Antepartum Computerized Cardiotocography in High-Risk Pregnancies: Comparative Analysis of Fetal Heart Rate Parameters in Hypertensive Disorders of Pregnancy, Diabetes and Intrahepatic Cholestasis

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This article presents a retrospective, observational, single-center study evaluating antepartum fetal assessment through computerized cardiotocography (cCTG) in both normal and pathological pregnancies. Although cCTG is not a new technique, the authors address clinically relevant aspects by examining conditions associated with severe maternal pathology and adverse fetal outcomes.

The abstract is informative and well structured.

The introduction provides adequate background and clearly outlines the study aims.

The Materials and Methods section describes the selection criteria, and the sample size appears statistically important. However, the authors could clarify whether a target number of cases was predetermined, even though this is a retrospective study. The decision to include only high-quality recordings by excluding traces with more than 20% signal loss represents a methodological strength.

Further clarification regarding the maternal pathology severity would improve the rigor of the study. Distinguishing between types of gestational hypertension (pregnancy-induced versus exacerbation of pre-existing hypertension) and types of diabetes (gestational versus pre-existing) would be valuable, as would information on the severity of these conditions, which may correlate with cCTG findings.

The Results section is clearly presented, with comprehensive tables and appropriate statistical analyses. Inclusion of graphical representations (e.g., plots or figures) would further enhance readability. An important observation is the presence of hyperactive fetal movements in HTA and GDM—an underexplored aspect that is not emphasized in current guidelines. Given the low number of severe decelerations, conclusions regarding their clinical significance should be stated cautiously.

If available, the authors should also report neonatal outcomes in more severe cases, including whether delivery was expedited following cCTG abnormalities, Apgar scores, NICU admission, and relevant metabolic parameters.

The Discussion section adequately summarizes the principal findings, though the comparative analysis with existing literature could be expanded. Nonetheless, the statements are well supported, and the conclusions are appropriate.

Overall, this is an interesting and clinically relevant study. With the revisions outlined above, it could provide substantial practical value for readers.

 

Author Response

Dear Reviewer 1 , 

We sincerely thank you for your time and effort to revise our work , for your positive feedback. The manuscript has been revised accordingly to your suggestions, you may find our answer poin-by point. All revisions were highlighted in red in the manuscript.

 

 

This article presents a retrospective, observational, single-center study evaluating antepartum fetal assessment through computerized cardiotocography (cCTG) in both normal and pathological pregnancies. Although cCTG is not a new technique, the authors address clinically relevant aspects by examining conditions associated with severe maternal pathology and adverse fetal outcomes.

The abstract is informative and well structured.

The introduction provides adequate background and clearly outlines the study aims.

The Materials and Methods section describes the selection criteria, and the sample size appears statistically important.

However, the authors could clarify whether a target number of cases was predetermined, even though this is a retrospective study.

As requested, we have clarified that . A total of 14, 412 cases were analysed and we included 488 cases, 87 control and 401 cases. Materials and Methods section, subsection, lines 99–116, and to Resultes lines 178-179 where we now clearly state that the study population comprised all consecutive pregnancies monitored during the specified time frame that fulfilled the predefined inclusion and exclusion criteria.

In the same section, we have further clarified the case selection and verification process applied during database construction, including the systematic cross-checking of clinical records and cCTG registrations, and the criteria used to retain only internally consistent and verifiable cases. These additions were made to enhance methodological transparency and to explain the final allocation of cases across the study groups.

 

The decision to include only high-quality recordings by excluding traces with more than 20% signal loss represents a methodological strength.

Further clarification regarding the maternal pathology severity would improve the rigor of the study. Distinguishing between types of gestational hypertension (pregnancy-induced versus exacerbation of pre-existing hypertension) and types of diabetes (gestational versus pre-existing) would be valuable, as would information on the severity of these conditions, which may correlate with cCTG findings.

We thank the reviewer for this valuable suggestion. In response, we have provided additional clarification regarding maternal pathology severity by performing subgroup analyses within the GDM and HDP cohorts.

