The Fetal Arrhythmia Program at Connecticut Children’s is a collaboration between the Fetal Surgery, Pediatric Cardiology, Electrophysiology, Fetal Echocardiography, Maternal Fetal Medicine, and Cardiac Surgery. The program provides comprehensive prenatal evaluation for the full range of fetal arrhythmias and tailors treatment to the underlying cause.  An initial evaluation of a fetal arrhythmia involves detailed fetal echocardiographic assessment for structural anomalies and characterization of the arrhythmia.  Maternal Fetal Medicine performs a level II ultrasound examination to rule out associated anomalies, assess the growth and wellbeing of the baby, and assess the health of the mother.  If associated structural anomalies are diagnosed, a fetal MRI may be indicated.  Once all data from the ultrasound, fetal echocardiography and fetal MRI have been obtained, the results are presented to the patient at a team meeting. The medical team discusses the nature of the arrhythmia, its prenatal natural history, whether transplacental medical therapy is indicated, and, in rare cases, if consideration for fetal surgery to place a fetal pacemaker is warranted.

Fetal Bradyarrhythmias

Atrio-ventricular (AV) block is a condition where the electrical signals that regulate the heartbeat are delayed or blocked as they travel from the upper chambers (atria) to the lower chambers (ventricles) of the heart. The severity of the block is categorized into three degrees: first, second, and third degree. In first-degree heart block, the electrical signals slow down as they pass from the atria to the ventricles and is characterized by a prolonged PR interval on an electrocardiogram.  In second degree heart block, the electrical signals between the atria and ventricles intermittently fail to conduct.  There are two types of second degree heart block.  In Mobitz Type I (Wenckebach), the electrical signals get progressively slower until a beat is skipped.  In Mobitz Type II some electrical signals reach the ventricles, while others don't, with no progressive slowing of the signal before the block. In third degree heart block, or complete heart block, the electrical signals from the atria do not reach the ventricles at all leading to a very slow ventricular response rate.

Fetal complete heart block (fCHB) is a rare cardiac dysrhythmia affecting approximately 1 in 15,000 patients (1).  fCHB is associated with increased risk of fetal hydrops and fetal demise (2,3).  In third degee fCHB, there is complete atrio-ventricular dissociation secondary to disruption of the conduction system resulting in significant bradycardia ventricular escape rates ranging from 40 to 90 bpm (4).  

Maternal risk factors for the development of fCHB include type 2 diabetes, the use of certain medications (including anticonvulsants and retinoic acid), viral infections and, most commonly, autoimmune disease.  fCHB can be associated with structural heart abnormalities such as congenitally corrected transposition of the great arteries, AV canal defects, and left atrial isomerism (heterotaxy syndrome) in 14 to 42% of cases (5).  Channelopathies are also a rare cause of fCHB, which can involve genetic variants of ion channel genes as well as genes encoding connexin proteins (6-9).  The most common cause of fCHB however is transplacental exposure to maternal SSA or SSB autoantibodies, which  accounts for up to 91% of cases of isolated fCHB (2,10).

Immune mediated fCHB is caused by transplacental passage of maternal autoantibodies specific for the Ro (Sjogren syndrome related antigen A, SSA) and La (Sjogren syndrome related antigen B, SSB) antigens, which can occur as early as 11 weeks gestation (11).  It is postulated that these antibodies bind to the L-type calcium channels in fetal conduction tissue leading to internalization of calcium channels.  This in turn leads to apoptosis and inflammation (12).  An alternative hypothesis, suggests that SSA and SSB nuclear proteins are brought to the cell surface during physiologic apoptosis, which are then bound by the anti-SSA and anti-SSB antibodies and phagocytized by fetal macrophages.  The ssRNA associated with the ribonucleoproteins triggers Toll-like receptor (TLR) 7/8 pathway leading to pro-inflammatory and pro-fibrotic cytokine release causing inflammation (13-15).

