Cardiovascular Disease in Pregnancy: When Two Hearts Beat as One

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This is an exceptionally comprehensive and well-organized review on cardiovascular disease in pregnancy. The manuscript demonstrates a clear command of current evidence, integrates recent ESC and AHA guidelines effectively, and provides a valuable multidisciplinary framework for clinicians. The structure is logical, and the writing is fluent and accessible. The inclusion of tables summarizing major disorders and key studies is particularly helpful. However, there are certain concerns thta require further assessement:

1)While broad coverage is a strength, some sections (e.g., on hemodynamic physiology and anticoagulation) could be condensed to reduce redundancy and enhance focus on novel insights or controversies. The authors should streamline these to maintain reader engagement.

2)The manuscript could further distinguish between guideline reiteration and areas of clinical uncertainty or debate (e.g., optimal anticoagulation strategies, role of bromocriptine in PPCM). Highlighting such gaps would increase the paper’s scholarly value.

3)Figure 2 (multidisciplinary pathway) would benefit from clearer labeling or a schematic structure to emphasize care phases (preconception, antepartum, postpartum). 

4)Most references are appropriate and up to date, though inclusion of a few key recent studies (2024–2025 ESC updates or registry data) could strengthen timeliness.

5)the text is polished, but several sentences are lengthy and densely packed with parenthetical clauses. Minor stylistic tightening would improve readability without loss of sophistication.

6)Line 18: “constitute a natural cardiovascular stress test” — the authors should cite a foundational reference here.

7)Table 1: “Preferred Management (Safe)”— the authors should rephrase to “Recommended Management (Preferred)” for consistency with guideline terminology.

8)All Abbreviations should be defined at first mention in both main text and tables.

Author Response

We thank the reviewer for the thoughtful and constructive feedback. Below we provide a detailed, point-by-point response describing how each suggestion has been addressed in the revised version of the manuscript.

Reviewer Comment 1: While broad coverage is a strength, some sections (e.g., on hemodynamic physiology and anticoagulation) could be condensed to reduce redundancy and enhance focus on novel insights or controversies. The authors should streamline these to maintain reader engagement.

Response 1: We agree with the reviewer. Both the hemodynamic physiology and anticoagulation sections were condensed to eliminate redundancy and maintain focus on the most clinically relevant and novel aspects.

• The discussion on physiological adaptations was summarized to emphasize only key mechanisms relevant to cardiovascular stress during pregnancy.

• The anticoagulation section now centers on unresolved issues such as anti-Xa monitoring and therapeutic targets rather than duplicating guideline content. (Revisions: Sections 2.2 and 3.3, pp. 5–8)

Reviewer Comment 2: The manuscript could further distinguish between guideline reiteration and areas of clinical uncertainty or debate (e.g., optimal anticoagulation strategies, role of bromocriptine in PPCM). Highlighting such gaps would increase the paper’s scholarly value.

Response 2: We have clarified the distinction between well-established recommendations and areas of uncertainty.

• New sentences explicitly highlight knowledge gaps in anticoagulation monitoring, PPCM pharmacotherapy, and risk stratification in valvular disease.

• A new paragraph in the Discussion synthesizes these controversies to underscore future research priorities.
  (Revisions: Sections 3.4 and 6.2, pp. 9–10 and 21–22)

Reviewer Comment 3: Figure 2 (multidisciplinary pathway) would benefit from clearer labeling or a schematic structure to emphasize care phases (preconception, antepartum, postpartum).

Response 3: We revised the figure extensively.

• The schematic now clearly delineates the three phases of care: Preconception, Antepartum, and Postpartum.

• Labels were simplified, and a legend was added to improve visual clarity.

• The text referring to the figure was updated accordingly.
  (Revisions: Figure 2 and legend, p. 16; Section 5.2)

Reviewer Comment 4: Most references are appropriate and up to date, though inclusion of a few key recent studies (2024–2025 ESC updates or registry data) could strengthen timeliness.

Response 4: We have updated the reference list to include recent 2024–2025 literature and guidelines, specifically:

• 2025 ESC Guidelines on Cardiovascular Diseases in Pregnancy (Ref. 1)

• ROPAC III registry (2025 update) (Ref. 34)

• EORP PPCM registry 2025 (Ref. 21)

• Countouris et al., Circulation 2025 (Ref. 41)
  These additions ensure that the review reflects the most recent data available.
  (Revisions: References section, pp. 24–28)

Reviewer Comment 5: The text is polished, but several sentences are lengthy and densely packed with parenthetical clauses. Minor stylistic tightening would improve readability without loss of sophistication.

Response 5: We carefully revised the manuscript for improved readability and flow.

• Long, multi-clause sentences were divided into shorter statements for clarity.

• Parentheses were reduced, and transitions improved for smoother progression.

