Male childlessness as independent predictor of risk of cardiovascular and all-cause mortality: A population-based cohort study with more than 30 years follow-up

Angel Elenkov; Aleksander Giwercman; Sandra Søgaard Tøttenborg; Jens Peter Ellekilde Bonde; Clara Helene Glazer; Katia Keglberg Haervig; Ane Berger Bungum; Peter M. Nilsson

doi:10.1371/journal.pone.0237422

Peer Review History

Original SubmissionJuly 8, 2019
17 Dec 2019 Decision Letter - Ying-Mei Feng, Editor PONE-D-19-18778 Male Childlessness as Independent Predictor of Risk of Cardiovascular and All-cause Mortality: A Population-based Cohort Study with more than 30 years follow-up PLOS ONE Dear Dr. Elenkov, 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. In this population-based cohort, Angel Elenkov et al evaluated the association between male childlessness and the risk of MACE, cardiovascular mortality, all-cause mortality, and incident diabetes. Authors found that, compared with men with children, childless men were featured with higher fasting blood glucose, triglycerides and blood pressure at the baseline. After adjusting for some co-variables, male childlessness was significantly associated with higher risk of cardiovascular death (HR=1.33) and all-cause death (HR=1.23). Whereas, childlessness was non-significantly associated with lower incidence of diabetes (HR=0.97). Overall, the study is interesting and the quality of this manuscript needs to be improved. Major concerns: 1.There was no information on why these men didn’t have a child, thus, I wonder whether it was accurate to use the male childlessness as a proxy of impaired fertility. 2.Some important co-variables, such as family history of cardiovascular disease and economic level, should enter into the regression model. Fasting blood glucose, triglycerides and blood pressure should be treated as continuous variable. 3.What’s the rationale of conducting sensitivity analysis? My suggestion is adding the interaction of male childlessness and marital status in the model. 4.Table 1 should present the basic characteristics of people included in the final analysis, not that of entire people of the cohort. Please modify the tables style to make them meet the general requirements of academic publication. 5.Please check the diagnosis criteria of diabetes. 6.The writing needs to be properly simplified. We would appreciate receiving your revised manuscript by Jan 30 2020 11:59PM. When you are 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. If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. 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Revision 1
29 Jan 2020 Author Response Comments to the Author: In this population-based cohort, Angel Elenkov et al evaluated the association between male childlessness and the risk of MACE, cardiovascular mortality, all-cause mortality, and incident diabetes. Authors found that, compared with men with children, childless men were featured with higher fasting blood glucose, triglycerides and blood pressure at the baseline. After adjusting for some co-variables, male childlessness was significantly associated with higher risk of cardiovascular death (HR=1.33) and all-cause death (HR=1.23). Whereas, childlessness was non-significantly associated with lower incidence of diabetes (HR=0.97). Overall, the study is interesting and the quality of this manuscript needs to be improved. Major concerns: 1.There was no information on why these men didn’t have a child, thus, I wonder whether it was accurate to use the male childlessness as a proxy of impaired fertility. Reply: The issue raised by the reviewer is highly relevant and has also been addressed in the Discussion section of the original version of the manuscript. The group of childless men represent a mixture of men with lowered fertility, those with a sub fertile partner and also subjects who decided not to father children. The registry data we use dates back to the first half of the 1970´s. The possibilities for fertility treatment in men at that time were very limited if present. The modern methods of assisted reproduction are developed in the beginning of the 1990´s. Before that men with a very low fertility potential did not have the possibility to use, for example, intracytoplasmic sperm injection to achieve fertilization and pregnancy. Presumably a big majority of men with infertility before the 1990´s have thus remained childless. We agree that childlessness as a proxy for male infertility has some limitations, for example the fact that we could not account for the participants´ paternal intention, nor the partner’s fertility status, marital strain etc. However, a nation-wide statistical data from Sweden have shown that only one in four childless men are voluntarily childless (Statistics Sweden, SCB: Childbearing patterns of different generations, 2011). This information has now been added to the Discussion part of the manuscript. Fathers of adopted children, or those who have sired offspring with the help of assisted reproduction techniques (ART), might have been included in the control group leading to misclassification bias. Nevertheless, these types of misclassifications related to fertility, family dynamics and other unaccountable factors would rather tend to reduce the difference between the childless men and fathers and thus cannot explain the statistically significant differences reported by us. Furthermore, we regard the 30 years of follow-up, which is the longest available among similar studies, as a major strength of our analysis. 2. Some important co-variables, such as family history of cardiovascular disease and economic level, should enter into the regression model. Fasting blood glucose, triglycerides and blood pressure should be treated as continuous variable. Reply: We have changed our analysis according to reviewer’s suggestions. We included a separate co-variate “called family history for CVD” (p.8, l.158 - 161): “… A positive family history for CVD was defined as reporting having at least one first-degree relative with MI before the age of 60 years as described previously (24). No family history was defined as no reported first‐degree relatives with MI before 60 years, or no answer in the questionnaire…” We have treated fasting blood glucose, triglycerides and blood pressure as continuous variables. Data on economic level of the subjects is not available from our data set. Our results are not significantly changed and are summarized in the revised table (p.15 l.290 - 298.) 