Fetal heart block usually develops between 16 and 24 weeks gestation (16).  Between 2 and 5% of autoantibody positive mothers will develop fetal complete heart block.  The risk increases to 12 to 15% in mothers with a previously affected fetus with complete heart block.  Only a third of mothers have a known diagnosis of autoimmune disease, such as Sjogren's syndrome or systemic lupus erythematosus, at the time fetal complete heart block is diagnosed (10).  

fCHB caused by autoimmune disease carries a mortality of 19%, of which approximately 70% die utero (4).  The mortality increases in cases with myocardial inflammation (4,10,17,18).  Factors that increase the risk of in utero demise include the presence of hydrops, diagnosis less than 20 weeks gestation, ventricular escape rate less than 55 bpm, and evidence of impaired left ventricular function (3).  Atrio-ventricular valve tensor apparatus dysfunction occurs in 1.6% of immune-mediated complete heart block, leading to severe AV valve regurgitation (19).  The US Research Registry for Neonatal Lupus found that fetal complete heart block had a mortality rate of over 50% when either dilated cardiomyopathy or endocardial fibroelastosis was present and a 100% mortality when both were present (20).  Over two thirds of fetal complete heart block patients require permanent pacemaker placement, most within the first 10 days of life.  If ventricular function is preserved, most children requiring pacemaker placement can anticipate a near normal life (21).

Despite more frequent and earlier diagnosis of fetal complete heart block, there is no consensus on the medical treatment.  The intent of medical treatment of fetal complete heart block is to prevent or slow the progression of heart block and functional deterioration as well as prevent hydrops.  The most commonly used agents to treat fetal complete heart block are corticosteroids (dexamethasone or betamethasone).  The rationale for their use is to reduce immune mediated damage to the atrio-ventricular node, the conduction system, and the fetal myocardium and stop or slow the progression of myocarditis and cardiomyopathy.  Although steroids are used in first or second-degree complete heart block in the hope of preventing progression to third-degree heart block, there is little evidence this is effective (22-24).  Once heart block develops, it is rarely reversible. 

A second line drug is the use of beta mimetic agents to increase heart rate and cardiac output.  Retrospective cohort studies have looked at patients treated with dexamethasone and beta mimetics for heart rates <55 bpm versus no treatment. They found improved survival at one year, and in half of the beta mimetic treated patients, small increases in heart rate (25).  Another study in similarly treated patients found no difference in outcome between treated and untreated (26).  A study looking at the combination of steroids, beta-mimetics, with digoxin with or without IVIG for fCHB with heart rates <56 bpm found a significant survival benefit, which was attributed by the authors to more aggressive echocardiographic surveillance as opposed to the medical therapy (27).  A recent meta-analysis comparing data from 162 fetuses across 8 studies found no difference in mortality or pacemaker placement in steroid treated versus non-treated patients (28).  Despite these discouraging results, the use of steroids and beta mimetic agents has been suggested in subsets of the fetal complete heart block with hydrops or requiring emergent treatment (28,29).  Prophylactic strategies, including intravenous gamma globulin (IVIG) and plasmapheresis, have been used to try to prevent the development of fetal complete heart block in at risk mothers with anti-SSA or anti-SSB antibodies with mixed results (30-33).

Crombleholme et al developed the first large animal model of fetal complete heart block in fetal lambs (34).  Fetal heart block was induced by injecting 0.1 mL of formalin into the AV node fetal lambs at 100 to 110 days gestation.  This model demonstrated that interruption of the conduction system alone, even with preservation of myocardial function, will progress to nonimmune hydrops and death if not treated with fetal cardiac pacing to restore fetal heart rate.  This observation was important as there was much thought that the hydrops and fetal demise associated with fetal complete heart block was secondary to progressive myocardial dysfunction, not merely the slow ventricular response rate.  Complete heart block was successfully induced and 19 of 21 fetal lambs at 100 to 110 days gestation.  The mean ventricular escape rate was 52 bpm and ranged from 45 to 60 bpm.  While there was compensatory increase in the stroke-volumes of the right and left ventricles, there was an overall 38% reduction in combined ventricular output as a result of complete heart block.  This study demonstrated that ventricular pacing could rescue fetal complete heart block but that better combined ventricular output was achieved with AV sequential fetal pacing as opposed to purely ventricular pacing.  Optimal fetal heart rate could be determined by calculating combined ventricular outputs at a range of fetal heart rates generating Starling curves.  (34,35). This model also demonstrated that pacing the fetal heart in a fetal lamb with hydrops due to complete heart block can restore combined ventricular output and resolve the hydrops.  This observation established proof of concept for fetal heart pacemaker placement in human fetal complete heart block.

