Ultrasound Obstet Gynecol 2006; 27: 599606 Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/uog.

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Editorial
Fetal arrhythmias
J. M. SIMPSON
Department of Congenital Heart Disease, Evelina Childrens Hospital, Guys and St Thomas Hospital NHS Foundation Trust, London SE1 7EH, UK (e-mail: john.simpson@gstt.nhs.uk)

Introduction
The aim of this Editorial is to examine current aspects of fetal cardiac arrhythmias. The types of cardiac arrhythmia likely to be encountered are summarized, but emphasis is given to techniques that can help to rene diagnosis and management. Controversial aspects of diagnosis and management are highlighted. Additional information regarding echocardiographic techniques for diagnosis of arrhythmias is available as a slide presentation to download from the website of this Journal (Figure S1).

Techniques
The approach to diagnosis of arrhythmias is entirely different during prenatal compared with postnatal life. After birth, electrocardiography (ECG) represents the gold standard technique, but clearly this approach is much more difcult during fetal life. In recent years, advances in signal processing have meant that fetal ECGs can be distinguished from the maternal ECG signal1 by application of multiple ECG electrodes to the maternal abdomen. Fetal ventricular depolarization (QRS complexes) can be detected in real time, although atrial signals are not readily distinguished in real time but can be observed in a signal-averaged trace. The technique is quite time-consuming, however, and is prone to interference from other electrical signals, such as maternal cardiac impulses and muscle contraction. Also, the lowest technical success rates are observed at the peak period of occurrence of fetal tachycardias and extrasystoles1 . An alternative technique is magnetocardiography, which detects small magnetic elds related to the electrical signals in the fetal heart2 . This technique is limited by the fact that it needs to be performed in a magnetically shielded room and is not available at many centers. However, recent reports have documented the use of the technique at the bedside in an unshielded environment, which could increase markedly its clinical utility3 . The above methods have the capability of measuring a variety of ECG time intervals, many of which, such as the QT interval3 , cannot be measured echocardiographically4 . Furthermore, by analysis of the electrical activity of the heart rather than mechanical events, detailed information can also be obtained on the mechanisms of fetal tachycardias5 .

Yet, despite the development of alternatives, echocardiography remains the dominant modality for assessment of fetal arrhythmias. This operates by inferring electrical events from the motion of cardiac chambers or ow signals within the heart, and there are two major methods: M-mode and Doppler6,7 . The approach used will depend on background training and experience with the technique. Most cardiologists are familiar with M-mode, while this is often less familiar to those from an obstetric background. The M-mode technique involves aligning the M-mode cursor through one of the atrial and one of the ventricular walls. This permits visualization of the relationship between atrial and ventricular contractions (Figure 1). This technique is simple when image quality is good and the fetal lie is favorable, but if image quality is poor, then other techniques, such as pulsed wave Doppler, may be preferable. Pulsed wave Doppler can be used to aid diagnosis of fetal arrhythmias by interrogation of intracardiac ows. The cursor is placed between the mitral and aortic valves with a relatively large sample volume, to detect ow into and out of the ventricle (Figure 2). An alternative method is simultaneous Doppler interrogation of venous ow (superior vena cava or pulmonary vein) and an adjacent artery (aorta or branch pulmonary artery) (Figure 3b). The types of arrhythmia which present in clinical practice can be divided pragmatically into irregular heart

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EDITORIAL

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Simpson

Figure 1 M-mode echocardiogram of sinus rhythm with single blocked atrial ectopic beat. Atrial contractions A1A3 are normal and followed by ventricular contractions V1V3. The fourth atrial contraction (A4) is premature and blocked at the atrioventricular node so that there is no corresponding ventricular contraction.

