NEWS FROM THE HEART RHYTHM SOCIETY 2023 HRS expert consensus statement on the management of arrhythmias during pregnancy

José A. Joglar, MD, FHRS (Chair),1,* Suraj Kapa, MD, FHRS (Vice-Chair),2,* Elizabeth V. Saarel, MD, FHRS, CEPS-P (Vice-Chair),3,* Anne M. Dubin, MD, FHRS, CEPS-P,4,† Bulent Gorenek, MD, FACC,5,‡

Afshan B. Hameed, MD, FACOG, FACC,6,x Sissy Lara de Melo, MD, PhD,7,{

Miguel A. Leal, MD, FHRS,8,* Blandine Mondésert, MD,9,* Luis D. Pacheco, MD,10,#

Melissa R. Robinson, MD, FHRS, CCDS,11,* Andrea Sarkozy, MD, PhD, FEHRA,12,** Candice K. Silversides, MD, FRCPC, FACC,13,* Danna Spears, MD,14,* Sindhu K. Srinivas, MD, MSCE,15,# Janette F. Strasburger, MD,16,†

Usha B. Tedrow, MD, MS, FHRS,17,* Jennifer M. Wright, MD, MA, FHRS,8,††

Carolyn M. Zelop, MD, FAHA,18,19,x Dominica Zentner, MBBS (Hons), FRACP, PhD20,‡‡

Document Reviewers: Elena Arbelo, MD, MSci, PhD; Carina Blomstr€om-Lundqvist, MD, PhD; Barbara J. Deal, MD, MS; M. Cecilia Gonzalez Corcia, PhD, CEPS-P; Rajesh Kabra, MD, FHRS; Magdalena J. Lagamayo, MD; Torri Metz, MD; Sarah Obican, MD; Alejandro Olaya, MD; Nisha Parikh, MD, MPH; Andrea M. Russo, MD, FHRS; Kamala P. Tamirisa, MD, FHRS

From the 1The University of Texas Southwestern Medical Center, Dallas, Texas, 2Mayo Clinic, Rochester, Minnesota, 3St. Luke’s Health System, Boise, Idaho, and Cleveland Clinic Lerner College of Medicine at Case Western Reserve University, Cleveland, Ohio, 4Stanford University, Palo Alto, California, 5Eskis ̧ehir Osmangazi University, Eskis ̧ehir, Turkey, 6University of California, Irvine, Irvine, California, 7University of S~ao Paulo, S~ao Paulo, Brazil, 8University of Wisconsin–Madison, Madison, Wisconsin, 9Montréal Heart Institute, Montréal, Quebec, Canada, 10The University of Texas Medical Branch at Galveston, Galveston, Texas, 11University of Washington, Seattle, Washington, 12University Hospital of Antwerp, University of Antwerp, Antwerp, Belgium, 13University of Toronto, Toronto, Ontario, Canada, 14University Health Network, Toronto, Ontario, Canada, 15University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, 16Children’s Hospital of Wisconsin, Milwaukee, Wisconsin, 17Brigham and Women’s Hospital, Boston, Massachusetts, 18The Valley Health System, Ridgewood, New Jersey, 19New York University Grossman School of Medicine, New York, New York, and 20The University of Melbourne, Melbourne, Victoria, Australia.

*Representative of the Heart Rhythm Society (HRS) †Representative of the Pediatric and Congenital Electrophysiology Society (PACES) ‡Representative of the American College of Cardiology (ACC) xRepresentative of the American College of Obstetricians and Gynecologists (ACOG) {Representative of the Latin American Heart Rhythm Society (LAHRS) #Representative of the Society for Maternal-Fetal Medicine (SMFM) **Representative of the European Heart Rhythm Association (EHRA) ††Representative of the American Heart Association (AHA) ‡‡Representative of the Asia Pacific Heart Rhythm Society (APHRS)

1547-5271/$-see front matter © 2023 Heart Rhythm Society. All rights reserved. https://doi.org/10.1016/j.hrthm.2023.05.017

Abstract This international multidisciplinary expert consensus statement is intended to provide comprehensive guidance that can be referenced at the point of care to cardiac electrophysiologists, cardiologists, and other health care professionals, on the management of cardiac arrhythmias in pregnant patients and in fetuses. This document covers general concepts related to arrhythmias, including both brady- and tachyarrhythmias, in both the patient and the fetus during pregnancy. Recommendations are provided for optimal approaches to diagnosis and evaluation of arrhythmias; selection of invasive and noninvasive options for treatment of arrhythmias; and disease- and patient-specific considerations when risk stratifying, diagnosing, and treating arrhythmias in pregnant patients and fetuses. Gaps in knowledge and new directions for future research are also identified.

KEYWORDS Antiarrhythmic; Atrial fibrillation; Bradyarrhythmia; Fetal arrhythmia; Inherited arrhythmia syndrome; Maternal arrhythmia; Pregnancy; Supraventricular tachycardia; Tachyarrhythmia; Ventricular tachycardia

ABBREVIATIONS 3D 5 3-dimensional; ACLS 5 advanced cardiac life support; ACM 5 arrhythmogenic cardiomyopathy; AF 5 atrial fibrillation; AFL 5 atrial flutter; AT 5 atrial tachycardia; AV 5 atrioventricular; BLS 5 basic life support; bpm 5 beats per minute; BrS 5 Brugada syndrome; CHD 5 congenital heart disease; COR 5 class of recommendation; CPR 5 cardiopulmonary resuscitation; CPVT 5 catecholaminergic polymorphic ventricular tachycardia; ECG 5 electrocardiogram; EF 5 ejection fraction; fMCG 5 fetal magnetocardiography; HCM 5 hypertrophic cardiomyopathy; IART 5 intra-atrial reentrant tachycardia; IAS 5 inherited arrhythmia syndrome; ICD 5 implantable cardioverter defibrillator; ICM 5 implantable cardiac monitor; IST 5 inappropriate sinus tachycardia; IVIG 5 intravenous immunoglobulin; LOE 5 level of evidence; LQTS 5 long QT syndrome; LV 5 left ventricular; MRI 5 magnetic resonance imaging; PAC 5 premature atrial contraction; PSVT 5 paroxysmal supraventricular tachycardia; PVC 5 premature ventricular contraction; QTc 5 corrected QT interval; RVR 5 rapid ventricular rate; RWI 5 relationships with industry and other entities; SHD 5 structural heart disease; SQTS 5 short QT syndrome; SVT 5 supraventricular tachycardia; TdP 5 torsades de pointes; VF 5 ventricular fibrillation; VT 5 ventricular tachycardia (Heart Rhythm 2023;20:e175–e259)

Developed in collaboration with and endorsed by the American College of Cardiology (ACC), the American College of Obstetricians and Gynecologists (ACOG), the American Heart Association (AHA), the Asia Pacific Heart Rhythm Society (APHRS), the European Heart Rhythm Association (EHRA), the Latin American Heart Rhythm Society (LAHRS), the Pediatric and Congenital Electrophysiology Society (PACES), and the Society for Maternal- Fetal Medicine (SMFM). For copies of this document, please contact the Elsevier Inc. Reprint Department (reprints@elsevier.com). Permissions: Multiple copies, modification, alteration, enhancement, and/or distribution of this document are not permitted without the express permission of the Heart Rhythm Society. Instructions for obtaining permission are located at https://www.elsevier.com/about/our-business/policies/copyright/permissions. Correspondence: Heart Rhythm Society, 1325 G St NW, Suite 500, Washington, DC 20005. E-mail address: clinicaldocs@hrsonline.org.

TABLE OF CONTENTS Top 10 take-home messages ................................. e177 Section 1 Introduction ........................................... e178 1.1. Preamble ...................................................... e178 1.2. Document scope and objectives .................. e178 1.3. Editorial independence ................................ e178 1.4. Organization of the writing committee ....... e178 1.5. Evidence review and formulation of recommendations ................................................. e179 1.6. Class of recommendation and level of evidence ............................................................... e179 1.7. Document review and approval .................. e180 1.8. Updating ....................................................... e180 1.9. Relevant clinical practice documents .......... e181 1.10. Definitions .................................................. e182 Section 2 General concepts for the management of arrhythmias during pregnancy ............................... e182 2.1. Epidemiology of arrhythmias ...................... e182 2.1.1. Etiology of palpitations ........................ e183 2.1.2. Epidemiology and classification of syncope ........................................................... e184 2.2. Physiological, hormonal, and autonomic changes related to arrhythmogenesis .................. e185 2.3. General considerations for antiarrhythmic drugs in pregnancy .............................................. e185 2.4. General considerations for management of fetal arrhythmias .................................................. e191 Section 3 Overarching principles .......................... e191 3.1. General electrophysiological management .... e191 3.2. Team-based care and shared decisionmaking ................................................................. e192 3.3. Genetic testing ............................................. e193 Section 4 Procedural considerations for arrhythmia management during pregnancy .............................. e194 4.1. Cardioversion during pregnancy ................. e194 4.2. Radiation exposure during cardiac procedures and hemodynamic concerns related to pregnancy ............................................................ e195 4.3. Anesthesia considerations ............................ e196 4.4. Delivery and lactation .................................. e198 Section 5 Diagnosis of pregnant patients with palpitations ............................................................. e199 Section 6 Diagnosis and management of pregnant patients with syncope ............................................ e202 6.1. Diagnosis and approach to the pregnant patient with syncope ........................................... e202 6.2. Management of syncope and orthostatic hypotension in the pregnant patient ................... e205 Section 7 Management of specific arrhythmias during pregnancy ................................................... e205 7.1. Management of atrial ectopy and supraventricular tachycardia during pregnancy .... e206 7.1.1. Management of acute supraventricular tachycardia during pregnancy ......................... e206

7.1.2. Management of nonacute atrial ectopy and supraventricular tachycardia during pregnancy ........................................................ e208 7.2. Management of atrial fibrillation and atrial flutter in pregnancy ............................................. e210 7.3. Management of ventricular arrhythmias in pregnancy not associated with inherited arrhythmia syndromes ......................................... e214 Section 8 Management of pregnant patients with bradycardia and/or heart block .............................. e217 Section 9 Advanced cardiac life support for the pregnant patient ...................................................... e220 Section 10 Arrhythmia management in the pregnant patient with arrhythmogenic structural cardiac substrates ................................................................ e223 10.1. Arrhythmia management in the pregnant patient with structural heart disease ................... e223 10.2. Arrhythmia management in the pregnant patient with congenital heart disease .................. e224 10.3. Arrhythmia management in the pregnant patient with valvular heart disease ..................... e227 10.4. Arrhythmia management in the pregnant patient with arrhythmogenic cardiomyopathy .... e228 10.5. Arrhythmia management in the pregnant patient with hypertrophic cardiomyopathy ......... e229 Section 11 Management of fetal arrhythmias ....... e230 11.1. Fetal atrial tachyarrhythmias ..................... e230 11.2. Fetal ventricular arrhythmias not associated with inherited arrhythmia syndromes ................. e234 11.3. Management of fetal bradycardia conduction system disorders ............................... e236 Section 12 Inherited arrhythmia syndromes ......... e238 12.1. Management and risk stratification of inherited arrhythmia syndromes during pregnancy ............................................................ e238 12.1.1. General management considerations for inherited arrhythmia syndromes in pregnancy ........................................................ e239 12.1.2. Management of long QT syndrome in pregnancy ........................................................ e242 12.1.3. Management of Brugada syndrome in pregnancy ........................................................ e244 12.1.4. Management of catecholaminergic polymorphic ventricular tachycardia in pregnancy ........................................................ e244 12.1.5. Management of short QT syndrome in pregnancy ........................................................ e245 12.2. Management of inherited fetal arrhythmias ... e245 12.2.1. Management of inherited arrhythmia syndromes in the fetus, specifically long QT syndrome ......................................................... e246 Section 13 Future directions .................................. e249 References ............................................................. e250 Appendix 1 .......................................................... e260 Appendix 2 .......................................................... e263 Top 10 take-home messages

1. The most common arrhythmias seen in pregnant patients are generally benign, including sinus arrhythmia, supraventricular tachycardia, and premature beats, whereas life-threatening arrhythmias, such as hemodynamically significant supraventricular tachycardia or ventricular tachycardia, are significantly less common. 2. Atrial fibrillation is increasingly becoming the most common newly diagnosed sustained arrhythmia during pregnancy. Some therapeutic decisions for atrial fibrillation, such as a rate-control strategy versus rhythm control strategy, should be based on hemodynamic tolerance and underlying substrate as in nonpregnant patients, whereas others, such as anticoagulation therapy protocols, are specific to pregnancy. 3. Care of arrhythmias in the pregnant patient should involve a multidisciplinary engagement of cardiologists and/or electrophysiologists, pediatric electrophysiologists, maternal-fetal medicine subspecialists, anesthesiologists, and neonatologists to optimize outcomes for both the mother and the fetus/newborn. 4. When arrhythmias occur in pregnancy, both the mother and the fetus may be affected; thus, shared decisionmaking should include a discussion of the risks and benefits to both the mother and the fetus of antiarrhythmic drugs, specific procedures, and monitoring, as well as the risks of withholding such therapies. 5. Fetal arrhythmia management decisions should be considered in the context of any concomitant maternal arrhythmias or diagnoses (eg, fetal bradycardia in mothers with long QT syndrome). Treatment of fetal arrhythmias generally involves either maternal systemic administration of antiarrhythmic agents; rarely, such as in cases of fetal hydrops, direct fetal intramuscular injection or intraperitoneal injection of antiarrhythmic drugs may be necessary. 6. Management of hemodynamically significant maternal arrhythmias should emphasize the prompt use of the most effective therapy available (cardioversion, antiarrhythmic drug infusion, or catheter ablation) to terminate the ongoing arrhythmia and/or prevent recurrent arrhythmias, with appropriate fetal monitoring, and measures to minimizeradiationexposurewhencatheterablationispursued. 7. Procedures such as catheter ablation and implantable devices, if indicated for arrhythmias with hemodynamic compromise or for sudden death prevention, can be performed at experienced centers with maximum possible mitigation of radiation exposure to the fetus, which is best achieved by overall reduction of total maternal radiation, since covering the maternal abdomen with a lead apron alone is generally of no benefit. 8. Due to the overall risk of aortocaval compression in pregnant patients, particularly in the third trimester, avoidance of prolonged supine positioning is warranted, especially during invasive procedures, with preference given to a left lateral tilt position to optimize hemodynamics.

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9. Use of antiarrhythmic drugs during pregnancy and the postpartum period should largely be similar to use in nonpregnant patients with some exceptions for the sake of fetal safety: selecting drugs with the longest record of safe use during pregnancy and lactation; using the lowest effective dose; and periodically reevaluating the continued need for the same dose/type of antiarrhythmic, including during the postpartum period, in light of potential drug concentration in breast milk. 10. For parents with a suspected or known inherited arrhythmia syndrome, genetic screening and counseling should be provided, ideally by genetic counselors or providers who are trained or specialize in genetics, to assess potential fetal risks and for therapeutic optimization.

Section 1 Introduction 1.1. Preamble The Heart Rhythm Society (HRS) has developed expert consensus documents that have guided clinical care in the management of cardiac arrhythmias since 1996. This HRSled expert consensus statement was developed in collaboration with the American College of Cardiology (ACC), the American College of Obstetricians and Gynecologists (ACOG), the American Heart Association (AHA), the Asia Pacific Heart Rhythm Society (APHRS), the European Heart Rhythm Association (EHRA), the Latin American Heart Rhythm Society (LAHRS), the Pediatric and Congenital Electrophysiology Society (PACES), and the Society for Maternal-Fetal Medicine (SMFM). This clinical practice document is intended to provide comprehensive guidance to cardiac electrophysiologists, cardiologists, and other health care professionals on the management of cardiac arrhythmias in pregnant patients, including arrhythmias that occur in the mother and in the fetus.

1.2 Document scope and objectives

Recommendations for the management of patients with arrhythmias during pregnancy have been addressed historically within the bodies ofbroader-scope clinicalpractice documents, which are focused primarily on nonpregnant patient populations; therefore, the issues related to pregnancies are limited in scope and specific to the guidelines discussed. Providers are thus in the position of looking at several documents that may not all agree or even address unique management considerations for arrhythmias in pregnant patients. This expert consensus statement on the management of arrhythmias in the pregnantpatient and fetusprovidesa broad and comprehensive resource for guidance in a format that can be referenced at the point of care. The primary goals of this document are as follows: 1. Introduce general concepts related to arrhythmias in both the patient and the fetus during pregnancy. 2. Discuss optimal approaches to diagnosis and evaluation of arrhythmias during pregnancy. 3. Review approaches to treatment of arrhythmias in the pregnantpatient,includinginvasiveandnoninvasivetreatments. 4. Identify disease- and patient-specific considerations when risk stratifying, diagnosing, and treating arrhythmias in pregnant patients. 5. Provide recommendations for management of fetal arrhythmias.

This expert consensus statement provides recommendations for care based on current evidence for best practices in the management of arrhythmias during pregnancy for patients of all ages. When evidence was lacking or contradictory, a consensus expert opinion was developed. Health benefits, side effects, and risks to both the pregnant patient and fetus were considered comprehensively in formulating the recommendations. This document is intended to set standards that can be applied worldwide, while recognizing that resources, availability of technology, disease prevalence, and health care delivery logistics vary in different parts of the world. This document is intended to improve the quality of patient care by providing practical guidance for the optimal management of pregnant patients and fetuses that reflects the current standard of care, with the understanding that some procedures are better performed, and some disease states are better managed, in settings where there is specific expertise. The recommendations are not a replacement for clinical judgment and are not intended to dictate management in every single scenario.

1.3 Editorial independence

This expert consensus statement was sponsored by the HRS and developed without commercial support; writing committee members volunteered their time to the writing and review efforts.

1.4 Organization of the writing committee

The writing committee consisted of experts from 6 countries in the fields of electrophysiology, cardiology, pediatric electrophysiology and cardiology, gynecology, maternal-fetal medicine, and obstetrics. Each writing committee member served as a representative of either the HRS or a collaborating society and was nominated according to each organization’s processes. The HRS strives to ensure that the writing committee contains both requisite expertise and diverse representation from the broader medical community. This is achieved by selecting experts from a wide range of backgrounds representing different geographic regions, genders, races, ethnicities, intellectual perspectives, and scopes of clinical practice, and by inviting organizations and professional societies with related interests and expertise to participate as partners or collaborators. HRS has rigorous policies and methods to ensure that documents are developed without bias or improper influence. The complete policy on relationships with industry and other entities (RWI) can be found in the HRS Code of Ethics and Professionalism: Appendix C and in the HRS Clinical Document Development Methodology Manual and

Policies. A majority of the writing committee was free of relevant RWI throughout the development of the document and sections with recommendations were written by the writing committee members who were free of relevant RWI. For full transparency, Appendix 1 is a comprehensive list of RWI (both relevant and not relevant to the document topic) disclosed by the writing committee members. Appendix 2 is a comprehensive list of RWI disclosed by the peer reviewers.

1.5 Evidence review and formulation of

recommendations This expert consensus statement was developed in accordance with the clinical practice document methodology processes detailed in the HRS Clinical Document Development Methodology Manual and Policies: Executive Summary,1 and with the standards issued in 2011 by the Institute of Medicine (now National Academy of Medicine).2 Consensus statements are evidence based, and recommendations are derived from the synthesis of published data or from a consensus of expert opinion when data are not available. The writing committee reviewed evidence gathered by electronic literature searches (MED- LINE, PubMed, Embase, Cochrane Library). No specific year was chosen for the oldest literature. Some literature databases allow the use of certain symbols to search for different forms or spellings of a word. The asterisk (*) was used for truncation to search for all forms of a word, the plus symbol (1) was used to search for plural and singular forms of a word, and the pound symbol (#) was used as a wildcard to search for variant spellings or hyphenation of a word. Search terms for this document included, but were not limited to the following: Adamsstokes syndrome, adenosine, amiodarone, Andersen syndrome, anesthesia, anti#arrhythmic drugs, atenolol, atrial fibrillation, Afib, atrial flutter, arrhythmi*, atrial premature complexes, atrioventric* block, AVB, beta#blocker1, bradycardia, Brugada, bundle#branch block, calcium channel blocker1, cardiac arrhythmia, cardiac sinus arrest, cardioversion1, catecholaminergic polymorphic ventricular tachycardia, CPVT, catheter ablation, defibrillat*, defibrillator placement, delivery, digoxin, diltiazem, dofetilide, dronedarone, electric countershock, electrocardiograph*, electroversion, evidence, fetal arrhythmia1, fetal magnetocardiograph*, flecainide, fluoroscopy, heart block, inherited arrhythmia syndrome1, IAS, ibutilide, inherited arrhythmi*, interatrial block, Jervell and Lange- Nielsen, JLNS, labetalol, labor, lidocaine, long QT, low fluoroscopy, Lown#Ganong#Levine, LGL, maternal anesthesia, metoprolol, mexiletine, no fluoroscopy obstetrical anesthesia, quinidine, parasystole, peripartum cardiomyopathy, post#partum, preconception counselling, pre#excitation, pregnan*, premature cardiac complexes, procainamide, propafenone, radiation, risk stratification, Romano#Ward, short QT, sick sinus syndrome, sinus node dysfunction, sin#atrial block, SA block, sinus arrhythmia, sotalol, stillbirth, tachycardia, Torsades de Pointes, ventricular arrhythmia1, ventricular fibrillation, ventricular flutter, ventricular premature complexes, ventricular tachycardia, verapamil, wearable defibrillator, Wolff#Parkinson#White. Literature searches focused whenever possible on randomized controlled trials, but systematic reviews, nonrandomized and registry studies, and cohort studies were included. Due to the limited randomized and/or blinded studies in the field of arrhythmia management in pregnant patients and fetuses, case series or registries and case reports that followed patients and documented outcomes were included in the evaluation of evidence to support recommendations in this document. Evidence tables are provided in Appendix 3 and summarize the evidence used by the writing committee to formulate recommendations. References are representative of the totality of data and are not meant to be all inclusive. Limitations of the evidence base are discussed in individual sections.

All recommendations were discussed by the writing committee, with consideration of the risks versus benefits of an intervention and the strength of the evidence. To assess consensus after discussions, the writing committee members participated in voting. A predefined threshold of 67% approval for each recommendation was required, with a quorum of two-thirds of the writing committee. An initial failure to reach consensus was resolved by subsequent discussions, revisions as needed, and revoting. The final mean consensus over all recommendations was 98.4%, with 123 of 163 recommendations receiving 100% consensus.

1.6 Class of recommendation and level of

evidence Recommendations in this expert consensus statement are designated with both a class of recommendation (COR) and a level of evidence (LOE) (Table 1).3 The COR denotes the strength of the recommendation based on the assessment of the magnitude and certainty of the benefits in proportion to the risks. The LOE reflects the quality of the evidence that supports the recommendation based on type, quantity, and consistency of data from clinical trials and other sources. For clarity and usefulness, each recommendation is linked to the supportive evidence through the specific references from the literature used to justify the LOE rating, which are also summarized in the evidence tables (Appendix 3). Each recommendation is accompanied by supportive text. Algorithms provide a summary of the recommendations, intended to assist clinicians at the point of care.

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1.7 Document review and approval

The HRS invites public and stakeholder involvement in document development, and draft recommendations were posted for public comment. This expert consensus statement was approved by the writing committee and underwent internal review and approval by the HRS Scientific and Clinical Documents Committee. The document underwent external peer review by reviewers appointed by HRS and each of the collaborating societies, and revisions were made by the writing committee chair and vice-chairs. A record of the writing committee’s response to reviewer comments and rationale is maintained by HRS. The final document was sent to the collaborating societies for endorsement consideration.

1.8 Updating

The HRS Scientific and Clinical Documents Committee reviews each clinical practice document for currency at least every 5 years, or earlier in the event of newly published data. Literature is routinely monitored to evaluate the continued validity of recommendations.

Table 1 ACC/AHA recommendation system: Applying class of recommendation and level of evidence to clinical strategies, interventions, treatments, and diagnostic testing in patient care (updated May 2019)*

Adapted with permission from the American College of Cardiology (ACC) and the American Heart Association (AHA).

1.9 Relevant clinical practice documents

Clinical practice documents relevant to the topic of arrhythmias during pregnancy were used to inform the development of this expert consensus statement. Table 2 lists applicable clinical practice documents (eg, guidelines and consensus statements) that the writing committee referenced during the development of this document.

Table 2 Relevant clinical practice documents

Title Publication year 2021 European Heart Rhythm Association Practical Guide on the Use of Non-Vitamin K Antagonist Oral Anticoagulants in Patients With Atrial Fibrillation4 2021 2020 ESC Guidelines for the Diagnosis and Management of Atrial Fibrillation5 2021 2020 AHA/ACC Guideline for the Diagnosis and Treatment of Patients With Hypertrophic Cardiomyopathy6 2020 Cardiovascular Considerations in Caring for Pregnant Patients: A Scientific Statement from the American Heart

Association7 2020 2019 ESC Guidelines for the Management of Patients With Supraventricular Tachycardia8 2020 2019 AHA/ACC/HRS Focused Update of the 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation9 2019 2019 HRS Expert Consensus Statement on Evaluation, Risk Stratification, and Management of Arrhythmogenic Cardiomyopathy10 2019 2018 ACC/AHA/HRS Guideline on the Evaluation and Management of Patients With Bradycardia and Cardiac Conduction Delay11 2019 2018 ESC Guidelines for the Management of Cardiovascular Diseases During Pregnancy12 2018 2018 ESC Guidelines for the Diagnosis and Management of Syncope13 2018 Antiarrhythmic Drugs—Clinical Use and Clinical Decision Making: A Consensus Document from the European Heart

Rhythm Association (EHRA) and European Society of Cardiology (ESC) Working Group on Cardiovascular Pharmacology14 2018 2017 AHA/ACC/HRS Guideline for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death15 2018 Management of Pregnancy in Patients With Complex Congenital Heart Disease: A Scientific Statement for Healthcare

Professionals from the American Heart Association16 2017 European Heart Rhythm Association (EHRA) Consensus Document on the Management of Supraventricular

Arrhythmias17 2017 2017 ACC/AHA/HRS Guideline for the Evaluation and Management of Patients With Syncope18 2017 2015 ACC/AHA/HRS Guideline for the Management of Adult Patients With Supraventricular Tachycardia19 2016 2015 ACC/AHA/HRS Advanced Training Statement on Clinical Cardiac Electrophysiology (A Revision of the ACC/AHA 2006 Update of the Clinical Competence Statement on Invasive Electrophysiology Studies, Catheter Ablation, and Cardioversion)20

2016

Cardiac Arrest in Pregnancy: A Scientific Statement from the American Heart Association21 2015 Part 5: Adult Basic Life Support and Cardiopulmonary Resuscitation Quality: 2015 American Heart Association

Guidelines Update for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care22 2015 Part 7: Adult Advanced Cardiovascular Life Support: 2015 American Heart Association Guidelines Update for

Cardiopulmonary Resuscitation and Emergency Cardiovascular Care23 2015 2015 ESC Guidelines for the Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death24 2015 Diagnosis and Treatment of Fetal Cardiac Disease: A Scientific Statement from the American Heart Association25 2014 Management of Patients With Atrial Fibrillation (Compilation of 2006 ACCF/AHA/ESC and 2011 ACCF/AHA/HRS

Recommendations)26 2013 HRS/EHRA/APHRS Expert Consensus Statement on the Diagnosis and Management of Patients With Inherited Primary

Arrhythmia Syndromes27 2013 HRS/EHRA Expert Consensus Statement on the State of Genetic Testing for the Channelopathies and

Cardiomyopathies28 2011 ACCF/ASE/AHA/ASNC/HFSA/HRS/SCAI/SCCM/SCCT/SCMR 2011 Appropriate Use Criteria for Echocardiography29 2011

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1.10 Definitions

The terms used in this expert consensus statement that are specific to pregnancy are defined in Table 3.

Section 2 General concepts for the management of arrhythmias during pregnancy 2.1. Epidemiology of arrhythmias Apart from sinus tachycardia, the most common rhythm abnormalities in pregnancy are premature ventricular or atrial ectopic beats, seen in 50-60% of pregnant patients presenting with palpitations and generally resolving spontaneously after delivery.33 Arrhythmias during pregnancy are more prevalent in the setting of structural heart disease (SHD); however, it is not uncommon for patients without an underlying cardiac defect to experience de novo rhythm disorders during pregnancy.33-35 The increased propensity for patients to present with arrhythmias when pregnant is multifactorial and thought to be related to a combination of the hemodynamic, hormonal, and autonomic milieu changes that occur during pregnancy.36 Hospital admissions for arrhythmias are much less frequent than other general causes for admission during pregnancy.37,38 The overall prevalence of arrhythmias among pregnancy-related hospitalizations is estimated at 68-166 per 100,000 pregnancy-related admissions, depending on how these are defined.38 In a study of 136,422 pregnancy-related hospitalizations between 1992 and 2000, 0.1% of the admissions were associated with arrhythmia. The most frequent arrhythmia diagnosis was sinus arrhythmia (60% of the diagnoses, 104 per 100,000 pregnancy-related hospitalizations) followed by atrial or ventricular extrasystole (19%) and paroxysmal supraventricular tachycardia (PSVT) (14%). Atrial fibrillation (AF) and atrial flutter (AFL) (1%), ventricular fibrillation (VF) (1%), and high-degree atrioventricular (AV) block (1%) were rarely diagnosed.38 In the nationwide 2000- 2012 US study by Vaidya et al37 of more than 57 million admissions of pregnant patients, the frequency of sustained arrhythmias was estimated at 68 per 100,000 pregnancyrelated hospitalizations. Of these, AF occurred in 27 per 100,000, supraventricular tachycardia (SVT) in 22 per 100,000, ventricular tachycardia (VT) in 16 per 100,000, and VF in 2 per 100,000 pregnancy-related hospitalizations. The frequency of arrhythmias (especially AF and VT) increased over the study period and was associated with a greater frequency of in-hospital death (5.9%) and maternal or fetal complications (36.5%) compared with pregnancy-related admissions without arrhythmias (0% and 21.8%, respectively; Figure 1).37 This recent increase in AF and VT frequency in pregnancy might be explained by the increase in maternal age accompanied by increase in risk factors such as obesity, hypertension, and diabetes mellitus, which are also on the rise. Increased survival and more frequent pregnancy of patients with congenital heart disease (CHD) is another contributing factor. Fortunately, the rate of mortality from arrhythmias decreased from 5.7% to 3.7% during the same time period. Arrhythmias during pregnancy are more frequently seen in Black women compared with White women (116 vs 73 per 100,000; P , 0.001).37

Pregnancy may aggravate preexisting arrhythmias, especially in older women (199 per 100,000 at 41-50 years of age vs 55 per 100,000 at 18-30 years of age), and in women with CHD.37-39 In the 1321 women enrolled in ROPAC (Registry Of Pregnancy And Cardiac disease), 17 (1.3%) had AF or AFL with a higher incidence (2.5%) noted in women with mitral valve disease.39 This is not surprising given that AF/AFL is traditionally associated with mitral valve disease.40 Life-threatening arrhythmias (VT, VF), and bradycardia/conduction system disorders are rare in pregnancy.37

Table 3 Terms used in this consensus statement that are specific to pregnancy

Term Definition Cardio-obstetrics

team A group ideally composed of maternal-fetal medicine subspecialists, cardiologists and/or electrophysiologists (pediatric

electrophysiologist when fetal arrhythmias are present), with experience managing pregnant patients. Neonatologists and anesthesiologistsmayalsobeinvolvedclosetothetimeofdelivery.Whiletheteammayvarydependingontheresourcesata given facility, at a minimum it should include a high-risk obstetrician and a cardiologist with expertise in arrhythmias in pregnancy.30

Close to term The term close to term, as used in this document, is purposely vague and not intended to represent a gestational age. The

determination of a close-to-term fetus implies viability and considers a number of factors, such as severity and potential consequences of the arrhythmias, biological factors, and the site-specific availability of the medical expertise and technology to support a preterm infant. Close to term could fall within the gestational categories defined by the American College of Obstetriciansand Gynecologists (ACOG): “late preterm” as 34 0/7 to 36 6/7 weeks of gestation, “early term” as 37 0/7 to386/7weeks ofgestation,“fullterm” as39 0/7 to 406/7 weeks of gestation,“late term” as41 0/7 to416/7weeks of gestation, and “post term” as 42 0/7 weeks of gestation and beyond.31,32

Supine

hypotensive syndrome Supine hypotensive syndrome is a condition in which, while lying flat, a pregnant patient may become light-headed or

syncopal due to compression of the inferior vena cava by the gravid uterus leading to reduction in venous return and resultant hypotension.