The first attempt to treat fetal complete heart block clinically by pacing the fetal heart was reported by Carpenter et al 1986 (36).  This was performed by percutaneous placement of an epicardial pacing lead attached to an external pulse generator.  The leads were displaced within hours of the replacement.  Walkinshaw et al attempted pacing lead placement by trans-umbilical vein to the right atrium to the right ventricle but the lead became dislodged and the fetus died presumed secondary to myocardial injury (37).  Assad et al attempted epicardial lead placement percutaneously but the fetus died with large pericardial effusion (38).  Each of these attempts were successful in pacing the fetal heart for only short periods from 4 to 36 hours. 

The first attempted open fetal surgery for placement of a fetal pacemaker was performed by Harrison and Crombleholme at UCSF in 1988 (39).  Although the pacemaker was able to capture and to pace the fetal heart, the combined ventricular output could not be increased, and the fetus died of progressive hydrops within 24 hours. This suggests the underlying process had progressed to multisystem organ failure before the treatment was attempted.  Our next attempt at open fetal surgery for fetal pacing was in a hydropic medically refractory case of fetal complete heart block (40).  The pacemaker placement was successful and we were able to pace the fetal heart for 5 days. Initial heart rate was 45 bpm, which we paced at 65 bpm with the goal of gradually increasing the fetal heart rate to optimize the combined ventricular output.  While the combined ventricular output doubled, the hydrops did not improve and oligohydramnios persisted before there was loss of communication with the pulse generator, making it impossible to increase the pacing rate above 65 bpm.  The fetus expired due to multisystem organ failure which was confirmed on autopsy. 

Recently we successfully employed the Ex Utero Intrapartum Treatment (EXIT) procedure for epicardial pacemaker placement in a fetus with medically refractory fetal complete heart block with a ventricular response rate of only 45 bpm.  The rationale for the EXIT-to-pacemaker procedure was that there would be marked increase afterload after clamping the umbilical cord at delivery, which would cause further hematologic hemodynamic deterioration. Placement of pacemaker prior to delivery would allow for an increase in fetal heart rate and combined ventricular output leading to a more stable transition to postnatal life until a permanent pacemaker could be inserted.  The newborn was stable after delivery and had a permanent pacemaker placed on the third day of life.

Fetal Tachyarrhythmias

Sinus tachycardia is characterized by rates of 160-200 bpm with preserved heart rate variability, 1:1 AV conduction and a long VA interval.  Etiologies include hyperthyroidism/fetal thyrotoxicosis, myocarditis, anemia, hypoxia, acidosis, and exposure to maternal stimulants. Maternal thyroid-stimulating hormone receptor antibodies (TRAb), found in 1-5% of mothers with Graves’ disease or Hashimoto’s thyroiditis, can cross the placenta to cause fetal hyperthyroidism and thyrotoxicosis. Complications of fetal thyrotoxicosis include fetal tachycardia, goiter, oligohydramnios, fetal growth restriction, accelerated bone maturation, and hydrops (42).  Women with hyperthyroidism or with hypothyroidism secondary to ablation or surgery for Graves’ disease should be screened for TRAb early in pregnancy and treated to prevent potentially life-threatening fetal disease. Methimazole or propylthiouracil and propranolol are standard treatment for fetal tachycardia secondary to thyrotoxicosis (43).  The risk of hydrops is related to gestational age and duration of tachycardia but not heart rate.  

