Transplacental Treatment of Fetal Tachyarrhythmia: Current Trends and Future Perspectives

Round 1

Reviewer 1 Report

The review article has a very interesting title and abstract, encouraging to read it. Unfortunately, reading the entire article leaves mixed feelings.

Where did the Authors find such a definition of fetal tachyarrhythmias? (line 95-96, I quote: “Fetal tachyarrhythmias are defined by a persistent elevation of the fetal heart 96 rate above 180 beats per minute”. Fetal tachyarrhythmias are defined by fetal heart rate >160 beats per minute.

The title indicates that the topic will be about fetal tachyarrhythmias. There is no systematic division, no specific definitions for various pathologies that can be included in this category.

Selected definitions that have been presented, e.g. supraventricular tachyarrhythmias (line 42; I quote: “Although there are many types of classifications, supraventricular tachyarrhythmias can be divided into supraventricular tachyarrhythmias (SVT), ventricular tachyarrhythmias (VT), and sinus tachycardias”), indicate a large inaccuracy by the authors, or a lack of careful correction of serious errors.

Fetal tachyarrhythmias include: sinus tachycardia, supraventricular tachycardia, atrial flutter, atrial fibrillation, and ventricular tachycardia and fibrillation.

The reader would like to find suggestions from the authors, what treatment should be considered in a particular fetal arrhythmia (at presentation and no hydrops), what is the transplacental transport of the presented medicaments. What percentage of the drug reaches the fetus from the maternal circulation? What is the placental distribution? In what percentage is the drug metabolized by placental enzymes?  The table would need to be expanded.

I expected a lot from the chapter entitled "2.3. Future perspectives in fetal therapy". Unfortunately, half of this chapter (lines 314-330) is based on two publications, which are from 2010 and 1996.

Many abbreviations are not explained.

Author Response

1. The review article has a very interesting title and abstract, encouraging to read it. Unfortunately, reading the entire article leaves mixed feelings.Where did the Authors find such a definition of fetal tachyarrhythmias? (line 95-96, I quote: “Fetal tachyarrhythmias are defined by a persistent elevation of the fetal heart 96 rate above 180 beats per minute”. Fetal tachyarrhythmias are defined by fetal heart rate >160 beats per minute.

1. We thank the reviewer for the appreciation. The definition of the normal range has varied over the years. The concept of defining tachyarrhythmia above 180 bpm stems from the 2009 ACOG Practice Bulletin [1]. In fact, today, although normal heart rate can be defined between 100 bpm and 160 bpm, some authors considering the 180 bpm cutoff to define sinus tachycardia and the different forms of fetal tachyarrhythmia [2,3].

However, we have taken their assessment into account and have corrected the data in the text as it may be misleading.

[1] ACOG ACoOaG. ACOG Practice Bulletin No. 106: Intrapartum fetal heart rate monitoring: nomenclature, interpretation, and general management principles. Obstet Gynecol. 2009;114:192-202.

[2] Levine J, Alexander M. Fetal arrhythmias. UpToDate 2023. Available from https://www.uptodate.com/contents/fetal-arrhythmias. Table: Summary of fetal arrhythmias

[3] Bravo-Valenzuela NJ, Rocha LA, Machado Nardozza LM, Araujo Júnior E. Fetal cardiac arrhythmias: Current evidence. Ann Pediatr Cardiol. 2018;11:148-163.

2. The title indicates that the topic will be about fetal tachyarrhythmias. There is no systematic division, no specific definitions for various pathologies that can be included in this category.

2. The subject of the article focuses on current and future strategies for the treatment of fetal tachyarrhythmias. To put the subject in context, we have added an "Introduction" section in which, over four pages, we discuss related topics such as epidemiology, classification and prenatal diagnosis. However, given the complexity of the classification and the lack of international standardization in this regard, we felt it wise not to expand on the different forms of fetal tachyarrhythmia. Furthermore, as will be discussed later, except for some specific forms of tachyarrhythmias that require specific treatment, the therapeutic strategies are common to most of them.

If finally required by the reviewer and editors, we can include an extensive description of the different forms of fetal tachyarrhythmia.

3. Selected definitions that have been presented, e.g. supraventricular tachyarrhythmias (line 42; I quote: “Although there are many types of classifications, supraventricular tachyarrhythmias can be divided into supraventricular tachyarrhythmias (SVT), ventricular tachyarrhythmias (VT), and sinus tachycardias”), indicate a large inaccuracy by the authors, or a lack of careful correction of serious errors. Fetal tachyarrhythmias include: sinus tachycardia, supraventricular tachycardia, atrial flutter, atrial fibrillation, and ventricular tachycardia and fibrillation.