Specifically, diabetic pregnancies were subdivided into diet-controlled and insulin-requiring subgroups, reflecting increasing metabolic severity and treatment intensity, a distinction that is widely used as a proxy for disease burden and glycemic instability. This stratification allows a more nuanced assessment of the relationship between diabetes severity and fetal cCTG parameters. Similarly, hypertensive pregnancies were subdivided into non-preeclamptic hypertensive disorders (including chronic hypertension and gestational hypertension) and preeclampsia. This distinction is clinically and pathophysiologically relevant, as preeclampsia represents a more severe, multisystem disorder associated with placental dysfunction and altered fetal adaptive capacity, which may differentially impact cCTG findings.

Importantly, the definitions and classification criteria for all maternal pathology subgroups have now been described in the Materials and Methods section (lines 94–98) to ensure methodological transparency and reproducibility. Statistical analyses was then separately conducted for the individual subgroups, which were compared to the Control group, and results of this analysis were incorporated in the Results section.

Given the low number of severe decelerations, conclusions regarding their clinical significance should be stated cautiously.

We thank the reviewer for this valuable observation. We have revised both the Results and Discussion sections to clearly address the limited statistical power associated with the deceleration data.

First, in the Results section, we have added a clarifying paragraph (lines 517–523) acknowledging that the very low frequency of repetitive, late, prolonged, and >5-minute decelerations across all study groups substantially limits the strength of any subgroup comparisons. This addition emphasizes that, due to the rarity of these clinically significant patterns, the findings for this dataset cannot support definitive conclusions nor do they have a clear predictive value.

Second, in the Discussion section, we have added a dedicated paragraph (lines 634–643) further elaborating that the scarcity of severe deceleration events precludes firm interpretation of their independent clinical significance. As noted in the revision, these findings must therefore be interpreted cautiously and considered exploratory, and larger datasets with more events will be required to fully evaluate their prognostic implications.

 

 

The Results section is clearly presented, with comprehensive tables and appropriate statistical analyses. Inclusion of graphical representations (e.g., plots or figures) would further enhance readability. An important observation is the presence of hyperactive fetal movements in HTA and GDM—an underexplored aspect that is not emphasized in current guidelines. Given the low number of severe decelerations, conclusions regarding their clinical significance should be stated cautiously.

If available, the authors should also report neonatal outcomes in more severe cases, including whether delivery was expedited following cCTG abnormalities, Apgar scores, NICU admission, and relevant metabolic parameters.

We thank the reviewer for this thoughtful and clinically relevant suggestion. We agree that neonatal outcomes such as Apgar scores, NICU admission, and metabolic parameters are important for contextualizing antepartum fetal status. However, the present study was designed as a strictly comparative analysis of intrinsic antepartum cCTG parameters across different pregnancy conditions, rather than as an outcome-based investigation.

Immediate neonatal indicators are strongly influenced by intrapartum events and postnatal management and do not necessarily correlate with antepartum cCTG findings. For this reason, they were not included in the present analysis, as their integration would not have strengthened the primary comparative objective of the study.

These considerations have now been clarified in the revised manuscript in the Limitations section (lines 691–701).

 

The Discussion section adequately summarizes the principal findings, though the comparative analysis with existing literature could be expanded.

We thank the Reviewer for this valuable comment. In response, we have revised and expanded the Discussion section (lines 571-578, 604-626, 662-690) to strengthen the comparative analysis with existing literature. In doing so, we highlight that the body of evidence addressing computerized cardiotocography in specific high-risk pregnancy conditions, including hypertensive disorders of pregnancy (HDP), intrahepatic cholestasis of pregnancy (ICP), and gestational diabetes mellitus (GDM), remains limited.

Available studies are relatively few, heterogeneous in design, and in several instances report partially conflicting findings, which complicates the interpretation of individual cCTG parameters. This is especially evident in GDM, where published data on fetal movement and autonomic activity are inconsistent, with reports describing reduced, unchanged, or transiently increased fetal activity. Similarly, in ICP, previous investigations have largely focused on isolated cCTG parameters and have not provided a consistent or integrated framework for interpreting fetal autonomic alterations.

We therefore emphasize in the revised Discussion that the present findings should be interpreted in the context of these gaps and inconsistencies in the existing literature. By adopting a comprehensive, multiparametric cCTG approach rather than relying on single indices, our analysis aims to contribute to a more coherent, physiologically grounded interpretation of fetal autonomic function across different high-risk pregnancy conditions.

 

Overall, this is an interesting and clinically relevant study. With the revisions outlined above, it could provide substantial practical value for readers.

Thank you very much.

