REVIEW URRENT C OPINION
Management of arrhythmia syndromes during pregnancy Jose A. Joglar a and Richard L. Page b
Purpose of review To discuss the diagnosis and management of maternal arrhythmias occurring during pregnancy. Recent findings When necessary, current technology allows implantation of arrhythmia management devices and performing catheter ablation procedures with little or no risk from radiation exposure to the fetus. Summary A variety of cardiac rhythm disturbances can occur during pregnancy, ranging from benign ectopy to life-threatening arrhythmias. In patients with normal hearts and minimally symptomatic arrhythmias, only reassurance is necessary. The quality of the data on managing more serious arrhythmias in pregnancy is somewhat limited, yet with a clear understanding of the maternal hemodynamic changes associated with pregnancy, and the appropriate antiarrhythmic therapies available, almost all cases can be treated successfully. The decision to treat should be based on careful consideration of risk and benefits, yet, when therapy is deemed necessary, it should be administered promptly and with confidence. Drug therapy should be avoided during the first trimester if possible and drugs with the longest record of safety are preferred. The decision to pursue an invasive strategy is complicated by the potential for procedural risks. Yet, the state of modern technology is such that invasive strategies, when justified, can be carried out effectively. Keywords antiarrhythmic drugs, cardiac arrhythmias, pregnancy
INTRODUCTION The full spectrum of cardiac arrhythmias and conduction disturbances can occur during pregnancy. Fortunately, most arrhythmias are benign in nature, but dangerous or hemodynamically important rhythm disturbances sometimes occur and should be treated promptly [1]. When considering therapeutic interventions, adverse effects to both the mother and fetus, such as proarrhythmia, must be considered. There are also unique risks pertaining strictly to the fetus, such as congenital malformations. With a clear understanding of the physiologic changes associated with pregnancy, and the appropriate invasive and noninvasive antiarrhythmic therapies available with knowledge of their potential risks, almost all such cases can be treated successfully.
EPIDEMIOLOGY OF ARRHYTHMIAS DURING PREGNANCY An increased incidence of maternal cardiac arrhythmias is observed during pregnancy, including new www.co-cardiology.com
arrhythmias, such as new-onset idiopathic ventricular tachycardia, as well as increased number of events in patients with a preexisting substrate, such as episodes of supraventricular tachycardia (SVT) in patients with the Wolff-Parkinson-White syndrome [2–4]. In some cases, arrhythmias that may have been preexistent and asymptomatic can become manifest, perhaps related to hemodynamic changes
a The University of Texas Southwestern Medical Center at Dallas, Dallas, Texas and bThe University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin USA
Correspondence to Jose A. Joglar, MD, Professor of Internal Medicine, Program Director, Clinical Cardiac Electrophysiology, Elizabeth Thaxton Page and Ellis Batten Page Professorship in Clinical Cardiac Electrophysiology Research, UT Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, Texas 75390-8837, USA. Tel: +1 214 590 5028; fax: +1 214 590 0402; e-mail: [email protected] Curr Opin Cardiol 2014, 29:36–44 DOI:10.1097/HCO.0000000000000020 Volume 29 Number 1 January 2014
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Management of arrhythmia syndromes during pregnancy Joglar and Page
KEY POINTS
THERAPIES
Cardiac arrhythmias manifest commonly during pregnancy.
Therapies for arrhythmias during pregnancy may include pharmacological as well as non pharmacological options.
Hemodynamically important arrhythmias should be treated promptly.
PHARMACOLOGICAL THERAPIES
Antiarrhythmic drug therapy should be avoided in the first trimester and drugs with longest record of safety should be used first. When absolutely necessary, interventional procedures can be performed with little risk from radiation exposure.
during pregnancy or simply in some cases due to increased medical attention during pregnancy. In addition, the physiologic changes related to pregnancy may stress the cardiovascular system in an increased number of women with underlying structural and congenital heart disease who today may reach reproductive age [5]. The most common arrhythmias noted during pregnancy are premature ventricular and atrial ectopy, reported in 50–60% of pregnant women, with the majority resolving after delivery [3]. An increased risk of life-threatening cardiac events has also been reported during the postpartum period in patients with congenital Long QT syndrome [6].
The evidence supporting the use of antiarrhythmic agents during pregnancy, when available, is often limited to small case series and individual reports; but, in general, the medications that have been available for longer periods of time have the greatest number of reports regarding safety. Fewer data are available on the newer drugs, yet their use may be justified if it is believed that the benefits outweigh the risk. One problem with older drugs is that, despite the longer record of safety in pregnancy, most modern physicians rarely or even never use them anymore, whereas there is very little published in pregnancy on the newer drugs that are now more commonly used. The majority are US Food and Drug Administration (FDA) category C (Table 1). All antiarrhythmic medications have potential side-effects to both the mother and the fetus, and as such should be avoided in the first trimester if possible. Generally, the lowest recommended dose should be used initially, accompanied with regular monitoring of clinical response. Proarrhythmia, such as torsade de pointes due to excessive QT
Table 1. Definition of FDA pregnancy categories and antiarrhythmic agents within each category Pregnancy category
Definition
Antiarrhythmic agents
A
Controlled studies show no risk. Adequate, well-controlled studies in pregnant women have failed to demonstrate risk to the fetus in any trimester of pregnancy.
B
No evidence of risk in humans. Adequate, well-controlled studies in pregnant women have not shown increased risk of fetal abnormalities despite adverse findings in animals, or, in the absence of adequate human studies, animal studies show no fetal risk. The chance of fetal harm is remote but remains a possibility. Risk cannot be ruled out. Adequate, well-controlled human studies are lacking, and animal studies have shown a risk to the fetus or are lacking as well. There is chance of fetal harm if the drug is administered during pregnancy; but the potential benefits outweigh the risk.
Lidocaine, Sotalol
D
Positive evidence of risk. Studies in humans have shown evidence of fetal risk. Nevertheless, the potential benefits from the use of the drug in pregnant women may outweigh the risk.
Phenytoin, Amiodarone, Atenolol
X
Contraindicated in pregnancy. Studies in animals or humans have shown fetal risk, which clearly outweighs any possible benefit to the patient.
C
Quinidine, Disopyramide, Procainamide, Mexiletine, Flecainide, Propafenone, Propranolol, Metoprolol, Bretylium, Ibutilide, Dofetilide, Dronedarone, Verapamil, Diltiazem, Digoxin, Adenosine
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/Labeling/ucm093307.htm. FDA, Food and Drug Administration.
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Arrhythmias
prolongation, is the most worrisome side-effect for the mother. A list of antiarrhythmic drugs is detailed in Table 2.
