrasound techniques still remain the dominating modality for prenatal diagnosis of AVB. Because of the significant mortality and morbidity seen in antibody-mediated CAVB, techniques to identify firstdegree AVB have been developed, with the aim of early detection and transplacental therapeutic intervention with fluorinated steroids. Reference values have been established, and protocols for surveillance during the period with highest risk of developing CAVB, from to weeks, have been designed. Prospective observational studies using the Doppler flow velocimetric techniques have demonstrated that a surprisingly large proportion of anti-ro SSA antibody-exposed foetuses have a transient prolongation of AV time intervals, normalizing before or shortly after birth. Follow-up studies are in progress to confirm a good long-term prognosis in these children. At present, studies have not succeeded to identify a degree of AV time prolongation predicting irreversible or unambiguously progressing AV conduction disturbances. This lack of knowledge is partly explained by the rarity of CAVB, also in the identified group at risk, but most likely also attributable to a quick progression from first-degree AVB to CAVB. Using foetal echocardiographic techniques, a correct diagnosis can be made in almost every case of 2:1 AVB and CAVB. Blocked atrial bigeminy has a tendency to be sustained and shows a high degree of resemblance with 2:1 AVB when diagnosed in mid-gestational. To correctly identify which of these two underlying mechanisms that generate the bradycardia becomes very important as 2:1 AVB might revert to normal sinus rhythm with steroid treatment, while blocked atrial bigeminy resolves spontaneously without treatment. Acknowledgment Financial support was provided by the Karolinska Institutet Research Foundations and the Swedish Heart Lung Foundation. References 1 Schmidt KG, Ulmer HE, Silverman NH, Kleinman CS, Copel JA. Perinatal outcome of fetal complete atrioventricular block: a multicenter experience. J Am Coll Cardiol 1991;17: Lopes LM, Tavares GM, Damiano AP et al. Perinatal outcome of fetal atrioventricular block: one-hundred-sixteen cases from a single institution. Circulation 2008;118: Jaeggi ET, Hornberger LK, Smallhorn JF, Fouron JC. Prenatal diagnosis of complete atrioventricular block associated with structural heart disease: combined experience of two tertiary care centers and review of the literature. Ultrasound Obstet Gynecol 2005;26: Brucato A, Frassi M, Franceschini F et al. Risk of congenital complete heart block in newborns of mothers with anti-ro SSA antibodies detected by counterimmunoelectrophoresis: a prospective study of 100 women. Arthritis Rheum 2001;44: Buyon JP, Hiebert R, Copel J et al. Autoimmune-associated congenital heart block: demographics, mortality, morbidity and recurrence rates obtained from a national neonatal lupus registry. J Am Coll Cardiol 1998;31: Julkunen H, Kaaja R, Siren MK et al. Immune-mediated congenital heart block (CHB): identifying and counseling patients at risk for having children with CHB. Semin Arthritis Rheum 1998;28: Groves AM, Allan LD, Rosenthal E. Outcome of isolated congenital complete heart block diagnosed in utero. Heart 1996;75: Jaeggi ET, Fouron JC, Silverman ED, Ryan G, Smallhorn J, Hornberger LK. Transplacental fetal treatment improves the outcome of prenatally diagnosed complete atrioventricular block without structural heart disease. Circulation 2004;110:

7 S.-E. Sonesson AVB Diagnosis Rosenthal E, Gordon PA, Simpson JM, Sharland GK. Letter regarding article by Jaeggi et al., transplacental fetal treatment improves the outcome of prenatally diagnosed complete atrioventricular block without structural heart disease. Circulation 2005;111:e Vesel S, Mazic U, Blejec T, Podnar T. First-degree heart block in the fetus of an anti-ssa Ro-positive mother: reversal after a short course of dexamethasone treatment. Arthritis Rheum 2004;50: Friedman DM, Kim MY, Copel JA et al. Utility of cardiac monitoring in fetuses at risk for congenital heart block: the PR Interval and Dexamethasone Evaluation (PRIDE) prospective study. Circulation 2008;117: Rein AJ, Mevorach D, Perles Z et al. Early diagnosis and treatment of atrioventricular block in the fetus exposed to maternal anti- SSA Ro-SSB La antibodies: a prospective, observational, fetal kinetocardiogram-based study. Circulation 2009;119: Saleeb S, Copel J, Friedman D, Buyon JP. Comparison of treatment with fluorinated glucocorticoids to the natural history of autoantibody-associated congenital heart block: retrospective review of the research registry for neonatal lupus. Arthritis Rheum 1999;42: Raboisson MJ, Fouron JC, Sonesson SE, Nyman M, Proulx F, Gamache S. Fetal Doppler echocardiographic diagnosis and successful steroid therapy of Luciani-Wenckebach phenomenon and endocardial fibroelastosis related to maternal anti-ro and anti-la antibodies. J Am Soc Echocardiogr 2005;18: Theander E, Brucato A, Gudmundsson S, Salomonsson S, Wahren- Herlenius M, Manthorpe R. Primary Sjogren s syndrome treatment of fetal incomplete atrioventricular block with dexamethasone. J Rheumatol 2001;28: Breur JM, Visser GH, Kruize AA, Stoutenbeek P, Meijboom EJ. Treatment of fetal heart block with maternal steroid therapy: case report and review of the literature. Ultrasound Obstet Gynecol 2004;24: Costedoat-Chalumeau N, Amoura Z, Le Thi Hong D et al. Questions about dexamethasone use for the prevention of anti-ssa related congenital heart block. Ann Rheum Dis 2003;62: Chia EL, Ho TF, Rauff M, Yip WC. Cardiac time intervals of normal fetuses using noninvasive fetal electrocardiography. Prenat Diagn 2005;25: Taylor MJ, Smith MJ, Thomas M et al. Non-invasive fetal electrocardiography in singleton and multiple pregnancies. BJOG 2003;110: Nii M, Hamilton RM, Fenwick L, Kingdom JC, Roman KS, Jaeggi ET. Assessment of fetal atrioventricular time intervals by tissue Doppler and pulse Doppler echocardiography: normal values and correlation with fetal electrocardiography. Heart 2006;92: Gardiner HM, Belmar C, Pasquini L et al. Fetal ECG: a novel predictor of atrioventricular block in anti-ro positive pregnancies. Heart 2007;93: Stinstra J, Golbach E, van Leeuwen P et al. Multicentre study of fetal cardiac time intervals using magnetocardiography. BJOG 2002;109: Zhao H, Cuneo BF, Strasburger JF, Huhta JC, Gotteiner NL, Wakai RT. Electrophysiological characteristics of fetal atrioventricular block. J Am Coll Cardiol 2008;51: Wakai RT, Leuthold AC, Cripe L, Martin CB. Assessment of fetal rhythm in complete congenital heart block by magnetocardiography. Pacing Clin Electrophysiol 2000;23: Zhao H, Strasburger JF, Cuneo BF, Wakai RT. Fetal cardiac repolarization abnormalities. Am J Cardiol 2006;98: Dancea A, Fouron JC, Miro J, Skoll A, Lessard M. Correlation between electrocardiographic and ultrasonographic time-interval measurements in fetal lamb heart. Pediatr Res 2000;47: Fouron JC, Proulx F, Miro J, Gosselin J. Doppler and M-mode ultrasonography to time fetal atrial and ventricular contractions. Obstet Gynecol 2000;96: Strasburger JF, Huhta JC, Carpenter RJ Jr, Garson A Jr, McNamara DG. Doppler echocardiography in the diagnosis and management of persistent fetal arrhythmias. J