SVTs are defined as an increased heart rate of >180-300 bpm, with either a 1:1 AV conduction (supraventricular tachycardia (SVT)) or > 1:1 AV conduction (atrial flutter).  SVT can be further categorized by the AV and VA interval durations.  The most common type of SVT is AV re-entry (AVRT) using an accessory AV connection and the AV node occurring in 66 to 90% of cases (45,46).  It is noteworthy that accessory AV connections are common in the developing fetal heart.  As gestation advances, the conductive properties change, which may explain why fetal AVRT can spontaneously resolve in utero (47). AVRT is acutely initiated by a premature atrial contraction and terminates in the AV node with a non-conducted atrial beat.  There are other types of ventriculo-atrial SVT such as re-entry (permanent junctional reciprocating tachycardia (PJRT) and junctional ectopic tachycardia (JET)) or automatic (sinus tachycardia and atrial ectopic tachycardia (AET)).  These types of VA SVT can occur earlier in gestation (<18 weeks), typically have slower rates (170-220 bpm) and are less common than AVRT.  Fetuses with Ebstein anomaly have an increased incidence of accessory connections predisposing them to AVRT or atrial flutter.

Atrial flutter is the second most common cause of fetal SVT, typically presenting after 28 weeks of gestation (48,49).  The atrial rates range from 300-500 bpm but with some degree of block with consequent slower ventricular rates of 160-260 bpm.  Despite being attributed to intra-atrial re-entry, up to 70% are found to have accessory pathways (48,50-52).  While atrial flutter most commonly occurs in structurally normal hearts, it can be associated with myocarditis, congenital heart disease, and immune-mediated heart block/myocarditis (53). 

Ventricular tachycardia (VT) is rare cause of fetal tachyarrhythmias accounting for only 1-3% of fetal arrhythmias (54).  VT is defined by three or more successive ventricular ectopic beats with a ventricular rate of 170-300 bpm (55-59).  When VT occurs, there is usually ventriculo-arterial (VA) dissociation resulting in a slower atrial than ventricular rate.  Because of retrograde ventriculo-atrial conduction, it may be difficult to distinguish VT from SVT. One clue is that heart rates are generally faster in SVT than in VT.  VT may be idiopathic or associated with myocardial disease (including myocarditis, cardiomyopathy, and aneurysms), intracardiac tumors such as fibromas and rhabdomyomas, myocardial ischemia or inherited channelopathies (58,60).  

There is no consensus on the medical treatment of fetal SVT.  The medications most commonly employed include digoxin, flecainide, sotalol, amiodarone or a combination of these drugs.  These can be administered to the mother in pill form or intravenously, or the medications can be administered directly to the fetus intramuscularly or intravenously by the umbilical cord (61-63).  Due to the inherent risk of direct fetal injection, this is usually reserved for the treatment of hydropic fetuses with non-reassuring biophysical profile score.  The presence of hydrops is thought to impair the transplacental transfer of anti-arrhythmic medications taking longer to restore normal rhythm. Our first choice for direct therapy is intramuscular fetal treatment with digoxin, which has been safe and effective in quickly restoring sinus rhythm in the hydropic fetus and does not incur the risks of single or repeated intracordal injections (63).  Concomitant transplacental treatment ensures that fetal drug levels will be maintained after direct therapy.  

There is no agreement on first line therapy for fetal SVTA (64-67).  However, sotalol or digoxin are considered best first-line therapy for atrial flutter (64,66).  This is because flecainide as a single agent can slow the atrial rate without corresponding delay in the AV node, leading to rapid 1:1 conduction and ventricular rates of >300 beats per minute (64,66).   The long VA tachycardias, including AET and JET, often respond best to flecainide or digoxin, while PJRT is often best treated with flecainide or sotalol (64,67,68).

