Findings of Reduced Head Circumference with COVID-19 Infection in the Third Trimester: A Retrospective Cohort Study

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

Thank you for the review opportunity!

Here are my suggestions:

Please mention in the title what type of study is it. 

Abstract: 

"Yet, Zika virus infection (ZIKV) during pregnancy is linked to abnormal newborn 13
growth measurements, specifically microcephaly without SGA or low birth weight. " i don't think this belongs in the abstract, since the study is not about the Zika virus. 

What does IRB stand for ?

PCR ? I'm guessing polymerase chain reaction. 

Since this study has nothing to do with the Zika virus, i would keep this part "Yet, Zika virus infection (ZIKV) during pregnancy is linked to abnormal newborn 13
growth measurements, specifically microcephaly without SGA or low birth weight." for the discussions section, not the abstract. 

Please remove Zika from the keywords.

Also please choose some keywords not found in the title. 

Introduction: please lengthen the Introduction with some general knowledge about SARS-CoV-2 and COVID-19.

Please include some epidemiological data, especially in females of child-bearing age and in newborns.

Materials and methods:

Please create a Figure so the readers can see the selection criteria at a glance.

"< 12 years of age," please mention it's the mother's age or else, it may be misinterpreted. 

Materials and methods are hard to comprehend in my point of view, please find a way to simplify the presented methods. Consider including more than one figure.

Fisher's test is commonly used for small groups, why did the authors choose this test ? It should be mentioned the reasoning.

Results: Please consider adding a figure for the first paragraph of the Results section.

Please include confidence intervals and odds ratios for all the results.

Please note that multivariate logistic regression presents the adjusted odds ratio which should be present in the table, materials and methods, results and abstract.

Discussions:

The discussion section needs a Limitation section.

 Conclusion: please shorten the conclusion only presenting the main studies and how can they can be used in order to aid the reader.

Abbreviations: please include all the abbreviations from your manuscript, i see quite a few missing.

 

 

Comments on the Quality of English Language

I recommend this manuscript to be revised by the authors and then be sent for re-evaluation.

Author Response

Thank you so much for the wonderful review. We have provided the following edits and look
forward to hearing from you.

Round 1:

Comment: Thank you for the review opportunity! Here are my suggestions: Please mention in the

title what type of study it is.

Response: Title changed [Line 2]: Findings of Reduced Head Circumference with COVID-19 Infection in the Third Trimester: A Retrospective Cohort Study

Comment: Abstract: "Yet, Zika virus infection (ZIKV) during pregnancy is linked to abnormal newborn 13 growth measurements, specifically microcephaly without SGA or low birth weight." i don't think this belongs in the abstract, since the study is not about the Zika virus.

Response: This sentence was removed, replacement “There is limited data on the impact of COVID-19 on neonatal growth measurements, specifically microcephaly without SGA or low birth weight.” [Line 13-14]

Comment: What does IRB stand for ?

Response: IRB abbreviation was changed to “An Institutional Review Board (IRB)” [Line 17]

Comment: PCR ? I'm guessing polymerase chain reaction.

Response: Abbreviation spelled out, polymerase chain reaction (PCR) [Line 20]

Comment: Since this study has nothing to do with the Zika virus, i would keep this part "Yet, Zika virus infection (ZIKV) during pregnancy is linked to abnormal newborn 13 growth measurements, specifically microcephaly without SGA or low birth weight." for the discussions section, not the abstract.

Response: This was changed to “There is limited data on the impact of COVID-19 on neonatal growth measurements, specifically microcephaly without SGA or low birth weight.” [Line 14]

Comment: Please remove Zika from the keywords.

Response: Zika was removed from the keywords [Line 35]

Comment: Also please choose some keywords not found in the title.

Response: Additional key words added include: SARS-COV-2, pregnancy, placental dysfunction, fetal brain growth, prenatal exposure to COVID-19, maternal-fetal health, maternal infection, neurodevelopmental impact, impact of viral infections on pregnancy [Line 35-38]

Comment: Introduction: please lengthen the Introduction with some general knowledge about SARS-CoV-2 and COVID-19.