Class I (sodium channel blocking agents) Of the class IA agents, quinidine has the longest record of safety in pregnancy, with over 60 years of experience treating arrhythmias and malaria [7–9]. Yet, this drug is seldom used anymore and clinical need must be balanced against lack of experience with its use. Monitoring of serum levels is mandatory in order to avoid proarrhythmia. Procainamide has electrophysiologic properties and clinical applications similar to quinidine, but can be used intravenously. It has proven well tolerated and effective in the management of maternal arrhythmias [10], and is an option for the acute treatment of undiagnosed wide complex tachycardia [11]. Procainamide is generally not appropriate for long-term therapy, as it can cause lupus-like syndrome. All class IA medications must be administered in the hospital during continuous cardiac monitoring, and serum drug levels should be carefully monitored. The class IB includes lidocaine and mexiletine. Lidocaine is used primarily for the acute management of ventricular arrhythmias. It has been widely used during pregnancy, mainly as an anesthetic agent, and has been shown to be generally well tolerated by both the mother and the fetus [12]. Mexiletine is an oral antiarrhythmic agent with structure similar to lidocaine. The experience with mexiletine during pregnancy is limited, but it also appears to be well tolerated [13,14]. The class IC agents include propafenone and flecainide, both of which appear to be relatively well tolerated during pregnancy. Flecainide is contraindicated in all patients with prior infarction or underlying structural heart disease [15]. Otherwise, it has proven well tolerated and effective in the treatment of diverse maternal atrial and ventricular arrhythmias [16,17]. Further evidence of safety for the mother comes from experience in the use of flecainide for fetal arrhythmias, in which it has been shown to be superior to digoxin and is considered the drug of choice for this problem [18]. Experience with propafenone is more limited, although no adverse effects to the mother or the fetus have been reported when administered during the third trimester [19]. This drug is also contraindicated in patients with prior myocardial infarction. 38
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Class II (b-adrenergic blocking agents) The b-adrenergic blocking drugs are often the firstline option for a variety of arrhythmias, as there is extensive experience on their use from treating other conditions during pregnancy, such as hypertension [20,21]. Although there have been rare reports of adverse effects to the fetus, such as bradycardia, the incidence of these complications is low. It is likely that some prior reports of fetal complications were likely due to high-risk conditions and not because of the drug itself [21]. The main concern associated to b-blockers is intrauterine growth retardation [22], although the evidence is conflicting [23,24]. One study reported growth retardation in babies receiving atenolol in the first trimester [25]. Although it is difficult to discern between growth retardation due to maternal disease versus drug, in view of these results, b-blockers should be avoided during the first trimester if possible (and atenolol avoided because of a category D designation by the FDA). Cardioselective b1 antagonists, such as metoprolol, are the preferred agents, as they may be less likely to interfere with b2-mediated uterine relaxation [21].
Class III (potassium channel-blocking agents) The class III agents primarily block potassium channels, causing delay of repolarization and prolonging the QT interval. This class includes amiodarone, sotalol, dronedarone, dofetilide and ibutilide. The most worrisome side-effect for this class of drugs is torsade de pointes, so patients must be closely monitored. Amiodarone is a potent antiarrhythmic agent used for the management of ventricular and, less often, supraventricular arrhythmias. Multiple adverse effects to the fetus have been reported with amiodarone, including fetal hypothyroidism. Congenital abnormalities have been reported as well [26,27], so the drug should especially be avoided during the first trimester. The side-effect profile has caused it to be contraindicated during pregnancy, except for life-threatening conditions in which other agents have failed and benefit outweighs the substantial risk. It is FDA category D. Sotalol is a class III agent with noncardiac selective b-receptor antagonist properties. Although sotalol has been used successfully during pregnancy, experience is limited so caution is advised [16,28]. Nevertheless, this drug is a reasonable option in pregnant women, as it is FDA category B. Dofetilide and dronedarone were more recently approved by the FDA. Dofetilide is approved for Volume 29 Number 1 January 2014
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II
III
b-blocking agents
Amiodarone
III
IC
Propafenone
III
IC
Flecainide
Dofetilide
IB
Phenytoin
Dronedarone
IB
Mexiletine
III
IB
Lidocaine
Ibutilide
IA
Disopyramide
III
C/D
IA
Procainamide
Sotalol
C
IA
Quinidine
C
X
C
B
D
C
D
C
B
C
C
C
Drug classa
Drug
FDA classb
Torsade de pointes
Torsade de pointes
Torsade de pointes
Torsade de pointes, b-blocker effects
Fetal hypothyroidism, prematurity, low birth weight, congenital malformations
Intrauterine growth retardation, fetal bradycardia, hypoglycemia, fetal apnea
Same concerns as flecainide, mild b-blocker effects
Increased mortality in patients with previous myocardial infarction, generally well tolerated in structurally normal hearts
Mental and growth retardation, fetal hydantoin syndrome
CNS adverse effects, fetal bradycardia, low APGAR
CNS adverse effects, bradycardia
Induction of uterine contractions, torsade de pointes
Lupus-like syndrome with long-term use, torsade de pointes
Maternal and fetal thrombocytopenia, eighth nerve toxicity, torsade de pointes
Potential adverse effects
Table 2. Experience with antiarrhythmic drugs during pregnancy
Atrial fibrillation in the setting of structural heart disease
Atrial fibrillation
Acute termination of atrial fibrillation /flutter
Maternal ventricular tachycardia and SVT, hypertension in the past
Life-threatening ventricular arrhythmias
Maternal SVT, idiopathic ventricular tachycardia, atrial fibrillation rate control
Variety of maternal ventricular tachycardia and SVT
Variety of maternal and fetal ventricular tachycardia and SVT
Arrhythmias due to digoxin toxicity
Ventricular tachycardia
Maternal ventricular tachycardia, arrhythmias due to digoxin toxicity
Limited experience, other alternatives available
Drug of choice for acute treatment of undiagnosed wide complex tachycardia
Variety of maternal and fetal arrhythmias
Primary indication(s)
Unknown
Contraindicated
Unknown
Generally compatible but caution advised
Avoid since a large amount of drug is absorbed by the infant
Avoid atenolol. Metoprolol and propranolol are compatible
Unknown
Compatible
Generally compatible but caution advised
Compatible
Compatible
Compatible
Compatible but long-term therapy should be avoided
Generally compatible but caution advised
Use during lactationc
(Continued )
No experience in pregnancy
Contraindicated
No experience in pregnancy
Limited experience
Avoid if possible especially during first trimester
Generally well tolerated, avoid during first trimester, cardiac selective are preferred
Limited experience
First line option for treating fetal SVT with hydrops
Better alternatives available, avoid if possible
Limited experience
Long record of safety, avoid if fetal distress
Limited experience
Has the advantage of intravenous dosing, long record of safety
Long record of safety
Comments
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40
First option for acute treatment of SVT Unknown, but probably well tolerated
Compatible
Acute termination of maternal SVT
Fetal and maternal SVT, atrial fibrillation rate control
Long record of safety
Verapamil preferred due to longer record in pregnancy Compatible Maternal SVT, atrial fibrillation rate control
CNS, central nervous system; FDA, Food and Drug Administration; N/A, not applicable; SVT, supraventricular tachycardia. a Vaughan Williams classification of antiarrhythmic drugs. b FDA risk category (see Table 1) c Committee on Drugs. Transfer of drugs and other chemicals into human milk. Pediatrics 1994; 93:137–150.