3. We thank the reviewer for the appreciation. Due to the wide variety of classifications found in the literature and the lack of consensus in this regard, we have based our manuscript on the latest UpToDate review [1]. In the section "TACHYARRHYTHMIAS" the following is stated: "Differential diagnosis includes: (1) Sinus tachycardia; (2) Supraventricular tachycardia (SVT) (Typical 1:1 reentrant tachycardia, Atrial flutter, Automatic mechanisms); (3) Ventricular tachycardia.

This seemed to us to be the most accurate classification, due to its simplicity, and it is the one we have taken into account in the text.

In addition, throughout the review we have find multiple classifications [e.g. 2-, and we believe that one cannot be dogmatic in this regard.

[1] Levine J, Alexander M. Fetal arrhythmias. UpToDate 2023. Available from https://www.uptodate.com/contents/fetal-arrhythmias.

[2] Strasburger JF, Eckstein G, Butler M, Noffke P, Wacker-Gussmann A. Fetal Arrhythmia Diagnosis and Pharmacologic Management. J Clin Pharmacol. 2022;62 Suppl 1(Suppl 1):S53-S66.

[3] Strasburger JF, Wakai RT. Fetal cardiac arrhythmia detection and in utero therapy. Nat Rev Cardiol. 2010;7(5):277-90.

[4] Bravo-Valenzuela NJ, Rocha LA, Machado Nardozza LM, Araujo Júnior E. Fetal cardiac arrhythmias: Current evidence. Ann Pediatr Cardiol. 2018;11:148-163.

[5] Yuan, SM., Xu, ZY. Fetal arrhythmias: prenatal evaluation and intrauterine therapeutics. Ital J Pediatr 2020;46:21.

4. The reader would like to find suggestions from the authors, what treatment should be considered in a particular fetal arrhythmia (at presentation and no hydrops), what is the transplacental transport of the presented medicaments. What percentage of the drug reaches the fetus from the maternal circulation? What is the placental distribution? In what percentage is the drug metabolized by placental enzymes? The table would need to be expanded.

4. The article includes a section where part of the questions proposed by the reviewer are answered (2.1.4 Drug selection). E.g. Digoxin: "Thus, while in the non-hydropic fetus it can be considered the treatment of choice, conversion rates in hydropic fetuses with SVT are low". "Digoxin is not effective in case of ectopic atrial tachycardia and permanent junctional tachycardia." "In the presence of hydrops, both sotalol and flecainide are considered to have good placental transfer capacity and should be used as first-line therapy." Sotalol: "It is considered the treatment of choice in cases of ectopic atrial tachycardia and permanent junctional tachycardia, as well as in the hydrops fetus. In addition, its combination with digoxin can be very effective in the treatment of atrial flutter". We therefore consider that, despite the current controversy and the lack of firm evidence in this respect, it is clear in this section that the authors support the use of flecainide and digoxin as first-line drugs, avoiding the use of digoxin in the case of hydrops fetalis.

On the other hand, considering the scope of the journal, we have expanded on the other issues raised by the reviewer in his critique.

5. I expected a lot from the chapter entitled "2.3. Future perspectives in fetal therapy". Unfortunately, half of this chapter (lines 314-330) is based on two publications, which are from 2010 and 1996.

5. As suggested, we have expanded the information regarding future perspectives in fetal therapy.

6. Many abbreviations are not explained.

6. After a careful reading of the text, we found three unexplained abbreviations, which we have defined and clarified in their first appearance in the manuscript: atrio-ventricula (AV), ventriculo-atrial (VA), and atrial flutter (AF).

Reviewer 2 Report

Please to refer to the enclosed file

Comments for author File: Comments.pdf

Author Response

1. The paper focuses on the treatment and path physiology of the fetal tachyarrhythmias, and it contributes to shed light on future perspectives towards drug administration during pregnancy.

The paper does not result significantly innovative anyway it seems of interest for pediatric cardiologists and obstetric gynecologists or neonatologists. That said it is important to define the best time for birth and the careful assessment of the risks facing invasive transplacental therapy vs. the dyad fetus maternal.

1. As suggested, we have expanded the information regarding the time of delivery based on the current evidence in the different scenarios.

2. It seems that minor revision can be made specially on the references style (please the authors to carefully check the pages number).

2. We thank the reviewer for the appreciation. We have carefully reviewed the references and have made the pertinent corrections.

Reviewer 3 Report

The paper is overall interesting and despite it does not represent something really new or surprising it can be considered for publication. I suggest to expand the context of what is known on the topic broadening the view. I enclose some contructive criticisms for the authors.