2.1.1. Etiology of palpitations Palpitations, or unpleasant awareness of the beating heart, are among the most common cardiac symptoms during pregnancy and a frequent reason for referral to maternal-fetal medicine subspecialists or pregnancy-devoted cardiology clinics.33,34,41 The exact incidence of palpitations during pregnancy is unknown, as patients frequently do not seek medical attention, but the spectrum of arrhythmias underlying the clinical symptom of palpitations ranges from benign conditions (eg, sinus tachycardia, atrial or ventricular extrasystole) to more seriousarrhythmias(eg,PSVT,AF,life-threateningventricular arrhythmias). In a small study of 110 consecutive pregnancies with symptoms of palpitations, dizziness, or syncope (study group) and 52 pregnancies with asymptomatic functional precordial murmur (control group) undergoing Holter monitoring in an outpatient setting, 23% of patients in the control group reported palpitations during the 24-hour monitoring period.33 In both the study and control groups there was a high incidence of premature beats but only 10% of the symptomatic episodes of palpitations during pregnancy were associated with an arrhythmia documented by 24-hour Holter monitoring in these women.33 Increase in resting sinus rate during pregnancy is common, and one can expect a 10% or greater rise in resting heart rate due to autonomic, hemodynamic, and whole-body volume fluctuations. In the case of sinus tachycardia, inappropriate sinus tachycardia (IST) (defined as a resting heart rate .100, a mean ambulatory heart rate .90, and associated symptoms) has been reported to be associated with a higher frequency of induction at term, but with no impact on maternal or fetal outcomes.42 Further, pregnancy is a common inciting event for IST, with about 8% of patients with IST identifying pregnancy as the inciting event. However, aside from symptoms, IST has not been associated with negative long-term outcomes.43

An arrhythmia that is documented during pregnancy can be the first onset of arrhythmia or the recurrence of a preexisting arrhythmia. In a study of 207 consecutive patients with PSVT referred for catheter ablation, only 3.9% of patients had first onset of PSVT in pregnancy. However, 22% of patients with PSVT prior to pregnancy had exacerbations of arrhythmia symptoms during pregnancy.44 In a study of 73 patients with 87 pregnancies diagnosed with heart disease prior to pregnancy (69% with complex congenital or acquired heart disease), 44% developed recurrences of tachyarrhythmias during pregnancy. Recurrence rates during pregnancy in patients with a history of SVT, paroxysmal AF/AFL, and VT were 50%, 52%, and 27%, respectively. Adverse fetal events,

Figure 1 Frequency of arrhythmia in pregnancy and associated mortality and complications. A, Frequency of any arrhythmia per 100,000 pregnancy-related hospitalizations for the entire study period, stratified by age. B, Frequency of arrhythmias per 100,000 pregnancy-related hospitalizations by arrhythmia type for the entire study period. C, All-cause mortality in percentage for the entire study period. D, Perinatal complications (including preterm labor, ante- or postpartum hemorrhage, preeclampsia, eclampsia, gestational hypertension, transfusion, postpartum infection, and fluid and electrolyte imbalance) in percentages for the entire study period. Reprinted with permission from Vaidya et al.37 AF 5 atrial fibrillation, PSVT 5 paroxysmal supraventricular tachycardia, PVT 5 paroxysmal ventricular tachycardia, SVT 5 supraventricular tachycardia, VT 5 ventricular tachycardia.

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such as prematurity, occurred more frequently in pregnant patients with antepartum arrhythmias.45 In several other studies, the presence of documented arrhythmia in pregnant patients with congenital or acquired heart disease was also an important risk factor for adverse maternal and fetal outcomes.16,46

2.1.2. Epidemiology and classification of syncope Syncope is defined as a sudden, transient loss of consciousness due to global cerebral hypoperfusion. In a recent Canadian retrospective population-based cohort study of close to 500,000 live births between 2005 and 2014, the overall incidence of syncope during pregnancy was 1% (9.7/1000 pregnancies).47 Patients with syncope were younger (age ,25 years: 35% vs 21%; P , 0.001) and more likely primiparous (52% vs 42%; P , 0.001). Syncope,aclinicalsymptomwithawidespectrumofunderlyingmechanismsand etiologies,isclassifiedsimilarly inpregnant patients as in the general population, but supine hypotensive syndrome is unique to pregnancy (Table 4). Early studies reported that in late pregnancy 8% to 11% of women developgreaterthan30%,or30mmHg,systolicbloodpressure drop with or without symptoms when lying in supine position.48,49 Symptoms may include dizziness, nausea, and—in rarecases—syncope.Morerecentmagneticresonanceimaging (MRI) studies confirmed earlier angiographic findings and showed that the gravid uterus begins to compress the inferior vena cava in the supine position, beginning at the 20th week of pregnancy, with very severe obstruction at term.50-52 Left tilt of 30 degrees or left lateral position of the pregnant patient increases the inferior vena cava volume and cardiac output significantly compared with supine position.51,52

The most frequent type of syncope occurring during pregnancy is reflex-mediated vasovagal syncope. Situational syncope occurs very rarely in pregnancy; in only 1 case report were 2 pregnant patients with micturition syncope reported.53 Carotid sinus syndrome has not been described in pregnancy. Itlikelyoccursveryrarelyinpatientswithaprepregnancydiagnosisofthiscondition.Theprevalenceofsyncopeinpregnancy duetoorthostatichypotensionisunknownbut mayoccurinpatients with volume depletion due to severe bleeding or vomiting, or in patients taking medications for an underlying SHD. Blood pressure measurement in supine, sitting, and standing positions, with a detailed history taking, should point to the diagnosisinthesepatients.Theexactprevalenceofcardiacsyncope in pregnancy is unknown (likely ,1-2% of all syncope episodes), but it is very important in the differential diagnosis of syncope, as it is associated with higher risk of adverse fetal and maternal outcomes, such as premature birth and congenital abnormalities.37,47 Sudden fast palpitations starting prior to syncope, preexisting diagnosis of tachyarrhythmias, underlying congenital or SHD or channelopathy, and family history ofsuddendeathorarrhythmiasshouldraisesuspicionofunderlying cardiac etiology. Detailed physical examination and 12lead electrocardiogram (ECG) should further help in the differential diagnosis, similar to diagnosis of nonpregnant patients.13,18

Table 4 Main features and clinical characteristics for the classification of syncope Classification of syncope Main features Clinical characteristics I. Neurally mediated reflex

syncope Mechanism is reflex-mediated bradycardia (cardioinhibitory type), vasodilatation (vasodepressor), or both (mixed type) Typical prodrome: diaphoresis, nausea, vomiting, feeling warmth, pallor

1 Vasovagal

B Orthostatic B Emotional B Occurs in upright or sitting posture with

specific triggers B Occurs in situational settings associated

with high stress or intense emotions, such as fear or sadness  Most common, history of preexisting

episodes B Triggered by longtime standing B Triggered by fear, pain, sight of blood

2. Situational  Occurs with specific triggers  Micturition, coughing, defecation  Very rare in pregnancy, history of preexisting

symptoms

3 Carotid sinus syndrome  Occurs with specific triggers and can be

reproduced with carotid sinus massage  Head turning or pressure on neck at carotid

sinus  Very rare in pregnancy, history of preexisting

symptoms

II. Syncope due to orthostatic hypotension A drop in systolic BP .20 mmHg or diastolic BP .10 mmHg with assuming upright position Exacerbated by thermal stress, or venous pooling during exercise or after meals

1 Volume depletion  May occur in pregnancy with hemorrhage or

vomiting

2. Drug-induced  Vasodilators or diuretics  Rare in pregnancy

(Continued)

2.2 Physiological, hormonal, and autonomic

changes related to arrhythmogenesis Despite the fact that new-onset malignant cardiac arrhythmias during pregnancy are extremely rare in the absence of SHD, more benign rhythm disturbances—such as sinus tachycardia and premature atrial contractions (PACs), and premature ventricular contractions (PVCs)—are quite common, particularly in the latter half of pregnancy.33 Pregnancy-induced cardiovascular changes (including increased resting heart rate, increased blood volume resulting in cardiac chamber dilation with greater end diastolic volumes, and higher levels of placental-originated potentially arrhythmogenic hormones) may predispose pregnant patients to cardiac arrhythmias. Effective blood volume increases by 50% during gestation, and up to 100% in twin pregnancies, which may result in myocardial atrial and ventricular stretching that leads to activation of stretch-sensitive ion channels, with subsequent membrane depolarization, shortened refractoriness, slowed conduction, and spatial dispersion of refractoriness, resulting in potential arrhythmogenesis.54,55 Similarly, pregnancy-induced heart chamber enlargement increases the length of reentrant pathways, facilitating development of reentrant arrhythmias.55 Pregnancy-induced increases in estradiol, progesterone, and free cortisol may also predispose pregnant patients to cardiac arrhythmias. Both animal and human studies have described the arrhythmogenic potential of estrogen and pro- gesterone by increasing the number and responsiveness of adrenergic receptors within the myocardium.56,57

Lastly, at the autonomic level, as pregnancy progresses there is a shift from a vagal to a higher sympathetic milieu, resulting in an increase in basal heart rate of 10 to 20 beats per minute (bpm).58 An increase in resting heart rate has been associated with a higher risk of new-onset arrhythmias among nonpregnant individuals.55 This increased sympathetic tone may predispose pregnant patients to new-onset arrhythmias or worsening burden of previous rhythm disturbances in those with a preexisting arrhythmic substrate.

2.3 General considerations for antiarrhythmic

drugs in pregnancy The overall approach to the treatment of arrhythmias in a pregnant patient is largely similar to the approach in a nonpregnant patient, but with modifications based on fetal safety. Importantly, the care of a pregnant patient with hemodynamically significant arrhythmias should not be compromised for fear of providing needed treatment in pregnancy, or potentially exposing the fetus to risk, since restoration of normal hemodynamics is the priority. Unfortunately, knowledge about specific medications/strategies in pregnancy or during breastfeeding is limited by a lack of robust scientific data. When pharmacological therapy is deemed necessary, a risk-versus-benefit discussion of maternal health and pregnancy outcomes should occur that considers treatment guide-

Table 4 Main features and clinical characteristics for the classification of syncope (Continued) Classification of syncope Main features Clinical characteristics 3. Neurogenic  Associated with systemic and/or

neurological disease  Preexisting autonomic nervous system

failure  Very rare in pregnancy

III. Cardiac syncope

1 Arrhythmic

B Tachyarrhythmia

B Bradyarrhythmia  ECG documentation during symptoms is

diagnostic  History of preexisting congenital or acquired

heart disease or primary channelopathy

B History of preexisting congenital AV block  History of preexisting symptoms/arrhythmia

is frequent  No or little prodrome  Short duration (,10 seconds), quick recovery  Very rare in pregnancy

B Fast, paroxysmal palpitations prior to

syncope

2 Structural cardiovascular disease associated  Obstruction to blood flow in the heart or

great vessels  Preexisting HCM, aortic stenosis, tamponade, cardiac masses  Pulmonary embolism  Associated symptoms and signs of

underlying heart disease  Disease-specific dyspnea, heart failure, angina, cyanosis  Disease-specific ECG abnormalities

IV. Supine orthostatic hypotension and syncope Inferior cava compression by the gravid uterus in late pregnancy in supine position Left lateral decubitus position obviates the symptoms V. Psychogenic pseudosyncope Apparent but not true loss of consciousness Symptoms are reproduced at tilt table test with normal blood pressure, heart rate, and EEG activity

AV 5 atrioventricular, BP 5 blood pressure, ECG 5 electrocardiogram, EEG 5 electroencephalogram, HCM 5 hypertrophic cardiomyopathy.

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lines for the arrhythmic condition, the mechanisms of action of the drug (or class of drug), the record of safe use of the drug during pregnancy, and the potential overall risk of the treatment. The use of antiarrhythmic drugs in pregnancy requires attention to potential changes in pharmacokinetics due to the changes in maternal physiology, such as metabolism and an increase in intravascular volume.59,60 For example, intravascular volume changes peak in the third trimester of pregnancy and pregnant patients often require a medication increase to achieve the same intended clinical effect. Therefore, it is important to monitor drug levels or, alternatively, to monitor the physiological effect of drugs (eg, ECG monitoring for QT prolongation).59 Maternal therapy with beta-blockers during pregnancy has been associated with intrauterine fetal growth restriction. Most of the studies on maternal beta-blocker therapy are based on pregnant patients with hypertensive disorders of pregnancy, where fetal growth could be affected by the underlying condition, in this case hypertension, and not necessarily the drug itself.61 However, a study of betablockers prescribed for maternal cardiac conditions, with a separate analysis of pregnant patients with isolated tachyarrhythmias as the indication, demonstrated a significant effect of beta-blockers on fetal growth after adjusting for other potential confounders.62 Although concern regarding fetal growth restriction has been highlighted for atenolol and labetalol particularly, it is important to recognize that the maternal indication for medications differed among the different beta-blockers, and the overrepresentation of maternal hypertensive disorders in these subgroups may have affected the results significantly.63 In a review of cardiovascular medications in pregnancy, atenolol had a former United States Food and Drug Administration (FDA) risk category D rating for its use during pregnancy.64 In a more recent study, Grewal et al65 reported the birth weight reduction associated with beta-blockers to be less than 200 grams, and therefore not of great clinical consequence in most instances. Thus, in the setting of potentially life-threatening scenarios (eg, some inherited arrhythmia syndromes [IAS]) a maternal indication for prescription of a betablocker takes priority over potential fetal growthrestriction concerns, and beta-blocker therapy should be continued during pregnancy and the postpartum period (Figure 2). Dosages and risks for common antiarrhythmic drugs are outlined in Table 5. Additional resources for drug safety during pregnancy include MotherToBaby (https://mothertobaby.org), Reprotox (https://reprotox.org/ member), and Teris (https://deohs.washington.edu/teris/). During lactation, special consideration should be given to medications that may adversely affect the newborn. While some medications are safe in pregnancy, their metabolism and concentration in breast milk can be of concern during lactation. One example of this is the beta-blocker nadolol, which has a high concentration in breast milk.66 The excretion of beta-blockers into breast milk is largely determined by the degree of protein binding; medications with low binding are more heavily excreted into breast milk.67 For example, based on protein binding and renal excretion, nadolol presents a high risk for accumulation in infants. If clinically acceptable for the maternal cardiac indication, propranolol or metoprolol might be preferred over nadolol in breastfeeding. Yet the discussion of medications during breastfeeding should include consideration of the underlying conditions of the pregnant patient, the optimal treatment for their arrhythmia, and whether there is a reasonable alternative that has similar efficacy but is safer for breastfeeding (Figure 2). If there are no medication alternatives that are efficacious for the patient and safe with lactation, lactation may need to be avoided or monitored closely for potential side effects (eg, excess bradycardia in the case of nadolol). This decision should be based on a shared decision-making discussion with the patient and family that considers the negative impact of deferring the recommended pharmacological therapy on maternal health in the postpartum period balanced against the importance of breastfeeding to the postpartum patient and baby. Risks of antiarrhythmic drugs during lactation are outlined in Table 5. More information on drug safety during lactation can be found in the Drugs and Lactation Database (LactMed) (https://www.ncbi.nlm.nih. gov/books/NBK501922).

Prior to 2015, the FDA used a 5-tier set of alphabet categories (A, B, C, D, and X), introduced in 1979, to designate the safety of a drug for use during pregnancy (Figure 3).64 The system was simple to understand for category A drugs, which were generally safe to use, and category X drugs, which were contraindicated. However, because the category system did not accurately or consistently communicate differences in degrees of fetal risk, its implementation led to misinterpretation and avoidance of drug categories B, C, and D, which generally had limited or ambiguous data Thus, on June 30, 2015, the FDA introduced the new Pregnancy and Lactation Labeling Rule to replace the prior risk categories and to help physicians better communicate the potential drug risks to patients during pregnancy and lactation (Figure 3).70,71 Under the Pregnancy and Lactation Labeling Rule, package

Figure 2 Antiarrhythmic drug safety for commonly used drugs in pregnancy.68,69

inserts are now to contain individualized narrative summaries for each medication that include the “risks of using a drug during pregnancy and lactation, a discussion of the data supporting that summary, and relevant information to help health care providers make prescribing decisions and counsel women about the use of drugs during pregnancy and lactation”71 (p. 72064) Despite this change, a recent study reported that human data on pregnancy and lactation are available in less than 20% of new product labeling.72

Figure 3 Comparison of prior (1979) FDA pregnancy risk categories to the (2015) Pregnancy and Lactation Labeling Rule, which eliminated the pregnancy risk categories and provides individualized summaries of risk for each medication.70,71 *Only included when there are recommendations or requirements for pregnancy testing and/or contraception before, during, or after drug therapy, and/or there are human and/or animal data suggesting drug-associated effects on fertility and/or preimplantation-loss effects.

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Table 5 Antiarrhythmic drugs for use in pregnancy*25,64,73-96

Drug Therapeutic maternal dose range† Therapeutic maternal serum level Toxicity/adverse events

Maternal Fetal/neonatal

Digoxin80,82,97-100

(mat/fetal PO, IV, direct fetal IM, IC) LD: 1.5-2.0 mg/24 h PO/IV,

divided Q 8 h MD: 0.125-0.5 mg/day PO, divided BID DFT: (fetal IM dose 88 mg/

kg, then 60-88 mg/kg fetal IM Q 12 h ! 2) 0.7-2.0 ng/mL F/M ratio @ 50-100%;

in hydrops 20% N/V111,

anorexia11, sinus bradycardia1 or Mobitz I AV block1, proarrhythmia 1, avoid in WPW Fetal IM: sciatic nerve injury

(w1:40 risk); fetal IC: cardiac arrest, consider IC or ICard epinephrine if this occurs Infant: Usually well

tolerated, often used in combination, vomiting11, sinus bradycardia11, AV block, proarrhythmia

Class IA: Na1 channel blockers Procainamide83,96

(mat IV, 1/– PO) LD: 15 mg/kg IV over 30 min

MD: 1-4 mg/min infusion 4-8 mg/mL N/V1, TdP, [QTc, IV,

uterine irritability, preterm labor Neonatal TdP1, [QTc

Quinidine gluconate101-103

(mat/fetal IV, PO) LD: 200-400 mg PO Q 2-3 h

until therapeutic effect (max 3 g/day) MD: XR 324-648 mg Q 8-12 h Parenteral: 10 mg/kg over 1-

2 h, then 0.02 mg/kg/min ! 72 h 2-6 mg/L F/M ratio 30-100% N/V111, CNS1,

[QTc1, proarrhythmia, TdP Neonatal TdP, concentrates

in breast milk

Class IB: Na1 channel blockers Lidocaine104-106

(mat/fetal IV) LD: 1-1.5 mg/kg LD IV, 300

mg max MD: infusion of 1-4 mg/min 1.5-5 mg/mL F/M ratio 1:1 N/V11, CNS1,

proarrhythmia (consider all sources of lidocaine, including regional anesthesia) can halt labor CNS11, bradycardia during

labor (consider all sources of lidocaine, including regional anesthesia)

Mexiletine107

(mat/fetal PO) LD: 6-8 mg mg/kg/day

Q 8-12 h (up to 400 mg Q 8 h or 450 mg Q 12 h) MD: 200-300 mg TID 0.5-2 mg/mL F/M ratio 1:1 NV11, CNS11,

proarrhythmia CNS11, concentrates in

breast milk

Class IC: Na1 channel blockers Flecainide90,98,108-111

(mat/fetal PO) MD: 200-400 mg/day

divided Q 8-12 h PO Avoid in SHD 0.2-1.0 mg/mL F/M ratio 50-86% Visual/CNS11, mild

P/QRS widening 1 and 1 AV block1, [QTc, AFL Fetal/neonatal QRS widening

with longer exposure (drug concentrates in amniotic fluid); [QTc1, proarrhythmia1; well tolerated in infants, commonly combined with other drugs Propafenone112-115 (mat/fetal PO) MD: 150 mg Q 8 h, increase slowly (max 900 mg/day), extended release 225-425 Q 12 h PO Avoid in SHD 500-600 ng/mL (range 65-1000) F/M ratio NA CNS11, [QTc, GI1, QRS widening, AFL, bradycardia CNS1, little data

(Continued)

Table 5 Antiarrhythmic drugs for use in pregnancy*25,64,73-96 (Continued)

Drug Therapeutic maternal dose range† Therapeutic maternal serum level Toxicity/adverse events

Maternal Fetal/neonatal Class II: Beta-blockers Propranolol88,116-121

(mat/fetal PO, IV) MD: 60-320 mg/day divided

Q 6-12 h Parenteral (caution): 1-3 mg

IV at ,1 mg/min, can repeat once; reserve for life-threatening arrhythmia 25-140 ng/mL F/M ratio 0.4 Fatigue11,

bradycardia11, hypotension11, AV block, [uterine tone

Metoprolol116,122,123

(mat/fetal PO/IV) MD: 50-450 mg/day PO,

divided BID if SR or Q 6 h if standard Parenteral (caution): 5 mg Q

2 min ! 3 then change to PO; for HTN, labetalol preferred 5-10 ng/mL Similar to propranolol

Nadolol116,122

(mat PO) MD: 40-80 mg/day PO; up to

240 mg has been used Not used clinically Same as other

beta-blockers; noncompliant patients may maintain levels due to long T1/2

Class III: K1 channel blockers and multimechanism Sotalol75,78,80,81,87,98-100,

108,115,124,125 (mat/fetal PO, mat PO/IV) MD: 160-320 mg/day

divided BID or Q 8 h Parenteral for life-

threatening maternal arrhythmia: 75-150 mg IV Q day or BID (if QTc ,450 ms) 200-1000 ng/mL, fetal can be . maternal, F/M ratio 100-107% N/V/fatigue/CNS11,

sinus bradycardia1, [QTc (hold or reduce dose if QTc .500 ms), proarrhythmia CNS, 1/-proarrhythmia,

bradycardia1, (concentrates in amniotic fluid), rare [QTc; well tolerated in infants

Amiodarone106,108,126-130

(mat/fetal PO, mat IV, DFT) LD: 1800-2400 mg/day PO

divided Q 6 h ! 48 h; lower LD (1200 mg) if concurrent drug therapy; no fetal advantage to maternal IV dosing Maternal parenteral LD: 1000 mg over 24 h as 150 mg/10 min, then 360 mg/ 6 h, then 540 mg/18 h IV MD: 800 mg ! 1 wk, then 200–600 mg/day; Maternal parenteral MD: 0.5 mg/min IV up to 3 wk Cardiac arrest: 5 mg/kg (max 300 mg) rapid IV/ IO/ET, repeat 1-2! DFT (hydrops only): IC 2.5-

5 mg/kg nonhydropic fetal weight up to 40 mg, diluted with glucose and given over 5-10 min; intraperitoneal 50-75 mg in D5W, repeat as needed, can remove excess ascitic fluid prior to amiodarone administration 0.7-2.8 mg/mL F/M ratio 10-30%, but

efficacy over time is seen due to fattytissue accumulation NV11, [thyroid11,

sinus bradycardia111, Yappetite, 1 AV block, P/QRS widening, [QTc, proarrhythmia, photosensitivity rash, TdP, [other drug concentrations (digoxin, flecainide), liver and lung toxicity with chronic use Parenteral:

hypotension if doses .2100 mg/24 h [Thyroid11, fetal TdP if

given for LQTS, goiter, neurodevelopmental concerns Intracordal: fetal death11 Intraperitoneal: possible GI adhesions (1 report only) Amiodarone, despite its side effects, can allow fetal survival in severe cases, especially prior to preterm delivery of a severely hydropic fetus ,35 wk GA; often used in combination with other drugs, and may take several weeks to slow, and then terminate tachycardia Absence of progression of

hydrops is usually a sign of early improvement

(Continued)

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Table 5 Antiarrhythmic drugs for use in pregnancy*25,64,73-96 (Continued)

Drug Therapeutic maternal dose range† Therapeutic maternal serum level Toxicity/adverse events

Maternal Fetal/neonatal Class III: K1 channel blockers and multimechanism (Continued) Ibutilide82,131,132

(mat only, IV only) LD: for acute termination of

drug-refractory atrial tachyarrhythmia: ,60 kg 5 0.01 mg/kg IV over 10 min, may repeat after 10 min .60 kg 5 1 mg IV over 10 min, may repeat after 10 min NA QT prolongation, TdP,

hold other QT prolonging drugs before and after; telemetry for at least 4 h post-infusion Embryotoxic, teratogenic,

avoid in first trimester

Dronedarone Contraindicated in pregnancy Fetal harm from visceral and

skeletal malformations in animal studies

Class IV: Calcium channel blockers Verapamil133

(mat only IV, PO) LD: 5-10 mg IV, can repeat

after 30 min MD: 120-480 mg/day PO 125-400 mg/mL (Substitute with

adenosine or betablocker if possible) mat hypotension, uterine muscle relaxant Embryotoxic, fetal

bradycardia, fetal hypoxia Infant: hypotension, hypocontractility, fetal demise, jaundice, seizures, hetatologic abnormalities; Concentrates in breast milk

Diltiazem83

(mat only IV, PO) LD: 0.25 mg/kg IV over 2

min, repeat 0.35 mg/kg, then 5-15 mg/h IV infusion (start immediately after bolus) MD: XR 180-360 mg PO Q day 50-200 ng/mL CNS11, potent

vasodilator11, hypotension, bradycardia, uterine muscle relaxant Embryotoxic, fetal demise,

hypocontractility, M/F serum:breast milk 5 1:1

Other arrhythmia drugs Adenosine25

(mat IV) LD: 6-12 mg rapid IV, up to

24 mg has been used NA Flushing, transient

chest pain and bradycardia Safe for fetus when mother is

treated IV; not useful for treatment of fetal SVT Intracordal: nonsustaining

cardioversion, fetal demise

Atropine

(mat IV) LD: 0.02 mg/kg IV, repeat Q

3-5 min for cardiac arrest (max 3 mg), lower doses for acute 2:1 AV block Not used Rebound sinus

tachycardia; improvements in AV conduction may be transient F/M ratio 0.13

Magnesium sulfate134

(mat/fetal IV, then PO) LD: 2-6 g IV over 20 min

MD: 1-2 g/h; treatment for .48 h is generally avoided though may consider redosing if VT recurs; PO 200-600 mg/day ,6 mEq/L; monitor

elbow and patellar reflexes GI11, fatigue11,

CNS11 symptoms; STOP for loss of patellar reflex and/or levels .6 mEq/L; levels .5 mEq/L associated with maternalECGchanges and proarrhythmia Hypotonia1, lower assigned

Apgar scores

*The PDR (Prescriber’s Digital Reference) website (https://www.pdr.net/) is an additional resource; the information provided may vary from the PDR based on other evidence for antiarrhythmic drug use during pregnancy and lactation. †Dosages may vary from those listed in the Food and Drug Administration–approved labeling (available at https://dailymed.nlm.nih.gov/dailymed/) and are not meant to replace clinical judgment. Drug doses provided here can be used for either maternal or fetal treatment. Maternal use, fetal use, or both are noted in the first column along with the routes available. Treatment during pregnancy requires a strong knowledge of pregnancy pharmacokinetics and is best done by the cardio-obstetrics team (Section 3.2). The lowest effective drug dose should be used, but higher drug doses may be required during the latter part of pregnancy to maintain therapeutic serum concentrations. In general, all of these drugs are started during a hospital stay. When intravenous drugs are used, telemetry, electrocardiogram (ECG), and blood pressure monitoring are important. For chronic outpatient administration, consider long-acting preparations if available. Transplacental drug treatment does not necessarily require continuation of the drug until delivery and does not mandate the need for neonatal drug therapy. 111 5 very common, 11 5 common, 1 5 occasional, AFL 5 atrial flutter, AV 5 atrioventricular, CNS 5 central nervous system, DFT 5 direct fetal therapy, F 5 fetal, GA 5 gestational age, GI 5 gastrointestinal, HTN 5 hypertension, IC 5 intracordal, IM 5 intramuscular, IV 5 intravenous, LD 5 loading dose, LQTS 5 long QT syndrome, M or Mat 5 maternal, MD 5 maintenance dose, NA 5 not applicable, N/V 5 nausea and vomiting, PO 5 by mouth, proarrhythmia 5 worsening of an arrhythmia as the result of treatment, QTc 5 corrected QT interval, SHD 5 structural heart disease, SVT 5 supraventricular tachycardia, SR 5 sustained-release, TdP 5 torsades de pointes, WPW 5 Wolff-Parkinson-White syndrome, VT 5 ventricular tachycardia.

2.4 General considerations for management of

fetal arrhythmias General principles for pharmacological therapy of fetal arrhythmias depend on factors such as underlying etiology, presence of cardiac failure (fetal hydrops), and gestational age (which may prompt delivery of a close-to-term fetus in lieu of in utero treatment). Maternal thyroid disease is common in pregnancy, and the mother should be treated if this is identified as the likely precipitant of fetal arrhythmias. The most common cause of referral for a fetal arrhythmia usually involves the presence of PACs or ventricular contractions. These are usually benign and, in the absence of SHD, do not require additional antenatal surveillance or changes in delivery planning. For a fetus with a channelopathy, avoidance of exacerbating maternal electrolyte abnormalities and medications is crucial. Additionally, it is important to educate pregnant patients and their partners with genetic conditions such as long QT syndrome (LQTS), in which fetal bradycardia most likely represents an in utero manifestation of the underlying diagnosis rather than an adverse effect of maternal medication. In that setting, the bradycardia should not lead to cessation of maternal beta-blocker therapy.15 Sustained fetal tachycardias are usually treated by transplacental (maternal) administration of antiarrhythmic drugs, unless delivery is determined to be the most appropriate approach. As such, pharmacological considerations are usually based on maternal dosing. Direct fetal administration has been described in hydropic fetuses where absorption is likely to be inadequate.25 The placenta is both a physical barrier as well as a metabolic interface between the maternal and fetal circulations. Though not well understood, it is quite likely that the amount of medication delivered to the fetus varies during the course of gestation.135 Additionally, it is important to acknowledge that there is at the present no randomized trial of medical therapy for fetal arrhythmias,136 and that treatment algorithms rely on observational studies, local experience, and monitoring of fetal response to therapy.

Diagnosis of a significant fetal arrhythmia should result in multidisciplinary planning of timing and location of delivery,25 balancing potential risks to the mother and fetus with response to therapy. Ideally, fetuses with complex arrhythmias and those associated with SHD should be delivered in centers with expertise in managing these complex cases. Baseline maternal assessment, including history, examination, ECG, and echocardiogram, as indicated, is appropriate prior to prescription of maternal antiarrhythmics for a fetal arrhythmia indication. When administering antiarrhythmic drugs, it is important to monitor the mother to mitigate the risk of potential drug-related side effects, such as excessive QT prolongation; FDA-mandated dosing and precautions should be observed.

Section 3 Overarching principles In recommendations for the management of all pregnant patients and fetuses with arrhythmias in this document, general principles apply shared decision-making, testing, and treatment, including the composition of the optimal medical care team, defined as the cardio-obstetrics team (see Section 3.2).30 The cardio-obstetrics team is ideally composed of maternal-fetal medicine subspecialists, electrophysiologists, and fetal or pediatric cardiologists/electrophysiologists, with the addition of anesthesiologists and neonatologists close to the time of delivery.30 It should be emphasized that recommendations will be applied in the context of the available resources and facilities at a given institution.

3.1 General electrophysiological management

Synopsis Treatment of pregnant patients affects both the mother and fetus. Certain principles must be considered in the treatment of pregnant patients to maximize benefits to the mother while minimizing the risk to the fetus. Every pregnant woman with an arrhythmia will face a decision about taking medicines or undergoing other treatment modalities, either during pregnancy or in the postpartum period. However, not all medicines or procedures are safe during pregnancy. Some medicines and other treatment modalities have potential to cause birth defects, pregnancy loss, prematurity, infant death, or developmental disabilities.21,137,138

Recommendations for general electrophysiological management

COR LOE Recommendations References

1 C-EO 1. In pregnant patients with cardiac arrhythmias, treatment should be maintained during the pregnancy, delivery, and postpartum periods, preferably using drugs with the longest record of safe use and efficacy in pregnancy, at the lowest effective dose possible, and with periodic reevaluation for continued need for medications.

1 C-EO 2. In pregnant patients with cardiac arrhythmias, the use and management of antiarrhythmic drugs should be informed by precautions provided by regulatory drug agencies, awareness of potential drug interactions, and knowledge of potential risk to the fetus.

