含胺碘酮方案治疗胎儿快速性心律失常的荟萃分析与系统评价。

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【Abstract】 OBJECTIVE: To analyze the efficacy of amiodarone-inclusive protocol and the safety of amiodarone in fetal tachyarrhythmia treatment. METHODS: PubMed, Web of Science, Medline and Embase were searched. Randomized controlled trials, cohort studies, case series and case reports on the efficacy of amiodarone-based therapy and the amiodarone-related safety in fetal tachycardia were included. Case reports were presented separately and descriptively synthesized, while case series and cohort studies were included in the meta-analysis. Outcomes included conversion of the fetal rhythm and the occurrence of adverse effects induced by amiodarone in the fetus. This research was registered in PROSPERO (No.CRD42024560291). RESULTS: We analyzed 107 pregnancies treated with amiodarone from 27 studies. A descriptive synthesis of 18 case reports yielded a cardioversion rate of 81.0% for amiodarone-inclusive protocol, which was further supported by a quantitative analysis of nine studies showing a pooled cardioversion rate of 69.9% (95% CI: 57.6%-81.2%). In the hydropic subgroup fetus, cardioversion rates ranged from 53.8% to 87.5% (median, 63.4%). Overall, adverse events were reported in 29 fetuses, with thyroid dysfunction being the most prevalent. The pooled incidence of thyroid dysfunction was 21.2% (95% CI:11.4%-32.6%). CONCLUSION: Amiodarone-inclusive protocol may be effective in fetal tachycardia management, particularly in refractory cases. These findings support amiodarone as an adjunctive therapy rather than monotherapy. Although its use was related to a risk of transient neonatal thyroid dysfunction, there was insufficient data to support an increase in the severe adverse reactions. SYSTEMATIC REVIEW RESGISTRATION: PROSPERO (No. CRD42024560291). 【Introduction】 Fetal tachyarrhythmia is defined as cardiac rhythms or heart rates greater than 180 beats per minute in fetuses and occurs in approximately 0.1% of pregnancies (). It mainly manifests as supraventricular tachycardia (SVT), atrial flutter (AF), or ventricular tachycardia (). While most cases of fetal tachyarrhythmias are benign and transient, persistent tachyarrhythmias can result in secondary damage to vital organs and are often associated with fetal hydrops and heart failure, as well as premature birth and death. Hydrops fetalis is observed in 30%–40% of fetuses with SVT and in 7%–43% of fetuses with AF, a condition relating to adverse outcomes during pregnancy (). Transplacental antiarrhythmic therapy via maternal administration is strongly recommended for sustained tachyarrhythmia. According to the AHA guidelines on fetal tachycardia, first-line pharmacotherapy includes digoxin, flecainide, and sotalol. Digoxin has a low and unpredictable transplacental passage rate, and its efficacy is markedly reduced in the presence of hydrops fetalis. Flecainide and sotalol have limitations in the treatment of refractory or life-threatening fetal tachyarrhythmias (). When first-line agents are ineffective or severe fetal hydrops develops, alternative treatments are urgently needed. Amiodarone, a broad-spectrum antiarrhythmic agent with Class I, II, III, and IV channel-blocking activity, plays a central role in the treatment of various cardiac arrhythmias, particularly shock-refractory ventricular fibrillation (VF) or pulseless ventricular tachycardia (VT). Several studies have mentioned the potential efficacy of amiodarone in the treatment of fetal tachyarrhythmia, particularly in cases complicated by hydrops fetalis or refractory arrhythmia (; ; ). The American Heart Association recommends the use of amiodarone as a third-line therapeutic agent during pregnancy, predominantly owing to its association with an increased risk of adverse reactions (). Nevertheless, the studies referred to are predominantly characterized by small sample sizes and single-center designs (; ). The objective of our systematic review and meta-analysis is to investigate the effectiveness of amiodarone-containing regimen and the safety of amiodarone in the treatment of fetal tachyarrhythmia, thereby providing more evidence on intrauterine medical therapy for fetal tachyarrhythmia. 【Materials and methods】 【Study protocol and registration】 The systematic review was performed according to the preferred reporting items for systematic reviews and meta-analyses (PRISMA) (). It followed a registered protocol that was developed a priori and registered (PROSPERO: CRD42024560291). 【Data sources and search strategy】 With the collaboration of the study’s lead investigator, an experienced librarian developed and implemented the search strategy. Studies were searched in the databases of PubMed, Web of Science, Medline and Embase by search terms of ((Tachyarrhythmia OR Tachycardia OR Tachycardia Supraventricular OR flutter) AND (fetal OR fetus) AND (Anti-Arrhythmia Agents OR Amiodarone)). We also reviewed the reference lists for recent reviews, editorials, and pertinent publications. 