PONE-D-21-13434

Plasma serpinA5 in conjunction with uterine artery pulsatility index and clinical risk factor for the early prediction of preeclampsia

PLOS ONE

Dear Dr. Yonggang Zhang,

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Reviewer #1: Yes

Reviewer #2: Partly

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Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #1: No

Reviewer #2: Yes

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Reviewer #1: Yes

Reviewer #2: Yes

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5. Review Comments to the Author

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Reviewer #1: The manuscript entitled “Plasma serpinA5 in conjunction with uterine artery pulsatility index and clinical risk factor for the early prediction of preeclampsia” evaluated the combined use of plasma protein SerpinA5, uterine artery doppler and clinical risk factors in the prediction of preeclampsia. The study is potentially interesting and well designed, but I have some suggestions before this paper is suitable to for publication as follows bellow.

Abstract: The objective needs to be clearer indicating which plasma protein was evaluated (SerpinA5).

Material and methods and results must inform about the in vitro assay performed with TEV-1 cells.

Keywords: Remove the abbreviation “PE”.

Material and methods:

Line 97: Inform the meaning of “ACOG”. Inform the other characteristics for classification within the preeclampsia group.

Line 115: Inform the proportion of cesarean and natural delivery in each group. Because the authors did not only standardize samples of cesarean deliveries, since natural delivery can alter the expression of some placental proteins.

Line 116: Remove a “)”. It's duplicated.

Lines 145-146: How many fields were evaluated per placenta and which augmentation used.

Line 179: Remove “and”.

Results:

Line 191: Rewrite the sentence. “UtA-PI of preeclampsia was signifcantly diferences than control”.

Subdivide the results into Clinical Characteristics, Proteomics and ELISA, SerpinA5 Immunohistochemistry, In vitro migration analysis, Prediction analysis and further describe each result. The description is superficial and does not adequately describe all results.

Figure captions are uninformative. Need to inform the statistical analysis, N sample, title of the figure. Ex.: What does MSP mean in figure 6? The authors need to graphically demonstrate the immunohistochemical analysis and in vitro migration test.

There are too many figures. Some results can be joined together to reduce the number of figures. (Ex: Figures 7 and 8).

Discussion

Lines 225-227: "Some substances (such as VEGF, FLT, and 226 ENG) from the placenta enter into the maternal circulation, resulting in endothelial cell injury and a series of clinical manifestations of PE." Misinterpretation. Does VEGF Cause Endothelial Cell Injury? sFlt1 and not FLT.

Authors need to better discuss their own results, including clinical data.

Reviewer #2: In the present study, Yonggang Zhang and colleagues examined the expression levels of plasma serpinA5 in order to identify a new biomarker for the early detection of PE. Moreover, the Authors discovered that higher sensitivity and specificity were obtained if plasma serpin A5 was used in combination with maternal factors and abnormal UtA-PI. Finally, Yonggang Zhang and collegues demonstrated that placental serpinA5 immunoistochemistry staining in PE is higher than controls and that SerpinA5 may interfere with trophoblastic cell invasion by inhibiting MSP. They concluded that SerpinA5 may be a novel biomarker for preeclampsia in conjunction with uterine artery pulsatility index and clinical risk factor may be helpful for the early prediction of preeclampsia.

This is an interesting study addressing, however, an extensively investigated issue as biomarkers in early diagnosis of Preeclampsia. Nevertheless, SerpinA5 role and its correlation with UtA-PI and maternal factors in PE placentae could be of interest to Plos One readers.

There are several issues that the Authors must address before publication.

1) The Authors enrolled PE and controls pregnant women however no complete clinical information were reported (e.g. mode of delivery, therapy, fetal sex, placental weight…). Moreover, they must clarify clinical criteria used for PE diagnosis: gestational age at delivery are not significantly different however the fetal weight is significantly decreased in PE. Therefore, did you consider PE with and/or without fetal-placental compromission? Please clarify. Finally, the Authors did not mention the possibility of a fetal-placenta disease in the PE group as the presence of Fetal Growth Restriction. These informations are mandatory to properly analyze and interpret study results.

2) Please add the number of patients included in table 1 and figures 2, 3, 4, 5, 6

3) The Authors performed immunohistochemistry and invasive trial and they demonstrated that SerpinA5 is over-expressed in PE placentae and inhibit MSP leading to a suboptimal trophoblast invasion explaining part of PE pathogenesis. Do you refer to PE with abnormal placental development? Do you think that this mechanism started during the first weeks (first trimester, when you discovered higher plasma SerpinA5?) Why did you chose TEV-1 cells? IHC is a semiquantitative techniques and you cannot conclude that SerpinA5 is over-expressed. You should perform a q quantitative techniques such as Real Time PCR and ELISA assay. Please, clarify

4) Please, better specify why SerpinA5 is better than sFlt-1/PlGF (e.g. higher sensitivity and specificity? Earlier diagnosis?)

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Reviewer #1: No

Reviewer #2: No

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Plasma serpinA5 in conjunction with uterine artery pulsatility index and clinical risk factor for the early prediction of preeclampsia

PONE-D-21-13434R1

Dear Dr. Yonggang Zhang,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

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Kind regards,

Maurizio Mandalà, Ph.D.

Academic Editor

PLOS ONE

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