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Recommendation-specific supportive text 1. In general, the approach to the evaluation of arrhythmias in the pregnant patient is similar to that in patients who are not pregnant, as a primary goal is to optimize treatment for the mother without compromising fetal safety.21,137,138

However, when deciding on the best and most appropriate therapy, factors to consider that are unique to the state of pregnancy include the physiological changes that accompany pregnancy; the effect of medications and other therapy on placental blood flow and breastfeeding; and the effects of medications and other therapy on the developing fetus, particularly during the first trimester. Generally, while data are scant on the use of antiarrhythmic drugs in pregnancy, a number of drugs have been used effectively and safely. In fact, very few drugs are contraindicated in pregnancy, and many are also compatible with breastfeeding (Table 5). Periodic reevaluation for continued need, including monitoring of levels and evaluation of the mother and infant for potential side effects, is best practice.55 2. If a decision to initiate drug therapy is made by the patient and caregiver, it is important to use the minimal number of drugs at the lowest effective dose to reduce drug exposure and potential risks to both the mother and the fetus.138-140

Ideally, the choice of medication should be limited to those with a history of "reasonable safety profile" during pregnancy. However, as alluded to above, a majority of antiarrhythmic medications fall into the former FDA risk category C for pregnancy, which means that, while adverse effects might have been found in animal studies, there are no well-controlled studies in humans. Nevertheless, if deemed necessary, drugs with limited experience during pregnancy may be administered after weighing risk versus benefit.141 When administering drugs that have the potential to cause proarrhythmias, FDA-mandated precautions are generally observed as in nonpregnant patients, including adjustments of drug dosing according to changes in physiological conditions such as renal function. Of note, as of June 30, 2015, the FDA has replaced the alphabetic risk categories with the Pregnancy and Lactation Labeling Rule to help physicians better communicate the potential risks and benefits of drugs to patients during pregnancy and lactation. Further details on the Pregnancy and Lactation Labeling Rule are provided in Section 2.3.

3.2 Team-based care and shared decision-making

Similar to other areas of clinical medicine, all treatment decisions result from an informed discussion among the patient and caregivers of potential risks, benefits, and alternatives for treatment.142 However, treatment decisions for patients who are pregnant are inherently more complex for multiple reasons. First, decisions involve estimates of risks and benefits to both the mother and fetus, which might be divergent. Second, the composition of the care team that estimates risks and benefits is heterogeneous since it includes those who primarily care for 1) people who are pregnant (ie, obstetricians), 2) patients with arrhythmias (ie, electrophysiologists or general cardiologists with expertise in arrhythmias in pregnancy), 3) fetuses and newborns (ie, pediatricians), 4) fetuses and newborns with arrhythmias (ie, pediatric cardiologists or electrophysiologists), and 5) patients with inherited genetic disorders (ie, genetic counselors). Third, patient preferences and decisions are complex as they affect both the mother and fetus. Finally, there is a dearth of high-quality scientific medical data about the safety and efficacy of medication and other treatment modalities in pregnant patients and fetuses.

Recommendations for team-based care and shared decision-making

COR LOE Recommendations References

1 C-EO 1. For the ongoing management and treatment of pregnant patients with cardiac arrhythmias, a cardio-obstetrics team that includes a maternal-fetal medicine subspecialist, a cardiologist and/or electrophysiologist, a pediatric electrophysiologist when fetal arrhythmias are present, an anesthesiologist, and a neonatologist, should be engaged in open communication regarding optimal management strategies, including a birth plan.

1 C-EO 2. In pregnancies complicated by documented or potential cardiac arrhythmias, shared decision-making that includes discussion of the risks and benefits to both the mother and the fetus of antiarrhythmic drug therapy, specific procedures, and monitoring, as well as the risks of withholding such therapies, is recommended.

1 C-EO 3. In pregnant patients with complex cardiac arrhythmias, engagement with anesthesiologists and obstetricians to optimize care, including preparations to perform an emergency cesarean delivery if necessary, is recommended when performing invasive electrophysiology procedures.

1 C-EO 4. In pregnant patients with complex cardiac arrhythmias, consultation with a cardiac electrophysiologist, if available locally, or a cardiologist with expertise in arrhythmias is recommended (preferably with experience with pregnant patients); management at centers with expertise in women with cardiovascular disease is preferable.

Synopsis Shared decision-making with the mother and an experienced clinical team with wide expertise using evidence-based data is optimal for improving pregnancy outcomes. The role of the patient as an active participant in the dialog and the importance of all caregiver roles—including nurses, advanced practice providers, genetic counselors, social workers, and physicians—is now emphasized. Modern ideal care models emphasize and promote patients’ informed (evidence-based) involvement in decision-making about management and treatment options. Components required for medical shared decision-making are involvement of the patient (and family for pediatrics) and the caregivers, shared information via dialog between all parties, parties taking steps to build a consensus about the preferred treatment, and, finally, agreement being reached on the care plan or treatment for the individual patient.143

Recommendation-specific supportive text 1. A coordinated team approach to patient care has been shown to improve outcomes in all areas of medicine. Recent guidance in obstetrics, CHD care, and cardiac resuscitation have included specific recommendations for key team members with the most relevant and important knowledge base.21,30,144,145 In this consensus statement, the cardio-obstetrics team (see Section 1.10) would ideally be composed of a maternal-fetal medicine subspecialist, an electrophysiologist and/or a cardiologist with expertise in arrhythmias during pregnancy, a pediatric electrophysiologist when fetal arrythmias are present, an anesthesiologist, and a neonatologist. 2. Shared medical decision-making is a process by which clinicians collaboratively help patients reach evidenceinformed and value-congruent medical decisions.143

This process is particularly important in pregnancy, where there can be competing risks and benefits for the pregnant patient and fetus.14 In the case of pregnancy, there are often disparate potential risks and benefits of testing or treatment on the mother and the fetus, and the absolute value of the potential benefits is determined in large part by the personal values and judgment of the mother. Support for shared decision-making in which women and their care providers discuss risks and benefits of their different options, disclose their preferences, and jointly make a decision is now an expectation in obstetric care.146 Also, for most women, participation in decision-making during maternity care has been shown to have a positive impact on their childbirth experiences.147

3. Obstetricians or maternal-fetal medicine subspecialists and anesthesiologists are among the important cardioobstetrics team members who care for all pregnant patients who are high risk. Recommendations for the care team members for pregnant patients and fetuses with arrhythmias are therefore similar to other high-risk pregnant patients and fetuses with potentially life-threatening disorders; the care team should include an anesthesiologist and obstetrician who are prepared to contribute care if the need for urgent delivery of the fetus is required.21,145 4. Medical science and practice are evolving rapidly toward further subspecialization by practitioners in all fields. The rapid evolution in diagnostic and therapeutic options for cardiac arrhythmia, including new medications and techniques, means that early referral to a cardiac electrophysiologist should be actively considered for management of arrhythmia in pregnant patients.20,142,148 The use of invasive technologies such as catheter ablation and device implantation can now be performed, when clinically indicated, more effectively and with minimal radiation exposure during pregnancy and can obviate the need for ongoing pharmacological therapies.

3.3 Genetic testing

Synopsis The evaluation and treatment of families with IAS or ACM require a multidisciplinary team approach.27,28 There are deep and often overwhelming medical and psychosocial implications of an IAS or ACM diagnosis and genetic testing on patients and families. The diagnosis of IAS or ACM and a positive or negative genetic test can raise many questions for the patient and family related to the reliability of testing; risks for sudden cardiac death; transmissibility of disease to future offspring; future participation in athletics; insurability; future employment prohibition; and other important, lifechanging topics. Evidence suggests that a structured cardiac genetics team approach improves the diagnosis rate and appropriate care for patients and families with IAS and ACM.27 Early diagnosis and treatment of newborns with IAS or ACM have the potential to improve patient outcomes.

Recommendation for genetic testing

COR LOE Recommendation References

1 C-LD 1. In pregnancies complicated by a documented or suspected family history of IAS or arrhythmogenic cardiomyopathy (ACM), clinical cardiac evaluation and genetic counseling with consideration of genetic testing are recommended, ideally provided by an experienced cardiac genetics team. 149-154

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Recommendation-specific supportive text 1. Early diagnoses and treatment of newborns with a family history of IAS or ACM through clinical evaluation and genetic testing allow for early interventions and potentially reduce the risk of sudden cardiac death. Including a 3-generational maternal and paternal medical history as part of genetic evaluation of offspring born to a parent with an IAS or ACM provides valuable information on the disease and cardiac risk.10 Genetic testing can also be informative in cases of stillbirths and sudden infant death syndrome, which can be secondary to IAS.153

Engaging a team of electrophysiologists or cardiologists, specialist nurses, and genetic counselors experienced in cardiovascular genetic diseases is important to address the medical, genetic, and psychological needs of the family.27,28,149

Section 4 Procedural considerations for arrhythmia management during pregnancy The purpose of this section is to provide recommendations on procedural interventions and considerations often required when treating arrhythmias in pregnancy. The interventions discussed in this section are universal in the sense that they can be applied to any number of different arrhythmias and, as such, are not arrhythmia-type specific; for this reason, they are presented at the beginning of this consensus statement.

4.1 Cardioversion during pregnancy

Direct current (or current, or electrical) cardioversion was first performed in the 1950s and is now performed routinely. Cardioversion is aimed primarily at termination of atrial and/ or ventricular tachyarrhythmias, typically with the goal of restoring a perfusing (ie, sinus or paced) rhythm that is better tolerated by the patient from a hemodynamic and symptomatic standpoint. Electrical cardioversion or defibrillation can be lifesaving when applied in urgent circumstances and should not be withheld because of concerns of pregnancy or fetal harm. The success rate is increased by accurate tachycardia diagnosis, careful patient selection, adequate electrode (paddles) application, determination of the optimal energy and anesthesia levels, prevention of embolic events and arrhythmia recurrence, and airway conservation, while minimizing possible complications. Potential complications are generally rare and transient, such as bradycardia and superficial skin burns, although serious consequences, such as ventricular fibrillation due to lack of synchronization between the direct current shock and the QRS complex, might occur if cardioversion is performed inappropriately.

Synopsis In pregnant patients, the safety and efficacy of cardioversion as a procedure for treating cardiac tachyarrhythmias have been topics of attention in case reports and case series because of concerns about the safety of the procedure and its potential effects on the fetus. Several case reports and case series have shown that this procedure is safe in pregnancy for the treatment of both SVT and VT accompanied by hemodynamic instability, significant symptoms, and/or refractoriness to antiarrhythmic drug therapy.155,158,162

Recommendation-specific supportive text 1. In scenarios where there is significant hemodynamic compromise, such as rapid VT or certain unstable forms of SVT, the priority is to restore normal hemodynamics; thus, direct current cardioversion should be performed in pregnant patients following the same resuscitation algorithms as in the general population, without delay out of concern for potential harm to the fetus.155,162 There is no evidence to support the use of difference shock energy outputs, other than what is already used traditionally to treat SVT or VT in the general population, as transthoracic impedances have been found to not change in a statistically significant manner before and after delivery.161

2. Cardioversion is safe and effective during pregnancy. The case reports and case series available in the medical literature have shown no evidence of harm to fetal circulation when umbilical artery indices are evaluated before and after cardioversion procedures performed on pregnant patients.158 Monitoring of the fetal heart rate is advised once fetal viability is reached, and treatment in facilities that have the capability of performing immediate cesarean deliveries is preferred.

Recommendations for cardioversion during pregnancy

COR LOE Recommendations References

1 C-LD 1. In pregnant patients with unstable SVT or VT, direct current synchronized cardioversion or defibrillation is recommended with energy dosing as in the nonpregnant patient.

155 1 C-LD

2. In pregnant patients with stable, symptomatic SVT or VT refractory or with contraindications to pharmacological therapy, elective synchronized cardioversion is recommended with fetal evaluation as indicated by the cardio-obstetrics team. 155-159

1 C-LD 3. In pregnant patients undergoing synchronized cardioversion or defibrillation, electrodes should be placed avoiding breast tissues to optimize current delivery to the heart. 155,160,161

3. Depending on the arrhythmia being treated, defibrillator paddles (or electrode pads) can be placed in different configurations, mainly sterno-apical or anteroposterior. The sterno-apical position (Figure 4A) requires having the sternal paddle or patch electrode placed just to the right of the upper sternal border and below the clavicle, with the apical paddle or electrode placed to the left of the nipple with the center of the electrode in the midaxillary line. This position is generally recommended for treatment of ventricular arrhythmias.155,161,162

An alternative shock vector, consisting of anteroposterior placement (Figure 4B) of the electrodes or pad- dles (parasternal and left infrascapular), has been proposed for treatment of atrial arrhythmias, and can be also used following unsuccessful initial attempts with the sterno-apical vector, as the antero-posterior vector may lead to lower transthoracic impedances. In pregnant patients, special attention should be dedicated to avoiding the breast tissue in order to maximize the total current delivery to the heart, as the adipose tissue associated with the breasts, particularly during pregnancy, may contribute to a higher resistance to the actual delivery of electrical current to the heart and theoretically decrease the efficacy of the procedure.155,160,162

4.2 Radiation exposure during cardiac procedures

and hemodynamic concerns related to pregnancy When arrhythmias occur during pregnancy, an important concern is the potential for adverse maternal and fetal outcomes.45 As such, therapy should be provided promptly and effectively, with the main goal of restoring normal hemodynamics. When an invasive procedure, such as cardiac ablation, is deemed necessary for manag- ing the arrhythmia, concerns universally arise about the potential risk to the fetus due to radiation exposure. Fortunately, a number of studies suggest that the risk of lifetime malignancy for the fetus from radiation exposure in utero during cardiac procedures is negligible. Furthermore, newer technologies allow for performing cardiac ablations and device implants with minimal or even zero fluoroscopy.

Figure 4 Electrode placement during pregnancy to avoid breast tissue. A, sterno-apical electrode placement, which is generally used for cardioversion or defibrillation of ventricular tachycardia (VT). B, antero-posterior electrode placement, which is generally used for cardioversion of atrial arrhythmias.

Recommendations for radiation exposure during cardiac procedures and hemodynamic concerns related to pregnancy

COR LOE Recommendations References

1 C-LD 1. In pregnant patients with hemodynamically significant sustained cardiac arrhythmias refractory or with contraindications to pharmacological therapy who are candidates for catheter ablation, the benefit of controlling maternal tachycardia should be prioritized over the potential radiation risks to the fetus, especially if the procedure is done after the first trimester and radiation exposure is minimized to as low as reasonably achievable. 163-165

1 C-LD 2. In pregnant patients undergoing catheter ablation, the use of techniques and technology to minimize radiation exposure to as low as reasonably achievable during the procedure is recommended. 163,164,166

1 C-EO 3. In pregnant patients undergoing high-risk catheter ablation procedures, care by a cardio-obstetrics team prepared to manage potential complications, including urgent delivery if the fetus is close to term, is recommended.

3: No benefit C-LD 4. In pregnant patients undergoing cardiac procedures requiring fluoroscopy, placing a pelvic lead apron over the patient is not beneficial because it does not substantially reduce radiation exposure to the fetus.

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Synopsis Although invasive cardiac procedures are best avoided during pregnancy, they can be performed safely when necessary, as most cardiovascular interventions, including ablation procedures, are unlikely to exceed the threshold dose for excess lifetime malignancy risk to the fetus. During catheter ablation procedures, modern technology allows for limiting the radiation dose to a minimum, and even zero radiation is possible. Planning of ablation procedures in pregnant patients, in coordination with a cardio-obstetrics team, should include planning for the potential need for urgent delivery, especially with high-risk interventions. The practice of placing a lead apron to shield the pelvis for the purpose of reducing radiation exposure to the fetus appears to offer limited benefit.

Recommendation-specific supportive text 1. Cardiac procedures in pregnant patients are generally avoided because of concerns that radiation may expose the fetus to an increased risk of malignancy and congenital malformations. However, the fetal radiation dose for most common cardiovascular interventions is not likely to exceed the 50 mGy negligible-risk threshold dose for excess malignancy.165 Damilakis et al163 studied radiation dose to the fetus in 20 women undergoing ablation procedures for SVT, using an anthropomorphic, realistic human-like model to simulate pregnancy. They estimated that radiation exposure during a typical SVT ablation procedure was well below the threshold of long-term risk of malignancy.163

Furthermore, Damilakis et al163 used traditional fluoroscopy, but technological advances, such as 3D mapping systems, allow ablation procedures to be done safely with minimal or no fluoroscopy.164 2. Szumowski et al164 reported their experience in 9 pregnant patients undergoing ablation procedures for drugrefractory SVT, ranging from 12 to 38 weeks of gestation. Three women had an electroanatomic map and ablation performed without X-ray exposure, whereas the mean fluoroscopy time in the whole group was 42 6 37 seconds. Zero fluoroscopy has been increasingly used as well, even for more complex ablation procedures using 3D/electroanatomical mapping.166 In addition, since the conceptus dose rate is dependent on the conceptus distance from the source (in this case, the heart) during the first trimester, Damilakis et al163 reported that fluoroscopic imaging with an empty bladder delivered the lowest dose to the conceptus. 3. In a pregnant patient in whom an ablation procedure is deemed necessary, the potential risk to the mother and fetus can vary greatly according to the severity and type of arrhythmia, the hemodynamic consequences, the complexity of the ablation procedure, and the underlying cardiovascular substrate. It is therefore optimal that the pregnant patient is cared for by a cardioobstetrics team (see Sections 1.10 and 3.2) prepared ahead of time to intervene in the case of complications, especially in high-risk cases, such as ablation of refractory VT, and in the event that urgent delivery is required. 4. Damilakis et al163 estimated radiation doses for a potential conceptus by using dose data obtained via an anthropomorphic, realistic human-like model simulating pregnancy at the first, second, and third trimesters in 20 women of childbearing age undergoing ablation procedures. Additional dose measurements were carried out with the abdomen and pelvis of the phantom shielded with 0.5 mm thick lead aprons, to investigate the effect of external shielding on conceptus dose. The authors concluded the dose of radiation the conceptus was exposed to with lead shielding was just 3% lower than that without shielding for all periods of gestation. This was explained by the fact that most of the conceptus radiation exposure came from scatter from the thorax of the mother, not directly from the beam. Furthermore, there is the possibility that under real-world scenarios, the presence of lead in the field of the radiation beam increases radiation output, and, as a result, there is more scattered radiation to the fetus.163 Thus, the use of a lead apron over the pelvis is unlikely to substantially reduce radiation exposure to the fetus.

4.3 Anesthesia considerations

Pregnant patients with cardiac arrhythmias may require anesthesia for treatment and for peripartum management. Anesthesia necessitates accommodation for a number of physiological changes observed during pregnancy. For example, there is an increased oxygen consumption with a tendency to desaturate due to changes in lung volumes leading to decreased residual volume caused by the rising uterus. Shunting also increases in the third trimester. Also, the laryngeal and pharyngeal landmarks change with anterior displacement of the trachea. Engorgement of the airway requires a smaller endotracheal tube (67.0 mm). Thus, the pregnant airway is difficult to manage, and specific expertise and experience are required. For induction of general anesthesia during pregnancy, rapid sequence is used to prevent aspiration. Cricoid pressure is no longer favored since there is minimal evidence to support its benefit. Accommodation for aortocaval compression warrants left lateral tilt to optimize maternal hemodynamics. Relaxation of gastroesophageal sphincter and prolonged intestinal transit time increase risk of aspiration due to abundance of progesterone.

Synopsis Pregnant patients with arrhythmias may require anesthesia in the peripartum period or when undergoing interventions required for the treatment of their arrhythmias. Anesthesia performed during pregnancy requires modifications that accommodate the physiological changes of pregnancy, particularly regarding airway management. Aortocaval compression, which decreases venous return and increases cardiac afterload, diminishes maternal cardiac output, which can compromise both maternal and fetal status. Uterine tilt or uterine displacement can ameliorate this hemodynamic perturbation during anesthesia for pregnant patients with arrhythmias. Intraoperative or intraprocedural fetal monitoring can be used for pregnant patients with arrhythmias receiving anesthesia to optimize fetal status. However, failure of corrective measures to reduce hemodynamic instability that affect uterine blood flow may require delivery by a cardioobstetrics team. Modification of medications used throughout the anesthesia process may be required in patients with susceptible arrhythmogenic substrates, such as LQTS. Recommendation-specific supportive text 1. Sustained arrhythmias during pregnancy increase the risk of hemodynamic instability. Although regional anesthesia is generally preferred during pregnancy to avoid more difficult airway management and, theoretically, to optimize fetal/neonatal risks,171 general anesthesia for cardiac procedures will optimize oxygenation during hemodynamic instability. When general anesthesia is planned, expertise in safe obstetric general anesthetic administration is optimal.172

2. Aortocaval compression occurs as a result of the enlarging uteroplacental unit as early as the second trimester of pregnancy.173,174 More contemporary cardiac MRI data corroborate this pregnancy phenomenon, demonstrating improvement in cardiac function with the left lateral tilt of 30 degrees, compared with parameters obtained in the supine position.52 If the supine position of the thorax is preferred or required to facilitate interventions, left lateral manual uterine displacement can be performed.175 3. Medications used throughout the anesthesia process may exacerbate the arrhythmogenic potential of the underlying substrate, such as prolongation of the QT interval.169,170 Modification of premedications, induction agents, inhalational agents, neuromuscular blocking, and reversal agents is required. For some drugs, such as atropine, the data are conflicting. See Table 6 for a list of QT-prolonging drugs commonly used in anesthesia. For an extensive list of QT-prolonging drugs, refer to https://crediblemeds.org. 4. Operative and nonoperative interventions aimed at treating arrhythmias may be accompanied by maternal hemodynamic instability that may exacerbate uteroplacental insufficiency in the viable fetus, leading to abnormal fetal heart rate patterns reflective of fetal hypoxia and or fetal acidosis. Corrective measures should be implemented by the anesthesia team members geared toward improving and restoring fetal well-being. Persistent abnormal fetal heart rate patterns may require urgent cesarean delivery necessitating the presence of a cardio-obstetrics team.176

Recommendations for anesthesia considerations

COR LOE Recommendations References

1 C-LD 1. In pregnant patients with arrhythmias associated with hemodynamic instability requiring cardiac interventions, general anesthesia is recommended in preference to regional anesthesia for the sake of a secure airway and improved oxygenation during hemodynamic instability. 167,168

1 C-LD 2. In pregnant patients undergoing cardiac procedures to manage maternal arrhythmias later in gestation (beyond 26 weeks), left lateral tilt positioning is recommended as feasible to minimize aortocaval compression and optimize maternal hemodynamics around and during the time of the procedure. 167,169

1 C-LD 3. In pregnant patients undergoing cardiac procedures to manage maternal arrhythmias, medications used for anesthesia should be reviewed and modified, when possible, to prevent exacerbation of underlying maternal arrhythmogenic conditions. 169,170

1 C-EO 4. In pregnant patients with arrhythmias associated with hemodynamic instability requiring operative and/or nonoperative cardiac interventions, intraprocedural monitoring of the viable fetus is recommended, in consultation with the cardioobstetrics team, to manage potential complications including urgent delivery.

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4.4 Delivery and lactation

The benefits of breastfeeding cannot be overstated. Human milk provides an optimal amount of micro- and macronutrients for the newborn with both immunologic and antibacterial properties. Breastfeeding favors maternal–infant bonding and is associated with decreased postpartum weight retention. Long term, exclusively breastfed infants commonly have optimal growth and development, decreased incidence of acute and chronic diseases, and fewer developmental and psychological disorders. Breastfeeding should be encouraged in the absence of medical contraindications.

Synopsis The available evidence on the safety of antiarrhythmic agents during lactation is limited to case reports and small case series. Overall, most of the commonly used agents in clinical practice appear to pose minimal harm when used while breastfeeding. Given the overwhelming evidence on the benefits of breastfeeding (for both the mother and the neonate), in most cases, continuing lactation will outweigh any theoretical risks associated with medication exposure. In all cases, extensive counseling is recommended with a detailed discussion of the riskbenefit ratio for each individual case. The safety of antiar- rhythmic drugs is outlined in Table 5. The route of delivery, vaginal or cesarean, is generally determined by obstetric considerations rather than the maternal arrhythmia. Pain management during labor in patients at risk of arrhythmic complications or receiving antiarrhythmic therapy is important to prevent triggering maternal arrhythmias.

Recommendation-specific supportive text 1. In the vast majority of cases, route of delivery is dictated by obstetrical factors rather than the maternal arrhythmia. A recent study that included 276 pregnant patients with a

Table 6 Perioperative medications that prolong the QT interval177,178 Pharmacology class Medications Antiemetics Ondansetron, droperidol Antihypertensive agents Nicardipine Antibiotics Quinolones, macrolides Antihistamines H1 blocker Terfenadine, diphenhydramine H2 blocker Famotidine Premedication and sedation Benzodiazepines (except midazolam) Induction agents Ketamine, thiopental Inhalational anesthetics Sevoflurane, desflurane, enflurane, halothane, isoflurane Neuromuscular blocking agents Pancuronium, succinylcholine Neuromuscular blocking reversal agents Edrophonium, neostigmine, glycopyrrolate Opioids Methadone, sufentanil Sympathomimetics Epinephrine, norepinephrine, dobutamine, dopamine, isoproterenol

Recommendations for delivery and lactation

COR LOE Recommendations References

1 C-LD 1. In pregnant patients with cardiac arrhythmias, the route of delivery (vaginal or cesarean) should be determined by the birth plan and obstetrical factors in accordance with best clinical practice, along with continuation of antiarrhythmic drug therapy.

179 1 C-LD

2. Pregnant patients receiving antiarrhythmic drug therapy or at risk of cardiac arrhythmias should receive adequate pain control during labor, ideally with the use of neuraxial anesthesia (epidural), to avoid pain-induced catecholamine surges that may trigger preexisting arrhythmias.

180 1 C-LD

3. In breastfeeding patients, antiarrhythmic drug therapy should be used when clinically indicated, with a preference for agents with the best safety profile during lactation. 181-192

1 C-LD 4. In breastfeeding patients with life-threatening cardiac arrhythmias refractory or with contraindications to other treatment, the decision to treat with amiodarone should balance the severity of the arrhythmia against the potential risk for longterm toxicity with consideration of the risks and benefits of breast milk compared with alternatives such as infant formula or donated breast milk. 183,191

large variety of cardiac diseases, including 11.2% of the cohort with arrhythmias, showed no difference in outcomes among women who delivered vaginally versus by elective cesarean section.179 Similarly, data from ROPAC show no advantage of planned-cesarean over vaginal delivery.193 Importantly, there is no reason to discontinue antiarrhythmic therapy during the delivery process. 2. Early adequate pain control is of paramount importance, as certain arrhythmias may be potentiated by increased sympathetic activity secondary to pain.180 Heightened sympathetic tone can lead to increased incidence of arrhythmias, such as in LQTS and catecholaminergic polymorphic ventricular tachycardia (CPVT),177 or arrhythmias due to increased automaticity. Furthermore, conduction in the AV node is enhanced with increased sympathetic tone, which could potentially exacerbate AV node–dependent arrhythmias. Although the data are limited, 1 study demonstrated a decrease in arrhythmic events using epidural anesthesia compared with no anesthesia.194 3. When antiarrhythmics are used during breastfeeding, the risk-benefit ratio must be evaluated in all cases. Agents that pose minimal risk for breastfed infants include digoxin, propranolol, metoprolol, and verapamil.181,184,188,192 Agents with a favorable safety profile during breastfeeding, albeit with limited available evidence, include carvedilol, esmolol, procainamide, diltiazem, flecainide, and sotalol.182,185,186,189,190 Amiodarone should be avoided during breastfeeding if possible; however, it may be used if clinically the benefit is thought to outweigh the risks. No data exist on the use of dronedarone or ibutilide; neither is recommended during breastfeeding. In all cases, it is important to educate parents about potential signs of toxicity in infants. Primary care providers involved in the infant’s care also need to be educated about potential side effects of the specific antiarrhythmic that is being used during breastfeeding. In very selected cases, evaluation of an infant’s serum levels may be required (eg, high doses of flecainide). More information on drugs and breastfeeding can be found in the Drugs and Lactation Database (LactMed; https://www.ncbi.nlm.nih.gov/books/ NBK501922). 4. During pregnancy, amiodarone is generally considered a last resort option in the setting of life-threatening arrhythmias. During breastfeeding, the infant receives just a fraction of the mother’s weight-adjusted dose, although the preciseamountisunpredictablewithamediandoseofabout 11%.195Therefore,potential fetal adverseeffectsdependon maternal dose and duration of drug exposure (cumulative dose). When amiodarone is used, the infant is closely monitored with periodic evaluation of thyroid function. Limited exposure is generally safe, but when prolonged therapy is required, patient and physician should engage in shareddecision discussion, balancing risks and benefits, and consider alternatives to breastfeeding, including the use of milk formulas or, if available, donor breast milk.

Section 5 Diagnosis of pregnant patients with palpitations Palpitations are frequent in pregnancy, but in the majority of patients they are caused by either no or minor arrhythmias. Pregnancy in healthy individuals is associated with an increase in physiological heart rate and with a slight increase in extrasystole burden. Preexisting arrhythmias in patients with an arrhythmogenic substrate may be exacerbated during pregnancy, but first-onset PSVT or another new-onset arrhythmia is uncommon. In recent reports, AF became the most frequent arrhythmia in pregnancy.37

Recommendations for the diagnosis of pregnant patients with palpitations

COR LOE Recommendations References

1 B-NR 1. Pregnant patients presenting with modest sinus tachycardia or extrasystoles, with an otherwise normal initial evaluation and without suspicion of underlying cardiopulmonary disease, should be reassured without additional testing. 33,41-43

1 B-NR 2. Pregnant patients with suspected arrhythmic etiology of unexplained palpitations who have concerning symptoms or suspected electrical or SHD on initial evaluation should undergo ambulatory monitoring as clinically indicated, in consultation with a cardiologist or electrophysiologist with expertise in cardiovascular diseases in pregnancy. 37,38,41,44-46

1 C-EO 3. In pregnant patients presenting with palpitations, a detailed history, physical examination, resting 12-lead ECG, and targeted blood testing should be performed at initial evaluation.

2a C-LD 4. In pregnant patients with suspected arrhythmic etiology of palpitations unexplained after noninvasive cardiac evaluation, especially in the presence of syncope and/or electrical or SHD, consideration of an implantable cardiac monitor (ICM) is reasonable.

41 3: No benefit C-EO

5. In pregnant patients with palpitations in the absence of a documented arrhythmia or other clinical evidence of potential arrhythmogenic substrate, electrophysiological study solely as a first-line diagnostic test should not be performed.

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Synopsis In pregnant patients, similar recommendations for diagnostic evaluation of palpitations apply as in nonpregnant patients, with additional consideration given to the increased risks that arrhythmias pose during pregnancy and the radiation risk to the fetus if an electrophysiological study was performed. In general, the diagnostic evaluation rules out the presence of underlying structural or electrical heart disease and ECG documentation during palpitations is performed for symptom–rhythm correlation.17,19,196 The choice of an arrhythmia monitoring device depends on the frequency of palpitations, with the longer recording duration providing higher diagnostic yield.17,19,196 Further management testing is specific to the underlying heart disease and type of arrhythmia. The presence of documented arrhythmia in pregnant patients with congenital or acquired heart disease is an important risk factor for adverse maternal and fetal pregnancy outcomes.16,46 A summary of the approach for the diagnosis of the pregnant patient with arrhythmias is provided in Figure 5.