Low birth weight C N/A Digoxin
Dyspnea, bradycardia C N/A Adenosine
Limited experience, same concerns as with verapamil IV Diltiazem
C
Relatively well tolerated but safer options are available Compatible Maternal and fetal SVT, idiopathic ventricular tachycardia, atrial fibrillation rate control Maternal hypotension, fetal bradycardia and heart block IV Verapamil
C
Drug classa
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atrial fibrillation, and is especially appropriate in patient with prior myocardial infarction and heart failure, conditions in which other agents can be contraindicated. The main risk is torsade de pointes, so initiation must occur under inpatient observation [29,30]. Dofetilide is category C, and should only be considered if benefits outweigh the risk, as the experience of use in pregnancy is very limited, yet dofetilide might have a role in situations in view of limited options for patients with underlying structural heart disease and in view of the high toxicity associated with amiodarone [29]. Dronedarone is contraindicated in pregnancy because of concerns for potential harm to the fetus [30].
Class IV (calcium channel-blocking agents)
Drug
Table 2 (Continued)
FDA classb
Potential adverse effects
Comments Use during lactationc Primary indication(s)
Arrhythmias
The calcium channel-blocking agents with significant antiarrhythmic action are verapamil and diltiazem. Favorable results have been reported with verapamil for the acute treatment of SVT in pregnant women, except for the occurrence of maternal hypotension [31,32]. Overall, the calcium channel blockers appear to be relatively well tolerated for the treatment of maternal conditions, but, because of occasional reports of adverse effects on the fetus, caution is advised and alternative therapies should be considered first (such as adenosine for acute conversion of supraventricular arrhythmias). When used in pregnancy, verapamil is the preferred agent based on more extensive experience in this condition.
Adenosine Adenosine is an endogenous nucleoside with a short half-life (under 2 s), which is highly effective in acute termination of SVT [33]. The drug has been used safely in pregnant women, with no significant adverse effects to the mother or fetus [34]. The initial dose is 6 mg rapid bolus IV, but this may be advanced to 12 mg as needed; well-tolerated administration of 24 mg has been reported [11]. Minor maternal side-effects, such as bradycardia and dyspnea, are usually transient and of no consequence. Adenosine should be considered the drug of choice for acute termination of SVT during pregnancy [35].
Digoxin There is extensive experience with digoxin and it is among the safest antiarrhythmic drugs for use during pregnancy. Digoxin freely crosses the placenta [36,37], and for many years has been used for the treatment of a variety of maternal and fetal SVT [38,39], including fetal SVT complicated by hydrops [40]. Volume 29 Number 1 January 2014
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Management of arrhythmia syndromes during pregnancy Joglar and Page
As in nonpregnant patients, the digoxin dose needs to be adjusted for renal impairment or for drug interactions. Serum drug levels need to be monitored, although in the third trimester the serum concentration measurement may be spuriously high, due to a circulating digoxin-like substance that interferes with the radioimmune assay for the drug [41].
Invasive therapies: catheter ablation and device implantation When arrhythmias lead to hemodynamic instability, two lives are in potential jeopardy. As such, despite concerns about potential risks, invasive therapies are sometimes necessary in patients who fail to respond to drugs. One concern in the past has been the risk of radiation exposure to the fetus, with possible teratogenicity or future risk of malignancy. The risk of malignancy is perhaps overstated; in one report in 2001, Damilakis et al. [42] estimated a low risk of malignancies to the conceptus from a typical ablation procedure, even when considering that their calculations were made with over 30 min of fluoroscopy time. Since their report was published, technology has evolved greatly, and today most ablation procedures are performed using electroanatomic navigation systems, obviating the need for significant (or any) use of radiation [43]. Implantable devices, such as defibrillators and pacemakers, can also be implanted safely, with small doses of fluoroscopy. Implantable cardioverter defibrillator (ICD) shocks have shown to cause no ill effects to the fetus, and therefore ICD implantation should be considered for life-threatening ventricular arrhythmias or sudden death prevention [44].
Arrhythmias that may occur during pregnancy The entire spectrum of cardiac arrhythmias can manifest during pregnancy, from benign to lifethreatening.
Bradycardia and atrioventricular conduction disturbances Sinus node dysfunction is uncommon in pregnancy, unless underlying congenital heart disease is present. Vasovagal or neurocardiogenic syncope can be seen, but the bradycardia is usually transient and best treated with abortive measures, such as isometric muscle tensing [45]. Congenital heart block (CHB) is occasionally first diagnosed during pregnancy. Asymptomatic
patients with isolated CHB and no other evidence of conduction system or structural heart disease have a favorable outcome, and supportive pacing during pregnancy is usually not necessary. In the past, temporary pacing was advocated during delivery for all women with CHB because of the high incidence of syncope and bradycardia related to Valsalva maneuvers, and to allow adequate heart rate response in case of emergency [46]. Yet, more recent reports question this approach and suggest, that, in stable patients, no intervention is generally well tolerated, and would therefore avoid the risk associated with temporary pacing [47]. For patients with CHB associated with symptoms and with unstable hemodynamics or heart failure, placement of a permanent pacemaker should be considered. There are many reports of permanent pacemaker implantation during pregnancy using a variety of technologies to guide the implant with a very low dose of radiation exposure [48,49]. As such, concerns about radiation exposure should not dissuade physicians from this intervention, especially since radiation risk is low after 8 weeks’ gestation.
Syncope during pregnancy Syncope is usually benign in pregnant patients without structural heart disease. When syncope occurs late in pregnancy while the patient is supine, it is usually due to impaired venous return to the heart, due to vena cava compression by the gravid uterus; the ‘supine hypotensive syndrome’ [50]. Symptoms usually subside when the patient rolls over her left side, or by placing a wedge under the right hip, which confirms the diagnosis. Syncope may also occur after standing upright suddenly or after long periods of standing, due to a fall in venous return as the result of increased venous pooling associated with pregnancy. When caval compression or changes in body position cannot explain recurrent syncope, other etiologies must be considered, including arrhythmias and volume depletion, as well as other causes that are specific to pregnant women, such as abruptio placentae and bleeding due to ruptured ectopic pregnancy [51,52].
Supraventricular tachyarrhythmias Patients with prior history of SVT are likely to have increased symptoms during pregnancy, and, in some cases, SVT first becomes manifested during pregnancy. Sustained SVT should be treated
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Arrhythmias
promptly, as it can result in impaired fetal blood flow [53]. Adenosine is the drug of choice for acute termination of SVT. For long-term treatment, b-adrenergic antagonists have the longest record of safety (except for atenolol, which is category D) [40]. Digoxin is well tolerated during pregnancy but is less effective; it is probably most useful in combination with b-adrenergic antagonists, achieving better efficacy while minimizing side-effects by allowing lower doses of two drugs. Calcium channel blockers may also be effective, but are a second line option. As addressed above, procedures that involve fluoroscopic radiation are best avoided, but can generally be performed at minimal risk after 8 weeks’ gestation [54].