Figure 2 Doppler tracing of normal sinus rhythm. The Doppler cursor has been placed in the left ventricular outow tract so that mitral valve (MV) inow (e- and a-waves) and aortic ow (v-wave) are both seen. There is a normal pattern of early diastolic ow across the MV (e-wave) followed by the phase associated with atrial contraction (a-wave). The solid horizontal gray line is the time interval between start of the a-wave and v-waves, i.e. the atrioventricular (AV) interval or mechanical PR interval.

rhythms with a normal overall rate, tachycardias and bradycardias. Irregular fetal heart rhythms Irregular heart rhythms are usually detected during routine auscultation of the fetal heart. Typically they are described as extra beats or missed beats and most commonly they are due to atrial extrasystoles (Figure 1)8 . The description of a missed beat on auscultation of the fetal heart is due to a compensatory pause after atrial extrasystole; ventricular extrasystoles can also occur, although these are rarer. Extrasystoles typically occur late in the second or third trimester, causing alarm for expectant parents. Such concern is usually unwarranted, because in the overwhelming majority of cases, these arrhythmias resolve spontaneously prior to delivery. Some cardiologists advise mothers to abstain from caffeine, but there is no evidence to suggest that this leads to more rapid resolution of ectopic beats. The available evidence does not indicate that atrial or ventricular extrasystoles are a marker of fetal distress9,10 ; however, if these extrasystoles persist during labor, then fetal monitoring may prove difcult by cardiotocography. In a small minority of cases, around 23%8,11 , multiple atrial extrasystoles can lead to a sustained tachycardia. Fetuses with multiple blocked atrial ectopic beats sufcient to cause a low

Figure 3 Echocardiographic assessment of fetal supraventricular tachycardia (type with short time interval between ventricular and atrial contraction (short VA type))17,18 . (a) shows the time relationship between atrial (A) and ventricular (V) contractions. There is a short time interval between ventricular contraction and atrial contraction, making a re-entry mechanism via an accessory pathway most likely. s, second. (b) shows the same type of tachycardia assessed by interrogation of the superior vena cava (SVC) and ascending aortic (AA) ow. Flow into the AA is during ventricular systole (V). During atrial contraction there is transient reversal of SVC ow (a). This permits measurement of the atrioventricular (AV) and VA intervals. Reproduced with permission from the BMJ Publishing Group17,18 .

ventricular rate appear to be at higher risk of tachycardia than are those with a normal ventricular rate8 . If a tachycardia does develop following multiple extrasystoles, supraventricular tachycardia via a re-entry mechanism is the most common nding, but atrial utter has also been observed8,11 .

Tachycardias
Types of tachycardia Pathological fetal tachycardias are dened as fetal heart rates above 180200 bpm, but most affected fetuses have ventricular rates ranging from 220 to 300 bpm. The most common type of fetal tachycardia is supraventricular tachycardia (6690%) followed by atrial utter (1030%)12 15 . Atrial brillation and chaotic atrial tachycardia are less common. Ventricular tachycardia can occur during fetal life but is rare.

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Ultrasound Obstet Gynecol 2006; 27: 599606.