Recommendation-specific supportive text 1. Pregnancy in healthy individuals is associated with an increase in sinus rhythm frequency and slight increase in extrasystole burden, which return to prepregnancy levels postpartum. In general, resting heart rate increases by 10% or more during pregnancy due to autonomic, hemodynamic, and whole-body volume fluctuations. Patients with extrasystole or sinus tachycardia on ECG documented during ongoing symptoms generally do not benefit from further extensive evaluation. In a study of 110 pregnant patients with structurally normal hearts who were referred for palpitations (87%), dizziness (13%), or syncope (6%), the results of ambulatory Holter monitoring were compared with those for 52 healthy pregnant patients. Sinus tachycardia was found in 9% and 10%, sinus bradycardia in 1% and 2%, atrial extrasystoles in 56% and 58%, and ventricular extrasystoles in 49% and 40% of the group with palpitations without significant difference, compared with the control group, respectively. The mean PVC burden was significantly higher in the symptomatic group than in the control group. However, there was no correlation between arrhythmia frequency and symptoms, as only 10% of symptomatic episodes were accompanied by the presence of any arrhythmia.33 These findings suggest that palpitation is a frequent symptom in pregnancy and that in the majority of patients it is caused by either no or minor arrhythmias. IST (defined as a resting heart rate .100, a mean ambulatory heart rate .90, and associated symptoms) has been associated with a higher frequency of induction at term, but without impact on maternal or fetal outcomes.42

Further, pregnancy is a common inciting event for IST, with about 8% of IST patients identifying pregnancy as the inciting event; however, aside from symptoms, IST has not been associated with negative long-term outcomes.43 That being said, some instances of high-burden PVCs may represent serious arrhythmias or cardiomyopathy. Similarly, persistent fast sinus tachycardia rates may indicate underlying disease processes that require further evaluation. 2. Similar to evaluation of nonpregnant patients, the evaluation of pregnant patients with unexplained palpitations of suspected arrhythmic origin aims at ECG correlation with symptoms. The type of arrhythmia monitoring device that is most diagnostic depends on the frequency of palpitations; longer duration of recording has higher diagnostic yield.17,19,196 In a recent study of 96 pregnant patients referred for ambulatory 24-hour Holter or external event loop recorder, 76% of the patients had no or benign arrhythmia and 24% had more severe arrhythmia; most frequently SVT and rarely AF or VT were documented.41 The loop monitor had a higher diagnostic yield. The history of arrhythmia prior to pregnancy predicted a higher likelihood of recurrent arrhythmia during pregnancy.41 Unexplained palpitations in pregnant patients with a history of congenital or SHD require thorough investigation of the status of the SHD and more aggressive attempts at arrhythmia documentation and diagnosis, to allow for the timely initiation of disease and arrhythmia-specific treatment. 3. The evidence supporting the value of detailed history, physical examination, and resting 12-lead ECG in nonpregnant patients presenting with palpitations and/or supraventricular arrhythmias has been recently reviewed in the 2015 ACC/AHA/HRS Guideline for the Management of Adult Patients with Supraventricular Tachycardia19; the 2019 ESC Guidelines for the Management of Patients with Supraventricular Tachycardia8; the 2017 EHRA Consensus Document on the Management of Supraventricular Arrhythmias17; and the 2011 EHRA position paper, Management of Patients with Palpitations.196 Although specific studies do not exist and pregnancy is frequently an exclusion criterion, especially in invasive studies of arrhythmias, similar recommendations for diagnostic evaluation of palpitations apply as in nonpregnant patients. In general, the initial evaluation should aim at ruling out potentially life-threatening arrhythmic etiology, ECG documentation of symptoms for specific arrhythmia diagnosis, and evaluation of the presence of underlying structural or electrical heart disease. Specifically, in pregnancy, targeted blood testing can exclude anemia due to bleeding, thyroid dysfunction, infection, electrolyte abnormalities, and other underlying medical conditions that can cause physiological tachycardia or ectopy. ECG documentation during ongoing palpitations will allow clear diagnosis of the type of arrhythmia (Figure 5).

4. Similar to nonpregnant patients, in cases when an arrhythmic origin of palpitation or syncope is strongly suspected based on the history but noninvasive ambulatory monitoring is nondiagnostic, especially when highrisk features are present (such as congenital or acquired structural or electrical heart disease or associated syncope), the insertion of an ICM allows for long-term monitoring and provides increased diagnostic yield in cases of sporadic arrhythmias.16,196 5. The adverse effects of radiation exposure to the fetus are discussed in Section 4.2. Electrophysiological study for diagnostic purposes in the absence of a documented arrhythmia or evidence of a potential arrhythmogenic substrate would be very low yield, since in most cases the etiology of palpitations is either no or a minor arrhythmia.19,33,37,41 In addition to the lack of demonstrated benefit, the risks associated with unnecessary interventions could be harmful.

Figure 5 Algorithm showing the approach to the diagnosis of pregnant patients presenting with palpitations. Colors correspond to class of recommendation (COR) in Table 1. *In consultation with a cardiologist or electrophysiologist with expertise in cardiovascular diseases in pregnancy. ECG 5 electrocardiogram, EPS 5 electrophysiological study.

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Section 6 Diagnosis and management of pregnant patients with syncope Syncope is a sudden, transient loss of consciousness as a result of global cerebral hypoperfusion.197 Hemodynamic changes of pregnancy, especially the reduced systemic vascular resistance, may predispose pregnant patients to syncope. The incidence of syncope in pregnancy is about 1%. Moreover, pregnant patients who experience syncope in the first trimester have an increased risk of adverse maternal-fetal outcomes, including recurrent syncope during pregnancy.47 In general, workup and management of syncope in pregnant patients is similar to that for their nonpregnant counterparts.18 The most common types of syncope in pregnancy are neurocardiogenic and/or positional syncope, also known as supine hypotensive syndrome. In supine hypotensive syndrome, syncope occurs because of aortocaval compression while in the supine position, and syncope often is accompanied by tachycardia, sweating, and nausea. In this condition, the cause of syncope is anatomic and positional. Orthostatic hypotension is also common, particularly in late pregnancy.198 While supine hypotensive syndrome is most often due to compression of the inferior vena cava and resulting decrease in blood return to the heart, orthostatic hypotension may be due to relative vasodilation, hypovolemia, or autonomic dysfunction.

6.1 Diagnosis and approach to the pregnant

patient with syncope

Synopsis The evaluation of pregnant patients with unexplained syncope requires a systematic approach. Initial evaluation should consist of a comprehensive history and physical exam. A 12lead ECG is also recommended during initial evaluation. Based on these factors, if the episodes are classic for reflex-mediated vasovagal syncope and physical exam and ECG are normal, no further evaluation is recommended. Otherwise, however, additional evaluations, including echocardiography, expert consultation, and long-term monitoring, are useful adjuncts. The use of electrophysiology studies in the absence of a compelling indication (such as conduction disease on baseline ECG or longer-term monitoring or SHD on echocardiography) is not recommended because of potential for harm related to radiation exposure to the fetus. An algorithm of the recommendations for the diagnosis of pregnant patients with syncope is provided in Figure 6.

Recommendation-specific supportive text 1. The evidence supporting the value of detailed history, physical examination, targeted blood testing, and resting 12-lead ECG in nonpregnant patients presenting with syncope has been recently reviewed in the 2017 ACC/AHA/ HRS Guideline for the Evaluation and Management of Patients with Syncope18 and in the 2018 ESC Guidelines for the Diagnosis and Management of Syncope.13 In pregnant patients, although specific studies do not exist and pregnancy is a frequent exclusion criterion in clinical studies, similar recommendations for diagnostic evalua-

Recommendations for the diagnosis and approach to the pregnant patient with syncope

COR LOE Recommendations References

1 B-NR 1. In pregnant patients presenting with syncope, a detailed history, physical examination (including orthostatic vitals), resting 12-lead ECG, and targeted blood testing should be performed at initial evaluation. 199-204

1 B-NR 2. Pregnant patients with new onset of unexplained syncope, especially if it occurs in the first trimester or recurs during pregnancy, are at higher risk of adverse pregnancy outcomes and should receive enhanced evaluation, including echocardiogram, followed by close periodic monitoring. 47,205

1 B-NR 3. Pregnant patients with syncope suspected to be of cardiac origin and/or due to suspected cardiovascular abnormalities after initial evaluation should undergo additional cardiac testing, including imaging, as clinically indicated in consultation with a cardiologist or electrophysiologist with expertise in cardiovascular diseases in pregnancy. 206-208

1 C-LD 4. In pregnant patients with recurrent syncope unexplained after comprehensive noninvasive evaluation, including external monitor, insertion of an ICM is recommended. 209-212

3: No benefit B-NR 5. In pregnant patients presenting with clinical characteristics typical for reflexmediated vasovagal syncope, a normal physical examination, and a normal resting 12-lead ECG at initial evaluation, further testing is not beneficial. 198,205,213-215

3: No benefit C-LD 6. In pregnant patients with unexplained syncope but without evidence of cardiac disease or conduction system disease, diagnostic electrophysiological study is not indicated. 216-218

tion of syncope apply as in nonpregnant patients, including initial comprehensive history, 12-lead ECG, and physical exam, to elucidate details surrounding the syncopal event and to identify any objective findings suggestive of electrical or other cardiac abnormalities. Basic blood tests, including a complete blood count and electrolytes, are also useful. Other blood tests, such as thyroid function studies or cardiac enzymes, should be ordered based on the clinical context (eg, in the presence of exertional chest pain associated with syncope, or with symptoms suggestive of another disease process). 2. In a recent Canadian retrospective, population-based cohort study of close to 500,000 live births between 2005 and 2014, the overall incidence of syncope during pregnancy was 1% (9.7 per 1000 pregnancies).47 In this study, the rate of preterm birth was higher in pregnancies with syncope occurring during the first trimester than in pregnancies with syncope in the second and third trimesters (18%, vs 16% and 14% respectively, P , 0.01). In this series, 8% of pregnancies had .1 episode of syncope. Also, the rate of congenital anomalies among children born from women with .1 syncope was higher (4.9%) than in those without syncope (2.9%, P , 0.01). The rate of arrhythmias and syncope within 1 year postpartum was higher in those with syncope while pregnant than in those without syncope.47 These findings suggest that pregnant patients with syncope in the first trimester or multiple syncope episodes during the pregnancy are at higher risk of adverse events. In these instances, echocardiogram can rule out the presence of SHD and prolonged cardiac monitoring may be necessary. 3. In cases in which history, examination, and ECG either do not support a clear vasovagal cause or may indicate another cause, further evaluation including echocardiography, tilt table or other autonomic testing, or cardiac MRI should be done as clinically indicated. Consultation with a cardiologist with expertise in pregnancy can ensure safety of the choice of testing and provide the pregnant patient with information on potential fetal risk. Echocardiography has been shown to be normal or nonrelevant in patients with a negative cardiac history and a normal ECG, but in those with a positive cardiac history or an abnormal ECG, relevant cardiac findings may be identified in as many as 27% of patients.207 Generally, most additional testing beyond an ECG impacts diagnosis or management in fewer than 5% of cases and determines an etiology in fewer than 2%.219 In general, MRI is preferred to computed tomography scan in pregnancy because of radiation concerns if more advanced cardiac imaging is required. Given the potential patient-specific risks, we recommend consultation with a cardiologist with expertise in managing pregnant patients. 4. ICMs have demonstrated benefit in elucidating a cause of syncope in otherwise undiagnosed cases. Linzer et al210 reported that the diagnostic yield of ICMs recording was as high as 25% in patients with undiagnosed causes of syncope. Similarly, Sivakumaran et al211 demonstrated that the probability of obtaining symptom–rhythm correlation was 56% for ICMs vs 22% for Holter monitors. Krahn et al209 demonstrated that prolonged monitoring strategies with ICMs are more likely to provide a diagnosis than conventional testing, including Holter or external-event monitors, in patients with unexplained syncope. Sliwa et al212

also showed that ICMs were more effective than 24hour Holter monitoring in detecting arrhythmias and were safe for pregnant patients. 5. The most frequent etiology of syncope during pregnancy by far is reflex-mediated vasovagal syncope, which can be diagnosed at initial evaluation. The majority of patients have a history of vasovagal syncope episodes prior to pregnancy with typical triggers and prodrome213,215

and continue to have episodes in the postnatal period.205 Longer duration of standing or in very rare cases sitting up from supine position,198 hypovolemia due to bleeding or vomiting (hyperemesis gravidarum), and warm environment may exacerbate symptoms. As in nonpregnant patients, initial evaluation with the detailed history is diagnostic for typical reflex-mediated vasovagal syncope during pregnancy. Reflex-mediated syncope is generally associated with favorable prognosis.213 There is only 1 case reported of fetal hypoxia due to very prolonged hypotension.214 Thus, when the history is suggestive of reflex-mediated vasovagal syncope and there are no other compelling findings from physical examination, ECG, or blood testing to suggest another disease process, no further evaluation is necessary, and the provider can reassure the patient this type of syncope is generally benign. 6. The adverse effects of radiation exposure to the fetus are discussed in Section 4.2. Thus, procedures that require fluoroscopic/radiation exposure are potentially harmful to the developing fetus and ought to be avoided unless they are of clear value to optimize treatment for the mother.216,218 There is a direct correlation between the presence of ECG abnormalities and the likelihood of relevant findings on an electrophysiology study, with an overall low likelihood of electrophysiology study–related abnormalities in the setting of an otherwise normal ECG.217

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Figure 6 Diagnosis of pregnant patients presenting with syncope. Colors correspond to class of recommendation (COR) in Table 1. *In consultation with a cardiologist or electrophysiologist with expertise in cardiovascular diseases in pregnancy. ECG 5 electrocardiogram, EPS 5 electrophysiology study.

6.2 Management of syncope and orthostatic

hypotension in the pregnant patient

Synopsis Once the cause of syncope in the pregnant patient has been determined based on comprehensive evaluation, management should be as indicated for nonpregnant patients with consideration of the health of both the mother and the fetus in the treatment strategy. In the pregnant patient, a specific consideration, in addition to standard causes of syncope, is supine hypotensive syndrome, which is anatomic and positional.

Recommendation-specific supportive text 1. Syncope is common in pregnancy due to decreased venous return and cardiac output. These physiological changes may lead to new presentations of common causes of syncope that may be seen in the nonpregnant patient. Vasovagal syncope is the most common type of syncope. Syncope in the pregnant patient is managed as indicated in the nonpregnant patient. First-line therapy consists of con- servative measures such as increasing salt and water intake, using compression garments, and avoiding triggers like rapid positional changes from lying or sitting to standing. After the first trimester, increased salt intake and fludrocortisone have been shown to be beneficial in refractory cases.223 Ultimately, it is still important to consider the type of workup and treatment strategy in light of the health of both the mother and the fetus. Thus, a multidisciplinary discussion among a maternal-fetal medicine subspecialist, electrophysiologist, and anesthesiologist is highly encouraged.12,18

2. In a study from the United Kingdom, investigators evaluated the hemodynamic impact of the degree of lateral tilt in 32 women in late third trimester. Stroke volume and cardiac output were highest with complete left lateral tilt with 17% decrease when on the right side.221 Others have confirmed a decrease in cardiac output in supine position later in pregnancy due to caval and aortic compression.224

Section 7 Management of specific arrhythmias during pregnancy Atrial arrhythmias, such as PACs and SVT, are the most common cardiac arrhythmias to present during pregnancy. The prevalence of SVT has been estimated at 24 per 100,000 pregnancy-related hospitalizations.38 Some patients have a history of palpitations or SVT, while others present for the first time during pregnancy. SVT can be secondary to AV node reentry or an accessory pathway, either overt or concealed. Most women with SVT present with symptoms of palpitations during pregnancy, but some present with presyncope, syncope, dyspnea, or chest pain. Palpitations are described as rapid regular heartbeats and have an abrupt onset. SVT occurs most commonly in the second or third trimester. The incidence of AF or AFL is low in pregnant patients without SHD (59.3 per 100,000 pregnancies).225

ROPAC showed that the incidence of AF during pregnancy in patients with SHD was 1.3%.226 This section covers maternal arrhythmias that are not related to IAS, which are covered in Section 12.1.

Recommendations for management of syncope and orthostatic hypotension in the pregnant patient

COR LOE Recommendations References 1 B-NR 1. In pregnant patients with syncope, therapy should be provided as indicated in the nonpregnant patient.

220 1 B-NR

2. In pregnant patients with syncope presumed to be due to supine hypotensive syndrome, left lateral decubitus position and adequate hydration are recommended. 221,222

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7.1 Management of atrial ectopy and

supraventricular tachycardia during pregnancy

7.1.1 Management of acute supraventricular tachycardia during pregnancy

Synopsis An algorithm for the management of acute SVT is provided in Figure 7. The management of acute SVT during pregnancy is similar to management in the nonpregnant population, although some important differences exist. Vagal maneuvers are generally considered first-line intervention, although data specific to pregnancy are scant, so the technique is an extrapolation from the general population. Adenosine, with its favorable safety profile in pregnancy, is the first-line medication option. When additional intravenous nodal blocking agents are needed, intravenous metoprolol or propranolol have the most robust safety. Experience with intravenous calcium channel blockers is less robust, and given the potential for hypotension, these agents are generally used in patients who are refractory or with contraindication to adenosine and beta-blockers. Procainamide and digoxin also remain options in these cases. Recommendation-specific supportive text 1. SVT may be secondary to atrial tachycardia (AT), AV nodal reentry tachycardia, or AV reciprocating tachycardia, with an accessory pathway either overt or concealed. For both AV nodal reentry tachycardia and AV reciprocating tachycardia, the AV node is a required component of the reentrant circuit, and maneuvers or medications that slow AV conduction can terminate the SVT. Vagal maneuvers, such as the Valsalva maneuver or carotid sinus massage, are simple methods for terminating SVT and are safe to attempt in pregnant patients before resorting to pharmacological therapy.162 The Valsalva maneuver requires that the patient bear down against a closed glottis for 10 to 30 seconds and is per- formed with the patient in a supine position.231,232 Carotid massage is performed by applying pressure over the right or left carotid sinus for 5 to 10 seconds.231 Carotid auscultation for bruits should be done prior to carotid massage. Ice-cold wet towels on the face or facial immersion in cold water are alternative vagal maneuvers.233 The practice of applying pressure to the eyeball as a vagal maneuver has been abandoned due to the risk of complications, including damage to the eye, and the existence of other options.21

2. SVT can usually be terminated with adenosine, which has been used effectively in pregnant patients.64,162,234 Side effects such as flushing, shortness of breath, or chest discomfort can occur after administration, but typically resolve quickly due to the short half-life of the drug. Adenosine is given as an intravenous bolus. Continuous ECG monitoring is important during adenosine administration to document rhythm changes. 3. Acute-onset SVT can be associated with hemodynamic instability, including syncope, pulmonary edema, cardiogenic shock, hypotension, and brain hypoperfusion. When acute SVT with hemodynamic instability occurs, it should be treated promptly. Direct current cardioversion is safe during pregnancy and effective for all women with signs of hemodynamic instability.159 Electrodes should not be applied to the breast tissue (see Section 4.1).159 The energy dose administered is similar to that in the nonpregnant patient.21 Fetal monitoring is appropriate after cardioversion, if warranted by concerns about fetal well-being. 4. Although less effective than adenosine, intravenous betablockers are an alternative treatment for acute SVT, espe-

Recommendations for the management of acute supraventricular tachycardia during pregnancy

COR LOE Recommendations References 1 C-LD 1. In pregnant patients with acute onset of SVT, vagal maneuvers are recommended as a first-line therapy for tachycardia termination. 38,227 1 C-LD 2. In hemodynamically stable pregnant patients with acute onset of SVT, intravenous adenosine is recommended as the first-line pharmacological therapy. 38,227

1 C-LD 3. In hemodynamically unstable pregnant patients with acute onset of SVT, synchronized direct current cardioversion is recommended, with energy dosing as in the nonpregnant patient. 38,227

2a C-LD 4. In hemodynamically stable pregnant patients with acute onset of SVT refractory or with contraindications to adenosine, intravenous beta-blockers, such as metoprolol or propranolol, are reasonable for termination of acute SVT. 38,227

2b C-LD 5. In hemodynamically stable pregnant patients with acute onset of SVT refractory or with contraindications to adenosine or beta-blockers, intravenous calcium channel blockers, such as verapamil or diltiazem, or intravenous procainamide may be considered. 228-230

cially in hemodynamically stable patients refractory or with contraindications to adenosine.64,162 Most studies of beta-blocker use during pregnancy use intravenous metoprolol or propranolol. The use of esmolol in pregnancy has not been studied, so this medication is less preferred. 5. There is less experience using intravenous verapamil to treat SVT during pregnancy. Intravenous verapamil can cause significant hypotension and therefore is usually considered only when SVT is refractory to adenosine or beta-blockers, or when there are contraindications to these 2 preferred agents.64,162 Although intravenous procainamide has been used safely during pregnancy, data on its use in treating acute onset SVT during pregnancy are limited.64,162 Long-term oral procainamide can be associated with a lupus-like syndrome and is usually avoided if other options are available.229

Intravenous beta-blockers, such as metoprolol or propranolol (COR 2a)

Acute onset

Symptomatic

focal AT

Synchronized direct current cardioversion

(COR 1)

Intravenous calcium blockers, such as verapamil

or diltazem, or intravenous procainamide

(COR 2b) Symptomatic

SVT in the absence of preexcitation

Metoprolol, propranolol, and/or digoxin as

first-line, and verapamil as second-line pharmacological

therapy (COR 1) WPW syndrome

Beta-blockers as first-line option

(COR 1) Recurrent or

persistent

Intravenous adenosine as first-line pharmacological

therapy (COR 1)

Alternative antiarrhythmic drugs including flecainide, propafenone, or sotalol

(COR 2a)

Hemodynamically

stable Hemodynamically

unstable

Refractory or contraindications to other pharmacological

therapies Tachycardia-

induced cardiomyopathy

Consult with an

EP (COR 1)

Pregnant patient

with SVT

Vagal maneuvers

as first-line

therapy (COR 1)

Therapy with oral

flecainide or propafenone

(COR 1)

Amiodarone

(COR 2b) Catheter ablation*

(*COR 2a)

Figure 7 Algorithm of recommendations for the management of pregnant patients with supraventricular tachycardia (SVT). Colors correspond to the class of recommendation (COR) in Table 1. *With attention to and techniques for minimizing radiation exposure to as low as reasonably achievable. AT 5 atrial tachycardia, EP 5 electrophysiologist, WPW 5 Wolff-Parkinson-White.

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7.1.2 Management of nonacute atrial ectopy and supraventricular tachycardia during pregnancy

Synopsis The most common arrhythmias during pregnancy are PACs, which generally require no intervention unless highly symptomatic, whereas sustained SVT can negatively impact maternal and fetal health.45,227 Ideally, patients with SVT who are considering pregnancy will undergo ablation therapy before conception. During pregnancy, SVT can usually be treated with medications.38 Cardioversion is sometimes necessary and can be performed safely during pregnancy. The treatment of atrial ectopy (Figure 8) and SVT (Figure 7) is based on several factors, including the severity of symptoms, the frequency and duration of the arrhythmia, concurrent cardiac disease (eg, underlying valve dysfunction, left ventricular [LV] systolic dysfunction), and the available treatment options and their effect on the developing fetus or the neonate (via breastfeeding). Drugs with the best safety record in pregnancy are generally first-line options. Catheter ablation procedures can be performed with minimal or zero fluoroscopy, avoiding radiation risk to the fetus. SVTs of all mechanisms, including focal AT, are amenable to ablation. Amiodarone, despite its risks, remains an option in hemodynamically significant refractory cases. Recommendation-specific supportive text

1. Occasionally, PACs are associated with intolerable symptoms during pregnancy and therapy is necessary. The studies on the treatment of PACs during pregnancy involve a beta-blocker, either metoprolol or propranolol.64,162,234 Atenolol is best avoided during pregnancy because it is associated with lower birth weight when compared with other agents. 2. PACs are common during pregnancy and are very rarely associated with adverse events in the mother or the fetus.33 PACs do not require treatment unless symptoms are intolerable for the mother. Avoiding potential precipitating factors, such as caffeine, alcohol, stimulants, and drugs with beta-agonist effects, can decrease the occurrence of PACs. 3. Digoxin, metoprolol, propranolol, and verapamil are not teratogenic and have been used to prevent recurrent symptomatic SVT in pregnant patients.64 When necessary, the lowest-possible dose of beta-blockers should be used because they are associated with low birth weight, bradycardia, and neonatal hypoglycemia.62,64 Digoxin, metoprolol, and propranolol have a robust safety record during pregnancy and as such are favored as initial options prior to using calcium channel blockers. Digoxin can be used alone or in combination with beta-blockers and calcium

Recommendations for the management of nonacute atrial ectopy and supraventricular tachycardia during pregnancy

COR LOE Recommendations References 1 B-NR 1. In pregnant patients with PACs and intolerable symptoms, treatment with betablockers is recommended, preferably with metoprolol or propranolol. 33,38 1 C-LD 2. In pregnant patients with PACs who either are asymptomatic or have tolerable symptoms, reassurance is recommended with no need for intervention.

33 1 C-LD

3. In pregnant patients with symptomatic SVT in the absence of preexcitation, metoprolol, propranolol, and/or digoxin should be used as first-line options and verapamil as the second-line option for the chronic oral prophylaxis of SVT. 38,227

1 C-LD 4. In pregnant patients with Wolff-Parkinson-White syndrome and poorly tolerated or frequent episodes of SVT, therapy with oral flecainide or propafenone is recommended for the pharmacological management of SVT. 235,236

1 C-LD 5. In pregnant patients with tachycardia-induced cardiomyopathy, aggressive treatment of the tachycardia with beta-blockers as a first-line option and early consultation with an electrophysiologist for escalation of pharmacological therapy and/or ablation are recommended. 237

2a C-LD 6. In pregnant patients with symptomatic recurrent SVT refractory or with contraindications to digoxin, beta-blockers, or calcium channel blockers, alternative antiarrhythmic drugs, including flecainide, propafenone, or sotalol, are reasonable. 108,238

2a C-LD 7. In pregnant patients with recurrent SVT refractory or with contraindications to pharmacological therapies, catheter ablation is reasonable with attention to and techniques for eliminating or minimizing radiation exposure to as low as reasonably achievable.

163 2b C-LD

8. In pregnant patients with poorly tolerated SVT refractory or with contraindications to other pharmacological and interventional therapies, therapy with amiodarone may be considered. 126

channel blockers. Atenolol, a former FDA risk category D medication, is better avoided because of the risk of fetal growthrestriction.Ingeneral,AVnodalblockersareavoided in the presence of ventricular preexcitation. 4. Treatment of SVT in the setting of Wolff-Parkinson-White syndrome is more complex due to the risk for development of preexcited AF. Beta-blockers, verapamil, diltiazem, digoxin, and amiodarone can enhance conduction over the accessory pathway and precipitate an unstable arrhythmia if women develop AF during SVT. Medications such as flecainide and propafenone slow or block conduction over the pathwayandpreventpreexcitedAF.Althoughexperienceis limited, flecainide or propafenone can be used for the prevention of SVT episodes in patients with Wolff- Parkinson-White syndrome during pregnancy.64 5. Tachycardia-induced cardiomyopathy can occur in pregnant patients, often as a consequence of sustained focal AT.239-241 In one study, tachycardia-induced cardiomyopathy was seen in 67% of patients, yet normalization of ejection fraction (EF) was common with therapy.237 In this study, the focal atrial tachycardia mechanism was automaticity in most cases; therefore, beta-blockers are reasonable options, although in cases of treatment failure catheter ablation may be necessary. Although nonsustained focal AT may not require treatment, cardioselective betablockers, such as metoprolol, are known to be safe for the treatment of symptomatic pregnant patients. When tachycardia-induced cardiomyopathy is suspected, early consultation with an electrophysiologist is suggested. 6. Alternative antiarrhythmic medications are sometimes required when digoxin, beta-blockers, or calcium channel blockers are not effective in preventing recurrent SVT, including focal AT. Antiarrhythmics such as flecainide, propafenone, or sotalol are reasonable options for treatment of SVT in pregnant patients.64 While there is limited expe- rience using flecainide and sotalol to treat maternal arrhythmias, these medications are often used to treat fetal arrhythmias. Flecainide and propafenone are generally avoided in patients with structural or ischemic heart disease because of an increased risk of death due to arrhythmia.242

When using antiarrhythmic drugs, FDA-mandated precautions are to be observed, with attention to using the lowestpossible effective dose. 7. Catheter ablation procedures are often avoided in pregnancy due to concerns of radiation exposure to the developing fetus; however, the risk of long-term malignancy to the fetus from the dose of radiation generally required for these procedures is negligible (see Section 4.2). Damilakis et al163 demonstrated that the radiation exposure to the fetus during a regular electrophysiological study would not reach a threshold to cause significant risk of lifetime malignancy. When catheter ablation is deemed necessary, procedures are performed ideally after the first trimester, when feasible, with procedures using minimal or zero fluoroscopy to reduce the chances of poor fetal outcomes. Techniques for decreasing radiation exposure to mother and fetus include 3D mapping system and intracardiac echocardiogram.243,244 Catheter ablation can be potentially curative for SVTs of diverse mechanisms, including focal atrial tachycardia. 8. Use of amiodarone in pregnancy is avoided due to its association with thyroid disorders, bradycardia, growth restriction in the fetus, and potential adverse effects in the neonate.126 However, in pregnant patients with acuteonset or persistent SVT refractory to all other pharmacological therapies, or when other therapies, including catheter ablation, are contraindicated, intravenous or oral amiodarone remains an option. Short-term exposure to amiodarone is likely associated with fewer adverse effects on the fetus than long-term exposure.

Figure 8 Algorithm of recommendations for the management of pregnant patients with atrial ectopy. Colors correspond to the class of recommendation (COR) in Table 1.

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7.2 Management of atrial fibrillation and atrial

flutter in pregnancy

Synopsis Management of patients with AF and AFL for acute care and ongoing therapy is outlined in Figure 9. Direct current cardioversion is the first line of therapy in patients with sustained AF or AFL and hemodynamic compromise. In cases requiring ongoing pharmacological management, drug selection is based on the underlying maternal cardiac substrate, although drugs with the longest record of safe use during pregnancy are preferred. Rate control is an acceptable strategy in asymptomatic patients, but rhythm control may be necessary in the case of persistent symptoms or difficult-tocontrol ventricular response. The CHA2DS2VASc scoring system is generally calculated for evaluating thromboembolism risk with AF and AFL.257 Catheter ablation procedures can be performed with minimal or zero fluoroscopy, with a lower threshold for performing procedures with lower complexity, such as typical AFL ablation. Amiodarone, despite its risks, remains an option in refractory cases, especially in the setting of underlying SHD.

Recommendation-specific supportive text 1. Cardioversion is generally safe during pregnancy. The majority of data show no adverse effects to the fetus with direct current cardioversion.245 Any possible risks

Recommendations for the management of atrial fibrillation and atrial flutter in pregnancy

COR LOE Recommendations References 1 C-LD 1. In pregnant patients with acute-onset AF or AFL, with accompanying hemodynamic compromise or preexcitation, direct current cardioversion is recommended, with energy dosing as in the nonpregnant patient. 225,245

1 C-LD 2. In hemodynamically stable pregnant patients with AF or AFL with rapid ventricular rates (RVR), intravenous beta-blockers are recommended as the first-line option and digoxin or nondihydropyridine calcium channel blockers, alone or in combination, are recommended as second-line options for initial rate control in the absence of preexcitation. 225,226,246

1 C-LD 3. In pregnant patients with AF or AFL with persistent symptoms or RVR refractory or with contraindications to beta-blockers or calcium channel blockers, elective direct current cardioversion is recommended with anticoagulation as in nonpregnant patients. 225,245

1 C-LD 4. In pregnant patients with AF or AFL and additional risk factors that place them at high risk for thromboembolism, anticoagulation is recommended as in the nonpregnant patient. 225,226,247

2a C-LD 5. In pregnant patients with AF or AFL with persistent symptoms or RVR refractory or with contraindications to beta-blockers or calcium channel blockers, pharmacological cardioversion with ibutilide, or flecainide in the absence of SHD, is reasonable, with the choice of drug dependent on the underlying maternal cardiac substrate. 248,249

2a C-LD 6. In pregnant patients with AF or AFL with RVR, beta-blockers, digoxin, or nondihydropyridine calcium channel blockers alone or in combination, are reasonable for rate control with the choice of drug dependent on the underlying maternal cardiac substrate. 62,78,225,250-255

2a C-LD 7. In pregnant patients with AF or AFL with continued symptoms or RVR despite rate control therapy, flecainide in the absence of SHD or sotalol in the absence of severe LV dysfunction are reasonable for rhythm control, with the choice of drug dependent on the underlying maternal cardiac substrate. 78,108,124,251,

252,254,256

2a C-LD 8. In pregnant patients with hemodynamically unstable typical AFL in whom pharmacological therapy is ineffective or contraindicated, catheter ablation is reasonable with attention to and techniques for eliminating or minimizing radiation exposure to as low as reasonably achievable. 163,166

2b C-LD 9. In pregnant patients with recurrent hemodynamically unstable AF or atypical AFL in whom pharmacological therapy is ineffective or contraindicated, catheter ablation may be considered with attention to and techniques for eliminating or minimizing radiation exposure to as low as reasonably achievable.

166 2b C-LD

10. In pregnant patients with AF or AFL with continued severe symptoms or RVR, amiodarone may be considered when alternative pharmacological therapy and/or catheter ablation are ineffective or contraindicated. 128

Figure 9 Algorithm of recommendations for the management of pregnant patients with atrial fibrillation (AF) and atrial flutter (AFL). Colors correspond to the class of recommendation (COR) in Table 1. 1Choice of drug dependent on the underlying maternal cardiac substrate. 2With attention to and techniques for minimizing radiation exposure to as low as reasonably achievable. LV 5 left ventricular, RVR 5 rapid ventricular rate, SHD 5 structural heart disease.