Anticoagulation for atrial fibrillation during pregnancy Atrial fibrillation during pregnancy is rare; the most common setting is rheumatic heart disease [55,56,57 ]. A very high incidence of systemic embolism has been reported in pregnant patients with coexistent atrial fibrillation and rheumatic mitral valve disease (over 20%) [56]. As these are high-risk patients for embolic events, it is recommended that these patients be fully anticoagulated throughout pregnancy, similarly to patients with mechanical valves. Some authors even recommend anticoagulating patients with persistent atrial fibrillation regardless of underlying disease in view of the hypercoagulable state of pregnancy, even though there are no specific series reported exclusively on pregnant patients with nonrheumatic atrial fibrillation. Current experience emanates from isolated case reports, or large series of patients with diverse arrhythmias [57 ]. As warfarin can lead to serious adverse effects to the fetus (warfarin embryopathy), low-molecular-weight heparin (LMWH) is an attractive option. Recommendations for anticoagulation in pregnant women are as follows: Recommendations for anticoagulation in pregnant women are twice a day LMWH, or adjusteddose unfractionated heparin, until the 13th week. At that time warfarin can then be safely administered (target international normalized ratio range 2.5–3.5) until 34–36 weeks. At 34–36 weeks, heparin is resumed until delivery [57 ]. There is also a new class of anticoagulants designed to replace warfarin, including the direct thrombin inhibitor dabigatran, and the factor 10a inhibitors rivaroxaban and apixaban. All three drugs are very new and therefore we have no experience in pregnancy. Of note, aspirin is considered category D by the FDA, as it can lead &&
&&
to serious complications to the fetus, such as premature closure of the ductus arteriosus.
Ventricular tachyarrhythmias and sudden cardiac arrest Ventricular arrhythmias can also occur during pregnancy. Idiopathic ventricular tachycardia, which is seen in patients with normal hearts and associated with a good prognosis, is commonly seen for the first time in pregnancy [20]. This group of patients may respond to b-blockers. Rashba et al. [6] reported an increased incidence of adverse cardiac events during the postpartum period (but not during pregnancy) in patients with the long QT syndrome. The authors found that therapy with b-blockers reduced the incidence of events, and suggested that patients with the long QT syndrome who become pregnant should be treated without interruption with b-blockers. When necessary, direct current cardioversion has been shown to be well tolerated at all stages of pregnancy with no significant ill effects to the mother or fetus [58]. For acute pharmacologic therapy of ventricular tachycardia, if a membranestabilizing agent is required, both lidocaine and procainamide have been shown to be well tolerated. When class I or III agents are required, procainamide offers a favorable profile. Therapy with an ICD is a reasonable alternative in patients who are at high risk for sudden cardiac death who are pregnant, or who plan to conceive in the future. Natale et al. [44] reported no increase in ICD-related or shock-related complications in 44 women who received ICDs during pregnancy. Fortunately, cardiac arrest during pregnancy is rare [1,59]. In addition to the standard causes, unusual etiologies specific to pregnant women should be considered, such as amniotic fluid embolism, bleeding, and aortic dissection. If cardiopulmonary resuscitation is necessary, it should be performed with the patient in the left lateral decubitus position, with a wedge placed under the right flank, or with the uterus displaced manually to the left such that compression of the aorta and inferior vena cava by the gravid uterus is avoided. Emergency cesarean section should be considered if the fetus is viable.
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CONCLUSION Almost all ventricular and supraventricular arrhythmias can manifest during pregnancy. For benign arrhythmias, conservative therapies are preferred. When the arrhythmias jeopardize the life of the mother or fetus, therapy should be provided Volume 29 Number 1 January 2014
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Management of arrhythmia syndromes during pregnancy Joglar and Page
without hesitation. Several therapeutic options exist for most arrhythmias, including pharmacologic therapy and interventional procedures. Modern technology allows performance of interventional procedures with negligible risk of radiation exposure to the fetus. Drug therapy should be avoided during the first trimester of pregnancy if possible and drugs with the longest record of safety should be used as first line. Newer drugs should also be considered if indicated. Acknowledgements None. Conflicts of interest There are no conflicts of interest.
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21. Frishman W, Chesner M. Beta-adrenergic blockers in pregnancy. Am Heart J 1988; 115:147–152. 22. Pryun S, Phelan J, Buchanan G. Long-term propanolol therapy in pregnancy: maternal and fetal outcome. Am J Obstet Gynecol 1979; 135:485–489. 23. Rubin P, Butters L, Clark D. Placebo-controlled trial of atenolol in treatment of pregnancy-associated hypertension. Lancet 1983; 2:431–434. 24. Wichman K, Ryulden G, Karberg B. A placebo controlled trial of metoprolol in the treatment of hypertension in pregnancy. Scand J Clin Lab Invest 1984; 169:90–94. 25. Lip G, Beevers M, Churchill D, et al. Effect of atenolol on birth weight. Am J Cardiol 1997; 79:1436–1438. 26. Magee LA, Downar E, Sermer M, et al. Pregnancy outcome after gestational exposure to amiodarone in Canada. Am J Obstet Gynecol 1995; 172 (4 Pt 1): 1307–1311. 27. Ovadia M, Brito M, Hoyer GL, Marcus FI. Human experience with amiodarone in the embryonic period. Am J Cardiol 1994; 73:316–317. 28. O’Hare M, Murnaghan H, Russel CJ, et al. Sotalol as hypotensive agent in pregnancy. Br J Obstet Gynaecol 1980; 87:814–820. 29. Roukoz H, Saliba W. Dofetilide: a new class III antiarrhythmic agent. Expert Rev Cardiovasc Ther 2007; 5:9–19. 30. Kozlowski D, Budrejko S, Lip GY, et al. Dronedarone: an overview. Ann Med 2012; 44:60–72. 31. Klein V, Repke J. Supraventricular tachycardia in pregnancy: cardioversion with verapamil. Obstet Gynecol 1984; 63:16S–18S. 32. Byerly WG, Hartmann A, Foster DE, Tannenbaum AK. Verapamil in the treatment of maternal paroxysmal supraventricular tachycardia. Ann Emerg Med 1991; 20:552–554. 33. Camm A, Garrat C. Adenosine and supraventricular tachycardia. N Engl J Med 1991; 325:1621–1629. 34. Elkayam U, Goodwin TM. Adenosine therapy for supraventricular tachycardia during pregnancy. Am J Cardiol 1995; 75:521–523. 35. Page R. Arrhythmias during pregnancy. Cardiac Electrophysiol Rev 1997; 1:278–282. 36. Chen V, Tse T, Wong V. Transfer of digoxin across the placenta and into breast milk. Br J Obstet Gynaecol 1978; 85:605–609. 37. Rogers M, Willerson JT, Goldblatt A, Smith TW. Serum digoxin concentrations in the human fetus, neonate and infant. N Engl J Med 1972; 287:1010– 1013. 38. Kerenyi T, Meller J, Steinfeld L, et al. Transplacental cardioversion of intrauterine supraventricular tachycardia with digitalis. Lancet 1980; 2:393– 395. 