Editorial Echocardiographic techniques to rene the management approach In supraventricular tachycardia there is a 1 : 1 ratio of atrial to ventricular impulses (A : V ratio), which can be observed readily using M-mode echocardiography or Doppler. An accessory conduction pathway between the atria and ventricles accounts for the arrhythmia in most cases. In susceptible fetuses, an electrical impulse passes from the atria to the ventricles via the atrioventricular node, to depolarize the ventricles. The presence of an accessory pathway means that this electrical impulse can pass rapidly retrograde, from the ventricles to the atria, establishing a re-entry circuit. Once the tachycardia is initiated by this mechanism, it is of uniform rate (typically around 240 bpm). The term supraventricular tachycardia has been applied to a number of types of tachycardia, of which the most common mechanism is atrioventricular reentry of the type described above. However, different tachycardias, including ectopic atrial tachycardia and junctional reciprocating tachycardia, are also associated with a 1 : 1 A : V contraction ratio. Diagrams of the mechanisms of such tachycardias are available in a recent review16 . Fetal echocardiographic assessment has focused on the use of M-mode echocardiography or Doppler echocardiography to differentiate, to some extent, between different types of tachycardia associated with a 1 : 1 A : V ratio. These methods examine the time intervals between atrial and ventricular contraction deduced from Doppler ow patterns in the superior vena cava and ascending aorta or M-mode interrogation of the timing of atrial and ventricular contraction (Figure 3)17,18 . If there is a short time interval between ventricular and atrial contraction (short VA tachycardia), then by far the most likely mechanism is a re-entry tachycardia via an accessory pathway. If there is a much longer delay between ventricular and atrial contraction, then the mechanism of tachycardia is likely to be different, for example in atrial ectopic tachycardia or permanent junctional reciprocating tachycardia. The clinical importance of time-interval measurements is that, by giving additional information on the mechanism of tachycardia, they may guide appropriate drug therapy19 . Atrial utter is characterized by a much faster rate of atrial contraction (rates of 350500/min) compared with ventricular contraction. The ventricles cannot respond in a 1 : 1 fashion to the extremely fast atrial rates and so there is 2 : 1 or variable atrioventricular block. It has been suggested that atrial utter is more difcult to control and is associated with a higher mortality rate and a higher incidence of fetal hydrops compared with supraventricular tachycardia. However, this was not borne out by a recent meta-analysis20 , which conrmed that atrial utter tends to occur slightly later in gestation than does supraventricular tachycardia. Ventricular tachycardia is a rare type of fetal arrhythmia. It can be seen in association with fetal long QT syndrome, which is a group of ion channelopathies

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characterized by prolongation of the QT interval on ECG, associated with an increased risk of sudden death. Prenatal measurement of the QT interval is not possible by echocardiography and so conrmation of such a diagnosis usually awaits postnatal investigation. Measurement of this interval during fetal life is an attraction of fetal ECG or magnetocardiography. Fetuses with long QT syndrome often demonstrate sinus bradycardia between the episodes of ventricular tachycardia, which is helpful in the differential diagnosis21,22 . Prolongation of the QT interval can also occur in fetuses with immune mediated congenital complete heart block, manifesting as complete heart block interspersed with periods of ventricular tachycardia23 . Management approach The precise management of fetal tachycardias will vary from center to center. There have been no systematic controlled trials of therapy, and licensing laws for some drugs differ between countries. When faced with a fetus with a tachycardia there are a number of options available, including: delivery of the baby for postnatal management; intrauterine therapy by maternal administration of drugs; direct administration of antiarrhythmic drugs into the fetal circulation; observation of the fetus without therapy. The approach that my center has adopted is to strive to deliver fetuses at term in normal sinus rhythm whenever possible. We have resisted elective preterm delivery of affected fetuses in the vast majority of cases given the high associated morbidity24 and the availability of intrauterine therapy. The majority of fetuses that have presented to my center have been managed by maternal administration of antiarrhythmic drugs. Most fetal tachycardias can be controlled effectively by this means, although hydropic fetuses have a lower response rate than do non-hydropic fetuses, due, in part at least, to impaired placental transfer of drugs to the fetus. If the tachycardia is resistant to transplacental treatment, then direct fetal therapy may be considered. From our published data this has been undertaken in only ve of 127 consecutive cases15 and since publications of that series we have only undertaken direct therapy on one further occasion, in a hydropic fetus with supraventricular tachycardia refractory to transplacental treatment. Elective preterm delivery of affected fetuses has been undertaken in a small minority of cases, typically when the fetus failed to respond to in-utero therapy, gestational age was sufciently advanced and, most importantly, there were clear advantages to delivery in terms of therapeutic options. The precise choice of drug will depend on the type of tachycardia identied, knowledge of the antiarrhythmic agents available and the familiarity and experience of those involved19,25 . Some of the drugs used have potential side effects, so both maternal and fetal well-being have to be considered. For non-hydropic fetuses with atrial utter or re-entry supraventricular tachycardia (short