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that may be imposed by shocks are generally balanced against the importance of restoring baseline maternal hemodynamics. 2. Retrospective database evaluations and case reports show relative safety and tolerance for the acute use of intravenous beta-blockers, digoxin, and/or calcium channel blockers for rate control in AF/AFL with RVR during pregnancy.225,246 3. Cardioversion is generally safe during pregnancy.245

Elective cardioversion is part of a rhythm-control strategy and can be done as a standalone procedure or in combination with antiarrhythmic drug therapy. When restoring sinus rhythm, stroke prevention strategies, such as anticoagulation and transesophageal echocardiogram, should be performed as in the nonpregnant state.5 4. With respect to thromboembolism risk, a populationbased study on the incidence of AF or AFL in the pregnant population reported an overall low CHA2DS2VASc score for patients without SHD, such that only 5 of 129 patients were prescribed anticoagulation with either lowmolecular-weight heparins or unfractionated heparins.225 ROPAC, however, showed that patients with SHD had a higher indication (11 of 17 patients) to receive anticoagulation.226 In the absence of valvular heart disease, anticoagulation is generally dictated by CHA2DS2VASc score, as in nonpregnant patients.9

While the thromboembolism risk is elevated during pregnancy and the immediate postpartum period, the magnitude of this risk is uncertain. Accordingly, as in the nonpregnant state, the CHA2DS2VASc scoring system or the presence of risk factors such as mitral stenosis are generally used to evaluate the thromboembolism risk in the case of AF and AFL.9,257,258 Anticoagulation protocols and dosing to minimize risk of thromboembolic events should be similar to those employed for mechanical valve management in absence of AF during pregnancy, since no anticoagulation strategy specific to AF in pregnancy exists. A thorough discussion with the mother regarding the risks and benefits of the different anticoagulation approaches as they pertain to both mother and fetus is essential. Table 7 shows anticoagulation strategies in pregnancy. Of note, direct oral anticoagulants are contraindicated in pregnancy and during breastfeeding.

Table 7 Anticoagulation protocols and dosing for pregnant patients with atrial fibrillation deemed at high risk of thromboembolic events are similar to those employed for mechanical valve

Goal INR (per valve guidelines) 1st trimester 2nd trimester 3rd trimester up to 36 weeks 36 weeks to 36 hours pre-delivery 36 hours pre-delivery Low-dose warfarin

(<5 mg daily) Continue warfarin Continue warfarin Continue warfarin LMWH UFH to stop 6 hours

before delivery

High-dose warfarin (‡5 mg daily) Continue warfarin or transition to LMWH* or UFH 6-12 weeks† with close monitoring of anti-Xa‡ or aPTT levels Continue LMWH or change to warfarin Continue LMWH or warfarin LMWH UFH to stop 6 hours before delivery

Additional information:

 Meta-analysis data in the pregnant population with mechanical heart valves show that low-dose warfarin (,5 mg daily) use throughout

pregnancy has a significantly lower risk for fetal embryopathy than higher-dose warfarin (8.25% vs 0.45%, P , 0.001).247  When higher-dose warfarin (5 mg daily) is needed to achieve goal INR, one may consider transitioning to heparin (UFH or LMWH) during the first trimester (6-12 weeks) vs continuation of warfarin.  Outcomes in the population receiving UFH throughout pregnancy were overall worse for the fetus and mother; thus this strategy is not

generally recommended in the valvular heart disease population unless other options do not exist (such as limited LMWH availability).247  Both the 2018 ESC Guidelines for the Management of Cardiovascular Diseases During pregnancy and the American Heart Association Scientific

Statement on the Management of Pregnancy in Patients with Complex Congenital Heart Disease recommend frequent monitoring of peak anti-Xa levels with the transition from warfarin to LMWH, as well as the transition from LMWH back to warfarin.12,16  Most data regarding DOAC use in pregnancy originates from pharmacovigilance and case report data. One review that evaluated 236 cases

of DOAC exposure during pregnancy found an association between DOAC use and miscarriage, along with a 4% anomaly rate with rivaroxaban use.267 Due to the paucity of data regarding DOAC use in pregnancy and possible safety concerns, DOAC use during pregnancy is contraindicated. Patients exposed to DOACs prior to becoming pregnant should discontinue the drug and undergo close pregnancy surveillance.268 *The decision regarding transitioning during this time must involve a thorough discussion with the patient as there is increased risk for embryopathy with higher-dose warfarin but a higher risk for maternal thromboembolic events with LMWH. †LMWH preferred; UFH if LMWH unavailable ‡Plasma anti-Xa levels in pregnant women with mechanical prosthetic heart valves are generally measured 4-6 hours after the morning LMWH injection (peak levels) and with dose adjustment to achieve levels between 0.7-1.2 units/mL. anti-Xa5 anti-factor Xa assay, aPTT 5 activated partial thromboplastin clotting time, DOAC 5 direct oral anticoagulants, ESC 5 European Society of Cardiology, INR 5 international normalized ratio, LMWH 5 low-molecular-weight heparin, UFH 5 unfractionated heparin.

5. A significant portion of the data regarding safety of antiarrhythmic medication use in pregnancy originates from studies related to the management of fetal arrhythmias.78,108,251,252 In addition, both case and database reports have demonstrated ibutilide safely administered for the acute conversion of AF or AT during pregnancy without reported adverse fetal outcomes.225,248 Intravenous magnesium is often administered prior to ibutilide to mitigate the risk of torsades de pointes (TdP).229 Oral flecainide bolus has been shown to be effective for acute termination of AF.259 Case reports have also shown this strategy to be effective in pregnancy, although numbers are small.249 6. A database report showed that up to two-thirds of women with AF or AFL and without SHD may not require continued medical therapy for AF during pregnancy.225 In cases requiring continued maintenance, digoxin appears to be well tolerated and safe for the fetus but less effective for lowering the maternal heart rate in the setting of high adrenergic state.78,251,252,254 While most retrospective studies have not associated beta-blocker use in pregnancy with teratogenicity, some studies have demonstrated an association of beta-blockers with low birth weight, as many of these studies cannot factor for the underlying maternal disease.250,255 However, a study looked at a subgroup of patients without SHD who were treated with beta-blockers and found that betablocker use was associated with an increased risk for low birth weight.62 With respect to the nondihydropyridine calcium channel blockers, there are reports of verapamil-associated fetal demise when used in combination with other nodal blockers, mainly in intravenous form.73,260 More recently, a retrospective database study on the use of calcium channel blockers in more than 800 women during pregnancy did not find a significantly increased risk for congenital anomalies.253 7. The majority of the data regarding the safety of flecainide has been obtained in the fetal SVT population but is applicable to other maternal arrhythmias, in view of the record of safety. Most of the studies have shown fairly good maternal and fetal tolerance to flecainide. In cases of maternal AFL, flecainide may increase conduction in the AV node and should be used with caution. Propafenone use during pregnancy has also been reported and is generally well tolerated, although the data are more limited compared with flecainide.78,108,251,252 Similar to flecainide, most data regarding the safety profile of sotalol during pregnancy have been collected in the setting of treatment for fetal SVT, and sotalol like- wise appears to be well tolerated by the fetus, particularly when used at a dose of less than 320 mg per day, with standard monitoring recommended for the mother. In absence of concomitant fetal hydrops, sotalol appears to be well tolerated when initiated between the second and third trimesters.124,254,256

8. Recent guidelines for the management of adult patients with SVT recommend catheter ablation as a class I option for rhythm management of AFL.8,19

Additionally, there is increasing operator experience with minimal to no fluoroscopy ablation, particularly for arrhythmias that are right atrial in origin.261,262 Owing to the highly successful nature of right-sided typical AFL ablation, catheter ablation is a reasonable option, after careful evaluation of the risks and benefits in the pregnant patient, and ideally should be performed in a center or by operators experienced in ablation techniques that eliminate or minimize fluoroscopy exposure.19,164,243,263,264 9. In select cases in which persistent AF or atypical AFL present a risk to the mother or fetus, and there is a contraindication to or failure of pharmacological therapy, catheter ablation utilizing minimal to no fluoroscopy remains an important option. An important consideration is the complexity of the procedure, as the risk of potential complications is higher and the ability to minimize fluoroscopy use may be less predictable. Ideally, the procedures should be performed in a center or by operators experienced in ablation techniques that eliminate or minimize fluoroscopy exposure.164,166,243,262,265 10. Amiodarone remains an option for treatment of refractory arrhythmias when the potential benefit warrants its use, despite potential risks, after a careful assessment of the risks and benefits and keeping in mind the duration of use, severity of the arrhythmia, fetal gestational age and underlying maternal substrate. Amiodarone therapy is indicated for the shortest duration possible. The most common fetal complication is fetal hypothyroidism, which is typically transient and treated effectively with shortterm maternal therapy.128 Therefore, fetal monitoring for signs of clinical hypothyroidism is necessary; it is also important to monitor and treat maternal thyroid indices in the setting of clinical thyroid dysfunction.266 In addition, amiodarone has the potential for direct neurotoxicity, which may lead to neurodevelopmental abnormalities.126 With respect to other antiarrhythmic medications, very limited data exist for the use of dofetilide during pregnancy; nevertheless it can be used with consideration of the risks versus benefits.

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7.3 Management of ventricular arrhythmias in

pregnancy not associated with inherited arrhythmia syndromes

Synopsis For hemodynamically significant VT, direct current cardioversion has been shown to be safe during pregnancy. When pharmacological therapy is deemed necessary, the choice of antiarrhythmic agent depends on the etiology of the specific ventricular arrhythmia and underlying cardiovascular substrate. It is ideal if patients considering pregnancy undergo ablation therapy or ICD placement before conception; however, the procedure can be performed safely during pregnancy when needed. When

Recommendations for the management of ventricular arrhythmias in the pregnancy not associated with inherited arrhythmia syndromes

COR LOE Recommendations References

1 C-LD 1. In pregnant patients with sustained VT and hemodynamic compromise, direct current cardioversion is recommended, with energy dosing as in the nonpregnant patient. 245,269,270

1 C-LD 2. In pregnant patients with idiopathic VT and hemodynamic stability, intravenous beta-blocker or adenosine for outflow tract VT and intravenous verapamil for fascicular VT are recommended as first-line options. 271-275

1 C-LD 3. In pregnant patients with hemodynamically stable VT, when pharmacological therapy is deemed necessary, intravenous procainamide is recommended for acute therapy. 229,276-278

1 C-LD 4. In pregnant patients with sustained VT refractory or with contraindications to beta-blockers and/or other antiarrhythmic drugs, synchronized cardioversion is recommended, with energy dosing as in the nonpregnant patient. 245,269,270

1 C-LD 5. In pregnant patients who meet indications for implantable cardioverter defibrillator (ICD) placement due to sustained ventricular arrhythmias or due to high risk for sudden cardiac death, device implantation is recommended with attention to and techniques for eliminating or minimizing radiation exposure to as low as reasonably achievable. 269,279-282

1 C-LD 6. In pregnant patients with ICDs prior to pregnancy, it is recommended to continue routine ICD care according to the underlying cardiac substrate. 269,279,283,284

1 C-LD 7. In women who are considering pregnancy and would otherwise meet indications for ICD, pacemaker, or cardiac resynchronization therapy device placement, these procedures should be performed prior to pregnancy and according to the underlying cardiac substrate. 280-282

1 C-LD 8. In pregnant patients with chronic or recurrent VT, beta-blockers, alone or in combination with other antiarrhythmic drugs, are recommended for arrhythmia suppression due to their overall safety profile in pregnancy. 62,255,285

1 C-LD 9. In pregnant patients with recurrent VT refractory or with contraindications to beta-blockers who require additional antiarrhythmic drug therapy, treatment with flecainide, sotalol, or mexiletine is recommended with the choice of drug based on the underlying cardiac substrate. 78,108,124,251,252,

254,256,286

2a C-LD 10. In pregnant patients with recurrent symptomatic or hemodynamically unstable VT in whom pharmacological therapy is either ineffective or contraindicated, catheter ablation is reasonable with an experienced operator and with attention to and techniques for eliminating or minimizing radiation exposure to as low as reasonably achievable. 166,287,288

2a C-LD 11. In pregnant patients with recurrent VT associated with hemodynamic impairment or ICD shocks, amiodarone is reasonable for arrhythmia suppression if alternative therapies, including ablation, are contraindicated or ineffective. 128,285

2b C-LD 12. In pregnant patients who meet indications for sudden death prevention due to high-risk features or VT that may be of a reversible etiology, such as peripartum cardiomyopathy, a wearable cardioverter defibrillator may be reasonable. 289,290

drug therapy is required, drugs with the longest record of safe use during pregnancy, such as sotalol or intracordal agents, are preferred in the absence of SHD. Catheter ablation can be done safely in pregnancy, especially when performed with minimal or no fluoroscopy use. Amiodarone remains an option for refractory cases, or when alternative options are contraindicated. An algorithm of the recommendations for the management of pregnant patients with ventricular arrhythmias is shown in Figure 10.

Recommendation-specific supportive text 1. Direct current cardioversion is generally safe during pregnancy and effective particularly in cases of hemodynamic compromise. The majority of data show no adverse effects to the fetus with direct current cardioversion.245,270,291 Furthermore, literature in the ICD population also supports the lack of significant risk to the fetus with maternal ICD shocks.269 Any possible risk to the fetus that may be imposed by shocks must be balanced against the importance of restoring baseline maternal hemodynamics. 2. Data show that outflow tract ventricular arrhythmias in pregnant patients with structurally normal hearts tend to respond well to beta-blockers.273,275 Additionally, adenosine appears to be well tolerated by both mother and fetus during pregnancy and may also be used to treat outflow tract VT.271,292 Importantly, repletion of potassium and/ or magnesium may be required for patients who are at risk for significant electrolyte disturbances presenting with outflow tract arrhythmias. One case report described such a situation in which outflow tract VT was successfully treated with magnesium repletion in a patient with severe hypomagnesemia and hypokalemia due to hyperemesis gravidarum.293 For the acute management of fascicular VT, intravenous verapamil has been used successfully without maternal or fetal complications.272,274 3. In the general population, data show that procainamide is better tolerated and more effective than amiodarone for acute termination of monomorphic VT.278

Similarly, procainamide efficacy was higher than lidocaine when evaluated in both small randomized prospective and retrospective studies.276,277 With respect to safety in pregnancy, a case report detailed procainamide use for successful management of sustained VT in a pregnant patient without any adverse fetal or maternal effects.229 There are no data on intravenous sotalol use in pregnancy. 4. Cardioversion is generally safe in pregnancy.245,269,270,291 Any possible risk that may be imposed by shocks must be balanced against the importance of restoring baseline maternal hemodynamics. 5. As with pacemakers, transvenous ICD placement can be performed safely during pregnancy when deemed appropriate with the utilization of strategies for minimizing fluoroscopy exposure, including use of singlelead or subcutaneous systems where possible (refer to Section 4.2 for radiation-reduction strategies). In general, the fluoroscopy requirements of transvenous ICD placement are low enough that the benefits to the mother outweigh the risks of radiation. While there does not appear to be harm when performing defibrillation testing, the necessity of such testing should be weighed against possible risk of arrhythmia-induced hypotension.279 While a subcutaneous ICD would negate the risk of fluoroscopy, and a single case report has described delivery management in the event of a previously placed subcutaneous ICD, data are lacking regarding implantation of subcutaneous ICDs during pregnancy.294

6. Most reports have not shown an increase in ICDrelated complications during pregnancy compared with the general ICD population, particularly for prepectoral transvenous systems.269,279,283,284 Measures, such as the use of beta-blockers or antiarrhythmic drugs, for avoiding sustained hemodynamically unstable arrhythmias may be considered in high-risk patients after weighing the risks and benefits of such approaches.283,284 Notably, appropriate ICD therapies, such as shocks, do not appear to have detrimental effects on the fetus.269,279,283,284 7. Device placement has been performed safely during pregnancy, with measures to avoid fetal fluoroscopy exposure; however, there is less risk to the fetus if devices are implanted prior to pregnancy.280-282 Since arrhythmias tend to worsen during pregnancy, pregnancy in women with indications for cardiovascular implantable electronic devices can carry some additional risks. In these cases, preconception counseling regarding maternal and fetal risk from the underlying disease is crucial. Device implantation prior to pregnancy in these cases can reduce both the risk of arrhythmic complications during pregnancy and risks to the fetus if the procedure became necessary during pregnancy.

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Figure 10 Algorithm of recommendations for the management of pregnant patients with ventricular arrhythmias. Colors correspond to the class of recommendation (COR) in Table 1. 1Choice of drug dependent on the underlying cardiac substrate. 2With techniques for minimizing fluoroscopy as low as reasonably achievable. CRT 5 cardiac resynchronization therapy, ICD 5 implantable cardioverter-defibrillator, SCD 5 sudden cardiac death, VT 5 ventricular tachycardia.

8. Registry data show that most pregnant women with SHD and VT treated with medications receive betablockers.285 Importantly, beta-blocker use has not been associated with teratogenicity, although some betablockers have been associated with low fetal birth weight. Therefore, prospective benefits for arrhythmia suppression must be thoroughly evaluated against that potential risk.62,255 9. Most safety data regarding the use of sotalol and flecainide during pregnancy are derived from the management of supraventricular fetal arrhythmias during pregnancy, and the most commonly studied class IC agent has been flecainide over propafenone.15 While propafenone appears to be safe and is used, data on its use are scant compared with that on flecainide. In general, flecainide and sotalol are well tolerated by both the fetus and the mother. For sotalol, the dose is less than 320 mg per day administered under standard cardiac monitoring. In the absence of concomitant fetal hydrops, sotalol appears to be well tolerated when initiated between the second and third trimesters.78,108,124,251,252,254,256 However, caution is advised when using sotalol in pregnant patients with significant ventricular dysfunction. Case report data show that mexiletine may be safe for both the pregnant patient and the fetus.286 10. Hemodynamically significant VT can be potentially life threatening to both the mother and fetus. Ablation during pregnancy for medically refractory VT has been reported. Sadek et al166 described a fluoroscopy-free ablation in a pregnant patient with refractory VT in the setting of ACM, whereas Lahiri et al288 described a fluoroscopy-free ablation for medically refractory fascicular VT in a pregnant patient. Kambiré et al287 reported on a patient with persistent outflow tract VT refractory to medical therapy necessitating ablation. All cases were notable for the lack of complications. 11. The ROPAC database reported the use of amiodarone in 7.1% of cases of VT in the setting of maternal heart disease.285 The most common fetal complication is fetal hypothyroidism, which is typically transient and effectively treated with short-term therapy.128 Therefore, fetal monitoring for signs of clinical hypothyroidism is necessary. In addition, amiodarone has the potential for direct neurotoxicity, which may lead to neurodevelopmental abnormalities.295 Nevertheless, the potential risk has to be balanced against the detrimental effects of intractable ventricular arrhythmia to both the mother and fetus. Dose and duration of amiodarone therapy should be minimized as much as possible. 12. Peripartum cardiomyopathy can be associated with ventricular arrhythmias.270 However, the prospective Investigations of Pregnancy Associated Cardiomyopathy study showed that 72% of patients with peripartum cardiomyopathy experienced recovery (EF .50%) by 1 year postpartum, thus negating the need for permanent sudden cardiac death prevention with an ICD.296 As such, an alternative to ICD placement during pregnancy is a wearable cardioverter defibrillator, particularly if the cardiomyopathy was expected to recover. However, predictors of those who would most benefit from this therapy are not well established. Notably, a database report of wearable cardioverter defibrillator use in 107 patients with peripartum cardiomyopathy showed no appropriate or inappropriate shocks in the population; 12 of the patients were prescribed the wearable cardioverter defibrillator prepartum.289 Conversely, Duncker et al290 showed that 3 of 7 patients with peripartum cardiomyopathy (mean EF 5 18%) received 4 appropriate and successful wearable cardioverter defibrillator shocks for VF, such that the authors of that study recommended consideration of the wearable cardioverter defibrillator in patients with peripartum cardiomyopathy and severely reduced EFs. Furthermore, the Investigations of Pregnancy Associated Cardiomyopathy study also showed that patients with peripartum cardiomyopathy and an EF 30% with an LV end diastolic diameter 6.0 cm did not recover by 1 year postpartum.296 As such, patients with a large LV enddiastolic diameter coupled with a severely reduced EF may warrant ICD implantation earlier in the process.

Section 8 Management of pregnant patients with bradycardia and/or heart block Bradycardia is an unusual finding in pregnancy. Pregnant patients with bradycardia should undergo evaluation similar to that indicated in the nonpregnant population, including a detailed history and physical examination.11 Complete AV block in the absence of SHD is generally well tolerated in pregnancy.297 Establishing an association between bradycardia and symptoms is the key to determining whether a pacemaker is indicated.298 When pacemaker implantation is deemed necessary during pregnancy, strategies can be used to minimize fluoroscopy exposure, including application of current technologies and single-lead systems (see Section 4.2 for radiation-reduction strategies).299 Temporary ventricular pacing remains a temporizing option that can be individualized as indicated.

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Synopsis Cardiac pacemakers appear to be well tolerated during pregnancy.269,279,283,284,303,306 The frequency of monitoring and follow-up should center around the underlying maternal disease. When cardiac device implantation is indicated during pregnancy, device placement should be performed with care to minimize fluoroscopy exposure to the fetus.280-282 Conversely, when there is no strong indication for device placement, particularly in cases of stable congenital AV block, pregnancy does not appear to increase the risk from this etiology of AV block. As such, temporary pacing during pregnancy or delivery is not usually necessary.306 Recommendations for the management of pregnant patients with bradycardia and/or heart block are summarized in Figure 11.

Recommendation-specific supportive text 1. Although in a majority of pregnant patients who present with advanced heart block the etiology is congenital, other diagnostic possibilities must be excluded. Transthoracic echocardiography can reveal conditions such as cardiomyopathy, valvular disease, congenital defects, tumors, infiltrative processes, and pericardial and great vessel abnormalities.29,308 Cardiac MRI is particularly useful if additional information is required to identify infiltrative disease processes in select cases, or when echocardiogra- phyis not feasible or of poor quality, especially when those diagnostic possibilities are suspected based on the clinical presentation.219 However, the use of gadolinium is typically avoided during pregnancy, in view of concerns for potential of causing harm to the fetus based on theoretical considerations and animal studies.309 Thus, gadolinium studies are best done in the postpartum period, except in cases where the benefits clearly outweigh the possible risks to the fetus, which are for the most part unknown. 2. Minimizing fluoroscopic exposure to the fetus is discussed in Section 4.2. In the case of pacemaker implantation, modern technology enables placement of the pacemaker with no fluoroscopy or with minimal exposure.280-282 Vascular access may be obtained utilizing landmark or ultrasound guidance.281,282 Evaluation of lead position may be obtained via intracardiac echocardiography; even when fluoroscopy is required, radiation can be kept to low amounts, in some cases even as low as ,1 second.282

3. The use of temporary transvenous pacemakers has been reported in pregnant women with symptomatic bradycardia around the time of delivery.310 Dalvi et al302 reported 3 cases that required temporary pacing during labor; however, only 2 required permanent pacemaker after delivery due to recurrence of symptoms with weaning of temporary pacing.302 Although data are limited, temporary pacing may be used as a bridge to permanent pace-

Recommendations for management of pregnant patients with bradycardia and/or heart block

COR LOE Recommendations References

1 C-LD 1. In pregnant patients who present with advanced heart block or conduction system disease, evaluation with transthoracic echocardiogram is recommended with cardiac MRI reserved for select cases when myocardial and/or infiltrative processes are suspected and if done in the postpartum period. 300,301

1 C-LD 2. In pregnant patients with irreversible symptomatic bradycardia due to third-degree or second-degree Mobitz type II heart block or severe sinus node dysfunction, with syncope or presyncope that may place the mother and/or the fetus at risk, permanent pacemaker placement is recommended, with attention to and techniques for eliminating or minimizing radiation exposure to as low as reasonably achievable. 280-282,299

1 C-LD 3. In pregnant patients with symptomatic bradycardia refractory or with contraindications to pharmacological therapy, temporary ventricular pacing is recommended for those at risk of hemodynamic instability and/or syncope in the peripartum period. 302-304

1 C-LD 4. In pregnant and postpartum patients with asymptomatic sinus bradycardia or Mobitz type I AV block without evidence of SHD, reassurance is recommended with no need for intervention.

305 2a B-NR

5. In pregnant patients with hemodynamically stable and asymptomatic congenital heart block who were deemed potential candidates for permanent pacemaker placement prior to pregnancy, it is reasonable to defer the decision on device implantation until after delivery. 303,304,306

3: No benefit B-NR 6. In pregnant patients with hemodynamically stable and asymptomatic congenital heart block with an acceptable ventricular rate, a narrow QRS complex, and normal ventricular function, prophylactic temporary pacemaker placement around the time of delivery is not recommended. 297,306,307

maker placement either before or after delivery, depending on the clinical circumstances, in a patient with hemodynamically significant bradycardia, especially if pharmacological options such as isoproterenol are ineffective or contraindicated.302,303 4. Sinus bradycardia is rare during pregnancy since the physiological response is for the pulse to accelerate 10- 20 bpm over baseline to increase cardiac output. Yet, modest bradycardia can be seen after delivery.311 Mobitz type I AV block is common and rarely implies progressive conduction system disease.11 Both situations can be benign in the absence of hemodynamic impairment and SHD.305 5. Hidaka et al306 reported their experience with 32 pregnancies in the setting of high-grade AV block without pacemaker. Of note, a significant portion of these patients had congenital heart block, and therefore had relatively stable junctional escape rhythms. While all patients did well during pregnancy, 1 patient suffered from syncope and sudden death 1 month postpartum; thus, close surveillance of pregnant patients with complete AV block is warranted, and implantation of pacemakers during or after pregnancy should follow guideline-based recommendations for the general population.306 Data also show that patients with baseline AV nodal block may experience worsening AV nodal function during pregnancy, with function usually improving to baseline postpartum.303,306

6. Delivery appears to be well tolerated in hemodynamically stable pregnant patients with advanced AV block who are asymptomatic with an acceptable ventricular rate, a narrow QRS complex, and normal ventricular function. Reported cases in the literature support conservative management, especially in the setting of congenital heart block patients with narrow escape rhythms. Pacemaker implantation is not indicated in these patients around the time of delivery.306

Figure 11 Management of bradycardia and/or heart block in the pregnant patient. Colors correspond to the class of recommendation (COR) in Table 1. 1Cardiac magnetic resonance imaging (MRI) should be reserved for select cases in which myocardial and/or infiltrative processes are suspected and if done in the postpartum period. 2Due to third-degree or second-degree Mobitz type II heart block or severe sinus node dysfunction. 3For patients at risk of hemodynamic instability and/or syncope in the peripartum period. 4With attention to and techniques for eliminating or minimizing radiation exposure to as low as reasonably achievable. AV 5 atrioventricular, SHD 5 structural heart disease.

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Section 9 Advanced cardiac life support for the pregnant patient Advanced cardiac life support (ACLS) recommendations are provided here because of their frequent association with arrhythmias during pregnancy; however, many of these recommendations also apply to nonarrhythmic cardiac arrests during pregnancy. Additional guidance can be found in the AHA Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care.312

Synopsis Except for some isolated differences, in general, the management of cardiac arrest in the pregnant patient is the same as in nonpregnant patients, although a multidisciplinary approach, including coordination among maternal, obstetric, and neonatal resuscitation teams, is critical to optimizing maternal and neonatal outcomes. Cardiac arrest is a rare obstetric complication that poses a great challenge to obstetric caregivers because of the need for simultaneous implementation of BLS and/or ACLS and preparation for resuscitative uterine evacuation. A sum- mary of the recommendations for management of the pregnant patient with ACLS is provided in Figure 12.

Recommendation-specific supportive text 1. Recognition of women at risk of clinical deterioration allows for initiation of monitoring and the opportunity for cardiovascular stabilization, resulting in significant reductions in maternal morbidity. The clinical criteria to be monitored include maternal heart rate .130/min, respiratory rate .30/min, mean arterial pressure ,55

Recommendations for advanced cardiovascular life support for the pregnant patient

COR LOE Recommendations References

1 B-NR 1. Obstetric caregivers should monitor high-risk pregnant patients for early warning signs of impending cardiovascular instability in order to activate cardiovascular life support teams in a timely manner.

313 1 C-LD

2. Basic life support (BLS) and ACLS response in obstetric centers should include plans for immediate activation of a specialized obstetric-oriented code team with preparation for resuscitative hysterotomy and simultaneous activation of a neonatal code team. 314-316

1 C-LD 3. In the pregnant patient with cardiac arrest in the earlier parts of gestation, cardiopulmonary resuscitation (CPR) should be performed as in nonpregnant patients.

317 1 C-LD

4. In the pregnant patient undergoing CPR in the latter part of gestation when the uterine fundus is above the level of the maternal umbilicus, leftward and upward displacement of the uterus should be performed. 174,175,318

1 C-LD 5. Chest compressions of the pregnant patient should be done with the hands placed in the center of the lower half of the sternum as in the nonpregnant patient.

319 1 C-LD

6. In pregnant patients with a shockable rhythm, immediate defibrillation and medical management of arrhythmia should be provided as in nonpregnant patients, including standard defibrillation energy dose recommendations.

161 1 C-LD

7. In pregnant patients, defibrillator pad placement should be in the anterolateral position as in nonpregnant patients, but the lateral pad should be placed below and/or lateral to avoid breast tissue. 155,160,161

1 C-LD 8. In pregnant patients with in-hospital cardiac arrest when uterine evacuation is deemed necessary, resuscitative hysterotomy should be performed at the site of the arrest. 317,320,321

1 C-EO 9. In pregnant patients with cardiac arrest, resuscitation efforts and defibrillation of a shockable rhythm should be administered immediately, without delays for fetal assessment/monitoring or the removal of fetal monitoring devices.

1 C-EO 10. In pregnant patients undergoing CPR, ACLS medication should be given as in the nonpregnant patient without concern for fetal exposure or teratogenicity.

2a C-LD 11. In pregnant patients with cardiac arrest at .20 weeks’ gestational age or if uterine fundus is palpable above the umbilicus, it is reasonable to perform resuscitative hysterotomy early in resuscitative efforts, with the goal of uterine evacuation ideally within 5 minutes of the onset of cardiac arrest, to maximize the chance of maternal survival. 317,322,323

2a C-LD 12. In pregnant patients with cardiac arrest, resuscitative uterine evacuation with assisted vaginal delivery is reasonable as an alternative to resuscitative hysterotomy, if deemed feasible by the obstetric team. 324

Figure 12 Management of cardiac arrest in the pregnant patient. Colors correspond to the class of recommendation (COR) in Table 1. ACLS 5 advanced cardiac life support, BLS 5 basic life support, GA 5 gestational age, VF 5 ventricular fibrillation.

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mmHg, oxygen saturation ,90%, abnormal body temperature, fetal heart rate .160/min, altered mental status, and pain out of proportion to stage of labor.313 2. Coordination of multidisciplinary emergency response teams is challenging and can result in delays in delivery of lifesaving care, particularly in the obstetric setting. Organization of specialized combined obstetric and neonatal emergency response teams has been shown to improve team performance in simulation-based training. Mobilization of multidisciplinary teams must be immediate and simultaneous, with caregivers initiating BLS, ACLS, and preparation for uterine evacuation simultaneously.314-316 3. Management of cardiac arrest during pregnancy is the same as for nonpregnant adult patients, especially in earlier stages of pregnancy, when a smaller uterus does not cause aortocaval compression and as such would not compromise blood return.22,23 4. At approximately 20 weeks, the uterine fundus is palpable at the level of the umbilicus and may start to adversely affect hemodynamics in the supine pregnant woman via aortocaval compression. Decompression of these major vessels by manual leftward and upward displacement of theuterus(Figure13)byafirstrespondermaysignificantly improve hemodynamics during resuscitation, without interfering with resuscitative efforts, including chest compressions.21,174,175 Alternatively, Butcher et al,318 using a manikin model, compared the effectiveness of chest compressions in the supine position with manual uterine displacement versus lateral tilt with a foam-rubber wedge, and concluded that either method was suitable for CPR in pregnant women, although a number of participants in the studyfounditeasiertoprovideCPR with manualdisplacement. Additional benefits of manual left uterine displacement over tilt may include easier airway management and defibrillation, since the patient remains supine.