Response: Additional information was added about the neurological implications of the virus as below [Lines 62-77] “SARS-COV-2 virus enters the central and peripheral nervous system and infects pericytes and astrocytes, compromising the blood brain barrier and spreading to vital brain structures. [21] Studies have found increased serological biomarkers associated with CNS damage in patients with COVID-19, such as increased plasma glial fibrillary acidic protein and neurofilament light chain.[22] Brain imaging performed at the time of death from patients infected with COVID-19 showed white matter changes, posterior reversible encephalopathy syndrome and more.[23] Moreover, neurological damage has been documented from extensive COVID-19 infections in the fetus [24-27]. In 2023, a case report noted massive cerebral hemorrhage in a fetus with severe maternal COVID-19 infection with post-mortem histologic neural analysis showed massive intervillous deposition of fibrin and inflammatory infiltration with hotspots of necrotic deciduitis.[24] Given the documented neurological insult potential for SARS-COV-2, it has become apparent the need to further understand changes in growth parameters in pregnancies complicated by COVID-19.

Comment: Please include some epidemiological data, especially in females of child-bearing age and in newborns.

Response: Lines 45-50 the following was provided “For example, a systematic review reported an increased odds for the development of women infected with COVID-19 for pre-eclampsia (odds ratio (OR) 1.33), preterm birth (OR 1.82), and stillbirth (OR 2.11).[7] Moreover, The INTERCOVID Multinational Cohort Study found that pregnant women with COVID-19 are twenty times more likely to die compared to unaffected pregnant women.[8]”

Materials and methods:

Comment: Please create a Figure so the readers can see the selection criteria at a glance.

Response: Please see Figure 1 [Line 94]

Comment:"< 12 years of age," Please mention it's the mother's age or else, it may be misinterpreted.

Response: Replaced to Less than 12 years of maternal age [Line 20 and Line 73]

Comment: Materials and methods are hard to comprehend in my point of view, please find a way to simplify the presented methods. Consider including more than one figure.

Response: A figure was added on line 94 including selection criteria and inclusion and exclusion criteria

Comment: Fisher's test is commonly used for small groups, why did the authors choose this test ? It should be mentioned the reasoning.

Response: Chi-square test or Fisher’s exact test, used for smaller numbers where appropriate, was used to analyze categorical variables.

Results:

Comment: Please consider adding a figure for the first paragraph of the Results section.

Response: A figure was added on line 94, please see above.

Comment: Please include confidence intervals and odds ratios for all the results.

Response: We have done a linear regression with the head circumference score as the response. The results do not use logistic regression (and, thus, there are no ORs) in this project.

Comment: Please note that multivariate logistic regression presents the adjusted odds ratio which should be present in the table, materials and methods, results and abstract.

Response: The multivariate logistic regression presents the Beta value, not the adjusted odds ratio. The exponential of the beta value (exp(β)) represents the adjusted odds ratio. The beta, CI and p value are included throughout now [line 185]

Discussions:

Comment: The discussion section needs a Limitation section.

Response: The discussion section contains limitations from Line 211-228. The phrase “Our study has some limitations in that” line 211 to help better guide the reader.

Conclusion:

Comment: Please shorten the conclusion only presenting the main studies and how can they can be used in order to aid the reader.

Response: The conclusion was edited to be more concise. Please see revised [Lines 265-278]

Comment: Abbreviations: please include all the abbreviations from your manuscript, i see quite a few missing.

Response: The following were added:

EMR	Electronic medical record
REDCap	Research Electronic Data Capture
ZKV	Zika Virus
SARS-COV-2	Acute Respiratory Syndrome Coronavirus-2
NICU	Neonatal intensive care unit
APO	Adverse pregnancy outcome
PCR	Polymerase chain reaction
IRB	Institutional Review Board
SGA	Small for gestational age
APGAR	Appearance, Pulse, Grimace, Activity and Respiration
GDMA2	Gestational diabetes treated with medication
GDMA1	Diet-controlled gestational diabetes

Reviewer 2 Report

Comments and Suggestions for Authors

The group of Kristen Lee Moriarty et al present finding of reduced head circumference with COVID-19 Infection in the Third Trimester. 

