Transplacental digoxin treatment for fetal supraventricular arrhythmias: Insights from Chinese fetuses

To the editor: Transplacental digoxin therapy has been proven effective in converting fetal supraventricular arrhythmia (SVA) to sinus rhythm or achieving ventricular rate control, significantly improving fetal intrauterine outcomes.[1–3] However, limited data exist from large patient populations in China. Additionally, concerns remain regarding the relatively high non-response and intrauterine relapse rates during prenatal digoxin treatment.[4,5] Studies exploring the underlying risk factors for digoxin non-response and intrauterine relapse are limited. Therefore, this study aimed to analyze the Chinese data on outcomes and follow-up of fetal SVA treated with prenatal digoxin monotherapy and investigate risk factors associated with unresponsiveness and intrauterine relapse after transplacental digoxin treatment. The clinical data of 32 singleton fetuses below 37 gestational weeks with persistent SVA, including supraventricular tachycardia (SVT, n = 14) and atrial flutter (AFL, n = 18), diagnosed at the West China Second Hospital of Sichuan University between January 2009 and February 2022, were retrospectively reviewed. Overview of the fetal treatment protocol is shown in Supplementary Figure 1, https://links.lww.com/CM9/C401. Several neurodevelopmental scales and echocardiography were prospectively applied at the mid-term follow-up period to evaluate neuromotor and cardiac functions. This study was approved by the University Ethics Committee on Human Subjects at Sichuan University (No. 2010002). Fetal persistent SVT and AFL were diagnoses followed previously published criteria and involved two fetal cardiologists and two experienced ultrasound experts. They used a Philips IE33 ultrasound system (Philips Healthcare, Bothell, WA, USA) with an S5-1 probe at a frequency of 1.0–5.0 MHz. The fetal cardiovascular profile score (CVPS) was used to evaluate fetal cardiac function. All fetuses initially received transplacental digoxin (0.25 mg twice daily), and sotalol served as the second-line therapy. Details regarding the standardized prenatal treatment regimens, definitions used (“fetal hydrops”, “rhythm converted”, “rate control”, and “intrauterine relapse”), and the neonatal/postneonatal management and follow-up protocols can be found in Supplementary Methods, https://links.lww.com/CM9/C401. The characteristics of fetal tachyarrhythmia and fetal outcomes are detailed in Figure 1 and Supplementary Tables 1 and 2, https://links.lww.com/CM9/C401. The mean gestational age at diagnosis was significantly lower in the SVT group than that in the AFL group (P = 0.010). Despite a seemingly short median interval between diagnosis and treatment initiation, the AFL group exhibited worse pre-treatment fetal cardiac function compared to the SVT group, evidenced by a low fetal CVPS (P = 0.019) and high cardiothoracic ratio (P = 0.008). All 32 patients initially received transplacental digoxin monotherapy. Among them, 14 (43.8%, 14/32) achieved intrauterine cardioversion within 3–7 days, with similar rates in the SVT (7/14) and AFL (7/18) groups. One fetus with AFL (1/18) achieved ventricular rate control. However, 17 fetuses (53.1%, 17/32) did not respond to prenatal digoxin treatment, including 7 (7/14) with SVT and 10 (10/18) with AFL.Figure 1: Outcomes of transplacental digoxin monotherapy. AFL: Atrial flutter; SVT: Supraventricular tachycardia.Of the 17 SVA fetuses who did not respond to digoxin, two (2/17) underwent induced abortion upon family request, two (2/17) were delivered prematurely at 35+2 weeks and 35+5 weeks due to maternal premature rupture of membranes. Four (4/17) continued with digoxin dosage adjustment due to family refusal to add sotalol, and nine (9/17) received combination treatment with sotalol. Of the four patients who continued digoxin dosage adjustment, one AFL fetus finally achieved cardioversion after 12 days, while the remaining three AFL fetuses did not respond and were delivered by cesarean section near full term (36+4 weeks, 37+1 weeks, and 37+1 weeks). Of the nine fetuses receiving combination therapy with sotalol, successful cardioversion was achieved in five fetuses (5/9). One fetus (1/9) achieved ventricular rate control but experienced relapse after 5 days and was delivered at 35 weeks. The remaining three fetuses failed treatment and were delivered prematurely (one at 33+6 weeks) and at full-term (two at 37+3 weeks and 37+1 weeks). Among the 15 fetuses with SVA who achieved successful intrauterine cardioversion or rate control after digoxin monotherapy, four (4/15) experienced intrauterine relapse. Among them, three experienced relapses within 3–5 days after digoxin dosage reduction following initial cardioversion. Two of the three experienced relapses achieved cardioversion gain after an increase in digoxin dosage or with the addition of sotalol. One fetus with progressive worsening of fetal hydrops despite increased digoxin dosage was terminated upon parental request. The remaining fetus experienced relapse 12 days after achieving rate control and was delivered upon parental request at 34+6 weeks. Importantly, no side effects were observed during prenatal treatment with digoxin or sotalol. Detailed results are described in Supplementary Table 3, https://links.lww.com/CM9/C401. Of the 32 SVA fetuses, three families opted for abortion and four were lost to follow-up, resulting in 25 live births (11 with SVT and 14 with AFL). Of the 11 live births with SVT, eight maintained normal sinus rhythm after birth and three continued to experience arrhythmias postnatally. Among these three, two infants were diagnosed with AFL on postnatal electrocardiogram (ECG). Of these two