3.What’s the rationale of conducting sensitivity analysis? My suggestion is adding the interaction of male childlessness and marital status in the model. Reply: The rational for including this sensitivity analysis refers to the point of criticism raised by the reviewer in item 1. By excluding men who remained unmarried we reduce the proportion of voluntarily childless men and men without opportunity to reproduce in the “exposed” group and to exclude non-marriage as cause of increased cardiovascular mortality risk in childless men. Our data seem to confirm that this risk increase is related to childlessness per se and not to being married or not. The suggestion of including interaction analysis is interesting, in case the hypothesis that the association between childlessness and increased mortality is modulated by marital status. This was not part of our hypothesis, why such interaction analysis was not included in the original version of the manuscript. However, we have performed these calculations: There was a statistically significant interaction between childlessness and marital status in the model evaluating the risk for all-cause mortality (p=0.037) in the partially adjusted model (model 1). However, the interaction was no longer statistically significant in the fully adjusted model 2 (p=0.95). Furthermore, the interaction was not statistically significant in the other analysis evaluating MACEs and CVD mortality in any of the models (data not presented). As mentioned above, we have omitted this analysis because it was not part of our hypothesis. If the Reviewer/Editor wishes it to be a part of the manuscript, we can easily implement it into the final version. However, for reason mentioned above, we suggest that even the sensitivity analysis is kept as it is now. 4. Table 1 should present the basic characteristics of people included in the final analysis, not that of entire people of the cohort. Please modify the tables style to make them meet the general requirements of academic publication. Reply: The table has been modified according to the reviewer’s suggestion (p.12). 5. Please check the diagnosis criteria of diabetes. Reply: A technical mistake on line 154: “…had fasting blood glucose > 6.5” was corrected to: “…had fasting blood glucose > 5.6...” 6.The writing needs to be properly simplified. Reply: We have now taken a second look in the text in order to make the writing concise and simple as much as possible. We would be however grateful if the editors/reviewers point to additional parts of the manuscript which may need re-writing. Attachments Attachment Submitted filename: Answer_reviewers-PlosOne_revsion2020_01_28.docx https://doi.org/10.1371/journal.pone.0237422.r002
22 Apr 2020 Decision Letter - Ying-Mei Feng, Editor PONE-D-19-18778R1 Male Childlessness as Independent Predictor of Risk of Cardiovascular and All-cause Mortality: A Population-based Cohort Study with more than 30 years follow-up PLOS ONE Dear Dr. Elenkov, 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. 1. Please describe the charactersitics of age, familiy history of CVD, and biochemical factors in the Table 1. Also, please add the univariate analysis to indicate whether there were significant difference between the two groups in the Table 1. 2. As the last row of Table 2 shows, the proportion of elevated BP in the two groups was equal, but the OR was more than 1.0. Please check it. 3. I think Table 2 should show the association of childlessness with metabolic features among participants included in the final analysis (45 years or older), rather than among participants of the entire cohort. Instead of presenting the reference group using a column, adding this information at the footnote would be better. The column of OR (95% CI) was supposed to be listed on the end of the table. 4. In Table 3, the three columns of HR (95% CI) should be listed on the right side of the two columns of endpoints incidence. Considering the “total” number of "Childless"/ "Fathers" was fixed in most rows, it should not be marked repetedly, which would simplify the table. 5. Both in Table 2 and Table 3, the first column indicating the different range of paritcipants included in the regression, and please keep the words of the first column consistent. We would appreciate receiving your revised manuscript by Jun 06 2020 11:59PM. When you are 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. If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. To enhance the reproducibility of your results, we recommend that if applicable you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols 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). This letter should be uploaded as separate file and labeled 'Response to Reviewers'. A marked-up copy of your manuscript that highlights changes made to the original version. This file should be uploaded as separate file and labeled 'Revised Manuscript with Track Changes'. An unmarked version of your revised paper without tracked changes. This file should be uploaded as separate file and labeled 'Manuscript'. Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out. We look forward to receiving your revised manuscript. Kind regards, Ying-Mei Feng Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0237422.r003
Revision 2
12 May 2020 Author Response Comments raised during the review process: 1. Please describe the charactersitics of age, familiy history of CVD, and biochemical factors in the Table 1. Also, please add the univariate analysis to indicate whether there were significant difference between the two groups in the Table 1. 2. As the last row of Table 2 shows, the proportion of elevated BP in the two groups was equal, but the OR was more than 1.0. Please check it. 3. I think Table 2 should show the association of childlessness with metabolic features among participants included in the final analysis (45 years or older), rather than among participants of the entire cohort. Instead of presenting the reference group using a column, adding this information at the footnote would be better. The column of OR (95% CI) was supposed to be listed on the end of the table. 4. In Table 3, the three columns of HR (95% CI) should be listed on the right side of the two columns of endpoints incidence. Considering the “total” number of "Childless"/ "Fathers" was fixed in most rows, it should not be marked repetedly, which would simplify the table. 5. Both in Table 2 and Table 3, the first column indicating the different range of paritcipants included in the regression, and please keep the words of the first column consistent. Reply: We have made all corrections to all tables as proposed. A number of calculations were also performed with new data included to the tables. The main results and conclusions from our study are not changed. Attachments Attachment Submitted filename: Answer_reviewers-PlosOne_revsion2020_05_06.docx https://doi.org/10.1371/journal.pone.0237422.r004
28 Jul 2020 Decision Letter - Ying-Mei Feng, Editor Male Childlessness as Independent Predictor of Risk of Cardiovascular and All-cause Mortality: A Population-based Cohort Study with more than 30 years follow-up PONE-D-19-18778R2 Dear Dr. Elenkov, 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, Ying-Mei Feng Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0237422.r005
Formally Accepted
19 Aug 2020 Acceptance Letter - Ying-Mei Feng, Editor PONE-D-19-18778R2 Male Childlessness as Independent Predictor of Risk of Cardiovascular and All-cause Mortality: A Population-based Cohort Study with more than 30 years follow-up Dear Dr. Elenkov: I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department. If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. 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. If we can help with anything else, please email us at plosone@plos.org. Thank you for submitting your work to PLOS ONE and supporting open access. Kind regards, PLOS ONE Editorial Office Staff on behalf of Dr Ying-Mei Feng Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0237422.r006

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