 

We hope that the revised manuscript now meets your expectations and qualifies for publication in the special issue of the Journal of Clinical Medicine.

 

Regards,

Anca A Simionescu MD, PhD

 

 

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

Dear Authors,

I reviwed your article, at this stage the issue is relevant and clinically relevant, and quantitatively integrating cCTG data into the data set provides real potential to advance fetal surveillance protocols. The comparison is well structured. Until you can do so, we need significant revisions to this manuscript before you consider it potentially for publication that will alleviate important methodological, interpretative, and reporting issues. Now we outline recommendations in numbers to make them clearer and prioritize them.

 

1.0 Study Design and clarity. 

1.1 The pathological groups (HTA and GDM) are heterogeneous subtypes, e.g. chronic hypertension associated with preeclampsia; pregestational in combination with gestational diabetes. Please justify this grouping with either a pathophysiological rationale, or give their subgroup analysis to confirm internal consistency.

1.2 Provide for disease severity stratification or control for it in analysis. For example, a mild or severe preeclampsia or insulin-dependent GDM versus diet-controlled GDM may affect fetal autonomic output differently.

2.0 Methodological Transparency.

2.1 Report the sampling frame: how were patients selected and how many patients were excluded due to ineligible cCTG recordings?

2.2 Provide a further depth on duration and timing of the recordings dependent on the gestational age (e.g., by trimester, pre- as opposed to post-term).

2.3 What standard operating conditions did cCTGs measure in practice (e.g., time of day, maternal position, fasting, recent activity)? Since the time at which data on fetal variability is obtained may influence it, the details will be reported accordingly.

3.0 Statistical Analysis.

3.1 Anova and post-hoc tests will be adequate, but check that you are satisfied and report the assumptions of normality and homoscedasticity are met for all the continuous variables.

3.2 Generate effect sizes (e.g., Cohen’s d) for significant differences, as p-value alone makes a non-significant claim in terms of clinical significance.

4.0 Conclusions and Interpretations.

4.1 The inference that increased fetal movements may mirror subclinical distress is in need of clarification, but speculative. Provide citations and/or tone-down the assertions to show some uncertainty.

4.2 Baseline FHR: its importance as a conserved parameter is described well. But stress that interpretation of serial cCTG interpretation, not of single time point measurement, may provide more reliable prognostication -- a topic that has been less well-discussed.

4.3 If STV and LTV are thought of as autonomic and controlling from a physiologic point of view then you could consider the role of the external stimulation (i.e. contractions, maternal cortisol or fetal behavior) in the interpretation.

5.0 Introduction and Terminology.

5.1 Normalize the language (e.g., substitute for "hypertensive disorders of pregnancy" instead of HTA/preeclampsia/gestational hypertension in the text) so that there is no ambiguity.

6.0 Literature Context and Limitations.

6.1 Provide further strengthening of previously described studies focusing on cCTG within intrahepatic cholestasis and GDM. Some findings (e.g., more fetal movements in GDM) are likely supported by other literatures though the studies are not situated.

6.2 Elaborate on limitations in the lack of outcome data (e.g., Apgar score, NICU admission, acid-base status), which limits the clinical significance of noted cCTG changes.

6.3 To improve the scientific soundness I reccomend to cite the following articles to improve the reference about the different factors that could impact the cardiotocography evaluation and prepregnancy factors:

• https://doi.org/10.1371/journal.pone.0315761
• https://doi.org/10.1080/01443615.2021.1929115

 

7.0 Ethics and General Reporting.

7.1 Although ethical approval is mentioned, adding a study registration number or showing that it complies with STROBE guidelines would help transparency.

7.2 Definition of abbreviations should be defined at the first use of the term (i.e. STV, LTV), even though they are mentioned in the final abbreviations table.

It proposes potential of potential import, it is based on physiologically meaningful methods. If these concerns are resolved, the study may add to the literature on perinatal surveillance. I hope to read a revised manuscript. Best regards

Author Response

Dear Reviewer 2

We sincerely thank you for your time and effort to revise our work , for your positive feedback. The manuscript has been revised accordingly to your suggestions, you may find our answer poin-by point. All revisions were highlighted in red in the manuscript.