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Simpson appendages) can present with sinus bradycardia. Most fetuses with laterality disturbance have major congenital heart defects, but this can be subtle, for example with interruption of the inferior vena cava as the only sonographic nding. Fetuses with long QT syndrome may present with sinus bradycardia21 . Newer techniques, such as fetal ECG and magnetocardiography, may be helpful to conrm this nding prenatally. Fetuses with long QT may also present with ventricular tachycardia and rarely atrioventricular block due to the prolonged refractory period of the ventricle22 . Sick sinus bradycardia, a sinus node abnormality, has been described during fetal life with an abnormal chronotropic response requiring postnatal pacemaker insertion22 . Atrioventricular block is usually evaluated using M-mode echocardiography to examine the relationship between contraction of the atrial and ventricular walls (Figure 4). Atrioventricular block can be subdivided into rst-degree, second-degree and third-degree (complete) heart block. In rst-degree heart block, there is prolongation of the mechanical PR interval (or atrioventricular (AV) interval) (Figure 2) which can be assessed by pulsed wave Doppler33,34 . In second-degree heart block, there is either a xed ratio of atrial to ventricular contractions e.g. 2 : 1 or 3 : 1 block, or progressive prolongation of the PR interval until an atrial beat is non-conducted (Wenkebach). In complete heart block there is complete dissociation between atrial and ventricular contractions (Figure 4). Complete atrioventricular block may be immunemediated (anti-Ro/La), with the cardiac structure usually (but not invariably) normal. Alternatively, it may be due to congenital heart defects, most commonly isomerism of the left atrial appendages or discordance of the atrioventricular connections35 38 . Two recent series have been published in this Journal examining this group of fetuses and were the subject of an accompanying Opinion39 . In one study, two infants of 10 continuing pregnancies survived37 and in the other series only three infants of 16 continuing pregnancies survived36 . These recent studies conrm the ndings of the original report of Schmidt et al.35 . In the setting of structural cardiac anomalies, complete heart block is a very poor

VA tachycardia) then maternal digoxin has been used widely. Maternal digoxin monotherapy is poorly effective in hydropic fetuses7 , due in large part to poor placental transfer. Therapies which have been used widely in these cases include ecainide (class 1c drug)14,15 , sotalol (beta blocker with some class III action)17,26 and amiodarone (class III antiarrhythmic action27 29 . Direct injection of drugs into the fetal circulation has been undertaken with amiodarone, digoxin and other agents12,15 . If direct therapy is to be undertaken, it certainly needs to be performed at a center with experience of the technique and it is important that the mother is also treated with the same agent, otherwise the drug administered to the fetus can simply redistribute to the maternal circulation, making repeat therapy necessary. At my center, direct therapy is only considered for hydropic fetuses unresponsive to transplacental therapy, accepting that the risk of cord access (or other vascular access) is higher in this group than it is in those with other indications for cordocentesis30 . Many of the drugs which have been employed are associated with side effects; for example, ecainide has been associated with proarrhythmic effects31 , sotalol causes prolongation of the QT interval and amiodarone has effects on the developing fetus including hypothyroidism32 . Thus, effective management of the mother and fetus involves a team including obstetricians, fetal medicine specialists and cardiologists.