Two recent meta-analyses evaluating transplacental therapies found that flecainide was superior to digoxin at converting fetal AVRT (short RP tachycardia) to sinus rhythm, especially if the fetus was hydropic (69,70).  Strizek et al reported a 3-day (range 1-7 days) median time to conversion of AVRT with flecainide in both hydropic and non-hydropic fetuses, which was substantially shorter than conversion to sinus rhythm with digoxin (64,68).

Although not randomized, a contemporary protocol driven study evaluated digoxin, sotalol and flecainide in short VA SVT(n=17) and atrial flutter (n=28) (67). For short VA tachycardia (86% conversion), the combination of digoxin and sotalol and flecainide alone was more successful than digoxin alone. Of those fetuses in atrial flutter, digoxin monotherapy (60% conversion) and digoxin and sotalol (73% conversion) were superior to flecainide and digoxin (50% conversion). In total, 93% of fetuses with atrial flutter could be converted to sinus rhythm. 

First-line treatment with IV magnesium sulfate in tocolytic doses is extremely successful in terminating or reducing salvos of TdP. It has been used with complete or partial success, either alone, in combination with IV lidocaine, or propranolol or mexiletine (76,77-85).  Infusion of magnesium has a rapid onset of action and most obstetricians are familiar with its usage in the management of maternal pre-eclampsia.  

Fetal tachyarrhythmia can become sustained resulting in progression of hydrops in up to 40% of cases despite the use of transplacental medical therapy.  Fetal demise in these medically refractory tachyarrhythmias occurs in up to 27% of cases.  The main causes of fetal tachyarrhythmia are atrial flutter in 20 to 30% of cases and reentrant tachyarrhythmia tachycardia that is mediated by an accessory pathway in 60% of cases.

Sternaman et al reported the first successful fetoscopic transesophageal pacing in a fetus with refractory atrial flutter with atrial and ventricular rates of 440 bpm and 220 bpm, respectively, at 29 weeks and 4 days gestation (86).  The baby had failed to respond to digoxin and flecainide and subsequently to amiodarone with worsening hydrops.  The mother elected to undergo in-utero transesophageal pacing (IUTP). A 10 French cannula was inserted through which 3.3 French fetoscope was inserted into the fetal esophagus and positioned just above the heart.  The fetoscope was removed and a 6 French bipolar pacing esophageal lead (FIAB Esokid 4S, Firenze Italy) was positioned right behind the left atrium.  The lead was attached to an asynchronous esophageal pacemaker (FIAB 2007, Firenze Italy).  Under continuous echocardiographic monitoring, the rate was increased to 640 bpm at a pulse amplitude of 5 mA with 2 ms pulse width.  266 and 6 seconds bursts were ineffective, so pacing parameters were increased to 10 mA per 5 ms at the same cycle length. Two bursts of 6 seconds converted the atrial fibrillation to intermittent sinus rhythm, the probe and cannula were removed and a follow-up echocardiogram 2 hours later demonstrated normal sinus rhythm without any paroxysms of atrial fibrillation.  At 32 weeks, the hydrops had resolved and the fetus remained in normal sinus rhythm and had induction of labor at 38 weeks and 2 days gestation.  Baby was discharged on no antiarrhythmic medications and a Holter monitor at 1 month of age showed prominent sinus rhythm.

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36.  Carpenter, R. J., Strasburger, J. F., Garson, A., Smith, R. T., Deter, R. L., & Engelhardt, H. T. (1986). Fetal ventricular pacing for hydrops secondary to complete atrioventricular block. J Am Coll Cardiol 8: 1434-1436

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38.  Assad, R. S., Zielinsky, P., Kalil, R., Lima, G., Aramayo, A., Santos, A., … Oliveira, S. A. (2003). New lead for in utero pacing for fetal congenital heart block. The Journal of Thoracic and Cardiovascular Surgery, 126(1), 300–302.

39.  Harrison MR, Crombleholme TM personal communication

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