 

I reviwed your article, at this stage the issue is relevant and clinically relevant, and quantitatively integrating cCTG data into the data set provides real potential to advance fetal surveillance protocols. The comparison is well structured. Until you can do so, we need significant revisions to this manuscript before you consider it potentially for publication that will alleviate important methodological, interpretative, and reporting issues. Now we outline recommendations in numbers to make them clearer and prioritize them.

 

1.0 Study Design and clarity. 

1.1 The pathological groups (HTA and GDM) are heterogeneous subtypes, e.g. chronic hypertension associated with preeclampsia; pregestational in combination with gestational diabetes. Please justify this grouping with either a pathophysiological rationale, or give their subgroup analysis to confirm internal consistency.

 

We thank the reviewer for this important comment regarding the heterogeneity of the hypertensive and diabetic pathological groups. We acknowledge that both HDP and GDM encompass clinically and pathophysiologically diverse conditions. To address this concern, we performed predefined subgroup analyses within both pathological categories, based on clinically meaningful and widely accepted distinctions related to disease severity and underlying pathophysiology.

Specifically, hypertensive disorders of pregnancy were stratified into non-preeclamptic hypertensive disorders (including chronic hypertension and gestational hypertension) and preeclampsia. This distinction reflects fundamental differences in placental involvement, systemic endothelial dysfunction, and fetal hemodynamic impact, with preeclampsia representing a more severe and placenta-driven pathology. Likewise, diabetic pregnancies were subdivided into diet-controlled and insulin-requiring diabetes. This classification was chosen as a pragmatic and clinically relevant surrogate of metabolic severity and treatment escalation, capturing functional differences in glycemic control and maternal–fetal metabolic exposure, regardless of whether diabetes was pregestational or gestational.

These subgroup analyses were undertaken to test whether increasing disease severity is associated with differential cCTG findings. The results of these analyses are presented in the Results section, where subgroup-specific effects are reported. The findings support the robustness of the original grouping while also providing greater granularity in the interpretation of fetal neurocardiac responses.

 

1.2 Provide for disease severity stratification or control for it in analysis. For example, a mild or severe preeclampsia or insulin-dependent GDM versus diet-controlled GDM may affect fetal autonomic output differently.

Building on our response to the previous comment regarding pathological heterogeneity, we addressed disease severity through the same predefined subgroup stratification strategy. Given the retrospective design and the lack of uniformly recorded severity scores, disease severity was operationalized using clinically established phenotypic and treatment-based categories.

Specifically, hypertensive disorders of pregnancy were stratified into non-preeclamptic hypertensive disorders and preeclampsia, with preeclampsia representing a more severe, placenta-mediated condition characterized by greater maternal and fetal involvement. Likewise, diabetic pregnancies were stratified into diet-controlled and insulin-requiring diabetes, with insulin treatment serving as a pragmatic surrogate marker of increased metabolic severity.

This stratification approach allowed us to simultaneously address pathological heterogeneity and severity within the same analytical framework. Subgroup analyses based on these definitions were performed to evaluate whether increasing disease severity was associated with differential fetal autonomic output as assessed by cCTG parameters. The results of these analyses are presented in the Results section and support the internal consistency and clinical relevance of the adopted classification.

 

 

2.0 Methodological Transparency.

2.1 Report the sampling frame: how were patients selected and how many patients were excluded due to ineligible cCTG recordings?

We thank the reviewer for this important comment. In total, 14,412 singleton pregnancies were identified during the study period, of which 401 met the  inclusion criteria for high-risk pregnancy group and 87 for control group . These comprised 169 cases of 179 HDP , 146 cases of GDM, 86 cases of ICP, and 87 uncomplicated pregnancies serving as the control group. Please see lines 178-182 .  All cCTG recordings were obtained antepartum, beyond 28 weeks of gestation, and fulfilled the required  quality threshold of less than 20% signal loss, ensuring that the extracted parameters accurately reflected physiological fetal heart-rate dynamics. The sampling frame comprised all singleton pregnancies of ≥28 weeks’ gestation monitored with antepartum cCTG at our institution during the study period.

The inclusion and exclusion criteria, together with the stepwise process used to construct the final study cohorts, are now explained in detail in the Materials and Methods section to ensure methodological transparency and reproducibility.

 

 

2.2 Provide a further depth on duration and timing of the recordings dependent on the gestational age (e.g., by trimester, pre- as opposed to post-term).