【Selection of studies】 In the absence of randomized controlled trials on the treatment of fetal tachyarrhythmia, we focused on retrospective and prospective cohort studies, case series, and case reports that reported amiodarone-containing treatment for fetal tachyarrhythmia. There were no restrictions on the sample size. A comprehensive search of multiple databases was conducted from the inception of each database until 23 March 2026. Two authors independently performed the literature search and conducted data extraction using a standardized, prespecified form that distinguished the types of tachycardia or whether hydrops existed. Inclusion criteria: (1) patients with fetal tachyarrhythmia, or patients with non-sustained fetal tachycardia with evidence of cardiac dysfunction and/or hydrops treated with amiodarone will be included in the analysis regardless of their ethnicity and background. (2) We defined amiodarone treatment as an experimental intervention, regardless of the treatment route. The efficacy of combinations of amiodarone-inclusive protocol and other drugs was also taken into account. (3) The primary outcome was the effect of amiodarone therapy, defined as the conversion of fetal rhythm to sinus rhythm (SR) or rate control in fetuses suffering from tachyarrhythmia. Secondary outcomes considered were the adverse effects of amiodarone on fetuses. Publications that fulfilled any of the subsequent requirements were excluded: (1) Patients with immunologic or non-sustained fetal tachyarrhythmias. (2) Research on outcomes not directly related to our specified primary outcomes. (3) Duplicate publications. (4) The search was not the English-language publications. 【Data extraction】 The identification and extraction of potentially eligible articles were conducted by two researchers independently. A third reviewer was invited to resolve any discrepancies. Subsequently, a comprehensive analysis of their full texts was performed after the identified articles were retrieved. The following study characteristics included: general information of the study (author, publication year, region), population (number, diagnosis), study design, amiodarone intervention (dosage, administration, duration), outcomes (conversion to SR, rate control, incidence of adverse events). In cases where these data were not available, calculations were made following the details provided within the articles. 【Quality assessment】 No randomized trials have been conducted on fetal tachycardia treated with amiodarone. The case series study were evaluated utilizing the Methodological Index for Non-Randomized Studies (MINORS). The MINORS score, which ranged from 0 to 16, consists of eight components. A 3-point rating system (0–2) was used for each item. The quality of studies was categorized as “high” (score of 13–16), “medium” (score of 9–12), or “low” (score of less than 8) (). Case reports were evaluated using the Joanna Briggs Institute (JBI) Critical Appraisal Checklist for Case Reports (8 items, score range, 0–8). Scores of 7–8 indicated high quality, 5–6 moderate quality, and less than 4 as low quality (). 【Risk of bias】 For the descriptive synthesis of case reports, formal assessment of publication bias was not undertaken. Case reports are subject to high selection bias, as clinicians selectively record and submit unusual or favorable outcomes. The included case reports were performed as the quantitative synthesis rather than pooled effect estimates, and they were evaluated for data completeness rather than methodological rigor. For the pooled analysis of nine single-arm studies, publication bias could not be assessed due to having fewer than ten studies and the lack of control groups. Evidence robustness was instead determined through systematically eliminating each study. Publication bias was evaluated using a funnel plot of the overall cardioversion rate. Funnel-plot asymmetry was analyzed qualitatively. Although any publication bias could not be completely ruled out, the symmetry was demonstrated to indicate the lack of a significant small-study effect. No Egger or Begg test was performed because of insufficient papers in small-study sets, in accordance with the Cochrane Handbook. 【Data synthesis and analysis】 We have divided the analysis into two distinct types. Certain outcomes permitted a pooled quantitative meta-analysis, while other variables lacked enough data for statistical pooling were summarized descriptively. Therefore, the case reports were summarized in tables and synthesized qualitatively. No quantitative pooling was performed for the section of case reports. In contrast, case series or retrospective studies were quantitatively analyzed using meta-analysis with R Studio software. The pooled proportion of cardioversion and adverse events were calculated separately, along with their 95% confidence intervals. The Freeman-Tukey double arcsine transformation was applied to stabilize the variance and compute reliable confidence intervals. A random-effects model was adopted to account for potential clinical heterogeneity across the included studies. In addition, subgroup analyses by hydrops, route of administration, and amiodarone monotherapy versus combination management were presented descriptively due to the limited number of studies and incomplete reporting data for formal meta‐analytic pooling. 