Understanding Antiarrhythmic Drug Therapy in the Pregnant Patient, Fetus, and Infant

The 2014 American Heart Association Scientific Statement on Diagnosis and Treatment of Fetal Cardiac Disease by Donofrio and colleagues¹ focused on fetal cardiac disease from referral indications, to evaluation, to treatment. In this issue, the 2023 Updated AHA Scientific Statement² by Dr. Batra and the writing group, discusses the mechanisms of arrhythmias, pharmacologic treatment options, and unique pharmacokinetics of the fetus and neonate. It is both timely and informative.

At the FDA 2021 Conference entitled Fetal Pharmacology and Therapeutics and the subsequent conference supplement³ speakers emphasized the need for better understanding of pregnancy and fetal pharmacology. Of the top 20 drugs with detailed pharmacological assessment during pregnancy, none have been antiarrhythmic drugs.

Several medication trends have taken place (both in general, and specific to cardiology) over the past decade since the original AHA Scientific Statement. First, the broader experience with both flecainide and sotalol have led to a better understanding of their efficacy, yet it remains undetermined (at least until the publication next year of the Fetal Atrial Flutter and Supraventricular Tachycardia Randomized Controlled (FAST) Clinical Trial, led by Edgar Jaeggi, MD⁴), whether there is superiority of one drug (digoxin, flecainide, or sotalol) over another for fetal tachyarrhythmia. While the writing group points out the study by Hill, et al⁵ suggesting that flecainide is superior for SVT, none of these previous studies were powered sufficiently, and therefore, the FAST Trial will hopefully shed light on the best treatment with the fewest side effects. Until then, this Scientific Statement provides guidance for each tachyarrhythmia. Dr. Batra and colleagues point out that fetal tachycardia is associated with a substantial rate of prematurity. With the goal of delivering a term infant in sinus rhythm, a new study by Holmes et al showed that transplacental treatment of the late pre-term and early term infant results in favorable outcome and greater chance of vaginal delivery.^{6, 7} This challenges the idea that infants of 35-36 weeks gestation or more should be delivered in order to directly manage the arrhythmia.

The writing group wrote that direct therapies should be used only in experienced hands, and that amiodarone has little role, however, intramuscular digoxin, and oral amiodarone have proven life-saving in drug-refractory cases and may be considered in the immature hydropic fetus after failure of standard therapies.^{8, 9}

A third trend has been the increased utilization of QTc prolonging medications and indeed, the increasing use of drugs during pregnancy. Certain medical conditions, such as bipolar disorder, opioid use disorder, and polypharmacy patients, are often exposed to multiple QTc prolonging drugs during the pregnancy, which along with poor nutrition, could lead to potential risk for the pregnant patient and her fetus. As pointed out by Batra et al, several commonly used medications in pregnancy are known to prolong QTc, such as morphine, ondansetron, and oxytocin. At least 4% of pregnancies are complicated by mental health conditions requiring pharmacologic treatment, and many mood stabilizers and SSRI's are associated with a risk for QTc prolongation, especially if combined with a Class I or III antiarrhythmic agents.

In the 2023 Heart Rhythm Consensus Statement on Management of Arrhythmias during Pregnancy¹⁰, the current practice recommendation is to keep women with inherited arrhythmia syndromes such as Long QT Syndrome, on beta blocker therapies during pregnancy, and following pregnancy when their risk is greatest. A recent report suggested that nadolol was not associated with fetal adverse events, at least no more than other beta blockers¹¹, leading to greater use of this popular drug during pregnancy for inherited arrhythmias, however, beta blockers, including nadolol are associated with growth restriction, and these pregnancies should be monitored for growth restriction by Cardio-Obstetrics teams.

The use of improved fetal diagnostics may have important impact in the near future. Our group¹² and others¹³ have identified denovo severe manifestations of ion channelopathies (Torsades de Pointes (TdP), T wave alternans, late-coupled PVCs¹⁴, and second degree AV block), that without advanced echo/Doppler imaging¹⁵ and fetal magnetocardiography would have gone unrecognized, with death attributed to non-cardiac causes.¹⁶ We recently showed that fetal magnetocardiography detected new silent rhythm, conduction, and repolarization disturbances not detected by echocardiography.^{3, 12, 13, 16, 17} and we hope to see the clinical emergence of fMCG, as new and less expensive Optically Pumped magnetometers progress through the regulatory process.^{18, 19} Others are hopeful that fetal ECG will allow such assessment as well, however, electrical insulation of the fetus by vernix, and maternal tissues remains a barrier, and if such ECG technology becomes available, it will need to provide as reliable of information as is currently possible using fMCG.

In this new AHA Scientific Statement, Batra and colleagues outline strategies for the management of not just the fetus, but also the infant. An interesting new concept is the use of direct-to-consumer home infant monitoring devices, that have been shown in one study²⁰ to detect more episodes of SVT. The Owlet Company has obtained FDA clearance for basic health monitoring in the healthy infant using a sock-like pulse-oximetry monitor, and it is likely that other companies will follow suit. At present, these are not specifically approved for SVT or medication monitoring, but some clinicians are satisfied that they can detect SVT, and severe hypoglycemic events causing poor peripheral perfusion.

Thus far, I have focused on tachyarrhythmias, but there are bradyarrhythmias that warrant treatment. One area of current controversy is the use of fluorinated glucocorticoids such as dexamethasone for isoimmune-related Congenital AV Block. Earlier this year, the Society for Maternal Fetal Medicine published a practice statement decrying the routine use of steroids, since this did not reverse AV block.²¹ In this AHA Statement, the authors point out that the treatment is primarily aimed at preventing progression of the associated valvulitis and cardiomyopathy, for which there is evidence that steroids are effective and that periodic echocardiographic monitoring is warranted.²² Previously, the 2014 AHA statement recommended echocardiograms every 1-2 weeks through 28 weeks GA, however, most cases of AV block occur prior to 26 weeks.²³ Titers helped predict risk of AV block. Those with anti-kD60 SSA/SSB in the top quartile had a 7.7% risk for development of AV block. The current AHA Scientific Statement supports the use of terbutaline for extreme bradycardia during AV block, which is in contrast to the HRS Statement, which recognized the potential for maternal morbidity and mortality related to the therapy, and the lack of clear evidence that increasing fetal heart rate by a few beats/min results in improved survival. However, faced with a fetus with heart rates in the 40's, many clinicians would consider the use of terbutaline after informed decision making with the patient. The authors also note the contribution of hydroxychloroquine for reducing the recurrence of AV block from 16 to 7%, if started at about 10 weeks' gestation.

Sinus bradycardia is not usually considered a condition that requires treatment, however, two recent studies have shown that heart rates less than the 3^rd percentile for gestation are highly associated with inherited arrhythmia syndromes of all kinds, and when discovered prenatally, can lead to risk-modifying opportunities both for the fetus and mother, as well as cascade genetic testing for the family.^{12, 24}

Finally, the authors of this Scientific Statement raise an important consideration. Both the unchecked arrhythmias, as well as the drugs used to treat them, have the potential for long-term neurodevelopmental impact, which has not yet been adequately studied, especially the late follow-up of those severely affected. Thus, in addition to the need to advance fetal recording technologies, and to study fetal pharmacology, late neurodevelopmental outcomes should be assessed.

I commend the writing group for establishing clear guidelines for treatment of the fetus with tachy- or bradyarrhythmias.