PONE-D-20-15840

Umbilical cord characteristics and their association with adverse pregnancy outcomes: a systematic review and meta-analysis

PLOS ONE

Dear Dr. Hayes,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Please address all reviewer comments including those in the provided attachment.

Please submit your revised manuscript by Aug 14 2020 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

• A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
• A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
• An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols

We look forward to receiving your revised manuscript.

Kind regards,

Kelli K Ryckman

Academic Editor

PLOS ONE

Journal Requirements:

When submitting your revision, we need you to address these additional requirements.

1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at

https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and

https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf

2. Please include captions for your Supporting Information files at the end of your manuscript, and update any in-text citations to match accordingly. Please see our Supporting Information guidelines for more information: http://journals.plos.org/plosone/s/supporting-information.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: No

Reviewer #2: Yes

Reviewer #4: Yes

**********

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: No

Reviewer #2: Yes

Reviewer #4: Yes

**********

3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #4: Yes

**********

4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #4: No

**********

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: 1. The heterogeneity of the studied included (see lines #143-148) (and graded subjectively by the authors as poor (n=7), fair (n=103), and good (n=35), in my assessment negates any statistical analysis in aggregate (essentially, the gist of this submission). I note the authors themselves acknowledge this major drawback (see line # 162 "Heterogeneity was very high").

2. The primary outcome criteria assessed "stillbirth" (see line # ), clearly falls short of the outcome as suggested in the title "adverse perinatal outcome". The authors later in the manuscript address "fetal compromise" (see lines # 351-361). Tools applied in these analyses are incomplete (see next point). The statement "and the observed effects sizes were comparatively modest" is unsubstantiated and lacks any clinical significance.

3. Apgar scores are highly subjective. More precise and scientifically correct perinatal outcome include umbilical artery pH and base excess, both absent in the data assessed in this submission.

4. It is methodologically incorrect to include cord prolapse in the context of "umbilical cord abnormalities" (see lines # 180-181 and later lines # 338-340), (often associated with artificial rupture of the membranes - ie, iatrogenic) in the analysis of nuchal and true knots of the umbilical cord (both spontaneous events).

5. Data pertaining to umbilical cord length are incomplete.

6. Data pertaining to prenatal sonography of nuchal cords and true knots of the umbilical cord, are incomplete.

7. The statement in line # regarding the relative higher sensitivity rates associated with intrapartum prenatal sonographic diagnosis (lines # 220-222) reflect the shorter time from diagnosis to delivery. Worded differently, a nuchal cord throughout gestation is a dynamic condition, often not seen at repeat sonographic assessment (and conversely).

8. I agree with the authors that tightness of the umbilical cord is highly subjective and cannot be addressed (lines # 246 -248).

9. The increased likelihood of stillbirth in cases of true knot of the umbilical cord (lines # 282-285), is well-established.

10. Lines # 363-369): Respectfully, I differ with the authors, in that this "systematic review" is weak (the fact that a pre-specified protocol by an international multidisciplinary review team, is irrelevant). A weak paper cannot be strengthened by these measures. In contrast, I do agree with the authors regarding the notable limitations of this submission - namely the heterogeneity of the included studies reflected in the variations of definitions utilized and associated outcomes.

11. Similarly, as the authors correctly state (lines # 368-369), all data presented may reflect publication bias.

12. Clinical implications stated by the authors (lines # 389-413), are well recognized within the Obstetrical community and do not reflect original previously unpublished data.

13. Line # 84: "Death of a baby" should be simply "stillbirth", or "intrauterine fetal demise".

14. Results: (line # 28): A sentence should not begin with numbers.

15. The final sentence of the Results section of the Abstract (lines # 34-35) is incomplete as written.

16. Abstract: The final comment regarding the need for future studies (lines 39-40), merely reflects the weakness of the secondary outcomes assessed.

17. The first sentence of the Conclusion (line # 37) is incorrect as written. Pregnancy itself "is associated with stillbirth". It appears that the authors intend to state: "True umbilical cord knots are associated with an increased risk of stillbirth". Regarding the remainder of the sentence (lines # 37-38) "the incidence of stillbirth is higher with multiple nuchal loops". Higher than what? Please clarify. It appears the authors mean to state, "in contrast to cases of a single nuchal cord, multiple nuchal loops have an increased risk of stillbirth".

18. The tables are exhaustive, and in my assessment do not contribute significantly to this effort. For example. regarding Lolis et al (1998), why would umbilical cord length increase with parity. I question whether such a "finding" is worthy of quoting?

Reviewer #2: The authors of the manuscript entitled “Umbilical cord characteristics and their association with adverse pregnancy outcomes: a Systematic review and meta-analysis” have produced a fine analysis of literature published in the last 50 years on the impact of umbilical cord abnormalities on stillbirths and other related adverse pregnancy outcomes.

There are a few comments:

1. Robert W Bendon is lacking his institutional address.

2. Introduction: page 4, line 63: duration of UCA: this is most difficult to know/assess (unless cord prolapse). I suggest to delete this element as a feature of variation in published results

3. M&M: page 5, line 87: low birth weight “at term “(<2500g)

4. Table 1: reference number to each paper included should be added

5. Tables 2: clarify at the bottom of the table: NC: nuchal cords

6. Table 3: clarify at the bottom of the Table the meaning of: CS, PTB, NICU, BW, SGA

7. Table 4: clarify at the bottom of the Table the meaning of: PTB, NICU, LBW, SGA/FGR, OR

8. Although Tables 2, 3 and 4 include the significant findings in bold, the readers would benefit from the addition of a Table with the findings related to UCA, which would be better placed at the end of SYNTHESIS OF RESULTS. I.E:

- Loose nuchal loops were more frequent than tight loops, with a summary frequency of 10% (95% CI 4, 18) compared to 5% (95% CI 4, 77).

- Cord prolapse incidence was 0.17%

- True knots at birth incidence was 1%

- etc

Reviewer #4: The manuscript is technically sound, with data supporting the conclusions and rigorous statistical analyses. Data has been made available. However, portions of the manuscript are not well written and need major revision for clarity. Please see attached document for review and further details.

**********

6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: Yes: Marta C Cohen

Reviewer #4: No

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

Umbilical cord characteristics and their association with adverse pregnancy outcomes: a systematic review and meta-analysis

PONE-D-20-15840R1

Dear Dr. Hayes,

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.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Kelli K Ryckman

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #2: All comments have been addressed

Reviewer #3: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #2: Yes

Reviewer #3: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #2: Yes

Reviewer #3: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #2: Yes

Reviewer #3: No

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #2: Yes

Reviewer #3: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #2: Thank you to the authors for a thorough review of their manuscript.

The review provides a very good up-date of literature about umbilical cord abnormalities and stillbirth. This manuscript will be a very useful resource to pathologists and obstetricians.

Reviewer #3: The manuscript can be accepted in its present form as the authors addressed all requets and there are no further changes requested.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #2: No

Reviewer #3: Yes: Vasilios Pergialiotis