 

1. The author made statistics on the data but did not analyze the causes, suggesting that the author conduct predictive analysis. The authors should discuss the mutation of the virus, or the virus changes metabolism and impairs nervous system development
2. The author only carried out statistical analysis, lacking sufficient data support. As noted in the conclusion, there is no conclusive evidence
3. line166, (p=.431) (p=.577), to (p=0.431?)
4. lin222 Farrell et al.11 found that, 11 represent..? lin227, 11 They also found a higher, 11 represent what? Line230, 11 A longitudinal cohort study by Ockene et a, 11 represent what?
5. Reference insertion is irregular,.(13, 16-18) Specifically, the Zika virus, a flavivirus, has received great attention due to its association with microcephaly. (13, 16-18) A systemic review by Antoniou et al. analyzed 15 articles and found an incidence rate of 15% of pregnancies affected with Zika., (13, 16-18) The author should make it clear that the paper made a difference

Author Response

Thank you so much for the wonderful review. We have provided the following edits and look
forward to hearing from you.

Round 1:

Comment: The author made statistics on the data but did not analyze the causes, suggesting that the author conduct predictive analysis. The authors should discuss the mutation of the virus, or the virus changes metabolism and impairs nervous system development.

Response: Additional information was added about the neurological impliations of the virus as below [Lines 62-77] “SARS-COV-2 virus enters the central and peripheral nervous system and infects pericytes and astrocytes, compromising the blood brain barrier and spreading to vital brain structures. [21] Studies have found increased serological biomarkers associated with CNS damage in patients with COVID-19, such as increased plasma glial fibrillary acidic protein and neurofilament light chain.[22] Brain imaging performed at the time of death from patients infected with COVID-19 showed white matter changes, posterior reversible encephalopathy syndrome and more.[23] Moreover, neurological damage has been documented from extensive COVID-19 infections in the fetus [24-27]. In 2023, a case report noted massive cerebral hemorrhage in a fetus with severe maternal COVID-19 infection with post-mortem histologic neural analysis showed massive intervillous deposition of fibrin and inflammatory infiltration with hotspots of necrotic deciduitis.[24] Given the documented neurological insult potential for SARS-COV-2, it has become apparent the need to further understand changes in growth parameters in pregnancies complicated by COVID-19."

Comment: The author only carried out statistical analysis, lacking sufficient data support. As noted in the conclusion, there is no conclusive evidence.

Response: Our findings did demonstrate reduced head circumference. Our findings for analysis of neonatal effects i.e. NICU admission, APGAR are limited by sample size. Yet, this vital information on head  circumference warrants contribution to the literature body.

Comment: line166, (p=.431) (p=.577), to (p=0.431?)

Response: Corrected to “There was no statistical significance for mean PI (p=0.417), birth weight (p=0.431), or birth length (p=0.577).” Line 179

Comment: lin222 Farrell et al.11 found that, 11 represent..? lin227, 11 They also found a higher, 11 represent what? Line230, 11 A longitudinal cohort study by Ockene et a, 11 represent what?

Response: The reference for Farrell citation was fixed.

Comment: Reference insertion is irregular,.(13, 16-18) Specifically, the Zika virus, a flavivirus, has received great attention due to its association with microcephaly. (13, 16-18) A systemic review by Antoniou et al. analyzed 15 articles and found an incidence rate of 15% of pregnancies affected with Zika., (13, 16-18) The author should make it clear that the paper made a difference.

Response: The reference was updated to reflect the accurate reference.

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

The authors adhered to my suggestions as much as they saw fit, i recommend publication.

Reviewer 2 Report

Comments and Suggestions for Authors    recommended to accept