5. There is no evidence of cardiac displacement by the effect of the gravid uterus, even in a full-term pregnancy. Modification of hand position for chest compressions is therefore not necessary for the resuscitation of the pregnant patient.22,319 As in nonpregnant patients, it is important to prioritize the efficacy of chest compressions during resuscitation, and chest compression quality is maximized when the pregnant patient is flat on a firm surface.318,325

6. Immediate defibrillation of a shockable rhythm is associated with improved survival. Thoracic impedance, which is an important determinant of defibrillation efficacy, is not significantly altered in pregnancy, and therefore standard energy doses are administered as in nonpregnant patients.22,23,161 7. Thoracic impedance, when measured through defibrillation pads placed in the standard anterolateral position, is adversely affected when the lateral defibrillation pad is placed on the breast, when compared with placement below breast tissue on the chest wall (see Section 4.1).160 8. Transportation of the patient from the site of cardiac arrest for resuscitative hysterotomy is associated with significant delay in completion of the procedure, and with worse maternal and neonatal outcomes. For this reason, it is crucial to prepare for and complete uterine evacuation wherever resuscitation is being performed (an operating room is not required).317,320,321 9. Identification of a shockable rhythm and immediate cardioversionordefibrillationarecritical tomaternalandfetal survival ofcardiac arrest. Maternaldefibrillation orcardioversion is unlikely to have adverse effects on fetal cardiac rhythm, or on fetal monitoring systems placed externally or internally (fetal scalp monitor). For this reason, it is critical that maternal defibrillation is not delayed for the initiation or discontinuation of fetal monitoring procedures. Additionally, fetal monitoring could interrupt or distract caregivers from maternal resuscitation efforts. 10. Although pregnancy can alter the pharmacokinetics of cardiovascular medications with respect to clearance and metabolism, as well as volume of distribution, there is insufficient evidence to warrant different pharmacological management of arrhythmias during resuscitation of pregnant patients from that indicated for nonpregnant patients.60,326,327 The ideal location for intravenous access is above the diaphragm. If it is not possible to place the IV centrally, the interosseus humerus is a good alternative location. 11. During cardiac arrest, the most immediate goal is restoring maternal hemodynamics. Uterine evacuation during maternal resuscitation has been shown to improve maternal and neonatal survival, particularly if completed very early after the onset of cardiac arrest. In fact, some case reports have demonstrated return of spontaneous circulation only after the uterus was evacuated.328 The goal is to initiate delivery within 5 minutes to minimize risk of hypoxic brain injury to the fetus. In a study of cardiac arrest in the United Kingdom, perimortem cesarean delivery was performed in 49 women; the time from collapse to perimortem cesarean section was significantly shorter in women who survived (median interval 3 vs 12 minutes, P 5 0.001).317 However, the goal to initiate delivery within 5 minutes is rarely achieved,

Figure 13 Manual leftward and upward uterine displacement.

and successful outcomes of evacuation have been reported after much longer intervals since the onset of the arrest.21 Preparation for resuscitative hysterotomy (or perimortem cesarean delivery) is therefore a key part of initial maternal resuscitative efforts to maximize maternal and neonatal survival.317,322,323,328,329 12. If maternal cardiac arrest occurs during labor, provided that the cervix is fully dilated, assisted vaginal delivery may be an alternative to resuscita- tive hysterotomy to evacuate the uterus. In 1 small series that included 5 pregnant patients with cardiac arrest, 2 underwent vaginal deliveries that resulted in good maternal and fetal outcomes regardless of the time between the arrest and delivery. The authors suggested as a possible explanation that the patients were either fully dilated or pushing at the time of arrest, allowing prompt delivery.324

Section 10 Arrhythmia management in the pregnant patient with arrhythmogenic structural cardiac substrates Patients with preexisting arrhythmogenic cardiac conditions (SHD, CHD, valvular heart disease, ACM, and hypertrophic cardiomyopathy [HCM]) are particularly at risk for arrhythmias during pregnancy. The arrhythmias associated with these conditions are likely more common during pregnancy due to physiological stress, including associated hormonal changes and increased volume. In turn, a first manifestation of arrhythmias duringpregnancy may indicate the presence of anundiagnosed underlying cardiac condition. Thus, comprehensive evaluation of a patient with no prior cardiac disease presenting with new arrhythmias should include evaluation for structural abnormalities. This is important because the selection of therapies can be dependent on the underlying condition.

10.1 Arrhythmia management in the pregnant

patient with structural heart disease

Synopsis SHD may coexist with incident arrhythmias during pregnancy. Given the physiological stress of pregnancy, previously undiagnosed structural abnormalities may manifest for the first time during the pregnancy period. Thus, when a patient presents with new arrhythmias, it is important to evaluate clinically and echocardiographically for new or worsening structural cardiac abnormalities. Furthermore, some medications used to manage patients with SHD may be contraindicated during pregnancy. Thus, preconception counseling is valuable to advise on risk during pregnancy to the mother and the fetus, and to consider appropriate medications. Recommendation-specific supportive text 1. Patients with preexisting SHD may be at higher risk of maternal and fetal complications than individuals without heart disease. Roos-Hesselink et al332 demonstrated that, among 1321 women with CHD, valvular heart disease, ischemic heart disease, and cardiomyopathy, maternal death occurred in 1% of the population, compared with 0.007% in an otherwise normal population. Similarly, fetal and neonatal mortality were higher than in the normal population. Of note, both maternal and fetal/neonatal mortality were higher in developing countries. Drenthen et al334 reported that the most common pregnancy-related complications include arrhythmias and heart failure. Thus, given the high incidence of events, it is important to have clear discussions regarding the risks and likelihood of successful pregnancy, with preconception counseling provided by a cardiologist or electrophysiologist and maternal-fetal medicine specialist with expertise in the management of pregnant patients with cardiovascular disease. 2. In general, new arrhythmias, such as atrial or ventricular arrhythmias, that occur during pregnancy are uncommon. However, when they do occur, they can indicate

Recommendations for arrhythmia management of the pregnant patient with structural heart disease

COR LOE Recommendations References 1 C-LD 1. Patients with SHD and a history of arrhythmias who are contemplating pregnancy should have preconception counseling. 46,330-332 1 C-LD 2. Pregnant patients who present with new complex SVT or VT should undergo an evaluation for SHD. 46,330-333

1 C-LD 3. Pregnant patients with preexisting SHD who develop new arrhythmias during pregnancy should have a clinical and echocardiographic evaluation to exclude changes in cardiac structure and/or function. 46,330-332

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the presence of preexisting or previously unrecognized SHD.15 This is relevant in nonpregnant and pregnant patients, with echocardiography and clinical evaluation being critical to rule out SHD. Recognition of the presence of underlying heart disease may, in turn, help inform the patient regarding risk of maternal or fetal events.330,332,334 In addition to clinical evaluation and echocardiography, an ECG is also important when the patient is in sinus rhythm, as the presence or absence of ECG abnormalities (eg, conduction system disease) may suggest the presence of disease requiring more advanced imaging (eg, MRI). 3. It is well recognized that pregnancy can be associated with increased physiological stress on the heart. Thus, in patients with known SHD, there is the potential for further decompensation depending on the specific cardiac lesion. This may manifest as incident arrhythmias during pregnancy. Thus, in patients with known SHD, it is important to ensure that there has not been deterioration in cardiac function or structure. Silversides et al46 and Drenthen et al334 demonstrated that while arrhythmias were the most common cardiac complication in patients with SHD, heart failure was second most common. The devel- opment of new arrhythmias may portend worsening cardiac status.

10.2 Arrhythmia management in the pregnant

patient with congenital heart disease Since the 1960s, surgical intervention for CHD, coupled with advances in medical and cardiac implantable electronic device therapy, have culminated in a growing cohort of patients with CHD who survive well into adulthood.335 Arrhythmias increase in prevalence as adults with CHD age, are the most frequent reason for hospital admission, and, along with heart failure, are the leading cause of death.336,337 A spectrum of arrhythmias may be encountered in adults, including pregnant women with CHD, with several types often coexisting. Bradyarrhythmias may involve disorders of the sinus node, AV node, His-Purkinje system, or intra-atrial propagation, and are often associated with tachycardias in bradycardiatachycardia syndrome. About 50% of patients with CHD will develop an atrial tachyarrhythmia by the time they reach young adulthood.338 Ventricular arrhythmias are the most frequent cause of sudden death in several types of CHD, with an overall risk up to 100-fold higher than age-matched controls.339

Recommendations for arrhythmia management in the pregnant patient with congenital heart disease

COR LOE Recommendations References

1 B-NR 1. Patients with CHD and arrhythmias who are considering pregnancy should receive preconception counseling, with input from an adult congenital cardiologist or electrophysiologist with expertise in adult CHD to determine maternal cardiac, obstetric, and fetal risks. 46,331

1 B-NR 2. Patients with Fontan circulation and refractory arrhythmias who are contemplating pregnancy should be advised that pregnancy is potentially harmful until the arrhythmias are addressed, due to the association with adverse maternal and fetal outcomes. 340-343

1 C-LD 3. In pregnant patients with CHD and intra-atrial reentrant tachycardia (IART), AF, or AFL, therapeutic anticoagulation regimen specific to pregnancy is recommended for stroke prevention. 226,344-346

1 C-LD 4. In pregnant patients with CHD and highly symptomatic or poorly tolerated acute onset IART, AF, or AFL, attempts to restore sinus rhythm (rhythm control) are recommended in preference to rate control only. 226,333,344,347-349

1 C-LD 5. In pregnant patients with complex CHD and hemodynamically unstable cardiac arrhythmias, urgent or emergency cardioversion is recommended as in the nonpregnant patient. 38,155,159

1 C-LD 6. In pregnant patients with CHD and recurrent VT, antiarrhythmic drug therapy should be tailored according to the underlying cardiac substrate and potential impact of the drug on the developing fetus, and preferably in conjunction with an electrophysiologist with expertise in CHD. 285,333

(Continued)

Synopsis Preconception counseling and anticipatory management before pregnancy is important for all patients with CHD starting in childhood, and ideally arrhythmias should be managed prior to pregnancy. In general, anticoagulation for atrial arrhythmias is the same as in nonpregnant patients. In highly symptomatic patients with atrial arrhythmias, a rhythm control strategy is generally pursued, and cardioversion can be administered safely when patients are unstable or refractory to pharmacological therapy. When pharmacological therapy is necessary, the drug of choice depends on the underlying individual substrate, but drugs with the longest record of safe use during pregnancy are generally first-line agents. When arrhythmias are refractory to medical therapy, catheter ablation remains an option. Amiodarone is generally reserved for refractory cases, balancing benefits versus potential risks of side effects to the fetus. An algorithm of recommendations for the management of pregnant patients with CHD is shown in Figure 14.

Recommendation-specific supportive text 1. Patients with CHD are at higher risk of maternal and fetal complications, morbidity, and mortality during pregnancy than individuals without heart disease,46,332 and Drenthen et al331 noted that the most common complications of pregnant patients with CHD include arrhythmias and heart failure. Thus, it is important to have clear discussions regarding risks of pregnancy and to take steps to mitigate these risks with patients who have CHD and arrhythmias before they become pregnant. 2. A systematic review by Garcia Ropero et al343 demonstrated that supraventricular arrhythmia was the most common adverse event in pregnant patients with Fontan circulation (8.4% of pregnancies with a range of 3-37%), and that supraventricular arrhythmias were generally managed successfully using conventional approaches. Refractory, persistent arrhythmias, however, are associated with poor fetal outcomes, and pregnancy may limit options for medications. Thus, it is optimal to address arrhythmias prior to pregnancy. 3. Patients with CHD are known to be at increased risk of thrombosis and thromboembolism, particularly in the setting of AF, AFL, and IART. Maternal CHD in particular increases maternal risk of thrombosis both during pregnancy and in the postpartum period. Thrombosis risk in the immediate postpartum period is as much as 4-fold higher than in the antepartum period.226,344-346

For specific guidance on anticoagulation in pregnancy, see Recommendation 4 in Section 7.2, and Table 7. 4. Atrial arrhythmias are common in patients with CHD. IART is by far the most common (61% of patients), though among older patients AF that eventually progresses to permanent AF becomes more frequent.353 In general, patients with CHD tolerate arrhythmias poorly, and LV function often suffers.349 Salam et al226 demonstrated that maternal mortality and low birth weight, but not heart failure, were higher in pregnant patients with

COR LOE Recommendations References

2a B-NR 7. In pregnant patients with CHD and recurrent IART, AF, or AFL, in whom a rhythmcontrol strategy is deemed necessary, it is reasonable to initiate antiarrhythmic drug therapy, alone or in combination with a beta-blocker, with the antiarrhythmic drug chosen according to the underlying cardiac substrate and potential impact of the drug on the developing fetus, and preferably in conjunction with an electrophysiologist with expertise in CHD. 45,226,333

2a C-LD 8. In pregnant patients with CHD and recurrent atrial arrhythmias in whom pharmacological therapy is ineffective or contraindicated, ablation of arrhythmias deemed to involve a simple arrhythmic substrate is reasonable with attention to and techniques for eliminating or minimizing radiation exposure to as low as reasonably achievable, and preferably in conjunction with an electrophysiologist with expertise in CHD. 350

2b C-LD 9. In pregnant patients with CHD and recurrent ventricular or atrial arrhythmias in whom other pharmacological or catheter ablation therapies are ineffective, contraindicated, or not preferred, amiodarone may be considered after a risksversus-benefits discussion with the patient. 45,226,351

2b C-LD 10. In pregnant patients with CHD and recurrent IART, AF, or AFL, in whom pharmacological therapy is ineffective or contraindicated, catheter ablation of arrhythmias deemed to involve a complex arrhythmic substrate may be considered, with attention to and techniques for eliminating or minimizing radiation exposure to as low as reasonably achievable, and preferably in conjunction with an electrophysiologist with expertise in CHD. 352

Recommendations for arrhythmia management in the pregnant patient with congenital heart disease (Continued)

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CHD who had atrial arrhythmias. This association suggests that maintaining sinus rhythm during pregnancy may be associated with improved outcomes. There is a lack of studies reviewing the relative benefit of rate versus rhythm control for atrial arrhythmias during pregnancy. However, extrapolating from studies in nonpregnant pa- tients, the association of arrhythmias with poor outcomes suggests that maintenance of sinus rhythm can offer benefit. 5. In pregnant patients who are unstable due to ongoing arrhythmia, restoration of normal rhythm to protect both the mother and the fetus is critical. Arrhythmias

Figure 14 Management algorithm for pregnant patients with congenital heart disease (CHD). Colors correspond to class of recommendation (COR) in Table 1. 1Arrhythmic drug chosen according to the underlying cardiac substrate and potential impact of the drug on the developing fetus. 2Preferably in conjunction with an electrophysiologist with expertise in CHD. 3With attention to and techniques for eliminating or minimizing radiation exposure to as low as reasonably achievable. 4After a risks-versus-benefits discussion with the patient. AF 5 atrial fibrillation, AFL 5 atrial flutter, IART 5 intra-atrial reentrant tachycardia, VT 5 ventricular tachycardia.

are particularly common in the setting of CHD. There is no obvious difference in risk conferred by cardioversion in patients with CHD compared with those without, and cardioversion is generally well tolerated in pregnancy.155,159 Refer to Section 4.1 for a full discussion of cardioversion in pregnancy. 6. VT during pregnancy is associated with maternal morbidity and mortality, and can also result in negative fetal outcomes. Overall, VT during pregnancy is uncommon, occurring in 1.4% of pregnancies and mainly during the third trimester.285 However, when VT is observed during pregnancy, the presence of heart failure is more likely, and there is a higher risk of maternal mortality, neonatal death, and preterm birth. Tateno et al333 demonstrated that VT is not uncommon among patients with CHD (9 of 31 patients). Thus, given potential associated negative outcomes, efforts to prevent VT during pregnancy in congenital patients are important. However, the choice of therapy should take into account underlying substrate and potential fetal effects. 7. IART, AFL, or AF are common in CHD, and thus many patients with CHD will have a history of atrial arrhythmias prior to pregnancy. Silversides et al45 demonstrated that 44% of patients with preexisting arrhythmias have recurrent episodes during pregnancy. Recurrence rates are highest for SVT and AF/AFL. Adverse fetal events may occur more frequently in the setting of arrhythmias. Thus, arrhythmia control can offer some benefit. Betablockers may offer some antiarrhythmic benefit in pregnancy and have a long record of safety when administered to pregnant women. If beta-blockers are not effective or result in excessive symptoms, antiarrhythmic drugs can be an effective treatment. However, given the potential variable risks of antiarrhythmic drugs to the fetus, clear discussion should be had with the patient about fetal and maternal risks. In general, drugs with a longer record of safety during pregnancy are preferred. 8. During pregnancy, ablation without use of fluoroscopy has been shown to be feasible.350 Driver et al243 have also suggested that ablation of arrhythmias in CHD is both feasible without X-ray and effective. However, consideration should be made of the substrate and the nature of the arrhythmia. For example, AV nodal reentry tachycardia and accessory pathways are associated with higher success rates. However, AV nodal reentry tachycardia in congenitally corrected transposition of the great arteries can be associated with higher complexity. Therefore, consideration of both the substrate and the arrhythmia to be ablated is needed prior to proceeding with an ablation strategy. 9. While amiodarone is an effective antiarrhythmic for many arrhythmias, it is associated with a risk of fetal abnormalities. Up to 17% of neonates may develop hypothyroidism and some evidence of neurotoxicity.126 Thus, use of amiodarone is generally limited to instances of refractory or life-threatening arrhythmias that cannot be controlled with other medications, and requires close monitoring for potential side effects. Shared decisionmaking with the mother in advance of therapy initiation includes discussion of potential long-term risks to mother and fetus. 10. IART, AFL, and AF may be amenable to ablation in CHD.352 In the setting of pregnancy, ablation is complicated by the need for avoiding use of X-ray and the more complex substrate associated with ablation of IART, AFL, AF, particularly in the setting of complex CHD. Thus, ablation strategies should be seen as a last-line option, after either pharmacologic failure or contraindication. In addition, ablation should be done at centers experienced with ablation in CHD and with minimizing fluoroscopy use.

10.3 Arrhythmia management in the pregnant

patient with valvular heart disease The increase in plasma volume, heart rate, and cardiac output during pregnancy can lead to cardiac complications in women with valvular heart disease. In women of childbearing age, valvular heart disease is usually diagnosed prior to pregnancy, but it may also be identified for the first time during pregnancy. The most common valve lesions in women of childbearing age are aortic stenosis and mitral stenosis. Aortic stenosis is usually due to bicuspid aortic valve disease. There have been a number of case series of pregnancy outcomes in women with aortic stenosis reporting variable rates of complications.40,354 In a meta-analysis, new or recurrent tachyarrhythmias occurred in 2% and 4% of pregnancies in women with moderate or severe aortic stenosis, respectively.355 Women with aortic stenosis are also at risk for developing heart failure during pregnancy, and these women are also at risk for developing VT. Mitral stenosis is usually due to rheumatic heart disease and is much more common in developing countries. Reported rates of complications in pregnant women with mitral stenosis have considerable geographical variability.40,354,356,357 In a meta-analysis of pregnancy outcomes in medium and higher Human Development Index countries, new or recurrent atrial tachyarrhythmias during pregnancy occurred in 5% and 16% of pregnancies in women with moderate or severe mitral stenosis, respectively.355 Management of anticoagulation during pregnancy is more complex than in the nonpregnant popula-

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tion due to the potential fetal effects of warfarin (warfarin embryopathy and warfarin fetopathy) and the risk of bleeding at the time of delivery and early postpartum.358 Direct oral anticoagulants are not used during pregnancy because safety data are not available. Low-molecular-weight heparin does not cross the placenta and for that reason is an acceptable alternative to warfarin during pregnancy. Refer to Table 7 for specific guidance on anticoagulation in pregnancy.

Synopsis Atrial tachyarrhythmias can precipitate heart failure and can also lead to thromboembolic complications, often secondary to left atrial thrombus. Beta-blockers, which slow the heart rate and prolong the diastolic filling time, are the mainstay of therapy for both prevention and treatment of acute AF and flutter.40,354,356 Women with mitral stenosis who are taking beta-blockers prior to pregnancy should continue their beta-blockers during pregnancy. As part of a rhythm control strategy, cardioversion is deemed safe during pregnancy. All women with mitral stenosis and AF or AFL benefit from therapeutic anticoagulation during pregnancy as in the nonpregnant population.

Recommendation-specific supportive text 1. AF and AFL are common cardiac complications in pregnant women with mitral stenosis, especially if moderate or severe, that predispose them to left atrial thrombus, particularly when the duration of the arrhythmias is prolonged beyond 48 hours. In general, these arrhythmias are poorly tolerated, which is why rhythm control strategies might be necessary. When cardioversion is being considered, the patient must be adequately anticoagulated unless the arrhythmia is ,48 hours in duration. For women with longer duration arrhythmias or in whom the duration of arrhythmia is unknown, a transesophageal echocardiogram to exclude left atrial thrombus is performed. In addition, anticoagulation is provided for a minimum of 4 weeks post-cardioversion, as in the nonpregnant population.26,359 2. Pregnancy is a prothrombotic state and is associated with increased risk of thromboembolic complications. During pregnancy, women with mitral stenosis and AF or AFL are at particularly high risk for developing thromboembolic complications.361 Anticoagulation recommendations for pregnant patients with mitral stenosis, AF, and AFL are similar to the nonpregnant state.362 Additionally, pregnant patients with a prior thromboembolic complications or documented left atrial thrombus are managed with the same therapeutic anticoagulation approach. Refer to Table 7 for anticoagulation in pregnancy protocols.

10.4 Arrhythmia management in the pregnant

patient with arrhythmogenic cardiomyopathy ACM is an inherited cardiomyopathy with a prevalence of 1:2000 to 1:5000. Although first defined as characterized by fibro-fatty replacement of the right ventricular myocardium, which predisposes patients to ventricular arrhythmias, right ventricular dysfunction, and sudden cardiac death, recognition has increasingly widened to include LV involvement, accounting for the change in nomenclature from ARVC (arrhythmogenic right ventricular cardiomyopathy) to ACM.10,150,363 Diagnosis of ACM is made using a set of criteria that includes clinical presentation and diagnostic modalities. Inheritance of ACM is autosomal dominant with reduced penetrance and marked variable expressivity, and affected genes are those encoding the cardiac desmosome.10,363

Recommendations for arrhythmia management in the pregnant patient with valvular heart disease

COR LOE Recommendations References

1 C-LD 1. In pregnant patients with mitral stenosis and acute onset of either AF or AFL of any duration, synchronized cardioversion is recommended, as long as the patient is adequately anticoagulated or atrial thrombus is excluded, and subsequent anticoagulation will be provided with the duration as in the nonpregnant patient. 40,354,356,359,360

1 C-LD 2. In pregnant patients with mitral stenosis and either AF or AFL, left atrial thrombosis, or prior embolism, therapeutic anticoagulation is recommended throughout pregnancy, unless there is contraindication. 40,354,356

Synopsis Evidence demonstrates that in patients with ACM, pregnancy is generally well tolerated, yet cardiac adverse events, such as ventricular arrhythmias and heart failure, can be observed, especially in high-risk patients. Antiarrhythmic drug therapy is generally well tolerated. Preconception genetic counseling, implantation of ICD if clinically indicated, and evaluation of cardiac function are ideal for the sake of better risk stratification and management. Recommendation-specific supportive text 1. In ACM, approximately 50-60% of patients will have an identifiable pathogenic mutation associated with the cardiac desmosome.10,151,363,366 Yet, genetic counseling is complicated by the fact that there is great variable expressivity and reduced penetrance, even within members of the same family, and by the fact that some patients can be compound heterozygotes, or carry more than 1 mutation. In addition, common sequence variants with high prevalence in healthy controls can act as modifiers in ACM.10,366 Therefore, preconception counseling of a woman or couple with ACM requires expertise in the complexities of genetic testing in ACM and cardiomyopathies in general.151,363 2. A number of observational studies and data from registries have shown that pregnancies in patients with ACM are generally uneventful with optimal surveillance and therapy. One study identified the third trimester of the pregnancy and the puerperium as high-risk periods for ventricular arrhythmias.364 The largest experience was published by Hodes et al,150 who used data from a combined registry that included 39 pregnancies. Though they concluded that pregnancy was generally well tolerated, with positive fetal outcomes and no cardiac mortality, sustained ventricular arrhythmias were reported in 13% and heart failure in 5% of pregnancies, respectively. In the 2 pregnancies during which heart failure was reported, both patients had prior-documented significant structural impairment.150 In this cohort, common drugs were sotalol, flecainide, and beta-blockers, and the majority had ICDs implanted previously. Of note, beta-blocker use was associated with low birth weight.150 Pregnancy does not seem to worsen the ACM phenotype over the long term.365

3. Decisions regarding a primary or secondary prevention ICD in a pregnant woman with ACM are guided by the usual decision-making process, not the pregnancy status. The procedure has been shown to be generally safe during pregnancy with negligible risk from radiation exposure in a small number of reports. Pregnancy subsequent to ICD insertion is a more frequently described and well tolerated situation.269 In the studies by Hodes et al150 that included 39 pregnancies, most patients had ICDs, and excess arrhythmia burden or shocks were not observed generally. 4. In the largest study, Hodes et al150 reported that although pregnancy was generally well tolerated, sustained ventricular arrhythmias were seen in 13% of the cohort. The 2 antiarrhythmic drugs used most commonly were flecainide and sotalol. Both drugs have a long record of safety in pregnancy, as both are well tolerated and drugs of choice for fetal SVT. In addition, both drugs, alone or in combination, have been used successfully in nonpregnant ACM cohorts.367,368 Amiodarone appears to be superior to sotalol, yet in view of risk of toxicity, it is best used as a last resort.369

10.5 Arrhythmia management in the pregnant

patient with hypertrophic cardiomyopathy HCM is one of the most common inherited forms of cardiomyopathy. The presentation is quite heterogeneous, yet most patients have favorable long-term outcomes with contemporary therapies and early diagnosis. In view of the increased hemodynamic demands associated with pregnancy, the safety of pregnancy in HCM has been an important question.

Recommendations for the arrhythmia management of the pregnant patient with arrhythmogenic cardiomyopathy

COR LOE Recommendations References 1 B-NR 1. Patients and/or their partners with ACM should be offered preconception counseling, including genetic counseling as indicated. 150-152

1 C-LD 2. Pregnant patients with ACM should be treated for documented or potential arrhythmias as in the nonpregnant patient, including continuation of beta-blockers and the use of antiarrhythmic drug– and device-based therapies as needed, favoring options with the best record of safety during pregnancy. 150,152,364,365

1 C-LD 3. In pregnant patients with ACM and high-risk features, the decision to implant an ICD should be made based on usual indications, regardless of pregnancy status, and ideally the procedure should be considered and performed prior to conception. 150,152,269

2a C-LD 4. In pregnant patients with ACM and recurrent VT or ICD shocks, it is reasonable to consider antiarrhythmic drug therapy, including sotalol or flecainide alone or in combination with a beta-blocker as first-line options. 150,152

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Synopsis A number of studies have shown generally good pregnancy outcomes among patients with HCM, although complications are observed especially in those previously identified as high risk.372 The third trimester appears to be a particularly high-risk period. Potential and documented maternal arrhythmias are generally treated as in the nonpregnant state, favoring therapeutic options with a record of safety in pregnancy. Recommendation-specific supportive text 1. Prenatal counseling can help parents understand the risk of transmission of heritable diseases, including HCM, and the risks of pregnancy for the mother and the baby. Genetic counseling can introduce options including, but not limited to, prepregnancy genetic diagnosis, fetal screening, maternal and paternal prenatal testing, and postnatal testing for the infant and family. The potential benefits, risks, and alternatives should be discussed for all of these options during preconception counseling, such that the patient or parents can make a fully informed decision about pregnancy, prenatal genetic testing, and fetal screening.6,370,371,377,378 2. Autore et al372 reported their experience with 100 women with HCM who had a total of 199 births. They concluded that, despite higher maternal mortality in patients with HCM compared with the general population, absolute maternal mortality was low and confined to women at a particularly high risk. The progression of symptoms, AF, and syncope was uncommon during pregnancy. Data from the ROPAC registry376 showed that despite overall good outcomes, 23% of pregnant women with HCM developed major cardiac events, including VT in 10% and AF in 1.7%. A particularly high-risk period was the third trimester, and most events occurred in patients already identified as high risk prior to pregnancy. Schinkel375 performed a systematic review of 11 studies, which included 237 women and 408 pregnancies, finding that, although the overall event rate was low, the maternal mortality rate was 0.5%, and complication or worsening of symptoms occurred in 29%. Across these studies, maternal arrhythmias were generally treated with standard therapies, and the great majority of patients were maintained on beta-blockers throughout the pregnancy.

Section 11 Management of fetal arrhythmias The normal fetal heart rate range is between 110 and 160 bpm. If the heart rate is beyond the normal range or the rhythm is irregular, then a fetal arrhythmia is detected. It is also possible to have a fetal arrhythmia that is regular and falls in the normal heart rate range, but these normal-rate dysrhythmias will often go undetected until after birth. The heart rate, duration, mechanism of the rhythm and degree of irregularity usually predict the hemodynamic consequences. Fetal arrhythmias are diagnosed in approximately 1% of all fetuses and up to 49% of referrals for fetal echocardiograms.379 This section covers general fetal arrhythmias not related to IAS, which are covered in Section 12.2.

11.1 Fetal atrial tachyarrhythmias

While intermittent atrial tachyarrhythmias in the fetus have an excellent prognosis, fetuses with sustained tachycardias are at increased risk of stillbirth and morbidity.380 Incessant (in tachycardia .50% of the time or .12 hours per day) fetal SVT is often associated with fetal hydrops and ventricular dysfunction.380 AFL accounts for approximately 30% of all fetal tachyarrhythmias and is often associated with CHD.232 Incessant (.50% of the time or greater than 12 hours per day) fetal AFL is often accompanied by fetal hydrops and ventricular dysfunction, and resultant neurologic sequelae and mortality (5-30%).78,380,381 In the setting of fetal arrhythmias, the cardio-obstetrics team in the context of the management of the fetus should include, if available, a fetal or pediatric cardiologist or electrophysiologist, perinatologist (maternal-fetal medicine subspecialist), and neonatologist.

Recommendations for arrhythmia management of the pregnant patient with hypertrophic cardiomyopathy

COR LOE Recommendations References 1 B-NR 1. Women and/or their partners with HCM should be offered preconception counseling, including genetic counseling. 370,371

1 C-LD 2. Pregnant patients with HCM should be treated for documented or potential arrhythmias as in the nonpregnant patient, including continuation of beta-blockers and the use of antiarrhythmic drug– and device-based therapies as needed, favoring options with the best record of safety in pregnancy. 372-376

Synopsis The management of fetal atrial tachyarrhythmias depends on gestational age, evidence of fetal hydrops, and potential risk to the mother. In the fetus noted to have SVT on auscultation of the fetal heart rate, it is important to assess the mechanism of tachycardia, as well as tachycardia burden, and to involve a cardio-obstetrics team (see Sections 1.10 and 3.2) in the development of a treatment plan. Flecainide has been found to be a superior first-line agent in fetal SVT, followed by digoxin and sotalol.108 In fetuses with recalcitrant SVT, multiple drug regimens or the addition of direct intraperitoneal or umbilical medication administration are often used.78,97,108,127,128,383,384,389,390 Digoxin or sotalol are considered the first line for management of AFL in fetuses with hemodynamic compromise.78,108,383 Due to the potential for adverse events, when pharmacological therapy is required to treat fetal tachyarrhythmias, a full discussion between the physician and parents about the maternal and fetal risks and benefits enables joint decision-making. Addition- ally, careful monitoring of mother and fetus is necessary to avoid drug toxicity and side effects. Delivery of fetuses diagnosed with incessant AFL or incessant SVT close to term, if deemed viable, generally results in better outcomes. An algorithm for the management of fetal tachyarrhythmias is shown in Figure 15.

Recommendation-specific supportive text 1. Several case reports and nonrandomized retrospective studies have found that intermittent AFL (,50% of the time or ,12 hours per day) in fetuses with no evidence of hydrops on fetal ultrasound or fetal echocardiogram is well tolerated with good outcomes.232,381 Cuneo and Strasburger74 found that in 15 fetuses with intermittent tachycardia, none progressed to sustained tachycardia or heart failure. Management of intermittent AFL with frequent monitoring is generally sufficient and is less risky to the mother than drug therapy.

Recommendations for fetal atrial tachyarrhythmias

COR LOE Recommendations References

1 B-NR 1. Fetuses with intermittent AFL or intermittent SVT (defined as tachycardia <50% of the time) and no hydrops should be managed with observation, frequent fetal heart rate monitoring (auscultation), and serial biophysical testing, ideally under the guidance of a cardio-obstetrics team. 74,232,381

1 B-NR 2. Fetuses with incessant AFL or incessant SVT (defined as tachycardia .50% of the time) and/or hydrops should be referred to a cardio-obstetrics team, due to the potential for high fetal and maternal morbidity and fetal mortality. 232,381,382

1 B-NR 3. Fetuses with incessant SVT or AFL with or without hydrops who are not considered to be mature enough for delivery should be treated transplacentally with flecainide or sotalol, alone or in combination with digoxin, with frequent monitoring of fetal well-being and maternal drug toxicity, and with drug selection according to the specific arrhythmia mechanism. 78,80,108,383,384

1 C-LD 4. Fetuses with incessant AFL or incessant SVT complicated by hydrops who are close to term should be delivered. 381,385,386

1 C-LD 5. In pregnancies complicated by either fetal irregular heart rate or tachyarrhythmias, fetal echocardiography is recommended to further characterize the rhythm and to screen for structural or functional abnormalities. 387,388

1 C-LD 6. In pregnancies complicated by fetal PACs, serial auscultation of the fetal heart rate or serial biophysical testing (or, if these are unavailable, non-stress testing) is recommended to exclude development of fetal SVT until the arrhythmia resolves.