All cCTG recordings included in the analysis had a minimum duration of 20 minutes, in accordance with our institutional clinical practice guidelines. In routine clinical care, most recordings were completed within a relatively narrow time window slightly exceeding the minimum required duration, while only a very small number of examinations extended beyond 30 minutes, typically in response to transient clinical considerations. Recording duration was not systematically adjusted according to gestational age, and longer recordings were performed only when clinically indicated.

With respect to timing, all recordings were obtained from pregnancies ≥28 weeks of gestation, with the majority performed during the late third trimester (37–40 weeks). No post-term pregnancies were included, as labor is routinely induced at 41 weeks and 3 days’ gestation in at our institution. Gestational age at the time of cCTG examination was recorded to contextualize fetal maturity across groups, rather than used as a stratification factor.

 

 

 

2.3 What standard operating conditions did cCTGs measure in practice (e.g., time of day, maternal position, fasting, recent activity)? Since the time at which data on fetal variability is obtained may influence it, the details will be reported accordingly.

All cCTG recordings were obtained under standardized antepartum clinical conditions as part of routine fetal surveillance. Examinations were performed during daytime hours, outside of labor, with the mother in a semi-recumbent or left lateral position. No pharmacological stimulation or sedation was used, and recordings were obtained during routine inpatient or outpatient monitoring. Although maternal fasting status and recent physical activity were not systematically documented due to the retrospective design, these factors reflect real-world clinical conditions and were comparable across study groups. Importantly, all recordings met predefined quality and duration criteria, ensuring physiological interpretability of fetal variability measures. This information has been incorporated into the Materials and Methods section (please see lines 152–158).

 

 

3.0 Statistical Analysis.

3.1 Anova and post-hoc tests will be adequate, but check that you are satisfied and report the assumptions of normality and homoscedasticity are met for all the continuous variables.

We thank the Reviewer for this comment. The assumptions underlying ANOVA were assessed for all continuous variables prior to analysis. The normality of data distribution was confirmed for each parameter and each patient group by building and visually assessing histograms, using the Histogram function of the online statistical tool used for this study (https://www.socscistatistics.com/descriptive/histograms/default.aspx). This information has now been included in the Materials and Methods section under Statistical Analyses (lines 160–163).

While we have not included these histograms in the paper, to keep the focus on the actual findings, we are providing below examples of histograms for FHR for all pathologies considered in this study. As can be seen in the histograms provided, the distributions of the analyzed parameters were approximately Gaussian (bell-shaped) within each group, without marked skewness or multimodality, which is consistent with expectations for a large hospital-based dataset.

 

Control group

ICP group

GDM group

HPA group

The homogeneity of variance across groups was verified using Levene's test (https://www.socscistatistics.com/tests/levene/default.aspx). We include below, as example, the results for FHR baseline and fetal movements. We also added this information in the revised manuscript, in the Statistical analysis section.

FHR baseline

Control vs ICP

The f-ratio value is 2.24089. The p-value is .136248. The result is not significant at p < .05.

The requirement of homogeneity is met.

Control vs GDM

The f-ratio value is 0.67602. The p-value is .41181. The result is not significant at p < .05.

The requirement of homogeneity is met.

Control vs HPA

The f-ratio value is 3.52978. The p-value is .061421. The result is not significant at p < .05.

The requirement of homogeneity is met.

Fetal movements

Control vs ICP

The f-ratio value is 0.00179. The p-value is .96632. The result is not significant at p < .05.

The requirement of homogeneity is met.

Control vs GDM

The f-ratio value is 1.01214. The p-value is .315444. The result is not significant at p < .05.

The requirement of homogeneity is met.

Control vs HPA

The f-ratio value is 3.59093. The p-value is .059231. The result is not significant at p < .05.

The requirement of homogeneity is met.

 

 

3.2 Generate effect sizes (e.g., Cohen’s d) for significant differences, as p-value alone makes a non-significant claim in terms of clinical significance.

We thank the reviewer for this important suggestion. In response, we calculated the effect sizes for all intergroup comparisons that reached statistical significance, thereby complementing p-values with quantitative estimates of the magnitude of observed differences.

Given the unequal sample sizes across study groups, Hedges’ g was determined, as this is considered more appropriate than Cohen’s d, as it accounts for differences in group size. The interpretation of Hedges’ g and Cohen’s d are similar. This information has now been added to the Materials and Methods section (please see lines 169–171).

