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Date: 10/14/2022 To: "John Morgan"
From: "The Green Journal" [email protected] Subject: Your Submission ONG-22-1538
RE: Manuscript Number ONG-22-1538
Pregnancy Outcomes in Patients After Completion of the mRNA COVID-19 Vaccination Series Compared to Unvaccinated Patients
Dear Dr. Morgan:
Thank you for sending us your work for consideration for publication in Obstetrics & Gynecology. Your manuscript has been reviewed by the Editorial Board and by special expert referees. The Editors would like to invite you to submit a revised version for further consideration.
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EDITOR COMMENTS:
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REVIEWER COMMENTS:
Reviewer #1:
This is a retrospective cohort study of pregnant patients who delivered at a multistate hospital system in 2021. Patients who were unvaccinated against COVID-19 were compared to those who had received two doses of an mRNA vaccine.
Patients were excluded if they received a viral vector vaccine, were only partially vaccinated, had major (fetal) congenital anomalies or higher order multiples. The primary outcome was perinatal death (including stillbirth and neonatal death).
1. Line 64 - a 13% vaccination rate at the time of delivery is quite low compared to the CDC data. According to the CDC at the end of 2021 approximately 67.7% of pregnant individuals were "fully" vaccinated against COVID-19
(https://covid.cdc.gov/covid-data-tracker/#vaccinations-pregnant-women). What is the difference in your population?
View Letter
1 of 3 11/7/2022, 3:19 PM
How does this very low vaccination rate affect the generalizability or validity of your data/findings?
2. Line 67 - why is higher BMI amongst vaccinated patients an expected finding?
3. Line 113 - The COVID-19 vaccine is now recommended for ages 6 months and up
4. Line 116 - your data regarding the vaccination rate in pregnancy is out of date, it is not 31%. And your reference is a paper, the CDC would be the preferred reference for vaccination rates
5. Line 152-153 - Please explain more as to why you excluded individuals who were vaccinated with the viral vector product
6. If you controlled for COVID-19 infection were outcomes still better? That is, if you compared vaccinated and unvaccinated individuals who 1. Had COVID and 2. Did not have COVID, what would your results be? Are these results just because COVID-19 rates were lower or is there some other explanation for the results?
7. Regarding maternal race; since the relationship between black race and adverse perinatal outcome is well established is the higher proportion of unvaccinated black patients a confounder? If you control for maternal race are the same results seen?
8. Line 221 - the term "full[y]" vaccinated is confusing as it is a changing definition - I would just specify that they received two mRNA doses or the first two doses/series.
9. Line 275-277 If it is not possible to determine if the improvements in neonatal and maternal outcomes in the groups of vaccinated patients are primarily due to maternal COVID-19 vaccination status then what is the point of the study/paper?
10. Was there any sample size/power calculation performed? If so, please include it. If not, please explain.
Reviewer #2:
Introduction:
Well written and informative Methods:
It would be good to include the scientific designation of the different variants.
Line 150: Can you please clarify the sentence, it can be confusing for the reader.
Results:
Did you look at the perinatal outcomes based on the severity of maternal infection? That could be more informative as it has been shown before that severe/critical disease is associated with worse perinatal outcomes.
Discussion:
Well written, citing the existing evidence. However, I would be more cautious is making a generalized conclusion based on the study results regarding perinatal death. Although statistically significant, the outcome is already rare with a reduction from 0.8 to 0.5 and when looking at stillbirth and neonatal death separately it is only significant for stillbirth with 95% CI (0.02-0.99).
Reviewer #3:
GENERAL COMMENTS: The authors present a retrospective cohort study of 15,865 pregnant patients compare the frequency of perinatal death and other adverse perinatal outcomes between pregnant patients who completed the mRNA COVID-19 vaccination series versus unvaccinated patients. This is part of an attempt to provide safety data to inform counseling and patient decisions regarding COVID-19 vaccination during pregnancy. The primary outcome was perinatal death (stillbirth + neonatal death). The large sample size allowed the evaluation of the relative rare outcome of perinatal death.
COMMENTS:
1. The large sample size is a strength
2. The low vaccination rate (13%) raises the question of whether patients receiving the vaccine were systematically different from those who did not (selection bias) and whether their characteristics are related to the risk of perinatal death
(confounding). This suspicion is confirmed by the significant 3. demographic and other differences between groups, most of which are risk factors for adverse perinatal outcomes
3. This makes it difficult to claim a causal relationship between COVID-19 vaccination and reduction in adverse perinatal outcomes. Although logistic regression was used to adjust for measured confounders, it is in adequate and cannot adjust for confounding by unmeasured variables. Maybe supplemental analysis using propensity score analysis or similar method would be helpful.
4.While the sample size is large the rare nature of the primary outcome results in very small frequencies and likely unstable estimates e.g. 1 neonatal death in the vaccinated group (Table 2)
Reviewer #4:
Table 1: Need units for age. Need to elaborate "Public"? Insurance provider?
Table 2: Insufficient counts to estimate aOR for neonatal deaths, likely over fitted model. Also, since # neonates (rather than # pregnancies) is the unit of observation, and there is some correlation among twins, there were not 2106 nor 14026 independent events. Need to adjust for intraclass correlation or randomly chose one among each twin pair. Could also do sensitivity analysis only considering singletons.
Table 3: Same issues as in Table 2 re: need to adjust for intraclass correlation etc.
Tables 3, 4: Need to include footnote listing the variables included as adjustors in the final model.
General:
Since there are many more in the unvaccinated than in the vaccinated cohort (approx 7:1) and they differ in multiple baseline characteristics (Table 1), should corroborate the multivariable regression model with matching algorithm (e.g., propensity score matching) hopefully to replicate the findings. For some of the rarer events, there may be insufficient counts and power, but for many of the findings, there likely are a sufficient number of matches. This would strengthen the case that the difference in outcomes was attributable to vaccination, rather than other factors.
-- Sincerely,
Torri D. Metz, MD, MS Associate Editor, Obstetrics
The Editors of Obstetrics & Gynecology
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