388 2a C-LD

7. In fetuses with incessant SVT complicated by hydrops or ventricular dysfunction refractory or with contraindications to first-line drug options, transplacental administration of oral amiodarone can be beneficial. 127,128

2a C-LD 8. In immature fetuses with incessant SVT or incessant AFL complicated by hydrops that do not respond to treatment with transplacental drug therapy alone, direct fetal intramuscular injection of digoxin added to transplacental drug therapy can be effective. 97

2b C-LD 9. In fetuses with incessant SVT or incessant AFL complicated by hydrops that do not respond to treatment with transplacental drug therapy, combination transplacental drugs, or direct injection of digoxin, direct umbilical intravenous injection or intraperitoneal injection of amiodarone may be effective as a last resort. 389-392 3: Harm C-LD 10. In fetuses with incessant SVT or incessant AFL, transplacental therapy with verapamil is potentially harmful. 393,394

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2. In contrast to fetuses with intermittent AFL or SVT, those with incessant AFL, incessant SVT (defined as tachycardia for .50% of the time or .12 hours per day), or hydrops have worse outcomes, with increased risk of mortality and morbidity.232,381,382 Therefore, pharmacological therapy is often necessary for these pregnancies. First-line therapy is transplacental and exposes the mother to the side effects and risks of antiarrhythmics. Therefore, management of the mother and fetus by a cardio-obstetrics team (see Sections 1.10 and 3.2) is optimal. In this context a pediatric cardiologist, or a pediatric electrophysiologist, if available, is an integral multidisciplinary team member. 3. A number of studies have compared different drugs for transplacental therapy of fetal SVT. Sridharan et al384 compared flecainide and digoxin in a nonrandomized study involving 84 patients; flecainide was superior to digoxin especially when hydrops was present. A metaanalysis of 10 studies and 537 patients found flecainide to be superior to digoxin and sotalol, with the relative effectiveness of flecainide over digoxin even more apparent once hydrops was present with SVT in general.108 In the same study, a trend toward a higher arrhythmia termination rate was observed for flecainide versus sotalol. Data are conflicting as to whether digoxin or sotalol therapy is superior to treat specifically fetal AFL and/or hydrops. Jaeggi et al78 performed a multicenter, nonrandomized trial of antiarrhythmics in fetuses with AFL, finding sotalol to be a superior therapy for fetuses with incessant flutter. However, a systemic review and meta-analysis of studies of fetuses with AFL found no difference when comparing sotalol and digoxin therapies.108 Thus, no data strongly indicate a preferred firstline agent for AFL; however, some studies suggest a better arrhythmia termination rate with sotalol. A high number of maternal adverse events from transplacental antiarrhythmics have been reported (although the majority of maternal side effects are not serious).80 Therefore, the choice of pharmacological therapy depends on a full discussion of the risks and benefits with the family. 4. Infants with AFL with or without hydrops respond well to cardioversion, with a low risk of recurrence.385 Hinkle et al386 found that infants with refractory SVT or hydrops did not have a higher risk of postnatal SVT. Therefore, the delivery of a close-to-term fetus with incessant AFL or incessant SVT with hydrops allows for optimal therapy and also avoids the potential for maternal side effects due to pharmacological therapy. Importantly, neonatal morbidity from hydrops may be reduced if rapid conversion is achievable. Certainly, the decision should be based on considerations such as gestational age, presence of hydrops, and response to therapy. The presence of hydrops requires a higher level of urgency. The term close to term is purposely vague, as defined in Section 1.10; in this instance, it refers to the fact that the fetus is deemed viable. 5. Irregular or rapid heart rate may be a sign of significant arrhythmia in the fetus and may be associated with CHD or poor function.25,76,388 Fetal echocardiography helps to determine arrhythmia etiology. Copel et al388 reported their experience with 595 cases referred for fetal irregular rhythms, with 2.4% of these presenting with hemodynamically significant arrhythmias. 6. PACs are a common finding in the fetus and are usually benign. However, monitoring by serial weekly fetal “doppler” auscultation can identify intermittent runs of SVT, which is seen in 1-3% of fetuses and could potentially lead to fetal compromise.76 This may be discontinued 1-2 weeks after resolution of the arrhythmia or until delivery. 7. Transplacental amiodarone has been shown to be a successful treatment for drug-refractory SVT.127,128 Strasburger et al128 found that amiodarone, either alone or in combination with other drugs, converted 14 out of 15 of fetuses with SVT. Amiodarone-related adverse effects were transient in 5 infants and 9 mothers. Of note, the time to therapeutic effect with amiodarone may be longer than with other antiarrhythmics; thus, close monitoring is essential to detect worsening hydrops and an abnormal biophysical profile. 8. Maternally administered digoxin for the treatment of fetal SVT and AFL is less effective when hydrops is present, as transplacental drug transfer is impaired. Parilla et al97 reported successful conversion in 8 fetuses with combined maternal and direct fetal intramuscular digoxin therapy. 9. Hansmann et al389 reported on 13 fetuses with refractory SVT and AFL complicated by hydrops, who received intraperitoneal and/or umbilical intravenous administrations of a number of drugs in addition to the transplacental therapy. Amiodarone was the most effective drug, and the authors described it as the first drug of choice for direct therapy.389 Direct amiodarone injections into the fetal peritoneal cavity has also been performed successfully.390 The risks and benefits of a direct intrafetal injection versus preterm delivery must be made on a case-by-case basis depending on gestational age. 10. A number of adverse outcomes have been reported with the use of verapamil in both the mother and the fetus.25,75

These include maternal hypotension and bradycardia, as well as fetal bradycardia, hypotension, depression of cardiac contractility, and asystole. Unexpected fetal death associated with the use of verapamil has been reported, although certainly other factors could have come into play and numbers are small.393 Reports of effective SVT termination with verapamil do exist, especially when combined with digoxin. Nevertheless, in view of concerning reports about the safety of verapamil and the availability of safer and more effective pharmacological options for fetal SVT and AFL, verapamil is best avoided for fetal SVT (Table 5).

Fetus with irregular

heart rate and/or

tachycardia

Fetal echocardiogram

(COR 1)

Intermittent1 arrhythmia

without hydrops

Observation, frequent heart rate monitoring, and serial biophysical

testing (COR 1) Incessant2 arrhythmias with or without hydrops

Referral to a cardio-

obstetrics team

(COR 1)

Fetal PACs

Serial auscultation of the fetal heart rate or

serial biophysical

testing3 (COR 1)

Preterm Close to term with

hydrops

Delivery

(COR 1) Transplacental flecainide or sotalol, alone or in combination with digoxin, with frequent monitoring of fetal well-being and maternal drug toxicity4

(COR 1)

Transplacental oral

amiodarone

(COR 2a)

Addition of direct fetal

injection of digoxin

(COR 2a)

Combination transplacental drugs, direct injection digoxin,

or direct umbilical intravenous or intraperitoneal injection

amiodarone

(COR 2b)

Transplacental therapy

with verapamil is potentially harmful

(COR 3: Harm)

With hydrops

Figure 15 Management of fetuses with irregular heart rate and tachycardia. Colors correspond to the class of recommendation (COR) in Table 1. 1Intermittent is defined as ,50% of the time. 2Incessant is defined as .50% of the time. 3If these are unavailable, nonstress testing is recommended. 4Drug selection according to the specific arrhythmia mechanism. The term close to term is purposely vague, as defined in Section 1.10, but it implies likely viability after delivery. PAC 5 premature atrial contraction.

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11.2 Fetal ventricular arrhythmias not associated

with inherited arrhythmia syndromes While fetal ventricular arrhythmias most often are associated with IAS, specifically LQTS (see Section 12.2 for fetal arrhythmias secondary to IAS), ventricular arrhythmias in the fetus can have several other causes. Fetuses with AV block, cardiac tumors, myocarditis, ventricular aneurysms, and cardiomyopathy can all present with VT.395-397 Accelerated idioventricular tachycardia, a generally benign rhythm of infancy, can also be seen in the prenatal period. Early involvement of a cardio-obstetrics team, including a pediatric electrophysiologist, is of great importance.

Synopsis VT in the fetus is an extremely rare occurrence but can be associated with hydrops and sudden fetal death. Therefore, referral to a cardio-obstetrics team, pharmacological therapy, or delivery of a close-to-term fetus may improve outcomes. An exception is accelerated idioventricular tachycardia, a generally benign rhythm seen in the prenatal period in healthy neonates, whichinmost cases doesnot requiretherapy,unlessthere isevidenceofhydrops.ThemajorityoffetuseswhopresentwithVT have an IAS, most commonly LQTS. Thus, most data on therapy refer to this population; therapy includes either maternal intravenous magnesium or oral propranolol, mexiletine, or lidocaine, alone or in combination. Treatment for VT not thought to be secondary to LQTS is generally extrapolated from the arrhythmia literature in the general population; as such, standard antiarrhythmic drugs such as sotalol, flecainide, and amiodarone are recommended. When VT is deemed to be secondary to myocarditis or isoimmunization, dexamethasone andIVIGareconsidered,althoughdataarelimitedandconflicting.An algorithm of the recommendations for the management of fetal ventricular arrhythmias not associated with IAS is shown in Figure 16. Recommendation-specific supportive text 1. In the majority of cases of sustained VT, the first-line therapy for the fetus includes maternal intravenous magnesium and lidocaine. Limiting maternal magnesium to ,48 hours’ duration134 reduces the risk of maternal toxicity. Monitoring of magnesium levels is advisable, and magnesium may be redosed if there is recurrent VT as long as maternal magnesium levels are ,6 mEq/L. In some reports, oral propranolol and mexiletine therapy have also been used as first-line agents for this indication.128,134

2. Simpson et al398 described a case of a fetus presenting at 30 weeks’ gestation with VT at a rate of 220 bpm and fetal hydrops. The tachycardia was unresponsive to flecainide but was controlled within 12 hours by an intravenous infusion of magnesium to the mother. In experimental prolonged QT interval canine models, magnesium has shown to be effective in treating LQTS.401 3. VT in the fetus can be due to a number of structural or genetic conditions.395,399,400 Sustained VT in the fetus is associated with high morbidity and mortality. Therefore, pharmacological therapy is often necessary in these patients. First-line therapy is usually transplacental administration of drugs, which exposes the mother to the side effectsandrisksofantiarrhythmics.Consequently,managementofthemotherandfetusbyacardio-obstetricsteam(see Sections1.10and3.2)isoptimalevenincaseswithintermittent tachycardia. 4. The efficacy of antiarrhythmic drugs delivered transplacentally can be limited, especially in the setting of hydrops. In the event of sustained VT in the close-to-term fetus, delivery and direct treatment by cardioversion or defibrillation, along with administration of antiarrhythmics, provide more effective drug delivery and avoid

Recommendations for fetal ventricular arrhythmias not associated with inherited arrhythmia syndromes

COR LOE Recommendations References

1 B-NR 1. Fetuses with sustained VT with or without hydrops who are not considered to be matureenough for deliveryshould be treatedtransplacentallywitheither intravenous magnesium or oral propranolol, mexiletine, or lidocaine, alone or in combination, or with other antiarrhythmic agents according to the specific arrhythmia etiology, with frequent monitoring of fetal well-being and maternal drug toxicity. 134,154,398

1 C-LD 2. In fetuses with sustained VT, maternal hypomagnesia and other correctable causes should be treated aggressively. 398 1 C-EO 3. Fetuses with VT should be referred to a cardio-obstetrics team, if available, for evaluation and treatment secondary to the high fetal morbidity and mortality. 1 C-EO 4. Fetuses with sustained VT with or without hydrops who are close to term or at term should be delivered.

2a B-NR 5. In fetuses with VT complicated by hydrops or ventricular dysfunction refractory or with contraindications to first-line drug options and not secondary to IAS, transplacental administration of flecainide, sotalol, or amiodarone can be beneficial, with the choice of drug according to the underlying maternal and fetal substrate. 128,134,154

2b B-NR 6. Fetuses with sustained VT suspected to be secondary to myocarditis or isoimmunization, depending on gestational age, may be treated with dexamethasone and/or intravenous immunoglobulin (IVIG). 395,399,400

exposure of the mother to potent antiarrhythmics. The exception is rapid and frequent polymorphic VT, in which stabilization of the arrhythmia through in utero therapy may be warranted prior to delivery. The term close to term is purposely vague, as defined in Section 1.10, but it implies likely viability after delivery. 5. Fetuses with VT refractory to first-line therapy have been found to beresponsive to a number of antiarrhythmic drugs, including sotalol, flecainide, and amiodarone.128,134,154,398

No one drug has been found to be superior to the others, and data are scant since these arrhythmias are rare, so drug options listed are based on the history of their use in pregnancy for other indications, such as fetal SVT. The drug choice also should be determined by arrhythmia severity and underlying maternal and fetal substrate. If the VT is suspected to be secondary to de novo LQTS or IAS, however, it is too risky to use these antiarrhythmic agents, as they all can prolong the QT interval. 6. Myocarditis in the fetus has been well described and can be associated with ventricular arrhythmias.395,400 Dexamethasone and IVIG have been used as effective therapies in this entity in a limited number of case reports. Nevertheless, data on this entity are extremely limited and mixed, and the consideration of the use of dexamethasone in utero requires a full discussion of risks versus benefits of therapy to enable joint decision-making.

Figure 16 Algorithm for management of ventricular tachycardia (VT) in the fetus not secondary to inherited arrhythmia syndrome (IAS). Colors correspond to the classof recommendation(COR)in Table 1. 1Choice ofdrugaccording to the arrhythmic etiologyand/or underlyingmaternal-fetalsubstrate. 2Dependingon gestational age. The term close to term is purposely vague, as defined in Section 1.10, but it implies likely viability after delivery. IV 5 intravenous, IVIG 5 intravenous immunoglobin.

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11.3 Management of fetal bradycardia conduction

system disorders

Synopsis The etiologies of fetal bradycardia (defined as fetal heart rate ,110 bpm or less than the third percentile corrected for gestational age) encompass several different mechanisms including SHD, conduction system disturbances manifesting as variable degrees of heart block, and IAS. (Figure 17 outlines the diagnosis and management of fetal bradycardia.) In fetuses with bradycardia, serial sonographic monitoring of fetal status is crucial to identify and treat the development of cardiomyopathy and/or fetal hydrops. Autoimmuneinduced heart block and cardiomyopathy may be amenable to antenatal interventions such as maternal steroid administration. However, the benefit of this therapy is uncertain, and its use requires patient-specific shared decision-making between the patient and the cardio-obstetrics team. Pregnan- cies with idiopathic fetal bradycardia may suggest an IAS, and prenatal and postnatal evaluation to diagnose or rule out IAS is warranted.

Recommendation-specific supportive text 1. While maternal antibody levels can fluctuate, when anti- Ro and anti-La antibodies are present in pregnancies complicated by autoimmune or rheumatologic conditions, fetuses are at risk for the development of cardiac complications, such as isoimmune heart block, hydrops, and cardiomyopathy, including endocardial fibroelastosis independent of conduction system involvement. Pregnancies with prior history of fetal/neonatal isoimmune cardiac disease have at least a 10% risk of recurrence.411

Recommendations for the management of fetal bradycardia conduction system disorders

COR LOE Recommendations References

1 B-NR 1. Pregnant patients with autoimmune and rheumatological disease should be evaluated for anti-Ro and anti-La antibodies in the first trimester of pregnancy or when care is initiated, even if previous titers were negative. 402-404

1 B-NR 2. In pregnancies complicated by third-degree fetal heart block, echocardiographic monitoring is recommended for surveillance of fetal hydrops and cardiomyopathy, since these conditions can lead to fetal compromise or the need for delivery. 405,406

1 C-LD 3. In pregnancies complicated by fetal bradycardia, fetal echocardiography is recommended to further characterize the rhythm and to screen for structural cardiac abnormalities. 403

1 C-LD 4. In pregnancies complicated by idiopathic fetal bradycardia, antenatal and postnatal evaluation of the neonate for IAS is recommended. 407 1 C-EO 5. In pregnancies complicated by fetal bradycardia, assessment of fetal well-being as appropriate for gestational age is recommended to exclude fetal compromise.

2a C-LD 6. In pregnant patients with positive anti-Ro and anti-La antibodies, periodic echocardiographic monitoring for the development of isoimmune heart block and isoimmune fetal cardiomyopathy is reasonable.

406 2b B-NR

7. In anti-Ro-positive pregnancies complicated by fetal heart block, the utilization of fluorinated steroids may be reasonable after shared decision-making discussions as the benefit is uncertain. 402,408

2b C-LD 8. In pregnancies complicated by fetal heart block secondary to maternal isoimmune disease with fetal cardiomyopathy or hydrops, maternal administration of combined therapy of fluorinated steroids and IVIG therapy may be considered after shared decision-making discussions. 403,404,409,410

3: No benefit C-LD 9. In pregnancies complicated by fetal bradycardia with a fetal heart rate <55 bpm, the benefit of antenatal maternal administration of beta-adrenergic medications is uncertain, as it has not been shown to improve fetal outcomes and could potentially lead to maternal complications. 403,405

2. Regardless of etiology, third-degree heart block can lead to fetal hydrops and fetal heart failure, depending upon gestational age. Management includes administration of steroids for fetal lung maturity since fetal deterioration should prompt consideration of premature delivery. Frequent assessment via biophysical profile testing is important in these cases to monitor fetal status.412

3. Fetal echocardiogram to evaluate fetal bradycardia may reveal structural cardiac disease, such as corrected

Figure 17 Diagnosis and management of fetal bradycardia. *Hamada et al.414 †Ishikawa et al.421 ‡Friedman et al.422 AV 5 atrioventricular, fMCG 5 fetal magnetocardiography, IAS 5 inherited arrhythmia syndromes, IVIG 5 intravenous immunoglobulin, LQTS 5 long QT syndrome, PAC 5 premature atrial contraction, SHD 5 structural heart disease.

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transposition, Ebstein’s anomaly, or left atrial isomerism. Detailed use of doppler velocimetry and motion-mode analysis may differentiate seconddegree heart block from atrial bigeminy resulting from frequent blocked premature atrial beats. Echocardiography may also reveal cardiomyopathy and heart failure that may evolve in the setting of autoimmune-mediated heart block.395 4. The presence of fetal bradycardia may suggest an underlying diagnosis of IAS.413 Options for prenatal diagnosis are limited, but magnetocardiography, if available, can provide diagnostic confirmation.414 Prenatal evaluation also includes monitoring fetuses for ventricular arrhythmias. Postnatal evaluation with assessment of neonatal QT interval and mutational ion panels can confirm the diagnosis of suspected IAS. Recommendations for the management of IAS during pregnancy are provided in Section 12. 5. Since the fetal cardiovascular system has an immature Starling capability, fetal cardiac output is rate dependent.415 Nonstress testing may be unreliable for assessing fetal status in the setting of fetal bradycardia because of blunted autonomic response, which impairs the normal variability of fetal heart patterns generally observed in otherwise healthy fetuses.416 A normal biophysical profile correlates with reassuring fetal oxygenation and acid/base status. 6. Autoimmune heart block and cardiomyopathy can evolve over a variable period of time and have been reported to occur between weekly fetal assessments.417 Periodic monitoring to detect evolving disease enables shared decision-making between the patient and her cardioobstetrics team regarding interventions such as maternal steroid initiation. Additionally, depending upon the gestational age, steroids for fetal lung maturity can be given if further fetal deterioration prompts consideration of preterm birth. 7. The literature demonstrates variables results in the efficacy of antenatal fluorinated steroids for the treatment of fetal heart block. Current literature reporting on steroid treatment for isoimmune heart block is nonrandomized and underpowered. While third-degree heart block has not been demonstrated to be reversible, at least 1 study demonstrates that mild forms of fetal heart block may be reversible.402 Chronic use of high-dose fluorinated steroids antenatally can lead to potential fetal complications including growth restriction and oligohydramnios. Detailed discussions between the patient and the cardioobstetrics team are required to weigh potential risks and benefits. 8. Treatment of maternal autoantibody-mediated fetal cardiomyopathy/endocardial fibroelastosis with dual therapy including fluorinated steroids and IVIG may improve outcomes.404 However, data are limited regarding timing, dosage, and frequency of treatment, and IVIG can cause maternal complications, including infection and hypersensitivity reactions, leading to premature delivery. 9. While beta-adrenergic agents can increase the heart rate in fetuses with fetal bradycardia, overall fetal outcome improvement has not been documented in the literature.418 Chronic maternal administration of beta-adrenergic agents can lead to severe maternal complications, including pulmonary edema, electrolyte abnormalities, and maternal cardiac dysfunction.419,420

Section 12 Inherited arrhythmia syndromes 12.1. Management and risk stratification of inherited arrhythmia syndromes during pregnancy Inherited arrhythmias syndromes (IAS) encompass a number of conditions, namely LQTS, Brugada syndrome (BrS), CPVT, early repolarization syndrome, Andersen- Tawil syndrome, and short QT syndrome (SQTS). Whether or not a genotype is identified, the vast majority are inherited in an autosomal dominant manner. To date, although genetic testing is exceptionally useful in confirming a clinical diagnosis and providing the opportunity for testing at-risk relatives, it is not universally diagnostic. As such, some individuals will have this diagnosis made clinically with no accompanying pathogenic variant identified. This is particularly the case for BrS, for which there is currently interest in whether the monogenic approach has limited the understanding of this condition, and advice to treat exists regardless of the results of genotyping availability.15 All of these conditions carry an increased risk for ventricular arrhythmias and sudden cardiac death. They often share the unusual features of being sensitive to precipitants, such as medications or particular environmental situations. Patient education is exceptionally important in these conditions, as affected individuals must learn to modulate their risk. Though many data center on genotype- and phenotype-positive individuals, in some conditions the advice to treat exists regardless of genotyping availability or results. Management of the pregnant woman with an inherited arrhythmia has a limited evidence base. In the absence of pregnancy-specific data, management is guided by evidence-based treatment established in nonpregnant patients. For the management of the fetus in pregnancies complicated by IAS, specifically LQTS, see Section 12.2.

12.1.1 General management considerations for inherited arrhythmia syndromes in pregnancy

Synopsis In general, women with IAS should continue to be treated throughout pregnancy and in the postpartum period as indicated by their underlying diagnosis. This includes both pharmacological and device therapy, if and as required. Although there are only a small number of case reports of ICD implantation during pregnancy, if an indication arises, ICD implantation is supported by a broader literature showing safety of an existing ICD in pregnancy. As the majority of cases of IAS are autosomal dominant, advice regarding in utero fetal screening for arrhythmias is pertinent regardless of which parent has the diagnosis. Monitoring for in utero fetal growth restriction is necessary during pregnancies in which beta-blockers are used. Delivery and the postpartum period are times of increased arrhythmia risk. Parental education, electrolyte replacement, the arrhythmic potential of medications, and the sympathetic drive of labor are all important considerations. Delivery and postpartum care in a location with cardiac monitoring and prompt life support, including defibrillation, are important because of the increased arrhythmic risk of IAS. An algorithm of recommendations for the general management of IAS during pregnancy is shown in Figure 18. Figure 19 shows the level of surveillance and management of IAS, based on risk during labor and delivery.

Recommendation-specific supportive text 1. Genetic testing results can predict severity of presentation, influence choice of antiarrhythmic drugs, and assist risk stratification for an affected fetus, as well as the pregnant patient, if affected.429-432 The risk of stillbirth and the incidence of fetal and neonatal life-threatening IASrelated rhythms vary with genotype; for SCN5A, phenotypic expression in the fetus and neonate can vary widely.77,79,153,154,407,429,430,433-438 Of women with prior unexplained stillbirth, 5-10% may have fetuses with IAS.439,440 2. Trained multidisciplinary cardio-obstetrics teams reduce mortality and provide consistency of care in high-risk conditions.25,79,154,429,436 Recently, Cuneo et al,153 examining 148 pregnancies retrospectively, found that pregnant patients with IAS had an 8-fold higher fetal stillbirth rate and a 2-fold higher miscarriage rate compared with the normal population. This was more

Recommendations for the general management considerations for inherited arrhythmia syndromes in pregnancy

COR LOE Recommendations References

1 B-NR 1. For pregnancies in families with IAS, genetic testing of the proband is recommended, if not previously performed, for antenatal risk stratification and for optimal management of the fetus and, if affected, the pregnant patient. 153,154

1 B-NR 2. Pregnancies in families with IAS should be evaluated and, preferably, managed by a specialized cardio-obstetrics team with expertise in IAS.

153 1 B-NR

3. In a pregnant patient with an IAS and presumed cardiac syncope or documented VT, referral to an electrophysiologist is recommended for consideration of additional therapeutic interventions, including escalation of pharmacological therapy and possible ICD implantation. 269,423-425

1 C-LD 4. For women and their partners with a documented IAS or who are at risk of an IAS, preconception genetic counseling is recommended, ideally by a trained genetic counselor with expertise in IAS. 153,426

1 C-LD 5. A pregnant patient who survives cardiac arrest due to an IAS should undergo ICD implantation, if indicated, as in the nonpregnant patient. 269,427,428

1 C-EO 6. In pregnant patients with IAS, arrhythmia management should include a review of medications and anesthetic agents for safety, the correction of electrolyte abnormalities, and discussion of situational precipitants.

1 C-EO 7. Pregnant patients with IAS should have a delivery plan formulated by a cardioobstetrics team in conjunction with an electrophysiologist or a cardiologist with expertise in arrhythmias during pregnancy, which may include continuous ECG monitoring in accordance with the level of risk and delivery at a facility capable of ACLS for pregnancy.

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prevalent when the mother had LQTS than when the father had LQTS. The study’s main limitation was that only 10% of the fetal deaths underwent genetic testing postmortem, and the mechanism of death remained uncertain; nonetheless, the study indicates a necessity for increased surveillance for fetal well-being. Cardio-obstetrics teams can provide increased surveillance in these cases. The role of nurses and genetic counselors on these teams is critical to provide support for these families. The fetus can be assessed by the cardio-obstetrics team for need for intrauterine transplacental therapy and postnatal treatments, such as antiarrhythmic drugs, pacemakers, and defibrillators. 3. Women with an IAS who experience a syncopal event during pregnancy are better served when evaluated by a cardiac electrophysiologist, if available, or a cardiologist with experience managing pregnant patients. While documentation of a ventricular arrhythmia during the syncopal event greatly assists decisionmaking, it is recognized that syncope is common in even normal pregnancies; thus, in the absence of arrhythmia documentation, an experienced assessment of the syncopal event can better inform the likely nature of the syncope. It is important to distinguish between common benign causes of syncope, such as vasovagal events, and more concerning syncope deemed to be of cardiac origin (eg, sudden loss of consciousness without a prodrome or clear precipitant). Consideration of alternative medical or therapeutic interventions, according to the underlying diagnosis (eg, addition of an antiarrhythmic agent, left cardiac sympathetic denervation, or an ICD), depends on the clinical scenario and the presumed etiology of the syncope event.24,27 There are no published cases of left cardiac sympathetic denervation during pregnancy for an IAS, although a single case report details chemical sympathectomy for ischemic VF.441 4. The majority of IAS are due to LQTS, of which genotypes LQT1, LQT2, and LQT3 account for about 75-85% of fetal presentations.25,154,407,429,438 These are primarily of autosomal dominant inheritance with 50% transmission from parent to fetus. In addition, double mutations can occur, especially for the SCN5A (LQT3) defects.407,430,434,437 Preconception genetic counseling is recommended for families affected by IAS to provide all options available to them and offer education to optimize fetal/maternal well-being (such as access to CPR/ automated external defibrillator training, support groups, nutritional optimization, medication avoidance, and post- natal genetic testing).25,79,429,442 Ideally, counseling is provided by a trained genetic counselor or, if unavailable, other providers with expertise in genetics, and includes topics such as risks associated with condition, mode of inheritance, therapy options, and risk to the fetus. An important consideration is the higher risk of miscarriage and fetal death in IAS pregnancies.153

5. Decision-making regarding a secondary-prevention ICD in a pregnant woman with an IAS is guided by the standard of care according to the underlying cardiovascular disorder, without regard to the pregnancy status. ICD implantation has been shown to be generally safe during pregnancy with negligible risk from radiation exposure (see Section 4.2). Device implantation after the first trimester is ideal but not essential, since the safety of the pregnant patient is the priority. Pregnancy subsequent to ICD insertion is more frequently described and welltolerated, and is the preferred clinical pathway if feasible.269 6. The usual advice regarding avoidance of arrhythmia precipitants remains significant in pregnancy. This includes the need to consider syndrome-specific drug safety, utilizing www.crediblemeds.org for LQTS, and www. brugadadrugs.org for BrS, checking for electrolyte abnormalities and avoiding situational triggers.69 As some commonly used drugs found on anesthetic carts and standard labor and delivery protocols are contraindicated in certain IAS, active consideration of drug choice is needed during administration of anesthesia and management of peripartum emergencies.69 7. There is a potential for arrhythmic risk during delivery, given the associated sympathetic drive, in women with IAS. A birth plan should be actively formulated, ideally with input from the treating cardiologist and/or electrophysiologist and cardio-obstetrics team. In particular, details need to be specified regarding continuation of medical therapy, location of delivery, type and frequency of monitoring (including whether monitoring needs be continuous), on-demand or stipulated analgesic options (eg, for regional anesthesia to reduce pain and sympathetic drive), vaginal or planned cesarean delivery, and location and duration of postpartum maternal monitoring. For women with an ICD, the location of delivery and duration of postpartum monitoring can potentially be altered; however, no evidence guiding decision-making exists on the optimal delivery location and monitoring duration in this population, and care should be individualized for each clinical situation.

Figure 18 Algorithm for the evaluation and management of pregnancies complicated by inherited arrhythmia syndromes (IAS). Colors correspond to class of recommendation (COR) in Table 1. 1Therapeutic interventions include escalation of pharmacological therapy and possible implantable cardioverter defibrillator (ICD) implantation. 2Delivery plan may include continuous electrocardiogram monitoring in accordance with the level of risk and delivery at a facility capable of advanced cardiac life support for pregnancy. EP 5 electrophysiologist.

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12.1.2. Management of long QT syndrome in pregnancy The most common types of the IAS LQTS are LQTS1, LQTS2, and LQTS3, caused by mutations in KCNQ1, KCNH2, and SCN5A, respectively. LQTS carries a risk of TdP, a form of polymorphic VT, which can manifest clinically as syncope or VF causing cardiac arrest and sudden cardiac death.27 High-risk features for adverse events include a corrected QT interval (QTc) .500 ms and a personal history of prior cardiac events. A gene–sex interaction appears to exist, particularly for women with LQTS2 postpuberty.443

Synopsis Preconception counseling of women with LQTS affords an opportunity to repeat risk assessment,450 including discussion of the potential risks and benefits of beta-blocker use. Retrospective studies have shown that the first cardiac event may occur in pregnancy. The postpartum period is a particularly high-risk time, especially for women with LQTS2 (Figure 20).423 Long-acting beta-blockers are preferred in LQTS,15,27 with recent evidence regarding the superiority of nadolol particularly.450 Although nadolol is generally not recommended during breastfeeding due to relatively high excretion into breast milk,451 a recent review has suggested it be continued during breastfeeding if it affords rhythm stability in pregnancy.69 In women with LQTS and an ICD, concomitant beta-blocker therapy is often used to reduce the risk of a cardiac event, including an ICD shock, and, in this circumstance, therapy should be continued during pregnancy.

Figure 19 Levelofsurveillanceandmanagementofinheritedarrhythmiasyndromesbasedonriskduringlaboranddelivery.Recenteventsaredefinedasarrhythmic syncope/seizures, cardiac arrest, and/or sustained ventricular arrhythmia in the preceding 1 year on appropriate therapy. Intravenous line is discretionary for mediumrisk situations. ACM 5 arrhythmogenic cardiomyopathy, BrS 5 Brugada syndrome, CPVT 5 catecholaminergic polymorphic ventricular tachycardia, ERS 5 early repolarization syndrome, EST 5 exercise stress test, IVF 5 idiopathic ventricular fibrillation, LQTS 5 long QT syndrome, NSVT 5 nonsustained ventricular tachycardia, PVC 5 premature ventricular contraction, QTc 5 corrected QT interval, SQTS 5 short QT syndrome. Adapted with permission from Roston et al.69

Recommendations for management of long QT syndrome in pregnancy

COR LOE Recommendations References

1 B-NR 1. In pregnant patients with LQTS and a preconception indication for beta-blocker therapy, beta-blockers should be continued throughout pregnancy, delivery, and the postpartum period, including breastfeeding. 423,444-448

1 B-NR 2. In pregnant patients with LQTS2, therapy with a beta-blocker, particularly nadolol or propranolol, is recommended particularly during the postpartum period, which represents a high-risk period for cardiac events. 423,445,448

1 C-LD 3. In pregnant patients with LQTS who experience cardiac arrest in pregnancy or in whom cardiac syncope or ventricular arrhythmias occur despite beta-blocker use, intensification of therapy including ICD implantation, if indicated, is recommended as in the nonpregnant patient.