Bradycardias
Types of bradycardia The denition of fetal bradycardia most commonly employed in this context is a persisting fetal heart rate of less than 100 bpm. Fetal bradycardia occurring during labor is not discussed here. The most common reasons for fetal bradycardia include multiple blocked atrial ectopic beats, sinus bradycardia and atrioventricular block. Echocardiographic techniques to rene the management approach In multiple blocked atrial ectopic beats the overall ventricular rate is reduced due to multiple non-conducted atrial extrasystoles. This type of arrhythmia is best demonstrated by M-mode through an atrial and a ventricular wall. This type of arrhythmia is almost always self-limiting and parents can be reassured to this effect. In a minority of cases, the atrial extrasystoles can be a marker of a re-entry pathway with the potential for a tachycardia8 . In sinus bradycardia there is a 1 : 1 A : V interval on M-mode evaluation of the atrial and ventricular walls. The likely causes include preterminal fetus or structural cardiac abnormalities. Evaluation of the cardiac structure is important for all fetuses demonstrating persistent bradycardia, as fetuses with disturbances of laterality (visceral heterotaxy/isomerism of the left atrial

Figure 4 M-mode echocardiogram of complete heart block. The ventricular (V) rate is slow and there is complete dissociation between atrial (a) and ventricular contractions.

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Ultrasound Obstet Gynecol 2006; 27: 599606.

Editorial prognostic sign, and remains so despite advances in perinatal supportive care and surgery. Management approach The optimal management of immune-mediated congenital heart block remains highly controversial. A recent paper reported improved mortality and reduced incidence of late complications for fetuses treated with dexamethasone with or without sympathomimetic agents compared with those who did not receive such therapy40 . This study reported an improvement in 1-year survival, from 44% to 80%, associated with increased use of dexamethasone with or without beta stimulation during fetal life. However, it should be emphasized that the study groups compared were from two different time periods, 19901996 and 19972003, rather than being randomized. The benets of such an approach were not supported by data from our own unit, which reported an increased 1-year survival, from 77% to 93%, during identical time periods to the previous study, but with no change in the use of intrauterine therapy, which was reserved only for fetuses with evidence of cardiac compromise41 . For complete heart block, there are few data to suggest that the use of dexamethasone can lead to sustained reversion to normal sinus rhythm. In one recent case report there was transient reversion to sinus rhythm42 but a review of the literature does not conrm corticosteroids as a very effective treatment in this situation43 . The latter study also provided important information regarding side effects of dexamethasone, including effects on fetal growth, oligohydramnios, body uid composition and hypothalamicpituitary axis. Others have demonstrated signicant effects on the fetal brain44 . There are also potential cardiac adverse effects. During fetal life, myocardial growth is by hyperplasia of myocytes, whereas after birth, growth of the heart is related mainly to myocyte hypertrophy. From studies in fetal lambs, corticosteroids appear to have a central role in the switch from prenatal myocyte hyperplasia to postnatal hypertrophy45 , raising concerns that exogenous corticosteroids may have a similar effect when administered in utero. In our practice, dexamethasone is not used to treat fetuses with immune-mediated congenital complete heart block in the absence of hydrops or evidence of impairment of ventricular function. The effect of corticosteroids is not simply on the conduction system and may be related to effects on associated myocarditis46 and improved cardiac function, without an effect on cardiac rhythm. Whether such prenatal treatment will reduce the incidence of postnatal cardiomyopathy in such patients remains unknown. The role of other agents such as beta sympathomimetic drugs also remains uncertain, with some reports suggesting clinical benet40,47 , while other series demonstrate favorable outcome without extensive use of such drugs41 . As for the lesser degrees of fetal heart block, there are some data to suggest that administration

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of dexamethasone to fetuses with second-degree heart block can lead to conversion to sinus rhythm46,48,49 . This provides the justication for consideration of corticosteroids in this subgroup of fetuses. Measurement of the mechanical PR interval by echocardiographic means (Figure 1) provides a possibility for detecting rstdegree heart block in fetuses at high risk of developing immune-mediated congenital complete heart block due to maternal anti-Ro/La antibodies. The question remains as to whether identifying such early echocardiographic changes justies initiation of dexamethasone with the aim of prevention of development of either seconddegree or complete heart block. One case report50 described normalization of the PR interval following treatment with corticosteroids. However, further reports have suggested that a third of fetuses of anti-Ro/Lapositive mothers have prolongation of the mechanical PR interval and that spontaneous normalization of the mechanical PR interval may occur51 . Thus the role of therapy in this context remains uncertain. A large multicenter trial is underway to address this question52 .