• The Abstract and Discussion, in particular, were refined for concision.
  (Revisions throughout Abstract, Introduction, and Discussion, pp. 2–4 and 20–22)

Reviewer Comment 6: Line 18: “constitute a natural cardiovascular stress test” — the authors should cite a foundational reference here.

Response 6: We added two foundational citations to support this statement:

• Sanghavi M, Rutherford JD. Circulation 2014;130:1003–1008.

• Soma-Pillay P et al. Cardiovasc J Afr 2016;27:89–94.
  (Revisions: Introduction, line 18; References 4 and 5)

Reviewer Comment 7: Table 1: “Preferred Management (Safe)”—the authors should rephrase to “Recommended Management (Preferred)” for consistency with guideline terminology.

Response 7: Table 1 has been updated as requested. The column heading now reads “Recommended Management (Preferred)”, aligning with official ESC and AHA guideline language.
(Revisions: Table 1, p. 7)

Reviewer Comment 8: All abbreviations should be defined at first mention in both main text and tables.

Response 8: All abbreviations are now defined upon first appearance in the main text and in table legends.

• Consistency checks were applied throughout, including for PPCM, LMWH, sFlt-1/PlGF, and LVEF.
  (Revisions throughout text and table legends, pp. 3–18)

All requested revisions have been fully implemented. The manuscript now presents a more focused, updated, and reader-friendly synthesis of cardiovascular disease in pregnancy, emphasizing current challenges and research directions while maintaining scientific rigor.

Signed on behalf of all authors,
Chiara Tognola, MD

Reviewer 2 Report

Comments and Suggestions for Authors

In its current form, the article is an overly broad and descriptive review that resembles a scientific textbook for students. The manuscript requires substantial revision. It is necessary to select a few of the most interesting and challenging topics, provide a detailed analysis of existing research on them, critically evaluate recommendations from different professional societies, and identify any discrepancies. The authors must offer up-to-date practical recommendations by addressing complex clinical questions. They are also encouraged to explore the pathophysiology of the selected conditions in greater detail.

Author Response

We thank the reviewer for the thoughtful and constructive comments, which have greatly improved the scientific focus and clinical relevance of our manuscript. In accordance with the recommendations, we have substantially revised the paper to reduce its descriptive breadth, enhance analytical depth, and strengthen its translational and critical perspective. Below, we detail each change and its location in the revised version.

Reviewer Comment 1: In its current form, the article is an overly broad and descriptive review that resembles a scientific textbook for students. The manuscript requires substantial revision.

Response 1: We appreciate this valuable feedback. The manuscript has been completely restructured to transform it from a broad descriptive overview into a focused, analytical, and evidence-driven review.

• Several general or didactic sections (e.g., basic physiological background, drug safety tables, and long guideline summaries) were condensed or removed.

• The revised manuscript now concentrates on clinically relevant controversies, societal guideline discrepancies, and unresolved research questions in cardiovascular disease during pregnancy.

• The writing style has been tightened to maintain an expert-level tone throughout, eliminating textbook-like explanations.
  (Revisions throughout Sections 2–5, pp. 5–17)

Reviewer Comment 2: It is necessary to select a few of the most interesting and challenging topics, provide a detailed analysis of existing research on them, critically evaluate recommendations from different professional societies, and identify any discrepancies.

Response 2: We have followed this recommendation and reorganized the manuscript around three major high-impact topics:

1. Anticoagulation and Thromboembolic Risk Management in Pregnancy

2. Peripartum Cardiomyopathy (PPCM): Pathophysiology and Therapeutic Controversies

3. Hypertensive Disorders of Pregnancy (HDP): Endothelial Dysfunction and Long-Term Cardiovascular Risk

For each topic, we now:

• Present a critical synthesis of current research, including registry data (ROPAC III, EORP PPCM 2025, CHAP, and WILL trials).

• Provide a side-by-side comparison of ESC (2025) and AHA (2020) guideline recommendations.

• Explicitly discuss areas of discordance, such as LMWH monitoring, bromocriptine use, and long-term surveillance after preeclampsia.

This restructuring has significantly enhanced the analytical rigor and clinical relevance of the review.
(Revisions: New subsections 3.1–3.4, 4.1–4.3, and Table 3 “Guideline Discrepancies and Clinical Implications,” pp. 9–18)

Reviewer Comment 3: The authors must offer up-to-date practical recommendations by addressing complex clinical questions.

Response 3: In each major section we have integrated available evidence with expert interpretation, thereby offering concise, pragmatic recommendations for clinicians.
Examples include:

• Anticoagulation: Clarified indications for LMWH vs. VKAs across trimesters, with explicit anti-Xa monitoring targets based on 2025 ESC updates.

• PPCM: Discussed management of heart failure medications during lactation, and current consensus on bromocriptine use.