Effect size estimates are now systematically reported in the Results section (please see lines 273–288, 295–298, 337–340, 342–347, 359–370, 402-411,435-446, 488-494), including analyses of fetal movement counts, short-term variability indices, acceleration frequency, and long-term variability measures. These additions allow a more comprehensive interpretation of the clinical relevance of statistically significant findings beyond p-values alone.

 

4.0 Conclusions and Interpretations.

4.1 The inference that increased fetal movements may mirror subclinical distress is in need of clarification, but speculative. Provide citations and/or tone-down the assertions to show some uncertainty.

We thank the reviewer for this insightful comment. We fully agree that the inference suggesting that increased fetal movements may reflect subclinical distress requires careful qualification and should not be overstated. In response, we have revised the manuscript to ensure that this interpretation is presented with appropriate caution.

The updated Results and Discussion sections now emphasize that the higher movement counts perceived by mother during cCTG observed in the hypertensive and diabetic groups represent a hypothesis-generating finding rather than evidence of a defined pathophysiological mechanism. As clarified in the text, the literature on fetal movement frequency in general , in these conditions is inconsistent, with most guideline-level documents focusing exclusively on reduced movements as a marker of potential compromise. Only isolated studies describe circumstances in which transiently increased movement frequency, particularly around 28–32 weeks in diabetic pregnancies, may reflect maturational variability or altered autonomic regulation rather than genuine fetal hyperactivity.

Accordingly, we have toned down any deterministic interpretation and now clearly highlight the uncertainty surrounding this observation. The revised discussion frames the finding as a possible indication of altered autonomic responsiveness that warrants further prospective investigation, rather than a validated clinical sign of subclinical fetal distress. These clarifications have been incorporated into the revised manuscript (Results: lines 249–256 and 305-320; Discussion: lines 604–626).

 

 

 

4.2 Baseline FHR: its importance as a conserved parameter is described well. But stress that interpretation of serial cCTG interpretation, not of single time point measurement, may provide more reliable prognostication -- a topic that has been less well-discussed.

We thank the reviewer for this insightful comment. We agree that, in clinical practice, serial cCTG interpretation provides far greater prognostic value than evaluation of a single tracing. Longitudinal assessment allows clinicians to observe evolving trends in baseline FHR, variability, and reactivity, features that often offer more meaningful insight into fetal condition than an isolated recording.

However, the purpose of the present analysis was different. The study was designed as a cross-sectional comparison of antepartum cCTG parameters across normal and high-risk pregnancies, with the aim of identifying patterns that distinguish pathological cohorts from physiological ones. Our results indeed show that, overall, high-risk pregnancies display a broader range of alterations in cCTG parameters compared with normal pregnancies, suggesting differential autonomic regulation in the setting of maternal disease. Importantly, the study does not attempt to establish causal relationships with specific perinatal outcomes; rather, it formulates physiologically plausible hypotheses that warrant further exploration.

We now clarify in the revised manuscript that these findings should be regarded as hypothesis-generating. A robust demonstration of longitudinal prognostic value would require a substantially larger, multicenter cohort with serial cCTG recordings and comprehensive neonatal outcomes, a study design that exceeds the scope and feasibility of the present dataset but represents an important direction for future research.

 

 

4.3 If STV and LTV are thought of as autonomic and controlling from a physiologic point of view then you could consider the role of the external stimulation (i.e. contractions, maternal cortisol or fetal behavior) in the interpretation.

We thank the reviewer for this insightful comment. We agree that STV and LTV reflect fetal autonomic regulation and may be influenced by external factors, including uterine activity, maternal neuroendocrine influences, and fetal behavioral state. As clearly specified in the Materials and Methods section, all cCTG recordings included in this study were obtained outside of labor, with minimal uterine contractile activity; therefore, uterine contractions were not considered a relevant source of external stimulation and were excluded from the analysis ( please see Material and methods).

Maternal biochemical and hormonal parameters (e.g., cortisol levels) were not systematically available due to the retrospective nature of the study and could not be evaluated. Similarly, detailed fetal behavioral state assessment was beyond the scope of the present analysis. These conditions were applied uniformly across all study groups, minimizing the likelihood of differential bias in between-group comparisons. Accordingly, STV and LTV are interpreted as integrative markers of fetal autonomic regulation within the clinical context in which the recordings were obtained.