【Results】 【Characteristics of the studies】 A total of 2,626 relevant articles were initially discovered. Titles and abstracts were screened for 1,759 records subsequent to the elimination of duplicates and retracted articles. Then, 51 full texts articles were evaluated for detailed information, of which 27 fulfilled the eligibility requirements () (; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ), including seven retrospective studies, two case series, and 18 case reports. However, after methodological assessment, none of the retrospective studies included a comparator group, and they were reclassified as case series in the final analysis. Of these, 18 case report were synthesized descriptively. The remaining nine case series were eligible for the quantitative meta-analysis. PRISMA for systematic reviews and meta-analyses flow diagram for study selection. 【Characteristics of patients】 presents the characteristics of fetuses receiving amiodarone monotherapy or combination therapy, as reported in the 27 included studies. A total of 107 patients were enrolled, of whom 21 were from case reports, 86 from the nine studies included in meta (). Considering medication, only 24 of 107 pregnancies with fetal tachyarrhythmias were treated with amiodarone as first-line therapy. Digoxin was the most frequently used antiarrhythmic drug, accounting for approximately 72.9% (78/107) of the total, regardless of whether it was the first-line treatment. Various antiarrhythmic drugs, such as flecainide, sotalol, and verapamil, were commonly used in these studies. There was also involvement with other classical antiarrhythmic drugs, such as procainamide, propafenone, atenolol, and propranolol. Summary of clinical characteristics (derived from case reports, case series). CHF, cardiac heart failure; SVT, supraventricular tachycardia; AE, atrial ectopic tachycardia; VT, ventricular tachycardia; JET, junctional ectopic tachycardia; TSH, thyroid-stimulating hormone; AVRT, atrioventricular reciprocating tachycardia; AF, atrial flutter; IP, intraperitoneal injection; IV: intravascular injection. 【Qualitative synthesis of case reports】 A descriptive statistical analysis was conducted on 21 fetuses with fetal tachycardia, derived from 18 case reports (; ) (; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ). The cardioversion rate for amiodarone-inclusive protocol was 81.0% (17/21). SVT was diagnosed in 90.5% (19/21) of the cases, but all were accompanied by non-immune hydrops. Amiodarone was selected as the first-line treatment in only four of the 21 cases. Two pregnancies were managed with amiodarone monotherapy, of which one failed to control the fetal heart rate. Regarding dosage and administration, the most prevalent routes of amiodarone application in fetal tachycardia were transplacental transfer and direct injection. The oral doses of amiodarone varied from 100 to 2,400 mg/d, and the fetal IV dosage was between 2.5 and 40 mg, depending on the fetal weight. Moreover, the duration of amiodarone exposure was approximately 2–11 weeks. Of the 21 fetues in the cases, nine experienced amiodarone-related ADR (9/21, 42.9%), all of which presented as thyroid dysfunction, like abnormality of TSH or T4 level, and hypothyroidism. Although the incidence of adverse reactions to amiodarone was high in these case reports, it is important to consider that case reports tend to predominantly highlight positive outcomes and are often limited in the number of cases reported, which may introduce some bias in accuracy. Therefore, we further conducted a meta-analysis of the included case series. Summary of case reports on fetal tachyarrhythmia treated with amiodarone. Y. yes; N, no; *M, Mother IV. 