Venous and arterial Doppler during cardiac arrhythmias

Venous Doppler has assumed a major role in the assessment of fetal hemodynamics. This is important for fetuses with cardiac arrhythmias such as tachycardias or heart block because such fetuses, particularly if hydropic, are at increased risk of intrauterine death. Accurate assessment of cardiovascular status may be useful to gauge the effectiveness of therapy or to aid decision-making when the risks of preterm delivery must be balanced against that of intrauterine death. Some authors have proposed scoring systems, of which venous Doppler is a part, to grade fetal cardiac failure (not specically related to fetal arrhythmias)53 . The difculties in interpretation of such venous Doppler, however, need to be emphasized, and are illustrated in Figures 57. Atrial ectopic beats, tachycardias and fetal heart block disturb the usual synchronization of events during the cardiac cycle, so that

Figure 5 Doppler trace of ductus venosus (DV) with atrial ectopic beats. The DV ow pattern is normal initially but a premature atrial contraction is associated with sudden reversal of ow (arrow).

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Simpson demonstrate how ow reversal in the ductus venosus may be seen with fetal atrial ectopic beats or complete heart block. Unusual patterns of umbilical venous ow, including reduced velocity of ow during ventricular contraction leading to a notched umbilical venous ow pattern, are also observed in the context of complete heart block. It is essential that the ow patterns observed are correlated with the mechanisms of arrhythmia so that the prognostic implication of such ow patterns are not extrapolated inappropriately to fetuses with arrhythmias.

Conclusions
Figure 6 Doppler trace of ductus venosus ow during atrial utter. The atrial utter waves (arrows) occur at a rate of 400500 bpm and permit measurement of the atrial rate but the normal ductus venosus ow pattern is lost.

Echocardiography remains the dominant modality for prenatal diagnosis of arrhythmias, although fetal ECG and magnetocardiography provide additional important information in selected groups of patients. With regard to fetal tachycardias, renements in the echocardiographic assessment can provide helpful additional information regarding the mechanism of tachycardias and so guide optimal prenatal therapy. The treatment of fetuses with immune-mediated heart block remains contentious and robust multicenter trial data will be required to examine fetal cardiac outcome and potential adverse effects of therapy on both the fetus and the mother. Venous and arterial Doppler ow proles must take account of the mechanism of arrhythmia and may not always be a valid marker of cardiac compromise.

REFERENCES
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Figure 7 Umbilical and ductus venosus ow patterns during complete heart block. (a) The heart rate is 60 bpm and there is a reduction in umbilical venous ow velocity corresponding to ventricular systole. This leads to a notched pattern on the umbilical venous ow signal. UA, umbilical artery; UV, umbilical vein. (b) The ductus venosus (DV) pattern is abnormal with occasional marked reversal of DV ow. Such reversal occurs when atrial contraction coincides with ventricular systole so that the atria are contracting against closed atrioventricular valves, explaining the degree of ow reversal. The arrows in (a) indicate the reduction in umbilical venous ow velocity coincident with ventricular contraction. In (b) they indicate the reversal of ow in the ductus venosus.

changes noted by Doppler may reect the mechanism of the arrhythmia itself rather than impaired cardiac function or cardiomyopathy. For instance, the examples shown

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SUPPLEMENTARY MATERIAL ON THE INTERNET

The following slide presentation is available from the Journal homepage: http://www.interscience.wiley. com/jpages/0960-7692/suppmat (restricted access) Figure S1 Approach to echocardiographic diagnosis and explanation of echocardiographic images obtained.

Copyright 2006 ISUOG. Published by John Wiley & Sons, Ltd.

Ultrasound Obstet Gynecol 2006; 27: 599606.