39. King C, Mattioli L, Goertz KK, Snodgrass W. Successful treatment of fetal supraventricular tachycardia with maternal digoxin therapy. Chest 1984; 85:573–575. 40. Parilla BV, Strasburger JF, Socol ML. Fetal supraventricular tachycardia complicated by hydrops fetalis: a role for direct fetal intramuscular therapy. Am J Perinat 1996; 13:483–486. 41. Gonzalez AR, Phelps SJ, Cochran EB, Sibai BM. Digoxin-like immunoreactive substance in pregnancy. Am J Obstet Gynecol 1987; 157:660–664. 42. Damilakis J, Theocharopoulos N, Perisinakis K, et al. Conceptus radiation dose and risk from cardiac catheter ablation procedures. Circulation 2001; 104:893–897. 43. Ferguson JD, Helms A, Mangrum M, Dimarco JP. Ablation of incessant left atrial tachycardia without fluoroscopy in a pregnant woman. J Cardiovasc Electrophysiol 2011; 22:346–349. 44. Natale A, Davidson T, Geiger MJ, Newby K. Implantable cardioverterdefibrillators and pregnancy: a safe combination? Circulation 1997; 96:2808–2812. 45. Croci F, Brignole M, Menozzi C, et al. Efficacy and feasibility of isometric arm counter-pressure manoeuvres to abort impending vasovagal syncope during real life. Europace 2004; 6:2871–2891. 46. Dalvi BV, Chaudhuri A, Kulkarni HL, Kale PA. Therapeutic guidelines for congenital complete heart block presenting in pregnancy. Obstet Gynecol 1992; 79 (5 Pt 2):802–804. 47. Hidaka N, Chiba Y, Fukushima K, Wake N. Pregnant women with complete atrioventricular block: perinatal risks and review of management. Pacing Clin Electrophysiol 2011; 34:1161–1171. 48. Ruiz-Granell R, Ferrero A, Morell Cabedo S, et al. Implantation of single-lead atrioventricular permanent pacemakers guided by electroanatomic navigation without the use of fluoroscopy. Europace 2008; 10:1048–1051. 49. Antonelli D, Bloch L, Rosenfeld T. Implantation of a permanent dual chamber pacemaker in a pregnant woman by transesophageal echocardiographic guidance. PACE 1999; 22:534–535. 50. Metcalfe J, McAnulty J, Ueland K. Burwell and Metcalfe’s heart disease and pregnancy: physiology and management. Boston: Little, Brown and Co; 1986; p. 58. 51. Mechem CC, Knopp RK, Feldman D. Painless abruptio placentae associated with disseminated intravascular coagulation and syncope. Ann Emerg Med 1992; 21:883–885. 52. Kniseley RM. Acute internal bleeding as a cause of syncope. Am Fam Phys 1995; 52:1278. 53. Peleg D, Orvieto R, Ferber A, Ben-Rafael Z. Maternal supraventricular tachycardia recorded as apparent fetal heart rate in a case of fetal demise. Acta Obstet Gynecol Scand 1998; 77:786–787.
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Arrhythmias 54. Dominguez A, Iturralde P, Hermosillo AG, et al. Successful radiofrequency ablation of an accessory pathway during pregnancy. PACE 1999; 22 (1 Pt 1): 131–134. 55. Ueland K. Rheumatic heart disease and pregnancy. In: Elkayam U, Gleicher N, editors. Cardiac problems in pregnancy: diagnosis and management of maternal and fetal disease. New York: Alan R. Liss, Inc.; 1990. 56. Mendelson C. Disorders of the heart beat during pregnancy. Am J Obstet Gynecol 1956; 72:1268–1301.
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57. Goland S, Elkayam U. Anticoagulation in pregnancy. Cardiol Clin 2012; 30:395–405. This article discusses the optimal management of anticoagulation during pregnancy. 58. Rosemond R. Cardioversion during pregnancy. JAMA 1993; 269:3167. 59. Kloeck W, Cummins RO, Chamberlain D, et al. Special resuscitation situations: an advisory statement from the International Liaison Committee on Resuscitation. Circulation 1997; 95:2196–2210.
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Management of arrhythmia syndromes during pregnancy Jose A. Joglar a and Richard L. Page b
Purpose of review To discuss the diagnosis and management of maternal arrhythmias occurring during pregnancy. Recent findings When necessary, current technology allows implantation of arrhythmia management devices and performing catheter ablation procedures with little or no risk from radiation exposure to the fetus. Summary A variety of cardiac rhythm disturbances can occur during pregnancy, ranging from benign ectopy to life-threatening arrhythmias. In patients with normal hearts and minimally symptomatic arrhythmias, only reassurance is necessary. The quality of the data on managing more serious arrhythmias in pregnancy is somewhat limited, yet with a clear understanding of the maternal hemodynamic changes associated with pregnancy, and the appropriate antiarrhythmic therapies available, almost all cases can be treated successfully. The decision to treat should be based on careful consideration of risk and benefits, yet, when therapy is deemed necessary, it should be administered promptly and with confidence. Drug therapy should be avoided during the first trimester if possible and drugs with the longest record of safety are preferred. The decision to pursue an invasive strategy is complicated by the potential for procedural risks. Yet, the state of modern technology is such that invasive strategies, when justified, can be carried out effectively. Keywords antiarrhythmic drugs, cardiac arrhythmias, pregnancy
INTRODUCTION The full spectrum of cardiac arrhythmias and conduction disturbances can occur during pregnancy. Fortunately, most arrhythmias are benign in nature, but dangerous or hemodynamically important rhythm disturbances sometimes occur and should be treated promptly [1]. When considering therapeutic interventions, adverse effects to both the mother and fetus, such as proarrhythmia, must be considered. There are also unique risks pertaining strictly to the fetus, such as congenital malformations. With a clear understanding of the physiologic changes associated with pregnancy, and the appropriate invasive and noninvasive antiarrhythmic therapies available with knowledge of their potential risks, almost all such cases can be treated successfully.
EPIDEMIOLOGY OF ARRHYTHMIAS DURING PREGNANCY An increased incidence of maternal cardiac arrhythmias is observed during pregnancy, including new www.co-cardiology.com
arrhythmias, such as new-onset idiopathic ventricular tachycardia, as well as increased number of events in patients with a preexisting substrate, such as episodes of supraventricular tachycardia (SVT) in patients with the Wolff-Parkinson-White syndrome [2–4]. In some cases, arrhythmias that may have been preexistent and asymptomatic can become manifest, perhaps related to hemodynamic changes
a The University of Texas Southwestern Medical Center at Dallas, Dallas, Texas and bThe University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin USA
Correspondence to Jose A. Joglar, MD, Professor of Internal Medicine, Program Director, Clinical Cardiac Electrophysiology, Elizabeth Thaxton Page and Ellis Batten Page Professorship in Clinical Cardiac Electrophysiology Research, UT Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, Texas 75390-8837, USA. Tel: +1 214 590 5028; fax: +1 214 590 0402; e-mail: [email protected] Curr Opin Cardiol 2014, 29:36–44 DOI:10.1097/HCO.0000000000000020 Volume 29 Number 1 January 2014
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Management of arrhythmia syndromes during pregnancy Joglar and Page
KEY POINTS
THERAPIES
Cardiac arrhythmias manifest commonly during pregnancy.
Therapies for arrhythmias during pregnancy may include pharmacological as well as non pharmacological options.
Hemodynamically important arrhythmias should be treated promptly.
