Umbilical cord length and neurodevelopmental disorders, a national cohort study

Cathrine Ebbing; Anne Halmoy; Svein Rasmussen; Karen K. Mauland; Jørg Kessler; Dag Moster

doi:10.1371/journal.pone.0322444

Peer Review History

Original SubmissionSeptember 4, 2024
4 Sep 2024 Author Response https://doi.org/10.1371/journal.pone.0322444.r001
10 Feb 2025 Decision Letter - Shivanand Kattimani, Editor PONE-D-24-37689Umbilical cord length and neurodevelopmental disorders, a national cohort studyPLOS ONE Dear Dr. Ebbing, 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 submit your revised manuscript by Mar 27 2025 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. 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Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #1: Yes Reviewer #2: Yes ****** 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: The objectives of this paper has been discussed and explored as mentioned. Proper ethical clearance has been taken from concerned departments .Strength and limitations have been mentioned. However in the methodology there is no clear definition of what is long and what is short cord. 108 "Exposures were short below 5th percentile and long above 95th percentile". This needs to have a reference to gestational age specific umbilical cord growth chart, as data regarding term and preterm and association with umbilical cord length and NDD have been presented in your study. In the Covariates, maternal socioeconomic status has not been considered and discussed, though Figure 1 acyclic graph has included sociodemography as a covariate. There was brief mention of the mothers' BMI and Ethnicity association with umbilical cord length. 205 "we repeated the analysis with NDD outcome restricted to cases with information on maternal BMI.We found no effect of maternal BMI on the risk estimate. This statement needs to be supported by data. Figure 4 of data sheet needs to be clearly labelled Reviewer #2: Very important study. calculation of sample size need clarification in methodology. Definition of short and long umbilical cord criteria or guideline and references is not addressed well in methodology. Avoid the abbreviations on abstract. The control of variances or standard competence process of midwife or physician who examine the neonate and measure the umbilical cord is not clear. ****** 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: Yes: Shabina Ahmed Reviewer #2: 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". 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Revision 1
3 Mar 2025 Author Response Response to review PONE-D-24-37689 Dear Academic Editor Shivanand Kattimani We thank you and referees for useful comments. Please find our responses to the comments itemised below. 3. Thank you for stating the following financial disclosure: [The project was supported by the Gerda Meyer Nyquist Gulbrandson and Gerdt Meyer Nyquist’s Fund, and the Norwegian SIDS and Stillbirth Society https://lub.no/. Prof. Dag Moster was awarded the grants. The funders played no role in conducting the research and writing the paper]. Please state what role the funders took in the study. If the funders had no role, please state: "The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript." • Reply: this is now changed.: Should read: “The project was supported by the Gerda Meyer Nyquist Gulbrandson and Gerdt Meyer Nyquist’s Fund, and the Norwegian SIDS and Stillbirth Society https://lub.no/. Prof. Dag Moster was awarded the grant with grant number 102230106. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.” …we will change the online submission form on your behalf. • Thank you. Reviewer: 1 The objectives of this paper has been discussed and explored as mentioned. Proper ethical clearance has been taken from concerned departments. Strength and limitations have been mentioned. However in the methodology there is no clear definition of what is long and what is short cord. 108 "Exposures were short below 5th percentile and long above 95th percentile". This needs to have a reference to gestational age specific umbilical cord growth chart, as data regarding term and preterm and association with umbilical cord length and NDD have been presented in your study. • Reply: We thank you for this comment. The percentiles of cord length were short (<5th empirical percentile) or long (≥95th empirical percentile) based on the cord lengths in the total study population. Empirical percentiles were constructed, based on gestational age at birth. We have previously published reference ranges for cord length in PLOS one (reference no 12 in the current manuscript) 1. However, as the current study population is the same as in Linde et al 2018, we calculated and applied empirical percentiles based on the current study population. The method applied is well described in the reference paper (Linde, 2018). We have amended the text to make this clearer: The paragraph now reads: “Exposures were short (<5th percentile) and long (≥95th percentile) umbilical cord. The cord length percentiles were empirical, i.e. constructed based on the distribution of umbilical cord length by parity, sex and gestational age in the study population. Since cord length increases with fetal size, we additionally constructed birthweight-specific percentiles for cord length. All data in the MBRN are registered prospectively. The attending midwife or physician conducted the examinations of the afterbirth and the neonate and entered the requested information into the registration form shortly after delivery. All neonates were examined by a physician and any malformation was noted. The umbilical cord was measured with a disposable tape and length reported in centimeters.” In the Covariates, maternal socioeconomic status has not been considered and discussed, though Figure 1 acyclic graph has included sociodemographic as a covariate. • Reply: Thank you. We had access to important socioeconomic variables, described in the “Covariates” section; ”maternal and paternal age and educational level, …marital status of the mother… maternal and paternal level of education (categorized into five levels) and immigrant status…”. We have added a footnote to Figure 1 Directed acyclic graph: “Social demographic factors contain maternal and paternal education level, marital status of the mother, immigration status of the child.” There was brief mention of the mothers' BMI and Ethnicity association with umbilical cord length. 