Pregnancy-Associated Plasma Protein A (PAPP-A) as a Predictor of Third Trimester Obesity: Insights from the CRIOBES Project

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

It is quite original/novel study on the early prediction of some later complications of pregnancy but it is difficult to understand the basic idea of the study. PAPPA-A is mainly a placental product which helps to predict different fetal/ placental complications of pregnancy. Why you tried to combine the level of PAPP-A with the weight gain during pregnancy or obesity in the third trimester whereas we know that there are so many factors influencing the weight gain which must be taken into account . So from methodological point of view the study is well prepared but from the clinical one , including the pathophysiological hypothesis , is rather poorly understood. 

1. I do recommend to present more clearly the pathophysiological idea, hypothesis of the study in the introduction to make it more understandable for the clinician

2. In Material and Methods section case and controls are described in the same way , check it and describe them more clear (what is the differnce between the stud and the control group?)

3. Is lower PAPPA-A associated with obesity in third trimester , what is a main conclusion of the study, make it clear!

4. Did you consider to present the reults of PAPP-A in MoMs to make it more clear for clinical utility ; I do recommend to prepare the table to compare MoMs from both group

Author Response

It is quite original/novel study on the early prediction of some later complications of pregnancy but it is difficult to understand the basic idea of the study. PAPPA-A is mainly a placental product which helps to predict different fetal/ placental complications of pregnancy. Why you tried to combine the level of PAPP-A with the weight gain during pregnancy or obesity in the third trimester whereas we know that there are so many factors influencing the weight gain which must be taken into account . So from methodological point of view the study is well prepared but from the clinical one , including the pathophysiological hypothesis , is rather poorly understood. 

1. I do recommend to present more clearly the pathophysiological idea, hypothesis of the study in the introduction to make it more understandable for the clinician  Authors´ answer : The hypothesis of the study is that PAPPA could be a clinical marker of obesity in the third trimester independent of diet in uncomplicated pregnancies..  We have added this statement at the beginning of Discussion. 

2. In Material and Methods section case and controls are described in the same way , check it and describe them more clear (what is the differnce between the stud and the control group?)

(Authors) The clearest difference between cases and controls is that cases were non-obese women in the first trimester who became obese in the second trimester. Controls were non-obese women in the first trimester who stay non obese in the second trimester. We have corrected the text.

3. Is lower PAPPA-A associated with obesity in third trimester , what is a main conclusion of the study, make it clear!

(Authors) -- Of course, it is a clear conclusion that can be drawn from reading table no. 5. The odds ration is less than one.

4. Did you consider to present the reults of PAPP-A in MoMs to make it more clear for clinical utility ; I do recommend to prepare the table to compare MoMs from both group. 

(Authors) We do not consider it necessary at this time. Based on the multivariate study, it is clear that PAPPA values ​​(Table 5 - OR 0.5) tend to decrease in women who develop obesity in the third trimester.

Reviewer 2 Report

Comments and Suggestions for Authors

The authors of this study had made an attempt to develop the predictive model of obesity in third trimester pregnancy women using the clinical and plasma parameters. 

Firstly, it's not clearly enough what is "epidemiological design". Also, "unmatched case-control" it is just observational study. 

In introduction, authors didn't provide sufficient justification why they decided to use the plasma level of PAPP-A as predictor factor . Many previous studies had already investigated this parameter as a predictive factor for diabetes mellitus and metabolic disorders, which are the most severe complications than obesity itself.

It's not clear enough if the study was retrospective or longitudinal. Also, as the collection of data was carried out from 7 different clinics authors didn't provide any information regarding bias associated with physicians (how many physicians conducted the examinations; what protocols was used?) and bias associated with different assays or equipment for plasma biomarkers. There is no any information regarding laboratory methods.

In the results socio-demographical data is absent. The authors practically didn't describe the results obtained. Despite that, authors found comparable OR for PAPP-A and SBP they made an emphasis on PAPP-A and didn't discuss the significance of SBP as a predictor of obesity. The discussion is more like results. 