infants, one returned to normal rhythm after treatment with digoxin, and sinus rhythm was finally restored in the other by electrical cardioversion after failed treatment with a combination of digoxin and sotalol or amiodarone. One infant was diagnosed with paroxysmal atrial tachycardia at birth and achieved ventricular rate control after treatment with digoxin, propafenone, and amiodarone. However, this infant experienced repeated arrhythmias after discharge. The child is now 2 years and 6 months old and still requires long-term oral digoxin combined with sotalol to control the ventricular rate. Telephone follow-ups revealed that the child had occasional episodes of SVA and normal cardiac function [Supplementary Table 4, https://links.lww.com/CM9/C401]. Nine of the 14 live births with fetal AFL continued to maintain sinus rhythm after birth. One infant experienced a recurrence of AFL 3 days later (considered neonatal arrhythmia recurrence) and treated with oral digoxin for cardioversion. Five infants still experienced arrhythmias postnatally and four of them achieved sinus rhythm after treatment with either digoxin (n = 2) or digoxin combined with propranolol (n = 2). The remaining infant did not respond to oral digoxin and transesophageal pacing therapy but eventually recovered to normal rhythm after electrical cardioversion. Regarding risk factors for unresponsiveness to prenatal digoxin monotherapy for SVA, it was found that the incidence of fetal tricuspid/mitral valve regurgitation in the rate-control/un-cardioversion group was significantly higher than that in the cardioversion group (44.5% vs. 7.1%, odds ratio: 1.67, 95% confidence interval: 1.08–2.06, P = 0.044). Additionally, concerning the risk factors for intrauterine relapse after prenatal digoxin monotherapy for SVA, the fetal CVPS at the first re-examination after digoxin therapy was significantly improved in the non-relapse group compared to the relapse group (P = 0.015). Detailed results are described in Supplementary Tables 5 and 6, https://links.lww.com/CM9/C401. A total of 25 live births were followed up beyond the neonatal period, ranging from 2 months to 154 months. Ten children (40.0%, 10/25) were followed up via telephone to inquire about their growth and neuromotor development, including 9 males and 1 female. Their physical and motor development was comparable to that of normal healthy children, and they did not report any symptoms, such as shortness of breath, palpitations, chest tightness, fatigue, or limitations in activity levels at any age. However, most of these children did not undergo systematic cardiac function tests, such as ECG or echocardiography. The remaining 15 children (10 males, 5 females) received follow-up care at the outpatient clinic. All these children had height and weight measurements exceeding the 10th percentile of the standard height and weight of healthy children of the same age and sex. Twelve children (12/15) were evaluated on the Pediatric Quality of Life 4.0 scale and received a mean score of 89.42 ± 5.20. Eleven children (11/15) underwent assessment using the Ages & Stages Questionnaires®, Third Edition (ASQ®-3). Of these 11 children, one child with fetal SVT had a fine motor assessment score at the threshold, one child with fetal AFL had a fine motor assessment score below the threshold, and one child with fetal AFL had a personal–social assessment score below the threshold. It is important to note that none of these children had a history of birth asphyxia or resuscitation, congenital abnormalities, central nervous system diseases, or a family history of intellectual disability. All three patients who completed the Gesell Developmental Scale had normal developmental quotient. Additionally, six children who completed the Gesell Developmental Scale during routine checkups demonstrated normal development quotients. Furthermore, routine ECG and echocardiography performed on 15 children during follow-up yielded normal results. Detailed results are described in Supplementary Table 7, https://links.lww.com/CM9/C401. In conclusion, compared to fetal SVT, AFL tended to be diagnosed late but caused more pronounced fetal cardiac hemodynamic changes. Early diagnosis and timely intervention were therefore crucial for fetuses with AFL. The overall cardioversion rate of digoxin monotherapy was low (less than 50.0%), especially among fetuses with AFL, underscoring the importance of individualized treatment strategies for SVA according to the type of SVA and fetal conditions.[2,3] The overall safety and tolerability of digoxin therapy were superior. Fetuses with SVA might experience both intrauterine and neonatal recurrences even after achieving intrauterine cardioversion or ventricular rate control and should be monitored closely during treatment. Aggressive therapy might be considered for fetuses with SVA with tricuspid/mitral valve regurgitation, and rapid drug dosage reduction should be avoided after cardioversion in fetuses with SVA without CVPS improvement. For children who survived SVA, mid-term physical growth and neuromotor development appeared to be favorable, but this should be verified in large datasets with longer follow-up durations. Data availability statement The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author. Funding This work was supported by grants from the Natural Science Foundation of Sichuan Province (Nos. 2024YFFK0272, 2024YFFK0078, 2024NSFSC1711, 2025ZNSFSC1674, and 2025ZNSFSC0705), Key research and development project of Chengdu Science and Technology Bureau (Nos. 2024-YF05-00237-SN and 2024-Y05-00506-SN); National Natural Science Foundation of China (No. 82370236); National Key Research and Development Program of China (No. 2022YFC2703902). Conflicts of interest None.