1.Please describe the protocol for assessment of the fetal heart. A recent statement from leading experts in the field summarizes the method for performing a fetal cardiac scan comparing different guidelines and clinical indications. Please the authors add mention of their protocol and align to the suggested standard, citing it (1)

2. Fetuses with congenital hear defects are smaller than normal, this is particularly true for structural defects, but we also know that arrithmias can coexist with structural problems. Plese describe the extent to which fetal weight and gestational age may affect the treatment protocol as far as modality, choice of medications and dose and please cite major referencing on reduced fetal growth in fetused with CHD (2-3)

2. Fetuses with congenital heart defects have an increased risk of adverse obstetric outcomes including prematurity and preeclampsia, besides reduced fetal growth (ref 3). It is likely that this issue applies to fetal arrhitmyas as well, particularly the severe forms, particularly for preterm birth. Please discuss briefly this issue and cite appropriate references including n 3.

4. Future perspectives. Please add a comment on prevention of AV heart block in anti rho antibodies patients vs treatment of the overt condition (please discuss the role of prophilactic vs therapeutic use of steroids?)

References

1. Quaresima P, Fesslova V, Farina A, Kagan KO, Candiani M, Morelli M, Crispi F, Cavoretto PI. How to do a fetal cardiac scan. Arch Gynecol Obstet. 2023 Apr;307(4):1269-1276. doi: 10.1007/s00404-023-06951-8. PMID: 36786908.

2. Inversetti A, Fesslova V, Deprest J, et al. Prenatal Growth in Fetuses with Isolated Cyanotic and Non-Cyanotic Congenital Heart Defects. Fetal Diagn Ther. 2020;47(5):411-419. doi: 10.1159/000493938. Epub 2018 Nov 9. PMID: 30415250.

3. Giorgione V, et al. Adverse perinatal outcome and placental abnormalities in pregnancies with major fetal congenital heart defects: A retrospective case-control study. Prenat Diagn. 2020 Oct;40(11):1390-1397. doi: 10.1002/pd.5770. Epub 2020 Aug 12. PMID: 32557693.

Author Response

1. The paper is overall interesting and despite it does not represent something really new or surprising it can be considered for publication. I suggest to expand the context of what is known on the topic broadening the view. I enclose some contructive criticisms for the authors. Please describe the protocol for assessment of the fetal heart. A recent statement from leading experts in the field summarizes the method for performing a fetal cardiac scan comparing different guidelines and clinical indications. Please the authors add mention of their protocol and align to the suggested standard, citing it (1)

1. As suggested, we have included a brief description of the fetal cardiac assessment protocol, referring to the reference article indicated.

2. Fetuses with congenital heart defects are smaller than normal, this is particularly true for structural defects, but we also know that arrithmias can coexist with structural problems. Please describe the extent to which fetal weight and gestational age may affect the treatment protocol as far as modality, choice of medications and dose and please cite major referencing on reduced fetal growth in fetused with CHD (2-3)

2. In our review of the literature, we found no restriction on the use of first-line drugs in relation to fetal weight or gestational age. Due to the prolonged half-life of amiodarone, tapering before delivery has limited benefits. Before 30 weeks, accepting the risks of amiodarone may be warranted to avoid delivery of a hydropic preterm neonate. We have expanded on this information in the text.

Although an association between fetal growth and the presence of CHD, as well as preeclampsia and preterm birth, has been suggested, this association has not been established for fetal tachyarrhythmias without associated congenital heart disease. We have included this information in the manuscript by adding the two references cited.

3. Fetuses with congenital heart defects have an increased risk of adverse obstetric outcomes including prematurity and preeclampsia, besides reduced fetal growth (ref 3). It is likely that this issue applies to fetal arrhitmyas as well, particularly the severe forms, particularly for preterm birth. Please discuss briefly this issue and cite appropriate references including n 3.

3. Following the reviewer's consideration, we performed an exhaustive review of the literatura, looking for a possible association between fetal tachyarrhythmia and preeclampsia, prematurity and/or fetal weight restriction. The conclusion is that, in the absence of congenital heart disease, there is no increased risk of these conditions in fetuses with fetal tachyarrhythmia. There may be an iatrogenic increased of prematurity, due to poor control with pharmacological treatment, culminating in preterm delivery. We have made reference to these findings in the text.

4. Future perspectives. Please add a comment on prevention of AV heart block in anti rho antibodies patients vs treatment of the overt condition (please discuss the role of prophilactic vs therapeutic use of steroids?)

4. The article we have submitted for publication focuses exclusively on fetal tachyarrhythmias, emphases on treatment, but addressing various aspects, such as etiopathogenesis or prenatal diagnosis.

At no point in the manuscript do we mention or address fetal bradyarrhythmias. Therefore, although the subject proposed by the reviewer is interesting, we consider that it does not fit in with the content of the article. Nevertheless, we will take his opinion into account for future publications.

Round 2

Reviewer 1 Report

The Authors have adequately addressed my concerns and suggestions in the revised version.