Efficacy of Low Doses of Acetylsalicylic Acid in the Prevention of Preeclampsia in Women with Type 1 and 2 Diabetes Mellitus

Round 1

Reviewer 1 Report

Efficacy of low doses of acetylsalicylic acid in the prevention of 2
preeclampsia in women with type 1 and 2 diabetes mellitus by Kypstein et al.

In Principle this is a very good study that shows the potential efficacy of first trimester administration of aspirin to prevent GDM in a retrospective stud

However, it is very hard to compare the study to previously published results as were found in ASPRE (N Engl J Med. 381, 2017;377(7):613-622) and in SPREE Study, Tan et al., Ultrasound Obstet Gynecol. 2018 Jun;51(6):743-750, . that has to be added to the reference list).

Each of these studies was very large and was randomized. They screened a population of ~ 30,000 patients. The treatment there was according to 1:100 risk to develop preterm preeclampsia according to first trimester risk algorithm of all comers. Risk was determined by prior risk calculated from  medical, obstetrics, and epidemiology factors while the posterior risk was calculated when this was combined with biophysical (Uterine Arteries Doppler Pulsatility Index, and mean arterial blood pressure), and biochemical markers (PAPP-A and PlGF). Here I was not clear how teh decision to treat with aspirin was made and whether all those treated should actually be treated (as otherwise, using only prior risk may affect aspirin efficacy from the beginning)

The time table of treatment in the current reviewed manuscript was similar to the above two large studies. However, in the above cited studies aspirin dose was uniform and was 150mg/day whereas here it was 100-150mg/day . I suggest to perform a secondary analysis of 100 and 150 mg/day separatly. (100 mg/day is implicated to reduce the efficacy, and thus a sub-analysis of  is essential and will add clarity).  

 2. The authors said that aspirin reduces the doppler Pulsatility index among patients at high risk for Preeclampsia who took aspirin from the first trimester. At SPREE and at ASPRE such reduction was not detected (lines 64-69).

3. ASPRE and SPREE studies also didn't find any reduction of PlGF with in the aspirin group and additional studies showed it has no effect of the level of sFlt-1 as well. (lines 69-74). This is quite expected given the short term effect of aspirin (half life 6-8 hr only in the human blood).

4. Diabetes Mellitus is a major risk factor to the development of preeclampsia, as was shown in the report from ASPRE Study by  Poon et al  (Poon et al. Am J Obstet Gynecol. 2017 Nov;217(5):585.e1-585.e5. ) and the subgroup with DM on its own is at the top risk factor to develop  preeclampsia 10.1016/j.ajog.2017.07.038. Epub 2017 Aug 4.

While a combined Preeclampsia and DM is provided in Table 3, I think a secondary analysis that analyses pure DM with/without aspirin is required (also figures) as the added value to pure DM is not shown in the manuscript. 

5. While a combined preterm delivery and DM analysis is provided in Table 3, I think there is a need to separate between pure DM and DM combined with preterm delivery and provide the separate effects. 

6. There are less women with chronic hypertension in diabetes type 1 and more in diabetes type 2 in the aspirin groups (table 1). Small percentile change - but this may affect the results of aspirin affects on the two groups. 

7. I think the conclusion that aspirin should be prescribed to women with DM lacks substantiation of the drug benefit in cases of DM not accompanied by preeclampsia or Preterm delivery  (lines 229-240)

8. I agree the authors proved the need to give aspirin in the first trimester. I wish they were using 150 mg/day as it appears more beneficial ( Rolnik et al.  Am J Obstet Gynecol. 2020 Aug 21:S0002-9378(20)30873-5. doi: 10.1016/j.ajog.2020.08.045. )

9. Finally, the manuscript can be enrich by citing Li et al., Hypertension. 2021 Jul 6:HYPERTENSIONAHA12117448. doi: 10.1161/HYPERTENSIONAHA.121.17448. given the metabolic nature of DM. 

Author Response

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Reviewer 2 Report

In Principle this is a very good study that shows the potential efficacy of first trimester administration of aspirin to prevent DM in a retrospective study.

The introduction is too long.

Lines 39 to 108 are somewhat of a distraction to the study at hand and would be better either shortened or placed in the discussion.

Throughout – is pregestational DM  the same as gestational DM?

Number of smokers – this is a key variable – do you have this information?

How was the aspirin assigned if not random allocation?

What is the definition of PE for this study? Moderate? Severe ?

Otherwise well written.

Table 1 column 4 & 8 need a clear label [or footnote]. Excess body weight – how was that determined and how is this different from obesity [footnotes please].

Table 2. When the due date is 38.1 weeks – is this 38 weeks and one day?

Can you define ‘Small for gestational age’ – footnote please

Is table 3 adjusted for risk factors e.g. mother’s age

Line 178/9 “In women of this group who took ASA, the overall incidence of PE was more than double less frequent.” DO you mean “In women of this group who took ASA, the overall incidence of PE was half as frequent.”

The findings in figures 1 to 4 are presumably nonsignificant due to small numbers – if so state this or state the numbers.

 

The study is not randomized – this is a major limitation and you are not able to make causal statements about the effects of ASA. [e.g. line 28, 229, 321] better to simply state an association. Does your study have other limitations – would be good to list them as this makes the study more transparent.  

Author Response

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