PHARMACOLOGICAL THERAPIES
Antiarrhythmic drug therapy should be avoided in the first trimester and drugs with longest record of safety should be used first. When absolutely necessary, interventional procedures can be performed with little risk from radiation exposure.
during pregnancy or simply in some cases due to increased medical attention during pregnancy. In addition, the physiologic changes related to pregnancy may stress the cardiovascular system in an increased number of women with underlying structural and congenital heart disease who today may reach reproductive age [5]. The most common arrhythmias noted during pregnancy are premature ventricular and atrial ectopy, reported in 50–60% of pregnant women, with the majority resolving after delivery [3]. An increased risk of life-threatening cardiac events has also been reported during the postpartum period in patients with congenital Long QT syndrome [6].
The evidence supporting the use of antiarrhythmic agents during pregnancy, when available, is often limited to small case series and individual reports; but, in general, the medications that have been available for longer periods of time have the greatest number of reports regarding safety. Fewer data are available on the newer drugs, yet their use may be justified if it is believed that the benefits outweigh the risk. One problem with older drugs is that, despite the longer record of safety in pregnancy, most modern physicians rarely or even never use them anymore, whereas there is very little published in pregnancy on the newer drugs that are now more commonly used. The majority are US Food and Drug Administration (FDA) category C (Table 1). All antiarrhythmic medications have potential side-effects to both the mother and the fetus, and as such should be avoided in the first trimester if possible. Generally, the lowest recommended dose should be used initially, accompanied with regular monitoring of clinical response. Proarrhythmia, such as torsade de pointes due to excessive QT
Table 1. Definition of FDA pregnancy categories and antiarrhythmic agents within each category Pregnancy category
Definition
Antiarrhythmic agents
A
Controlled studies show no risk. Adequate, well-controlled studies in pregnant women have failed to demonstrate risk to the fetus in any trimester of pregnancy.
B
No evidence of risk in humans. Adequate, well-controlled studies in pregnant women have not shown increased risk of fetal abnormalities despite adverse findings in animals, or, in the absence of adequate human studies, animal studies show no fetal risk. The chance of fetal harm is remote but remains a possibility. Risk cannot be ruled out. Adequate, well-controlled human studies are lacking, and animal studies have shown a risk to the fetus or are lacking as well. There is chance of fetal harm if the drug is administered during pregnancy; but the potential benefits outweigh the risk.
Lidocaine, Sotalol
D
Positive evidence of risk. Studies in humans have shown evidence of fetal risk. Nevertheless, the potential benefits from the use of the drug in pregnant women may outweigh the risk.
Phenytoin, Amiodarone, Atenolol
X
Contraindicated in pregnancy. Studies in animals or humans have shown fetal risk, which clearly outweighs any possible benefit to the patient.
C
Quinidine, Disopyramide, Procainamide, Mexiletine, Flecainide, Propafenone, Propranolol, Metoprolol, Bretylium, Ibutilide, Dofetilide, Dronedarone, Verapamil, Diltiazem, Digoxin, Adenosine
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/Labeling/ucm093307.htm. FDA, Food and Drug Administration.
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Arrhythmias
prolongation, is the most worrisome side-effect for the mother. A list of antiarrhythmic drugs is detailed in Table 2.
Class I (sodium channel blocking agents) Of the class IA agents, quinidine has the longest record of safety in pregnancy, with over 60 years of experience treating arrhythmias and malaria [7–9]. Yet, this drug is seldom used anymore and clinical need must be balanced against lack of experience with its use. Monitoring of serum levels is mandatory in order to avoid proarrhythmia. Procainamide has electrophysiologic properties and clinical applications similar to quinidine, but can be used intravenously. It has proven well tolerated and effective in the management of maternal arrhythmias [10], and is an option for the acute treatment of undiagnosed wide complex tachycardia [11]. Procainamide is generally not appropriate for long-term therapy, as it can cause lupus-like syndrome. All class IA medications must be administered in the hospital during continuous cardiac monitoring, and serum drug levels should be carefully monitored. The class IB includes lidocaine and mexiletine. Lidocaine is used primarily for the acute management of ventricular arrhythmias. It has been widely used during pregnancy, mainly as an anesthetic agent, and has been shown to be generally well tolerated by both the mother and the fetus [12]. Mexiletine is an oral antiarrhythmic agent with structure similar to lidocaine. The experience with mexiletine during pregnancy is limited, but it also appears to be well tolerated [13,14]. The class IC agents include propafenone and flecainide, both of which appear to be relatively well tolerated during pregnancy. Flecainide is contraindicated in all patients with prior infarction or underlying structural heart disease [15]. Otherwise, it has proven well tolerated and effective in the treatment of diverse maternal atrial and ventricular arrhythmias [16,17]. Further evidence of safety for the mother comes from experience in the use of flecainide for fetal arrhythmias, in which it has been shown to be superior to digoxin and is considered the drug of choice for this problem [18]. Experience with propafenone is more limited, although no adverse effects to the mother or the fetus have been reported when administered during the third trimester [19]. This drug is also contraindicated in patients with prior myocardial infarction. 38
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Class II (b-adrenergic blocking agents) The b-adrenergic blocking drugs are often the firstline option for a variety of arrhythmias, as there is extensive experience on their use from treating other conditions during pregnancy, such as hypertension [20,21]. Although there have been rare reports of adverse effects to the fetus, such as bradycardia, the incidence of these complications is low. It is likely that some prior reports of fetal complications were likely due to high-risk conditions and not because of the drug itself [21]. The main concern associated to b-blockers is intrauterine growth retardation [22], although the evidence is conflicting [23,24]. One study reported growth retardation in babies receiving atenolol in the first trimester [25]. Although it is difficult to discern between growth retardation due to maternal disease versus drug, in view of these results, b-blockers should be avoided during the first trimester if possible (and atenolol avoided because of a category D designation by the FDA). Cardioselective b1 antagonists, such as metoprolol, are the preferred agents, as they may be less likely to interfere with b2-mediated uterine relaxation [21].