• HDP: Summarized the timing and structure of postpartum cardiovascular follow-up and preventive interventions.
  (Revisions: End of Sections 3–5, pp. 14–22)

Reviewer Comment 4: They are also encouraged to explore the pathophysiology of the selected conditions in greater detail.

Response 4: We expanded the pathophysiological analysis substantially in each major topic area:

• PPCM: Detailed discussion of oxidative stress, mitochondrial dysfunction, and prolactin-cleavage hypothesis, integrating emerging translational studies (Refs 32–35).

• HDP: Added mechanistic overview of endothelial dysfunction, angiogenic imbalance (sFlt-1/PlGF), and microvascular remodeling as precursors of chronic hypertension and heart failure.

• Thrombosis: Elaborated on pregnancy-related hypercoagulability and placental vascular adaptations linked to prothrombotic states.
  These expansions deepen the mechanistic understanding while maintaining clinical focus.
  (Revisions: Sections 3.2, 4.1, and 5.1, pp. 9–20)

Additional Structural Improvements

• The Introduction now clearly defines the scope and rationale of the review, positioning it within recent clinical developments rather than general physiology.

• The Discussion synthesizes knowledge gaps and suggests future research priorities, such as registry-based pharmacovigilance and individualized cardio-obstetric risk models.

• The Conclusion emphasizes translational implications and integrates pregnancy-related CVD within the broader continuum of women’s cardiovascular health.
  (Revisions: pp. 3–4 and 22–23)

The revised manuscript is now a focused, critical, and up-to-date synthesis of some of the most clinically and scientifically relevant topics in cardiovascular disease during pregnancy.

Signed on behalf of all authors,
Chiara Tognola, MD

Reviewer 3 Report

Comments and Suggestions for Authors

The paper is interesting but it should be reorganized to avoid repetitions, overlaps and improve clarity.

It appears in fact somewhat confusing and difficult to follow the double numeration as Paragraphs (in arabic numbers) and Themes in roman numbers. I would suggest to avoid Theme classification and try to use only the arabic numeration of paragraphs with their specific title for content clarification. 

It should be also considered that there are situations which greatly impact on CVD in pregnancy like diabetes, smoking habits, alcohol and drug abuse, obesity and women with known congenital heart diseases, all which situations should be probably also considered and discussed in more detail.

Line 120 “hydralazine” > “Hydralazine”

Valvular heart diseases and valvular prosthesis are partly discussed in Paragraph 5, Theme III Mechanical Obstuction, and partly in Paragraph 10, Theme VII, Anticoagulation strategies. All valvular problems could be probably better discussed in a single Paragraph.

Line 183: The title appears equivocal and apparently not inclusive of all the contents of the paragraph, dealing also with valve insufficiency. Perhaps a more pertinent title for this Paragraph could be “Valvular heart diseases, Prosthetic heart valves, Hypertrohic cardiomyopathy, Aortopathy.” However, please consider to rearrange the Paragraphs’ order and contents, as suggested above.

Table 1, Table 2 and Figure 2 are located at the end of Paragraph 10, Theme VIII Anticoagulation therapies. They shoud be probably separated or better localized and presented along the text or in a separate Paragraph, like a “Discussion”.  Part of the actual “Conclusions” could be in fact part of the “Discussion” instead. In this way Conclusions could be better shortened.

Author Response

We sincerely thank the reviewer for the thoughtful and constructive feedback, which has been invaluable in improving the organization, clarity, and completeness of our manuscript. All suggestions have been carefully considered and incorporated. Below is our detailed, point-by-point response.

Reviewer Comment 1: The paper is interesting but it should be reorganized to avoid repetitions, overlaps and improve clarity.

Response 1: We fully agree with the reviewer. The manuscript has been reorganized and streamlined to eliminate redundancy and overlapping content.

• Repeated explanations of physiological mechanisms, overlapping references to pregnancy complications, and duplicated mentions of guideline recommendations were removed or merged.

• Each section now follows a clear and progressive structure: Pathophysiology → Clinical Implications → Management → Key Evidence → Clinical Takeaway.

• Transitions between topics were rewritten for smoother logical flow.
  (Revisions throughout Sections 2–6, pp. 5–21)

Reviewer Comment 2: It appears in fact somewhat confusing and difficult to follow the double numeration as Paragraphs (in arabic numbers) and Themes in roman numbers. I would suggest to avoid Theme classification and try to use only the arabic numeration of paragraphs with their specific title for content clarification.

Response 2: We appreciate this valuable observation.

• The Theme classification in Roman numerals has been completely removed.

• The entire manuscript now uses only Arabic paragraph numbering (1, 2, 3, …) for clarity and easier navigation.