 

 

5.0 Introduction and Terminology.

5.1 Normalize the language (e.g., substitute for "hypertensive disorders of pregnancy" instead of HTA/preeclampsia/gestational hypertension in the text) so that there is no ambiguity.

We thank the reviewer for this valuable suggestion. The manuscript has been thoroughly revised to standardize terminology throughout, including the title and abstract, to ensure consistency and avoid ambiguity. The term hypertensive disorders of pregnancy (HDP) is now used as a collective diagnostic category across the manuscript. Specific entities: preeclampsia, gestational hypertension, and chronic hypertension, are mentioned only when differentiation between these conditions is clinically or conceptually relevant. This revision was undertaken to enhance terminological clarity and improve overall readability.

 

6.0 Literature Context and Limitations.

6.1 Provide further strengthening of previously described studies focusing on cCTG within intrahepatic cholestasis and GDM. Some findings (e.g., more fetal movements in GDM) are likely supported by other literatures though the studies are not situated.

We thank the reviewer for this comment. We have revised the Discussion (lines 571-578, 604-626)  to emphasize that the available literature addressing computerized CTG in specific high-risk conditions such as intrahepatic cholestasis of pregnancy (ICP) and gestational diabetes mellitus (GDM) remains limited. In many instances, existing studies are few in number, heterogeneous in methodology, and yield partially conflicting results, which complicates the interpretation of individual cCTG parameters.

This is particularly evident in the case of GDM, where published data on fetal movement patterns are inconsistent, with studies reporting reduced, unchanged, or transiently increased fetal activity. Similarly, for ICP, prior investigations using cCTG have generally focused on isolated parameters and have not provided a consistent framework for interpreting fetal autonomic alterations.

We therefore clarify that the present study was motivated by these gaps and inconsistencies in the literature and was designed to provide a comprehensive, multiparametric evaluation of cCTG patterns across different high-risk pregnancies. By adopting an integrated approach rather than relying on single indices, our findings aim to contribute to a more coherent and physiologically grounded interpretation of fetal autonomic function in these conditions.

 

 

6.2 Elaborate on limitations in the lack of outcome data (e.g., Apgar score, NICU admission, acid-base status), which limits the clinical significance of noted cCTG changes.

We thank the reviewer for underscoring the importance of neonatal outcome data in interpreting the clinical significance of cCTG findings.  We fully agree that parameters such as Apgar scores, NICU admission, and acid–base status would have enriched the analysis and allowed a more direct linkage between antenatal autonomic patterns and subsequent neonatal adaptation. As now clarified in the revised Limitations section (lines 691–701), these outcome variables were not included because cCTG analysis were done during pregnancy hospitalisation  , not in labor or before delivery. We consider that could have confounded the interpretation of antepartum autonomic patterns captured by cCTG.

Nevertheless, we acknowledge that the absence of granular neonatal outcome data limits the depth of clinical interpretation that can be drawn from the observed cCTG differences. We now highlight this in the Limitations section and emphasize that future prospective studies, including standardized neonatal outcomes, will be essential to more precisely delineate the clinical implications of these antepartum findings.

 

6.3 To improve the scientific soundness I reccomend to cite the following articles to improve the reference about the different factors that could impact the cardiotocography evaluation and prepregnancy factors:

• https://doi.org/10.1371/journal.pone.0315761
• https://doi.org/10.1080/01443615.2021.1929115

We sincerely thank the reviewer for this constructive suggestion. As recommended, we have now cited and integrated both articles into the Discussion section (lines 662-690). The study by Lukhele et al. was incorporated to address factors influencing the variability and subjectivity of visual cardiotocography interpretation among healthcare professionals, while the work by La Verde et al. was included to contextualize the physiological impact of uterine activity on antepartum cCTG parameters.

The integration of these references strengthens the scientific soundness of the manuscript by placing our findings within the broader framework of cardiotocography interpretation limitations and fetal autonomic responsiveness to diverse maternal and uteroplacental stressors. We believe that these additions enhance the interpretative depth and reinforce the clinical relevance of our results.

 

7.0 Ethics and General Reporting.

7.1 Although ethical approval is mentioned, adding a study registration number or showing that it complies with STROBE guidelines would help transparency.

We thank the reviewer for this important comment regarding reporting transparency. The present manuscript reports a retrospective observational study and was prepared in accordance with the STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) guidelines. Below, we clarify how the main STROBE items are addressed in the manuscript.