205 "we repeated the analysis with NDD outcome restricted to cases with information on maternal BMI. We found no effect of maternal BMI on the risk estimate. This statement needs to be supported by data. • Reply: We carried out analyses in the selection of the population where BMI was available. Including BMI in the model did not change the results; for the association between a long cord and ADHD OR in this subset was 1.07 (95%CI 0.93-1.24) and including BMI in the model aOR 1.02 (95%CI 0.88-1.17) and short cord and ID; OR 2.67 (95%CI 2.06-3.47) including BMI in the model; aOR 2.75 (95%CI 2,12-3.58). Please see the results in the table below. At the discretion of the Editor, we may add this as supplemental material, although we feel this may be too much information. The paragraph now reads: “Since maternal BMI before pregnancy was available only in a subset of the population , we repeated the analyses (with NDD as outcomes) restricted to cases with information on maternal BMI (n=174,692). We found no effect of adjusting for maternal BMI on the risk estimates. Likewise, no effect was observed on the risk estimates when we adjusted for ART.” Population with 174692 BMI data: Exposure Outcome OR 95%CI aOR with BMI 95%CI long cord ADHD 1.07 0.93 1.24 1.02 0.88 1.17 short cord ID 2.67 2.06 3.47 2.75 2.12 3.58 short cord Impaired hearing 1.42 1.17 1.74 1.45 1.19 1.77 short cord Epilepsy 1.48 1.16 1.89 1.51 1.18 1.92 short cord CP 1.47 0.91 2.37 1.52 0.94 2.44 long cord CP 1.18 0.75 1.86 1.12 0.71 1.76 Figure 4 of data sheet needs to be clearly labelled • Reply: We have now inserted the requested information in the Figure text. Figure text now reads: “Figure 1 Directed acyclic graph (DAG) describing the relationship between pregnancy, maternal and paternal factors, umbilical cord length and neurodevelopmental disorder in the child. White nodules represent covariates that are included in the model. Social demographic factors contain maternal and paternal education level, marital status of the mother, immigration status of the child. Grey nodule; Unknown confounding factors, e.g. genetic confounding. Figure 2 The prevalence of neurodevelopmental disorders according to year of birth in Norway Figure 3 The prevalence of neurodevelopmental disorders according to cord length percentile Figure 4 Long or short umbilical cord (≥95th or <5th percentile) and risk of neurodevelopmental disorders among singletons. Panel A; exposure Long Cord, panel B; exposure Short Cord. CP; Cerebral Palsy, ADHD; Attention-deficit/hyperactivity disorder, ASD; Autism Spectrum Disorder; ID; Intellectual Disability, OR; Odds Ratio, CI; Confidence Interval” Reviewer #2: Very important study. • Reply: Thank you. • calculation of sample size need clarification in methodology. • Reply: This is an observational population study, including all births in Norway during the study period, thus a sample size calculation is not relevant in this setting. Definition of short and long umbilical cord criteria or guideline and references is not addressed well in methodology. • Reply: Thank you! Please see reply to Reviewer no1 above. Avoid the abbreviations on abstract. • Reply; this is difficult due to word limit. The guide for authors states that abbreviations should be avoided ”if possible”. In our situation both ADHD and ASD should be easier to read than the full description. The control of variances or standard competence process of midwife or physician who examine the neonate and measure the umbilical cord is not clear. • Reply: We have included a reference in the discussion section regarding the strengths and limitations (ref no 53 in the manuscript and ref 2 here below). This study was a validation study of the classification and measurements of the placenta, membranes and cord carried out by midwives in a clinical setting. The inter- and intra-observer study showed no significant differences regarding placental weight and cord length, indicating that the validity of data regarding placenta and cord in the Norwegian birth register is sufficiently high to justify future large-scale epidemiologic research based on this database. • 1. Linde LE, Rasmussen S, Kessler J, Ebbing C. Extreme umbilical cord lengths, cord knot and entanglement: Risk factors and risk of adverse outcomes, a population-based study. PloS one. 2018;13(3):e0194814. doi:10.1371/journal.pone.0194814 2. Sunde ID, Vekseth C, Rasmussen S, Mahjoob E, Collett K, Ebbing C. Placenta, cord and membranes: a dual center validation study of midwives' classifications and notifications to the Medical Birth Registry of Norway. Acta Obstet Gynecol Scand. Sep 2017;96(9):1120-1127. doi:10.1111/aogs.13164 Attachments Attachment Submitted filename: Response to reviewers_PONE-D-24-37689_final_25.02..docx https://doi.org/10.1371/journal.pone.0322444.r003
23 Mar 2025 Decision Letter - Shivanand Kattimani, Editor Umbilical cord length and neurodevelopmental disorders, a national cohort study PONE-D-24-37689R1 Dear Dr. Ebbing, 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 will be generated when your article is formally accepted. Please note, if your institution has a publishing partnership with PLOS and your article meets the relevant criteria, all or part of your publication costs will be covered. Please make sure your user information is up-to-date by logging into Editorial Manager at Editorial Manager® and clicking the ‘Update My Information' link at the top of the page. If you have any questions relating to publication charges, 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, Shivanand Kattimani Academic Editor PLOS ONE 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 #1: All comments have been addressed Reviewer #2: 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 #1: Yes Reviewer #2: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: 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 #1: Yes Reviewer #2: Yes ****** 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 #1: Yes Reviewer #2: 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 #1: (No Response) Reviewer #2: The article is good and presented an important clinical outcome. There is no ethical concern, the article is designed well, address important aim and conclusion ****** 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 #1: Yes: Shabina Ahmed Reviewer #2: No ******** https://doi.org/10.1371/journal.pone.0322444.r004
Formally Accepted
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