A Critical Assessment of Antenatal Monitoring for Fetal Well-Being in Down Syndrome Pregnancies

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

Dear authors, thank you very much for your work focusing on the outcome of fetuses with Down Syndrome. 

The limitation is really in the smallness of the sample. 

It would be great if you could state the time frame of the investigation

And it would be interesting what you would suggest for the reader? What would be the suggestion for daily clinical routine?

Author Response

Please see attachment

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

The manuscript addresses an important and clinically relevant question: whether current antenatal surveillance modalities can predict intrauterine fetal demise (IUFD) in ongoing Down syndrome (DS) pregnancies.

 

1. The total sample is 41 pregnancies, with only 8 IUFDs, which is insufficient for meaningful comparative analysis. With 8 events, no valid multivariable analysis can be performed, yet the manuscript still attempts to make predictor-based conclusions. There is no sample size justification or power calculation.
2. No correction for multiple comparisons is performed, despite dozens of hypothesis tests. The statistical approach is therefore insufficient for the stated objectives.
3. Structural anomaly burden (especially cardiac anomalies) is high in DS pregnancies but is not analyzed by severity or functional impact. Standard fetal growth references may not be appropriate for DS fetuses, introducing misclassification bias in FGR determination. Please discuss.
4. The study is not powered to detect such an association; therefore the correct conclusion should be “no statistically significant association was detected within this limited sample.”
5. “UA Doppler is not predictive of IUFD.” UA Doppler abnormalities occurred in 80–85% of all DS fetuses—high prevalence alone reduces predictive discrimination. This does not mean the test is “non-predictive”; it means the test may be detecting a physiological characteristic common to DS, not necessarily related to placental insufficiency.
6. Some statements in the Discussion imply causality or clinical recommendation despite limited evidence. The manuscript would benefit from reorganizing the Results and condensing redundant comparisons.
7. Right now, the manuscript overstates its ability to predict IUFD. Instead, reframe the work as: “A phenotypic characterization of antenatal Doppler, growth, and fluid patterns in DS pregnancies.”
8. If individual tests lack predictive value, perhaps combinations show a pattern.

For example:

Polyhydramnios + abnormal NST + abnormal UA Doppler

or

Abnormal Doppler + major cardiac anomaly

 

You can report:

 

descriptive frequencies,

 

effect size trends,

 

graphical patterns (heatmap, phenotypic cluster charts).

Author Response

Please see attachment.

Author Response File: Author Response.pdf

Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

After careful review of the revised manuscript, I found that the authors adequately addressed the key methodological and interpretive concerns that arose during the review process. The study presents a well-defined retrospective cohort of ongoing Down syndrome pregnancies and offers a clear, data-driven assessment of commonly used antenatal monitoring parameters associated with intrauterine fetal death.

The authors appropriately acknowledged the limitations related to sample size, retrospective design, and lack of multivariate modeling, and avoided overstating the clinical implications of their findings. Importantly, the manuscript provides significant confirmatory evidence that fetal growth restriction and umbilical artery Doppler abnormalities are poor single predictors of intrauterine fetal death in Down syndrome pregnancies, while highlighting polyhydramnios as a potential signal requiring closer monitoring. This finding is clinically significant given the scarcity of data guiding antenatal management in this particular population.

The study is clearly written, methodologically transparent, and appropriately cautious in its conclusions. Although the study does not employ a mechanistic approach, it fills a significant gap in the perinatal monitoring literature and fits well with the scope of a diagnosis-focused journal. Therefore, I recommend that the article be accepted in its current form.