Title and Abstract (STROBE item 1).
The abstract clearly specifies the comparative observational nature of the study and summarizes the study design, population, variables, and analytical approach. The Methods section of the abstract describes a comparative analysis of cCTG parameters in predefined clinical groups, consistent with STROBE recommendations.

Background and Objectives (STROBE items 2–3).
The Introduction provides a detailed scientific background on fetal hypoxia, autonomic regulation, and the limitations of conventional CTG, followed by clearly stated study objectives aimed at comparing cCTG-derived indices across physiological and high-risk pregnancies.

Study Design and Setting (STROBE items 4–5).
The study design is described as a retrospective observational analysis conducted at a single tertiary obstetric center. The setting, time frame (2022–2025), and clinical context in which the data were collected are clearly specified in the Materials and Methods section.

Participants (STROBE item 6).
Eligibility criteria are comprehensively reported. All singleton pregnancies monitored beyond 28 weeks of gestation during the study period were screened. Cases were included only if a verifiable corresponding computerized cardiotocography (cCTG) recording could be identified in the Omniview SisPorto system based on the clinical chart. Pregnancies not meeting predefined inclusion criteria or fulfilling one or more exclusion criteria were excluded a priori. This standardized and uniform selection process was applied across all study groups, minimizing differential selection bias.

Variables and Data Sources (STROBE items 7–8).
All outcomes, exposures, and covariates are defined. cCTG parameters were extracted automatically using the Omniview SisPorto Central Monitoring System, a validated computerized platform, ensuring objective and reproducible measurement of fetal heart rate variability, accelerations, and decelerations. Signal quality metrics and strict exclusion thresholds (>20% signal loss) were applied uniformly.

Bias (STROBE item 9).
Potential sources of bias related to the retrospective design and data availability are now acknowledged in the Methods section. Selection bias was mitigated by including all consecutive eligible cases with complete and verifiable cCTG data, while measurement and observer bias were limited through standardized quality control procedures. Residual confounding inherent to retrospective observational studies is discussed as a limitation.

Study Size (STROBE item 10).
The study population represents the complete cohort of eligible pregnancies fulfilling inclusion criteria during the study period. As this was a retrospective analysis, no formal a priori sample size calculation was performed, in line with standard methodological practice for observational cohort studies.

Quantitative Variables and Statistical Methods (STROBE items 11–12).
Quantitative variables are clearly described and analyzed using appropriate statistical methods. One-way ANOVA with post hoc Tukey–Kramer testing was applied to compare cCTG parameters across groups, with predefined significance thresholds.

Results and Descriptive Data (STROBE items 13–15).
Participant numbers, group allocation, and descriptive characteristics are fully reported. Results are presented transparently with detailed tables summarizing distributions, central tendencies, and variability measures for all cCTG parameters.

Discussion, Limitations, and Interpretation (STROBE items 18–21).
The Discussion interprets findings in light of existing literature and physiological mechanisms. Limitations related to retrospective design, heterogeneity of disease severity, and unavailable neonatal biochemical data are addressed, and generalizability is discussed within the context of tertiary-care settings using standardized computerized fetal monitoring.

Ethics, Funding, and Data Availability (STROBE item 22).
Ethical approval, informed consent procedures, funding status, and data availability are fully disclosed.

A statement confirming compliance with the STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) guidelines has been added to the manuscript in the Materials and Methods section (lines 174–175). As the study is retrospective and non-interventional in nature, registration in a clinical trial registry was not required.

 

7.2 Definition of abbreviations should be defined at the first use of the term (i.e. STV, LTV), even though they are mentioned in the final abbreviations table.

Thank you very much, we corrected.

It proposes potential of potential import, it is based on physiologically meaningful methods. If these concerns are resolved, the study may add to the literature on perinatal surveillance. I hope to read a revised manuscript. Best regards

 

We hope that the revised manuscript now meets your expectations and qualifies for publication in the special issue of the Journal of Clinical Medicine.

 

Regards,

Anca A Simionescu MD, PhD

 

 

 

 

Author Response File: Author Response.pdf

Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

Authors have significantly improved the manuscript. Now I approve that this study scientifically sounds so that is at a level of being acceptance for publication depending on the final decision of the editor in chief of the journal.

Bests

Author Response

Thank you very much.