• Each paragraph title has been rewritten to be self-explanatory and content-specific, ensuring immediate understanding of its focus (e.g., “Anticoagulation Strategies during Pregnancy” rather than “Theme VIII: Anticoagulation Therapies”).
  (Revisions applied globally across the manuscript headings, pp. 2–23)

Reviewer Comment 3: It should be also considered that there are situations which greatly impact on CVD in pregnancy like diabetes, smoking habits, alcohol and drug abuse, obesity and women with known congenital heart diseases, all which situations should be probably also considered and discussed in more detail.

Response 3: We thank the reviewer for highlighting this essential point. We have now added a dedicated subsection discussing modifiable cardiovascular risk factors and comorbidities affecting pregnancy outcomes, including:

• Diabetes mellitus: interaction with hypertensive disorders and gestational cardiomyopathy.

• Obesity: association with preeclampsia, PPCM, and increased cesarean risk.

• Smoking, alcohol, and substance abuse: effects on endothelial function, arrhythmia risk, and fetal growth restriction.

• Congenital heart disease (CHD): updated data from the 2025 ROPAC registry and management of repaired versus unrepaired lesions.
  This addition ensures the review addresses the full spectrum of predisposing factors influencing maternal cardiovascular risk.
  (Revisions: New Section 4.3 “Comorbidities and Modifiable Risk Factors,” pp. 15–16)

Reviewer Comment 4: Line 120 “hydralazine” > “Hydralazine”

Response 4: Corrected as suggested. The drug name “Hydralazine” now appears with proper capitalization.
(Revisions: Section 3.2, line 120, p. 8)

Reviewer Comment 5: Valvular heart diseases and valvular prosthesis are partly discussed in Paragraph 5, Theme III Mechanical Obstruction, and partly in Paragraph 10, Theme VII, Anticoagulation strategies. All valvular problems could be probably better discussed in a single Paragraph.

Response 5: We agree completely and have merged all content related to valvular heart disease and prosthetic valves into a single unified section titled: “Valvular Heart Diseases and Prosthetic Valve Management During Pregnancy.”

• This section now integrates mechanical obstruction, valve insufficiency, and anticoagulation considerations into a comprehensive discussion.

• The redundant parts from the former “Mechanical Obstruction” and “Anticoagulation” sections have been removed to improve coherence and readability.
  (Revisions: New Section 5.1, pp. 17–19)

Reviewer Comment 6: Line 183: The title appears equivocal and apparently not inclusive of all the contents of the paragraph, dealing also with valve insufficiency. Perhaps a more pertinent title for this Paragraph could be “Valvular heart diseases, Prosthetic heart valves, Hypertrophic cardiomyopathy, Aortopathy.” However, please consider to rearrange the Paragraphs’ order and contents, as suggested above.

Response 6: Thank you for this precise suggestion.

• The paragraph has been modified and renamed.

• The section order has been restructured to follow clinical prevalence and pathophysiologic logic: congenital heart disease → valvular disease → cardiomyopathy → aortopathy → anticoagulation strategies.
  This reorganization ensures better alignment with clinical reasoning and guideline structure.
  (Revisions: Section 5.1 and reordering of Sections 5–6, pp. 16–20)

Reviewer Comment 7: Table 1, Table 2 and Figure 2 are located at the end of Paragraph 10, Theme VIII Anticoagulation therapies. They should be probably separated or better localized and presented along the text or in a separate Paragraph, like a “Discussion”. Part of the actual “Conclusions” could be in fact part of the “Discussion” instead. In this way Conclusions could be better shortened.

Response: We have followed this structural advice:

• Tables 1 and 2 are now repositioned within the corresponding text sections (Table 1 under “Pharmacologic Management,” Table 2 under “Anticoagulation Strategies”).

• Figure 2 has been moved to the section discussing the multidisciplinary Pregnancy Heart Team, with an improved legend and layout.

• A new “Discussion” section has been created to synthesize evidence, highlight uncertainties, and integrate guideline differences.

• The Conclusions section has been shortened and made more focused, emphasizing key take-home messages and future perspectives.
  (Revisions: Reorganization of Tables/Figures, new Discussion section pp. 20–22, revised Conclusions pp. 23–24)

All reviewer suggestions have been implemented. The manuscript has been reorganized to ensure clarity, logical flow, and full thematic coherence. 

Signed on behalf of all authors,
Chiara Tognola, MD

Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

The article can be published

Author Response

Dear Reviewer,

We sincerely thank you for your positive evaluation and for recommending our manuscript for publication. We appreciate your time and consideration.

Kind regards,
The Authors

Reviewer 3 Report

Comments and Suggestions for Authors

The Authors made so many corrections that it is very difficult to read the final approved draft. 

I would suggest to submit a final draft showing only with the approved text, to help the final review process.  Many thanks.  

Author Response

Dear Reviewer,

We fully understand your concern regarding readability. We have uploaded the final version including track changes, so that all modifications can be easily reviewed.

We appreciate your time and support.

Kind regards,
The Authors