I recommend to use the checklist for observational study (STROBE) to correct all deficiencies of this paper and also to reconsider the conclusions of this study.

Author Response

The authors of this study had made an attempt to develop the predictive model of obesity in third trimester pregnancy women using the clinical and plasma parameters. 

(Authors) Of course this statement is correct.

Firstly, it's not clearly enough what is "epidemiological design". Also, "unmatched case-control" it is just observational study. 

(Authors) On first line of Methods we have added "unmatched"

In introduction, authors didn't provide sufficient justification why they decided to use the plasma level of PAPP-A as predictor factor . Many previous studies had already investigated this parameter as a predictive factor for diabetes mellitus and metabolic disorders, which are the most severe complications than obesity itself.

(Authors) Of course, but third trimester obesity is also a significant risk factor for both the pregnant woman and the fetus.  References 4 and 5 treat obesity as a risk factor. Mainly obstetric complications and those derived from obesity of the mother and the product.

It's not clear enough if the study was retrospective or longitudinal. Also, as the collection of data was carried out from 7 different clinics authors didn't provide any information regarding bias associated with physicians (how many physicians conducted the examinations; what protocols was used?) and bias associated with different assays or equipment for plasma biomarkers. There is no any information regarding laboratory methods.

(Authors) The laboratory methodology is the conventional one for the Pregnancy Process in Andalusia. The information is recorded centrally in the clinical history. The various family doctors who worked at the health centres pointed out the record to us and the team researchers, generally only two, transferred it to the data package. This study is ambispective  as we show on Methods.

In the results socio-demographical data is absent. The authors practically didn't describe the results obtained. Despite that, authors found comparable OR for PAPP-A and SBP they made an emphasis on PAPP-A and didn't discuss the significance of SBP as a predictor of obesity. The discussion is more like results. 

(Authors) Out of respect for data protection legislation, we have not been more explanatory. There were no socio-demographic variables except those shown in Table 3. 

I recommend to use the checklist for observational study (STROBE) to correct all deficiencies of this paper and also to reconsider the conclusions of this study. 

(Authors) Of course we have followed the STROBE regulations:.  Quote #14 from the  first corrected version. 

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

Thank You for the explanation of most of questions concerning the study. 

Unfortunately I still do not understand why You chose to combine first trimester routine screening for chromosomal aberrations with obesity which is even no pregnancy complications by itself (any previous publications). In my opinion You did not explain it properly in the Introduction 

Author Response

Rev. 1

 

Unfortunately I still do not understand why You chose to combine first trimester routine screening for chromosomal aberrations with obesity which is even no pregnancy complications by itself (any previous publications). In my opinion You did not explain it properly in the Introduction.

 

We have added a specific paragraph in the introduction.

Third trimester obesity is associated with risks for both the mother and the fetus (5,8) .

 

Reviewer 2 Report

Comments and Suggestions for Authors

I agree with the most suggestions of authors regarding my questions and notes.

But some parts of the duscussion it seems to be moving to Results.

For example information regarding missing data and its exclusion should be noticed in the beginning of section Results, as well as narration of the logic of data analysis. In the section Discussion this information may be pointed as the limits or the strengths of the study.

The Section Discussion should include more reasoning about immediate results and conclusions, and less about data and analysis.

 

Author Response

But some parts of the discussion it seems to be moving to Results.

For example information regarding missing data and its exclusion should be noticed in the beginning of section Results, as well as narration of the logic of data analysis. In the section Discussion this information may be pointed as the limits or the strengths of the study.

The Section Discussion should include more reasoning about immediate results and conclusions, and less about data and analysis.

 

 

We have added a specific paragraph at the end of discussion.

 

We believe that this work provides an additional instrument (PAPP-A) as a predictor of obesity risk in pregnancies not complicated from an obstetric point of view.