448 1 C-LD

4. In pregnancies in which either of the parents carry a diagnosis of LQTS, fetal echocardiography is recommended to detect channelopathy-related rhythm abnormalities.

449 2a B-NR

5. In pregnant patients with LQTS who are genotype-positive but phenotype-negative, it is reasonable to treat with a beta-blocker, particularly nadolol or propranolol, after a shared decision-making discussion with the affected woman. 423,444,448

The general advice regarding avoidance of electrolyte abnormalities, QT-prolonging drugs, and situational triggers that is given to all individuals with this diagnosis (Table 6 and Section 4.3, Recommendation 3) holds true throughout pregnancy and the postpartumperiod.Additionally,thisadvice extends to genotype-positive,phenotype-negative(asymptomatic) individuals.15 This advice is also true for a genotypenegative mother in whom the fetus has inherited an LQTS genotype paternally.25 As for other types of IAS, labor, delivery, and postpartum monitoring for pregnancies complicated by LQTS should be actively planned and managed (Figure 19 and Section 12.1.1, Recommendation 7). Recommendation-specific supportive text 1. A number of retrospective studies have shown reduced events in women with LQTS who are treated with betablockers during pregnancy and the postpartum period.423,444-446 Although these are not randomized, the demonstration of serious adverse events in these studies, including cardiac arrest and death, highlights the risk for both mother and fetus/baby. Guidelines recommend longer-acting beta-blockers (eg, nadolol and sustainedreleasepropranolol).15,24,27,69Dataareinsufficientregarding the comparative benefits of different beta-blockers for pregnant patients; therefore, extrapolation from studies in the general LQTS patient population is necessary.24 2. WomenwithLQTS2arethehighest-risksubgroupwiththis condition in pregnancy and, particularly, the postpartum period. Data strongly support continuation of beta-blocker postdelivery, particularly for the first 9 months postpartum, a period associated with increased risk. The 2017 AHA/ ACC/HRSGuidelineforManagementofPatientsWithVentricularArrhythmiasand the PreventionofSuddenCardiac Death15 suggests that women with LQTS2 with a QTc .500 ms are at particularly highrisk and may becandidates for an ICD or a wearable cardioverter defibrillator in the postpartum period.450 Yet, data on wearable cardioverter defibrillators are scant; to date only a single woman with a wearable cardioverter defibrillator prescribed postpartum could be identified in the literature, and that woman was genotype LQTS1.452

3. In pregnant patients with LQTS, serious adverse events, such as cardiac arrest and death, pose greater risk for both mother and fetus/baby than do potential adverse effects from medical therapies. ICDs have been shown to be safe in pregnancy269 and can be implanted safely with negligible risk from radiation exposure. Defibrillation therapy has also been shown to be well tolerated. In instances when ICD implantation is not feasible, a wearable cardioverter defibrillator is an available option, although data on its use during pregnancy are scant. 4. A fetus witha parentthathas a diagnosis of anIAS isat50% risk of inheriting the same genotype. Fetal echocardiography, including an assessment of the fetal heart rate and rhythm, may help detect ion channelopathy–related rhythm abnormalities, including bradycardia, second-degree heart block, and TdP, all of which can be manifestations of LQTS. Fetal echocardiography is usually performed at around 20 to 22 weeks’ gestation, although rhythm disorders are more reliably diagnosed after 27 weeks’ gestation. 5. It is reasonable to consider the prescription of beta-blocker to all, including women who are genotype-positive and phenotype-negative (ie, with a normal QTc duration). Identifying the LQTS genotype assists with risk stratification.450,453,454 Goldenberg et al453 reported that the cumulative probability of aborted cardiac arrest or sudden cardiac death in patients with LQTS with normal-range QTc intervals (4%) was significantly lower than in those with prolonged QTc intervals (15%) (P , 0.001) but higher than in unaffected family members (0.4%). In general terms, women with LQTS2, and all with LQTS2 and LQTS3, appear to be at higher risk than those with LQTS1.15,455

Decision-making should include a cardiologist, ideally an electrophysiologist,andanobstetrician,aswellasthepatient.

Figure 20 Cardiac event rate according to long QT syndrome (LQTS) genotype and pregnancy status. Reprinted with permission from Seth et al.423

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12.1.3 Management of Brugada syndrome in pregnancy

Synopsis BrS is an inherited arrhythmia that carries a risk for VF and sudden cardiac death. Fever is a recognized precipitant for arrhythmia in this condition.458 Although male gender and a spontaneous type 1 BrS–pattern ECG convey an increased risk for events, risk prognostication in this condition remains challenging. In general, women are understood to be at lower risk than men, and pregnancy does not seem to increase risk. Complicating risk prognostication in women, however, are data from meta-analyses suggesting that neither the relationship between a spontaneous type 1 BrS–pattern ECG nor symptom status and future risk in women is helpful.459,460 Yet, women with this diagnosis should continue to follow general management advice for BrS throughout pregnancy and the postpartum period, namely, treating fever aggressively and avoiding large carbohydrate meals and excess alcohol.461 It is important to check all medications prescribed in pregnancy, labor, and delivery (www.brugadadrugs.org) and avoid those of concern. Recommendation-specific supportive text 1. The currently available data on BrS and pregnancy are limited to a single-center retrospective series and a small number of single-case reports. This has been deemed insufficient evidence on which to conclude whether pregnancy is a risk factor for VF and sudden cardiac death in BrS. However, in a report that included 104 women, the risk of arrhythmia did not seem to increase during pregnancy or the postpartum period.424,462 Care is generally continued during the pregnancy and lactation as in nonpregnant patients, with the avoidance of contraindicated drugs (www. brugadadrugs.org). 2. Fever is known to induce cardiac events in patients with BrS.456 Given the risk thatfever will bea precipitant for sudden cardiac death in patients with BrS, pregnant and postpartum patients with BrS benefit from education about the signs and symptoms of common infections associated with fever, such as mastitis in breastfeeding patients, emphasizing the prompt treatment of fever with antipyretics.461

The most widely used antipyretic in pregnancy is acetaminophen.

12.1.4 Management of catecholaminergic polymorphic ventricular tachycardia in pregnancy

Synopsis CPVT is an uncommon inherited arrhythmia in which polymorphic VT is classically triggered by an adrenergic stressor.464 Most individuals with this condition become symptomatic early in life.465 Cardiac events, including death, have been documented in the follow-up of genotype-positive individuals with previously normal exercise stress tests.465

This underpins the advice in the literature regarding the use

Recommendations for management of Brugada syndrome in pregnancy

COR LOE Recommendations References

1 C-LD 1. Pregnant and postpartum patients with BrS should be provided with care as in the nonpregnant patient, including continuing therapies for sudden death prevention and avoidance of contraindicated drugs throughout pregnancy and lactation.

424 1 C-LD

2. In pregnant and postpartum breastfeeding patients with BrS, education about the prompt treatment of fever, such as in cases of mastitis, with antipyretics is recommended, as fever is a potential precipitant for sudden death. 456,457

Recommendations for management of catecholaminergic polymorphic ventricular tachycardia in pregnancy

COR LOE Recommendations References

1 C-LD 1. In pregnant patients with CPVT, pharmacological therapy as in the nonpregnant patient should be continued throughout pregnancy and the postpartum period, including during delivery and breastfeeding.

463 1 C-LD

2. In pregnant patients with CPVT, with symptoms ongoing despite beta-blocker therapy, such as recurrent syncope, VT, or cardiac arrest, intensification of therapy with either the addition of flecainide and/or a left cardiac sympathetic denervation, and/or an ICD is recommended as in the nonpregnant patient. 463

2a C-LD 3. In pregnant patients with CPVT who are genotype-positive and phenotypenegative, use of beta-blockers during pregnancy and postpartum is reasonable. 463

of beta-blockers in CPVT regardless of phenotypic status.24,464 Guidelines also recommend the addition of flecainide to beta-blockers for individuals with recurrent syncope or sustained VT.24 In general, an ICD is the first-line option post–cardiac arrest; however, the capacity for a defibrillator shock to perpetuate a VT storm by further adrenergic stimulation has resulted in significant interest in the combined use of beta-blockers, flecainide, and cardiac sympathectomy as a treatment approach, and needs to be taken into account when programming the device.438,466 The highly malignant nature of this condition means that recommendations in pregnancy should follow those made for the nonpregnant population. Recommendation-specific supportive text 1. The quality of evidence regarding CPVT in pregnancy is limited. The largest series, a single retrospective study involving 96 women and 228 pregnancies, did not show an increase in events in women with CPVT during pregnancy or the postpartum period. However, as 80% of women in the study underwent pregnancy prior to their CPVT diagnosis, and the average age at diagnosis was 40 years, this appears likely to have been a lower risk subgroup. Furthermore, the cohort did not include women with a CPVT diagnosis who did not undergo pregnancy or in whom death occurred prior to pregnancy, both of whom may have had a higher risk profile. With that said, cardiac events did not occur at a higher rate during pregnancy and the postpartum period than in the nonpregnant state.463 2. CPVT presents a unique management situation in the treatment algorithm of cardiac arrest, as epinephrine is contraindicated.467 Management of VF in CPVT, after direct current shock, consists of intravenous betablockers, flecainide, and anesthesia. This diagnosis needs to be identified early, ideally preconception, as it will influence pregnancy-care decision-making, particularly regarding delivery location and associated support. It is important that the delivery plan includes details regarding early regional anesthesia for a vaginal delivery, continuous ECG monitoring, and awareness of the adrenergic stressor of intubation if required. Ventricular arrhythmias are generally managed with intravenous beta-blockers, and these events should result in an immediate call for assistance from the cardiology team. Cardiac arrest will require defibrillation; however, as this may potentiate repeated lifethreatening arrhythmias, early utilization of alternative therapies (ie, general anesthesia, antiarrhythmics) is important. Due to the potential for ICD shocks to be an adrenergic stress that perpetuates life-threatening arrhythmias, ICD programming in CPVT should be optimized to deliver therapy for VF.455

3. For women with a CPVT pathogenic variant but in whom exercise testing has not revealed a phenotype, there is no available pregnancy-specific literature to guide management. Pharmacological therapy, as in nonpregnant patients,24,464 is based on the established low risk of betablockers during pregnancy and postpartum.468

12.1.5 Management of short QT syndrome in pregnancy

Synopsis SQTS is a rare, inherited, and highly lethal arrhythmia condition. Both diagnostic and prognostic criteria remain unclear.469 Medical therapy evidence is small, but quinidine appears to be the best therapeutic option.15,27,469 AF is common in SQTS, and, though SQTS is rare during pregnancy, SQTS is a diagnostic possibility if a pregnant woman or fetus develops AF.470

Recommendation-specific supportive text 1. There are no reported cases in the literature of pregnancy in patients with SQTS. Therefore, it is not possible to provide any advice beyond the generally available literature in this condition. In general, as in most IAS, the standard therapies should be continued throughout pregnancy since the safety of the mother and fetus takes priority. Furthermore, a number of therapies proven effective for SQTS have been used safely during pregnancy, such as ICD implantation; the drugs used in this syndrome, such as quinidine, have a long record of safety in pregnancy and lactation.69,468

12.2 Management of inherited fetal arrhythmias

LQTS is the primary IAS in which the fetus manifests arrhythmias. The management of pregnancies of families with IAS should be evaluated and preferably managed by a specialized cardio-obstetrics team, and fetuses should be thoroughly evaluated and closely monitored, since they

Recommendations for management of short QT syndrome in pregnancy

COR LOE Recommendations References

1 C-EO 1. In pregnant patients with SQTS, arrhythmia-specific treatment should be administered as in the nonpregnant patient and continued throughout pregnancy and the postpartum period.

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have a 50% chance of inheriting IAS and thus are at risk. Potential manifestations of an IAS in the fetus may include bradyarrhythmias; tachyarrhythmias, such as TdP; hydrops; and even fetal demise. A number of clinical tools, such as echocardiography and fetal magnetocardiography (fMCG), are available for evaluation of IAS in the fetus. When arrhythmias are observed, understanding of transplacental administration of pharmacological therapies is essential, with preference given to drugs with the longest experience and record of apparent safe use during pregnancy.

12.2.1. Management of inherited arrhythmia syndromes in the fetus, specifically long QT syndrome Fetal IAS is used generally in this section, but LQTS is the primary IAS setting in which the fetus manifests arrhythmias.

Synopsis Of the fetal IAS, most of the arrhythmic events are observed in the setting of LQTS. Fetuses with arrhythmias potentially suggestive of IAS (such as fetal sinus bradycardia, seconddegree AV block, complex tachy-brady rhythms, and/or TdP VT) should be referred to a cardio-obstetrics team with expertise in IAS management. When IAS is suspected, the fetal heart rate should be compared against gestationspecific normative values, since bradycardia is a common disease manifestation. Fetal echocardiography can determine the presence of structural defects or hydrops. fMCG can be beneficial for further assessing the type and severity of IAS-related arrhythmias. For TdP in the fetus, magnesium infusion is first-line therapy, followed by lidocaine and non-cardioselective beta-blocker, such as propranolol. Drugs that prolong the QT should not be used to treat TdP in the fetus. Fetuses with prenatal and postnatal persistent bradycardia in the setting of familial IAS should be observed and potentially also referred to specialized centers for further evaluation and management. An algorithm of recommendations for the management of the fetus in pregnancies complicated by potential or documented IAS is shown in Figure 21.

Recommendations for management of inherited arrhythmia syndromes in the fetus, specifically long QT syndrome

COR LOE Recommendations References

1 B-NR 1. In pregnancies complicated by suspected or documented IAS-related fetal arrhythmias, complete fetal echocardiography is recommended to better evaluate heart anatomy, ventricular function, and arrhythmia mechanisms. 407,426,435,442,471

1 B-NR 2. Fetuses with arrhythmias potentially suggestive of IAS should be referred to a cardio-obstetrics team with expertise in IAS management. 154,426,430,435,

437,472

1 B-NR 3. In pregnancies complicated by suspected or documented IAS, the fetal heart rate should be assessed initially as a baseline and at each prenatal visit and compared against gestation-specific normative values. 153,407,429,435,471

1 B-NR 4. In fetuses with TdP, a maternal intravenous loading dose of magnesium sulfate followed by continuous infusion should be administered as first-line therapy at all stages of pregnancy before considering urgent delivery. 154,426,430

1 C-LD 5. In pregnancies complicated by suspected or documented maternal or fetal IAS, limiting medications that could potentially lengthen the QTc or trigger arrhythmias in the fetus is recommended. 154,426,434,472

2a B-NR 6. In pregnancies complicated by suspected or documented fetal IAS, fMCG can be beneficial, if available, to identify affected fetuses and IAS-related repolarization abnormalities, and to better assess the severity of the IAS-related arrhythmias. 154,426,430,431,472

2a B-NR 7. In fetuses with TdP despite magnesium administration, maternal treatment with lidocaine or with a beta-blocker (preferably propranolol) is reasonable at all stages of pregnancy before considering urgent delivery. 154,426,430

2a C-LD 8. In fetuses with prenatal and postnatal persistent bradycardia, it is reasonable to obtain a postnatal ECG and referral to a pediatric cardiologist or electrophysiologist for further clinical evaluation and genetic testing as indicated to exclude IAS. 154,435

2a C-LD 9. In fetuses manifesting arrhythmias associated with exposure to QT-prolonging medications, evaluation for maternal nutritional deficiency or concealed maternal or fetal diseases associated with QT prolongation is reasonable. 154,426,429,435,471

3: Harm C-LD 10. In fetuses with TdP or polymorphic VT associated with potential or documented LQTS, sotalol, procainamide, and amiodarone should not be administered because they can further lengthen QTc and exacerbate arrhythmias. 154,426,435

Recommendation-specific supportive text 1. Fetal echocardiography can determine some features of fetal conduction and, most importantly, can detect structural and functional heart conditions, such as hydrops fetalis, LV dysfunction, cardiomyopathy, LV noncompaction, and structural cardiac defects. Anomalies of structure and function are particularly common in fetuses that present with severe symptoms.432 Fetal echocardiography is readily available and assesses fetal heart rate and rhythm, isovolumic relaxation time, and whether mechanical alternans is present.436,473 Bundle branch block can sometimes be inferred from flow patterns in the pulmonary veins and aortic arch.473,474 Yet 45% of TdP was missed by echocardiography in a recent study by Strand et al,431 because it was not sustained or rapid, and it mimicked other rhythms, including sinus rhythm.154,430-432,435 2. Fetuses with suspected TdP or second-degree AV block should be referred to centers with experience in perinatal management of high-risk pregnancies with IAS. Suddenonset hydrops fetalis or fetal demise in this setting is often due to TdP. At its worst, TdP can be almost continuous, and is usually fatal in these cases.430 De novo genetic channelopathy variants often present with much more serious symptoms and arrhythmias, including serious novel rhythms, such as slow monomorphic VT and long-cycle-length TdP.430-432 For a fetal QTc .600 ms, detected by magnetocardiography, the risk of TdP is extremely high. Labor and delivery preparations might include a scheduled delivery with specialists present, having drugs such as intravenous magnesium on hand, and having a neonatal defibrillator/pacer and resuscitation cart readily available. 3. The most common benign IAS-related fetal rhythm is a relative sinus bradycardia for gestation.154,407,430,434,435,437 Other more serious IASrelated arrhythmias are discussed below. Persistent sinus bradycardia may be suggestive of an IAS, particularly LQT1, although in general, low atrial rhythm and familial bradycardia syndromes with sinus node dysfunction can also cause persistent fetal sinus bradycardia.25,79,430,435 Nearly all fetuses with LQT1 and roughly half of those with LQT2 had heart rates below the third percentile for gestation.407,429,430,435,471 Double mutations or uncharacterized mutations have the lowest fetal sinus rates.434 It is likely that many more LQTS cases could be detected if fetal heart rates were recorded and if gestation-based fetal heart rate normative graphs were used.25,79,407,471 The fetal heart rate often declines between the 15th and 20th weeks of gestation.407,429,430,435 About one-third will have blunted fetal heart rate reactivity, making it difficult to use nonstress testing in later pregnancy for obstetrical surveillance.407,429,430 Biophysical profile assessment is a good alternative to nonstress testing. 4. Unlike SVT, in which early delivery in the close-to-term fetus with hydrops is the treatment of choice, it is reasonable with TdP to attempt to control the tachycardia in utero at any gestation, because TdP is poorly tolerated in the neonate.430 First-line treatment for fetal TdP consists of transplacental intravenous magnesium sulfate in the same dosing as used for preterm labor (2-6 g loading, then 1-2 g/h infusion for ,48 hours, and at levels lower than 6 mEq/L [Table 5]). Magnesium has shown to be extremely effective acutely.25,79 Transition to alternative drugs within 48 hours is recommended due to neurologic effects to the fetus. It is best if this is managed under the supervision of an expert in IAS, which is often a pediatric electrophysiologist. 5. The most commonly used drugs cross the placenta, and over 165 drugs are now listed as potentially causing QTc prolongation in the population at large. Further, many drugs, such as sotalol, accumulate over time in the amniotic space at concentrations sometimes 20-fold higher than in the maternal serum, and can be recirculated over time through fetal swallowing. A QTc .600 ms has been reported with exposure to opioids and less frequently antiarrhythmic agents, as well as other medications or illicit drugs that are known to lengthen maternal QTc.426 It is prudent for women with known risk of LQTS to avoid medications that lengthen QTc (https://crediblemeds.org/); furthermore, even if the pregnant patient does not have an IAS but the father does, the fetus has roughly a 50% risk of having an IAS. Acquired QTc prolongation has only recently come to light, and multiple QT-prolonging drug scenarios are additive, and are seen with treatment of mental health conditions.440 However, not all QT-prolonging drugs can be avoided, such as oxytocin (Pitocin). 6. fMCG, currently the only method to detect repolarization abnormalities,25,77,154,430,473 is a safe procedure similar to postnatal ECG; despite its name, fMCG does not produce magnetism (unlike MRI). Because fMCG is over 90% sensitive and specific for identifying QT prolongation due to IAS or de novo IAS, it allows the provider to clearly define rhythms and to risk-stratify the fetus. The fMCG test is unparalleled for detecting IAS-related arrhythmias, including TdP, VT, seconddegree AV block (2:1, 3:1, 4:1), QTc .600 ms, and QRS or T-wave alternans, low fetal heart rate variability, AFL, and bundle branch block, in various combinations.431,432 Using fMCG, life-threatening arrhythmias have been seen in w14% of fetuses with IAS and in

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Figure 21 Management of the fetus in pregnancies complicated by potential or documented inherited arrhythmia syndrome (IAS). Colors correspond to the class of recommendation (COR) in Table 1. *Long QT syndrome (LQTS) is the most common IAS setting in which fetuses manifest arrhythmias. ECG 5 electrocardiogram, fMCG 5 fetal magnetocardiography, QTc 5 corrected QT interval, TdP 5 torsades de pointes.

up to 2/3 of fetuses with de novo arrhythmia syndromes.407,429,430 In almost all cases, fMCG reduced ambiguity and identified new arrhythmias that had not been suspected based on echocardiography alone, including TdP.79,430,431,442,473 Although additional sites for fMCG are being established in the United States and Europe, fMCG is currently not widely available. When fMCG is unavailable, fetal echocardiography with weekly obstetric monitoring is an alternative. Fetal ECG, although not FDA-approved, could also be considered, but its efficacy in detecting and characterizing TdP has not been determined. 7. Second-line acute drug treatments for TdP are lidocaine and beta-blockers. Lidocaine (1-1.5 mg/kg intravenous loading, then 1-4 mg/min) can be transitioned to oral mexiletine, but transplacental transfer for mexiletine may not be as consistent. Transplacental transfer of oral propranolol is about 25-40% of the maternal serum concentration.25,79 There is significant experience with both oral propranolol and metoprolol during pregnancy; however, propranolol may be a preferred option for LQTS. Care must be taken to ensure that short-acting forms are not substituted when sustained release forms are desired and vice versa. Recently, for subjects with poor beta-blocker compliance, nadolol has been used. Labetalol, used frequently for preeclampsia, is not an effective antiarrhythmic treatment, even though its transplacental transfer exceeds that of other betablockers. The dosing for these drugs is shown in Table 5. 8. Some IAS manifestations can lead to bradycardia syndromes, such as those caused by HCN4, NKX- 2.5, KCNJ5, SCN5A, and other IAS. No reports of fetal arrhythmias due to CPVT or type I BrS have been found. There is often quite remarkable overlap between the various manifestations of SCN5A, as cardiac conduction disorders and overlap arrhythmias are the most common manifestation regardless of the specific syndromes.434,437 9. Opioids, antiarrhythmic drugs, and polypharmacy with multiple QT-prolonging drugs have been associated with excessive QT prolongation (https://www. crediblemeds.org), especially in the presence of electrolyte, mineral, or vitamin D deficiencies. These should be corrected if possible. While therapeutic response is seen in the patient, 25-hydroxy vitamin D levels themselves rarely show a major recovery until after the pregnancy, and thus repeat assessment of levels is not required. Vitamin D serves a critical function of promoting absorption of calcium and magnesium from the gut, and it can be difficult to correct these when 25-hydroxy vitamin D is low. 10. Due to underlying LQTS, antiarrhythmic drugs that lengthen the QTc—especially sotalol, procainamide, and amiodarone—can be proarrhythmic and harmful to the fetus with TdP. In a symptomatic fetus with an SCN5A mutation, an alternative option is mexiletine as second-line therapy in conjunction with a betablocker.432 Combination therapies may be considered in situations where delivery is contraindicated and maternal risk is low, and where the parents wish to proceed following counseling on risk. Fetal pacing at this time is not an option.

Section 13 Future directions Palpitations are one of the most frequent symptoms experienced during pregnancy, and arrhythmias are one of the most frequently encountered cardiac diagnoses. Furthermore, as women are increasingly becoming pregnant later in life and as more women with underlying heart disease survive until childbearing age, the rate of pregnancy-related hospitalizations due to arrhythmias has increased in recent decades. Important gaps in knowledge and areas of uncertainty remain. An important limitation is the fact that most, if not all, of the data on the management of arrhythmias in pregnancy, for both mother and fetus, are derived from observational studies with small sample sizes. Certainly registries (such as RO- PAC) have become important sources of epidemiological knowledge on general risk and outcomes in mother and fetus during pregnancy, as well as the peripartum period, for a number of cardiac conditions.475 However, registries only collect data on practice patterns already established and as such have limitations. Expanding research by different means, such as creating additional registries, conducting prospective randomized studies, and allocating more funding for research in pregnant populations, is necessary. The diagnosis and management of patients with an inheritable arrhythmia syndrome require addressing a number of concerns with affected families, such as accuracy and appropriateness of genetic testing, estimated risks for sudden cardiac death, and advising them on transmissibility of the disease to future offspring. Further, implications of genetic testing on future participation in athletics, insurability, and future employment prohibition are important considerations. Thus, a structured approach using a cardiac-genetics team composed of specialized providers, including genetic counselors, would enhance the care and satisfaction of these patients and families; however, those specialized teams and centers remain extremely limited. Thus, increasing the availability of genetic counselors is important. Sustained fetal arrhythmias may lead to hydrops, cardiac dysfunction, or even stillbirth, and must be recognized and

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treated promptly. Recent studies, including some randomized studies on transplacental administration of antiarrhythmic agents, have shed light on pharmacological options in cases of tachyarrhythmia and provide further evidence-based treatment strategies.108 Yet, the best management of fetuses already affected by hydrops is less clear, and whether direct intrauterine administration of antiarrhythmic drugs or cardiac device therapy should be pursued more aggressively remains uncertain. Also, more widespread use of specialized diagnostic technologies, such as fMCG, could enhance the diagnosis and care of life-threatening arrhythmias in the fetus. Questions also remain related to optimal positioning of pregnant patients undergoing CPR; these are understandably difficult to answer but could be addressed with studies that use computational modeling, imaging, or registries. The benefit of anticoagulation in pregnant patients with atrial arrhythmias is uncertain in some populations, unless there is a well-defined high-risk substrate, such as mitral stenosis or a mechanical valve. AF is becoming an increasingly common arrhythmia in pregnancy; however, the decision to administer anticoagulants to these patients is generally based on the CHA2DS2VASc score, which has not been validated in pregnant patients. Lastly, data on drug efficacy, safety, and pharmacokinetics are limited, and, in general, drug choices are driven by anecdotal experience with administration in pregnancy and not necessarily by best option in terms of perceived efficacy for a given arrhythmia. This is because most modern antiarrhythmic drug labels state that drugs have not been properly tested in patients who are pregnant or breastfeeding. Thus, potentially beneficial drugs are frequently deemed dangerous or potentially dangerous in this setting based on the lack of data. One example is dofetilide, a drug that could potentially be used as an alternative to amiodarone in view of the latter’s significant side effect profile, yet reports on dofetilide use during pregnancy are essentially nonexistent. Similarly, data on the safety and efficacy of direct oral anticoagulants during pregnancy are lacking. In addition to targeted studies of drugs for use in pregnant patients and fetuses with arrhythmias, inclusion rather than exclusion of pregnant patients in new clinical trials of antiarrhythmic and anticoagulant drugs may be warranted.

Appendix Supplementary Data Supplementary data (Appendix 3) associated with this article can be found in the online version at https://doi.org/10.1016/ j.hrthm.2023.05.017.

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Appendix 1 Writing committee member disclosure of relationships with industry and other entities Honoraria/ Speaking/

Consulting Speakers’

bureau Research* Fellowship

support*

Ownership/ Partnership/ Principal/ Majority

stockholder Stock or stock

options

Intellectual property/ Royalties Other None None None None None None None None 0: Myant Canada 1: Biosig Technologies 1: Philips

1: Abbott 3: Abbott 3: Boston Scientific 3: Toray Industries Inc. 4: Aegis Medical

None None None None None None None None None None None None None Palo Alto, California 1: Guidepoint Global Advisors None None None None None 1: Elsevier 1: UpToDate None 1: Bayer Healthcare Pharmaceuticals 1: Daiichi 1: Pfizer, Inc.

None None None None None None None None None None None None None None None None None None None None None None None None None None 1: Medtronic 1: Philips None None None None 2: Abbott Vascular 2: Cook Medical, Inc. 2: Medtronic 2: Boston Scientific

None 5: Boston Scientific None None None None None

None None None None None None None None 1: Abbott 1: Biosense Webster, Inc. 1: Biotronik

None 0: Abbott 0: Medtronic None None None None None

1: Biosense Webster, Inc. 1: Biotronik

None None None None None None 0:European Heart Rhythm Association None None None None None None None None None None None None None None None None None None None None None None None 0: Babyscripts None None 4: National Institutes of Health 2: Scholl Foundation

None None None None None

1: Biosense Webster, Inc. 1: Medtronic 1: Abbott 1: Thermedical

None None None None None None None None None None None None None None None (Continued)

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(Continued) Appendix 1 Writing committee member disclosure of relationships with industry and other entities (Continued) Honoraria/ Speaking/

Consulting Speakers’

bureau Research* Fellowship

support*

Ownership/ Partnership/ Principal/ Majority

stockholder Stock or stock

options

Intellectual property/ Royalties Other None None None None None None None None None None None None None None None 0: Johnson & Johnson Number value: 0 5 $0; 1 5  $10,000; 2 5 . $10,000 to  $25,000; 3 5 . $25,000 to  $50,000; 4 5 . $50,000 to  $100,000; 5 5 . $100,000. This table is a comprehensive list of the relationships with industry and other entities (RWI)—regardless of relevance to the document topic—disclosed by each writing committee member for the 12 months prior to the initial meeting of the writing committee and up through the completion of the document. The table does not necessarily reflect the RWI of the writing committee members at the time of publication. Please refer to the HRS Code of Ethics and Professionalism for definitions of disclosure categories or additional information about the HRS policy on the disclosure of relationships with industry and other entities. To mitigate potential bias and conflict of interest, the recommendations and supportive text were written by writing committee members who were free of relevant RWI. *Research and fellowship support are classed as programmatic support. Sources of programmatic support are disclosed but are not regarded as a relevant relationship with industry for writing committee members.

Appendix 2 Reviewer disclosure of relationships with industry and other entities Honoraria/ Speaking/

Consulting Speakers’

bureau Research* Fellowship

support*

Ownership/ Partnership/ Principal/ Majority

stockholder Stock or stock

options

Intellectual property/ Royalties Other 1: Biosense Webster, Inc. None None None None None None 0: European Heart Rhythm Association 0: European Society of Cardiology €Orebro, Sweden 1: Bayer Healthcare Pharmaceuticals 1: Boston Scientific 1: Cathprint 1: Medtronic 1: Bakken Research Center 1: Merck 1: Philips 1: Sanofi

None 1: Cardiome Pharma/Astellas None None None None None None None None None None None None None None None None None None None None None None None None None None None None None (Continued)

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(Continued) Appendix 2 Reviewer disclosure of relationships with industry and other entities (Continued) Honoraria/ Speaking/

Consulting Speakers’

bureau Research* Fellowship

support*

Ownership/ Partnership/ Principal/ Majority

stockholder Stock or stock

options

Intellectual property/ Royalties Other Quezon City, Philippines None None None None None None None None None None 0: GestVision 0: Pfizer None None None 0: UpToDate None Florida, Tampa, Florida None None None None None None None None None None None None None None None 1: Abbott 1: Medtronic None None None None None None None None 1: Abbott 1: AtriCure, Inc. 1: Bayer Healthcare Pharmaceuticals 1: Biosense Webster, Inc. 1: Biotronik 1: BMS/Pfizer Alliance 1: Boston Scientific 1: Medtronic 1: PaceMate 1: Sanofi

None 1: Kestra 1: MediLynx 1: Medtronic 2: Boston Scientific

1: Medtronic None None 1: UpToDate 1: American Board of Internal Medicine 0: Abbott 1: Medscape None None None None None None None Number value: 0 5 $0; 1 5  $10,000; 2 5 . $10,000 to  $25,000; 3 5 . $25,000 to  $50,000; 4 5 . $50,000 to  $100,000; 5 5 . $100,000. This table is a comprehensive list of the relationships with industry and other entities (RWI)—regardless of relevance to the document topic—disclosed by the reviewers at the time the document was under review. The table does not necessarily reflect the RWI of the reviewers at the time of publication. Please refer to the HRS Code of Ethics and Professionalism for definitions of disclosure categories or additional information about the HRS policy on the disclosure of relationships with industry and other entities. *Research and fellowship support are classed as programmatic support. Sources of programmatic support are disclosed but are not regarded as a relevant relationship with industry for writing group members or reviewers.