【Quantitative synthesis with meta-analysis】 9 case series were included in this single-arm meta-analysis (; ; ; ; ; ; ; ; ). Amiodarone was administered to a total of 86 fetuses with fetal tachycardia, of which 59 pregnancies displayed rhythm conversion to SR or heart rate control. The proportion of fetus achieving cardioversion with amiodarone-containing therapy ranged from 40% to 87.5% across these nine studies (). A random-effects model with the Freeman-Tukey double arcsine transformation was subsequently performed to calculate the pooled cardioversion rate. The result showed a pooled cardioversion rate of 69.9% (95% CI: 57.6%–81.2%) with low heterogeneity (I2 = 4.3%, p = 0.40) for amiodarone-inclusive protocol (). For safety outcomes, the present analysis examined the adverse reactions (ADRs) associated with amiodarone treatment for fetal tachycardia. Two studies (; ) did not refer to safety outcomes and were therefore excluded from this analysis. Among 86 fetuses from seven studies, twenty developed ADRs following amiodarone exposure (; ; ; ; ; ; ) (), with a pooled rate of 23.98% (95% CI: 13.7%–35.7%, I2 = 0%, p = 0.52) (). The most prevalent ADRs was thyroid dysfunction which occurred in 18 cases (90%), presented as abnormal TSH, T4 levels or mild hypothyroidism. As a result, the pooled incidence of thyroid dysfunction was 21.2% (95% CI: 11.4%–32.6%, I2 = 0%, p = 0.57), and there was no heterogeneity (). All cases of thyroid dysfunction completely recovered following levothyroxine treatment. The remaining two infants had delayed language acquisition at birth, which subsequently normalized with age without any intervention (). However, a causal relationship between amiodarone exposure and the speech delay in them could not be surely established. Summary of included studies for meta-analysis. Forest plot of the pooled cardioversion rate for amiodarone-inclusive protocols in fetal tachycardia. *Used to distinguish two articles by the same author. Forest plot of the pooled ADRs rate of amiodarone treatment in fetal tachycardia. *Used to distinguish two articles by the same author. Forest plot of the pooled rate of thyroid dysfunction. *Used to distinguish two articles by the same author. 【Descriptive subgroup analyses】 Formal subgroup meta analysis were not performed owing to the limited number of studies and insufficient data. Subgroup analyses based on hydrops status, arrhythmia type, and route of administration were presented descriptively. Of the nine studies in the meta-analysis, four enrolled exclusively hydropic fetuses, with cardioversion rates ranging from 53.8% to 87.5% (median, 63.4%). A single study of non-hydropic fetuses reported a rate of 42.9% (). Three studies included a mixed population with a cardioversion rate of 40%–85.7% (median, 73.1%). Six studies used oral amiodarone only (cardioversion rate 40%–85.7%, median 63.5%) (). Three research involved direct fetal injection (with or without oral administration), showing cardioversion rates of 60.0%, 66.7%, and 87.5% (median 66.7%) (). Regarding adverse events, five of the six studies reporting oral amiodarone administration showed adverse event rates ranging from 0% to 42.8% (median, 20%) (). Two studies combining oral and injection routes noted the ADR rates of 20.0% and 25.0% (), whereas the third similar study did not provide such data. Furthermore, all eight studies that reported the treatment included both amiodarone monotherapy and combination management. The proportion of monotherapy was 71.4% and 60% in the two studies, with corresponding cardioversion rates of 42.9% and 85.7%, respectively (). In the remaining six studies, the proportion of combination therapy ranged from 64.3% to 100% (median, 91.8%), with cardioversion rates of 40.0%–87.5% (median, 76.6%) (). Adverse event data were available in six of eight studies (0%–42.8%, median, 22.5%), since two studies did not report the safty outcome (). 【Risk of bias assessment】 Risk of bias for non-randomized studies was measured by the MINORS tool. All studies scored 11∼12 points (), indicating a moderate risk of bias (). Case reports were evaluated via the JBI Critical Appraisal Checklist. All case reports received a score of at least 5, with 13 articles receiving a 7, one receiving a 5, as well as two articles scored 8 two scoring 6, respectively (). Quality assessment of the studies included in the meta-analysis. Numbers Q1-Q8 in heading signified. Q1, A clearly stated aim. Q2, Inclusion of consecutive patients. Q3, Prospective collection of data. Q4, Endpoints appropriate to the aim of the study. Q5, Unbiased assessment of the study endpoint. Q6, Follow-up period appropriate to the aim of the study. Q7, Loss to follow up less than 5%. Q8, Prospective calculation of the study size. The risk of bias assessment of studies included in the single-arm meta-analysis. *Used to distinguish two articles by the same author. Quality assessment of the case report. Numbers Q1-Q8 in heading signified. Q1, Were patient’s demographic characteristics clearly described? Q2, Was the patient’s history clearly described and presented as a timeline? Q3, Was the current clinical condition of the patient on presentation clearly described? Q4, Were diagnostic tests or assessment methods and the results clearly described? Q5, Was the intervention(s) or treatment procedure(s) clearly described? Q6, Was the post-intervention clinical condition clearly described? Q7, Were adverse events (harms) or unanticipated events identified and described? Q8, Does the case report provide takeaway lessons? 【Sensitivity analysis】 Leave-one-out sensi