Class III (potassium channel-blocking agents) The class III agents primarily block potassium channels, causing delay of repolarization and prolonging the QT interval. This class includes amiodarone, sotalol, dronedarone, dofetilide and ibutilide. The most worrisome side-effect for this class of drugs is torsade de pointes, so patients must be closely monitored. Amiodarone is a potent antiarrhythmic agent used for the management of ventricular and, less often, supraventricular arrhythmias. Multiple adverse effects to the fetus have been reported with amiodarone, including fetal hypothyroidism. Congenital abnormalities have been reported as well [26,27], so the drug should especially be avoided during the first trimester. The side-effect profile has caused it to be contraindicated during pregnancy, except for life-threatening conditions in which other agents have failed and benefit outweighs the substantial risk. It is FDA category D. Sotalol is a class III agent with noncardiac selective b-receptor antagonist properties. Although sotalol has been used successfully during pregnancy, experience is limited so caution is advised [16,28]. Nevertheless, this drug is a reasonable option in pregnant women, as it is FDA category B. Dofetilide and dronedarone were more recently approved by the FDA. Dofetilide is approved for Volume 29 Number 1 January 2014
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II
III
b-blocking agents
Amiodarone
III
IC
Propafenone
III
IC
Flecainide
Dofetilide
IB
Phenytoin
Dronedarone
IB
Mexiletine
III
IB
Lidocaine
Ibutilide
IA
Disopyramide
III
C/D
IA
Procainamide
Sotalol
C
IA
Quinidine
C
X
C
B
D
C
D
C
B
C
C
C
Drug classa
Drug
FDA classb
Torsade de pointes
Torsade de pointes
Torsade de pointes
Torsade de pointes, b-blocker effects
Fetal hypothyroidism, prematurity, low birth weight, congenital malformations
Intrauterine growth retardation, fetal bradycardia, hypoglycemia, fetal apnea
Same concerns as flecainide, mild b-blocker effects
Increased mortality in patients with previous myocardial infarction, generally well tolerated in structurally normal hearts
Mental and growth retardation, fetal hydantoin syndrome
CNS adverse effects, fetal bradycardia, low APGAR
CNS adverse effects, bradycardia
Induction of uterine contractions, torsade de pointes
Lupus-like syndrome with long-term use, torsade de pointes
Maternal and fetal thrombocytopenia, eighth nerve toxicity, torsade de pointes
Potential adverse effects
Table 2. Experience with antiarrhythmic drugs during pregnancy
Atrial fibrillation in the setting of structural heart disease
Atrial fibrillation
Acute termination of atrial fibrillation /flutter
Maternal ventricular tachycardia and SVT, hypertension in the past
Life-threatening ventricular arrhythmias
Maternal SVT, idiopathic ventricular tachycardia, atrial fibrillation rate control
Variety of maternal ventricular tachycardia and SVT
Variety of maternal and fetal ventricular tachycardia and SVT
Arrhythmias due to digoxin toxicity
Ventricular tachycardia
Maternal ventricular tachycardia, arrhythmias due to digoxin toxicity
Limited experience, other alternatives available
Drug of choice for acute treatment of undiagnosed wide complex tachycardia
Variety of maternal and fetal arrhythmias
Primary indication(s)
Unknown
Contraindicated
Unknown
Generally compatible but caution advised
Avoid since a large amount of drug is absorbed by the infant
Avoid atenolol. Metoprolol and propranolol are compatible
Unknown
Compatible
Generally compatible but caution advised
Compatible
Compatible
Compatible
Compatible but long-term therapy should be avoided
Generally compatible but caution advised
Use during lactationc
(Continued )
No experience in pregnancy
Contraindicated
No experience in pregnancy
Limited experience
Avoid if possible especially during first trimester
Generally well tolerated, avoid during first trimester, cardiac selective are preferred
Limited experience
First line option for treating fetal SVT with hydrops
Better alternatives available, avoid if possible
Limited experience
Long record of safety, avoid if fetal distress
Limited experience
Has the advantage of intravenous dosing, long record of safety
Long record of safety
Comments
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40
First option for acute treatment of SVT Unknown, but probably well tolerated
Compatible
Acute termination of maternal SVT
Fetal and maternal SVT, atrial fibrillation rate control
Long record of safety
Verapamil preferred due to longer record in pregnancy Compatible Maternal SVT, atrial fibrillation rate control
CNS, central nervous system; FDA, Food and Drug Administration; N/A, not applicable; SVT, supraventricular tachycardia. a Vaughan Williams classification of antiarrhythmic drugs. b FDA risk category (see Table 1) c Committee on Drugs. Transfer of drugs and other chemicals into human milk. Pediatrics 1994; 93:137–150.
Low birth weight C N/A Digoxin
Dyspnea, bradycardia C N/A Adenosine
Limited experience, same concerns as with verapamil IV Diltiazem
C
Relatively well tolerated but safer options are available Compatible Maternal and fetal SVT, idiopathic ventricular tachycardia, atrial fibrillation rate control Maternal hypotension, fetal bradycardia and heart block IV Verapamil
C
Drug classa
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atrial fibrillation, and is especially appropriate in patient with prior myocardial infarction and heart failure, conditions in which other agents can be contraindicated. The main risk is torsade de pointes, so initiation must occur under inpatient observation [29,30]. Dofetilide is category C, and should only be considered if benefits outweigh the risk, as the experience of use in pregnancy is very limited, yet dofetilide might have a role in situations in view of limited options for patients with underlying structural heart disease and in view of the high toxicity associated with amiodarone [29]. Dronedarone is contraindicated in pregnancy because of concerns for potential harm to the fetus [30].
Class IV (calcium channel-blocking agents)
Drug
Table 2 (Continued)
FDA classb
Potential adverse effects
Comments Use during lactationc Primary indication(s)
Arrhythmias
The calcium channel-blocking agents with significant antiarrhythmic action are verapamil and diltiazem. Favorable results have been reported with verapamil for the acute treatment of SVT in pregnant women, except for the occurrence of maternal hypotension [31,32]. Overall, the calcium channel blockers appear to be relatively well tolerated for the treatment of maternal conditions, but, because of occasional reports of adverse effects on the fetus, caution is advised and alternative therapies should be considered first (such as adenosine for acute conversion of supraventricular arrhythmias). When used in pregnancy, verapamil is the preferred agent based on more extensive experience in this condition.
Adenosine Adenosine is an endogenous nucleoside with a short half-life (under 2 s), which is highly effective in acute termination of SVT [33]. The drug has been used safely in pregnant women, with no significant adverse effects to the mother or fetus [34]. The initial dose is 6 mg rapid bolus IV, but this may be advanced to 12 mg as needed; well-tolerated administration of 24 mg has been reported [11]. Minor maternal side-effects, such as bradycardia and dyspnea, are usually transient and of no consequence. Adenosine should be considered the drug of choice for acute termination of SVT during pregnancy [35].
Digoxin There is extensive experience with digoxin and it is among the safest antiarrhythmic drugs for use during pregnancy. Digoxin freely crosses the placenta [36,37], and for many years has been used for the treatment of a variety of maternal and fetal SVT [38,39], including fetal SVT complicated by hydrops [40]. Volume 29 Number 1 January 2014
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Management of arrhythmia syndromes during pregnancy Joglar and Page
As in nonpregnant patients, the digoxin dose needs to be adjusted for renal impairment or for drug interactions. Serum drug levels need to be monitored, although in the third trimester the serum concentration measurement may be spuriously high, due to a circulating digoxin-like substance that interferes with the radioimmune assay for the drug [41].
Invasive therapies: catheter ablation and device implantation When arrhythmias lead to hemodynamic instability, two lives are in potential jeopardy. As such, despite concerns about potential risks, invasive therapies are sometimes necessary in patients who fail to respond to drugs. One concern in the past has been the risk of radiation exposure to the fetus, with possible teratogenicity or future risk of malignancy. The risk of malignancy is perhaps overstated; in one report in 2001, Damilakis et al. [42] estimated a low risk of malignancies to the conceptus from a typical ablation procedure, even when considering that their calculations were made with over 30 min of fluoroscopy time. Since their report was published, technology has evolved greatly, and today most ablation procedures are performed using electroanatomic navigation systems, obviating the need for significant (or any) use of radiation [43]. Implantable devices, such as defibrillators and pacemakers, can also be implanted safely, with small doses of fluoroscopy. Implantable cardioverter defibrillator (ICD) shocks have shown to cause no ill effects to the fetus, and therefore ICD implantation should be considered for life-threatening ventricular arrhythmias or sudden death prevention [44].