Am Coll Cardiol 1986;7: Reed KL, Appleton CP, Anderson CF, Shenker L, Sahn DJ. Doppler studies of vena cava flows in human fetuses. Insights into normal and abnormal cardiac physiology. Circulation 1990;81: Fouron JC. Fetal arrhythmias: the Saint-Justine hospital experience. Prenat Diagn 2004;24: Carvalho JS, Prefumo F, Ciardelli V, Sairam S, Bhide A, Shinebourne EA. Evaluation of fetal arrhythmias from simultaneous pulsed wave Doppler in pulmonary artery and vein. Heart 2007;93: Kiserud T, Eik-Nes SH, Blaas HG, Hellevik LR. Ultrasonographic velocimetry of the fetal ductus venosus. Lancet 1991;338: Rein AJ, O Donnell C, Geva T et al. Use of tissue velocity imaging in the diagnosis of fetal cardiac arrhythmias. Circulation 2002;106: Glickstein JS, Buyon J, Friedman D. Pulsed Doppler echocardiographic assessment of the fetal PR interval. Am J Cardiol 2000;86: Bergman G, Jacobsson LA, Wahren-Herlenius M, Sonesson SE. Doppler echocardiographic and electrocardiographic atrioventricular time intervals in newborn infants: evaluation of techniques for surveillance of fetuses at risk for congenital heart block. Ultrasound Obstet Gynecol 2006;28: Pasquini L, Seale AN, Belmar C et al. PR interval: a comparison of electrical and mechanical methods in the fetus. Early Hum Dev 2007;83: Andelfinger G, Fouron JC, Sonesson SE, Proulx F. Reference values for time intervals between atrial and ventricular contractions of the fetal heart measured by two Doppler techniques. Am J Cardiol 2001;88: Van Bergen AH, Cuneo BF, Davis N. Prospective echocardiographic evaluation of atrioventricular conduction in fetuses with maternal Sjogren s antibodies. Am J Obstet Gynecol 2004;191: Wojakowski A, Izbizky G, Carcano ME, Aiello H, Marantz P, Otano L. Fetal Doppler mechanical PR interval: correlation with fetal heart rate, gestational age and fetal sex. Ultrasound Obstet Gynecol 2009;34: Bergman G, Eliasson H, Bremme K, Wahren-Herlenius M, Sonesson SE. Anti-Ro52 SSA antibody-exposed fetuses with prolonged atrioventricular time intervals show signs of decreased cardiac performance. Ultrasound Obstet Gynecol 2009;34: Sonesson SE, Salomonsson S, Jacobsson LA, Bremme K, Wahren- Herlenius M. Signs of first-degree heart block occur in one-third of fetuses of pregnant women with anti-ssa Ro 52-kd antibodies. Arthritis Rheum 2004;50: Bergman G, Wahren-Herlenius M, Sonesson SE. Diagnostic precision of Doppler flow echocardiography in fetuses at risk for atrioventricular block. Ultrasound Obstet Gynecol DOI / uog Nii M, Shimizu M, Roman KS et al. Doppler tissue imaging in the assessment of atrioventricular conduction time: validation of a novel technique and comparison with electrophysiologic and pulsed wave Doppler-derived equivalents in an animal model. J Am Soc Echocardiogr 2006;19: Rein AJ, O Donnell CP, Colan SD, Marx GR. Tissue velocity Doppler assessment of atrial and ventricular electromechanical cou-

8 212 AVB Diagnosis S.-E. Sonesson pling and atrioventricular time intervals in normal subjects. Am J Cardiol 2003;92: Carvalho JS, Jaeggi E. Sustained fetal bradycardia: mechanisms and pitfalls. Ultrasound Obstet Gynecol 2006;28: Lin MT, Hsieh FJ, Shyu MK, Lee CN, Wang JK, Wu MH. Postnatal outcome of fetal bradycardia without significant cardiac abnormalities. Am Heart J 2004;147: Hofbeck M, Ulmer H, Beinder E, Sieber E, Singer H. Prenatal findings in patients with prolonged QT interval in the neonatal period. Heart 1997;77: Sonesson SE, Eliasson H. Mechanisms in fetal bradyarrhythmia: seventeen years experience with established and new Doppler echocardiographic techniques. Cardiol Young 2008;18:68.