Arrhythmias that may occur during pregnancy The entire spectrum of cardiac arrhythmias can manifest during pregnancy, from benign to lifethreatening.
Bradycardia and atrioventricular conduction disturbances Sinus node dysfunction is uncommon in pregnancy, unless underlying congenital heart disease is present. Vasovagal or neurocardiogenic syncope can be seen, but the bradycardia is usually transient and best treated with abortive measures, such as isometric muscle tensing [45]. Congenital heart block (CHB) is occasionally first diagnosed during pregnancy. Asymptomatic
patients with isolated CHB and no other evidence of conduction system or structural heart disease have a favorable outcome, and supportive pacing during pregnancy is usually not necessary. In the past, temporary pacing was advocated during delivery for all women with CHB because of the high incidence of syncope and bradycardia related to Valsalva maneuvers, and to allow adequate heart rate response in case of emergency [46]. Yet, more recent reports question this approach and suggest, that, in stable patients, no intervention is generally well tolerated, and would therefore avoid the risk associated with temporary pacing [47]. For patients with CHB associated with symptoms and with unstable hemodynamics or heart failure, placement of a permanent pacemaker should be considered. There are many reports of permanent pacemaker implantation during pregnancy using a variety of technologies to guide the implant with a very low dose of radiation exposure [48,49]. As such, concerns about radiation exposure should not dissuade physicians from this intervention, especially since radiation risk is low after 8 weeks’ gestation.
Syncope during pregnancy Syncope is usually benign in pregnant patients without structural heart disease. When syncope occurs late in pregnancy while the patient is supine, it is usually due to impaired venous return to the heart, due to vena cava compression by the gravid uterus; the ‘supine hypotensive syndrome’ [50]. Symptoms usually subside when the patient rolls over her left side, or by placing a wedge under the right hip, which confirms the diagnosis. Syncope may also occur after standing upright suddenly or after long periods of standing, due to a fall in venous return as the result of increased venous pooling associated with pregnancy. When caval compression or changes in body position cannot explain recurrent syncope, other etiologies must be considered, including arrhythmias and volume depletion, as well as other causes that are specific to pregnant women, such as abruptio placentae and bleeding due to ruptured ectopic pregnancy [51,52].
Supraventricular tachyarrhythmias Patients with prior history of SVT are likely to have increased symptoms during pregnancy, and, in some cases, SVT first becomes manifested during pregnancy. Sustained SVT should be treated
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Arrhythmias
promptly, as it can result in impaired fetal blood flow [53]. Adenosine is the drug of choice for acute termination of SVT. For long-term treatment, b-adrenergic antagonists have the longest record of safety (except for atenolol, which is category D) [40]. Digoxin is well tolerated during pregnancy but is less effective; it is probably most useful in combination with b-adrenergic antagonists, achieving better efficacy while minimizing side-effects by allowing lower doses of two drugs. Calcium channel blockers may also be effective, but are a second line option. As addressed above, procedures that involve fluoroscopic radiation are best avoided, but can generally be performed at minimal risk after 8 weeks’ gestation [54].
Anticoagulation for atrial fibrillation during pregnancy Atrial fibrillation during pregnancy is rare; the most common setting is rheumatic heart disease [55,56,57 ]. A very high incidence of systemic embolism has been reported in pregnant patients with coexistent atrial fibrillation and rheumatic mitral valve disease (over 20%) [56]. As these are high-risk patients for embolic events, it is recommended that these patients be fully anticoagulated throughout pregnancy, similarly to patients with mechanical valves. Some authors even recommend anticoagulating patients with persistent atrial fibrillation regardless of underlying disease in view of the hypercoagulable state of pregnancy, even though there are no specific series reported exclusively on pregnant patients with nonrheumatic atrial fibrillation. Current experience emanates from isolated case reports, or large series of patients with diverse arrhythmias [57 ]. As warfarin can lead to serious adverse effects to the fetus (warfarin embryopathy), low-molecular-weight heparin (LMWH) is an attractive option. Recommendations for anticoagulation in pregnant women are as follows: Recommendations for anticoagulation in pregnant women are twice a day LMWH, or adjusteddose unfractionated heparin, until the 13th week. At that time warfarin can then be safely administered (target international normalized ratio range 2.5–3.5) until 34–36 weeks. At 34–36 weeks, heparin is resumed until delivery [57 ]. There is also a new class of anticoagulants designed to replace warfarin, including the direct thrombin inhibitor dabigatran, and the factor 10a inhibitors rivaroxaban and apixaban. All three drugs are very new and therefore we have no experience in pregnancy. Of note, aspirin is considered category D by the FDA, as it can lead &&
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to serious complications to the fetus, such as premature closure of the ductus arteriosus.
Ventricular tachyarrhythmias and sudden cardiac arrest Ventricular arrhythmias can also occur during pregnancy. Idiopathic ventricular tachycardia, which is seen in patients with normal hearts and associated with a good prognosis, is commonly seen for the first time in pregnancy [20]. This group of patients may respond to b-blockers. Rashba et al. [6] reported an increased incidence of adverse cardiac events during the postpartum period (but not during pregnancy) in patients with the long QT syndrome. The authors found that therapy with b-blockers reduced the incidence of events, and suggested that patients with the long QT syndrome who become pregnant should be treated without interruption with b-blockers. When necessary, direct current cardioversion has been shown to be well tolerated at all stages of pregnancy with no significant ill effects to the mother or fetus [58]. For acute pharmacologic therapy of ventricular tachycardia, if a membranestabilizing agent is required, both lidocaine and procainamide have been shown to be well tolerated. When class I or III agents are required, procainamide offers a favorable profile. Therapy with an ICD is a reasonable alternative in patients who are at high risk for sudden cardiac death who are pregnant, or who plan to conceive in the future. Natale et al. [44] reported no increase in ICD-related or shock-related complications in 44 women who received ICDs during pregnancy. Fortunately, cardiac arrest during pregnancy is rare [1,59]. In addition to the standard causes, unusual etiologies specific to pregnant women should be considered, such as amniotic fluid embolism, bleeding, and aortic dissection. If cardiopulmonary resuscitation is necessary, it should be performed with the patient in the left lateral decubitus position, with a wedge placed under the right flank, or with the uterus displaced manually to the left such that compression of the aorta and inferior vena cava by the gravid uterus is avoided. Emergency cesarean section should be considered if the fetus is viable.
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CONCLUSION Almost all ventricular and supraventricular arrhythmias can manifest during pregnancy. For benign arrhythmias, conservative therapies are preferred. When the arrhythmias jeopardize the life of the mother or fetus, therapy should be provided Volume 29 Number 1 January 2014
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Management of arrhythmia syndromes during pregnancy Joglar and Page
without hesitation. Several therapeutic options exist for most arrhythmias, including pharmacologic therapy and interventional procedures. Modern technology allows performance of interventional procedures with negligible risk of radiation exposure to the fetus. Drug therapy should be avoided during the first trimester of pregnancy if possible and drugs with the longest record of safety should be used as first line. Newer drugs should also be considered if indicated. Acknowledgements None. Conflicts of interest There are no conflicts of interest.
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