Dear Dr. Yu,

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Academic Editor

PLOS One

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

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

Reviewer #1: Partly

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Yes

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

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Yes

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

The PLOS Data policy

Reviewer #1: Yes

Reviewer #2: No

Reviewer #3: Yes

Reviewer #4: Yes

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

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Yes

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Reviewer #1: 1. On page 6, line 88, the author states: “Cancer treatment was categorized as surgery only; radiation without chemotherapy; chemotherapy; and other.” It is unclear whether these categories are mutually exclusive or if they include combinations. For instance, does "radiation without chemotherapy" also include patients who underwent surgery? Please clarify the specific composition of each treatment group to avoid ambiguity.

2. The authors should provide a clearer rationale for their choice of adjustment variables in the multivariable models. While the models adjusted for cancer type, age at diagnosis, and period of cancer onset, they did not account for the level of urbanization and cancer treatment. This is particularly concerning given that cancer treatment showed a significant association with childbirth in the results. Please justify why these potentially confounding factors were excluded from the final multivariable analysis.

Reviewer #2: This nationwide registry-linkage study from Taiwan assesses childbirth after cancer among women diagnosed at age ≤39 years. Strengths include the use of linked national registries, the large sample size, and the clinical and public health importance of the topic, in addition to being written very clearly and concisely. Overall, with several revisions, this manuscript should be of interest to readers of PLOS One, fills an important gap in the literature, and has clear implications for survivorship care, fertility counseling, and policy.

Major comments

My primary concern is the SBR analysis. This comparison would be substantially stronger if the authors used a matched non-cancer comparison group rather than an indirectly standardized birth ratio. If a matched analysis is not feasible, the authors should justify more clearly why the SBR approach was selected and discuss its limitations, particularly given that it appears to standardize only by age and calendar year.

Please justify the use of cause-specific Cox models rather than a competing-risk regression model for the correlates analysis. A cause-specific Cox model estimates the instantaneous hazard among women who remain event-free, whereas a competing-risk regression more directly models the cumulative incidence of the outcome in the presence of death as a competing event. Because the descriptive analyses treat death as a competing risk, a competing-risk regression would appear more closely aligned with the overall analytic framework.

The manuscript appears to use different outcome definitions across analyses. The competing-risk and Cox analyses focus on first post-diagnosis livebirth, whereas the SBR analysis seems to include all post-diagnosis livebirths. Please clarify in the Methods whether this is correct, provide a rationale for using different estimands, and add descriptive information for all livebirths if those data are retained in the SBR analysis, since descriptive tables currently describes first livebirth only.

The policy discussion could be strengthened. Lines 236–238 note that the current policy provides fertility preservation subsidies for young adults with breast or hematologic malignancies. However, the results identify particularly low likelihood of livebirth among survivors of gynecologic cancers. This finding should be discussed more directly as a potential opportunity to improve or expand current fertility preservation policies.

Minor comments

1. Please justify the exclusion of women with <1 year of follow-up. Most of the main analyses, including the competing-risk and Cox models, already account for follow-up time, so this exclusion does not seem necessary unless it was specifically required for the SBR analysis.

2. Please add 1–2 sentences describing the quality and completeness of the linked registries for readers who may be unfamiliar with these data sources. It would also be helpful to state when the cancer registry, birth registry, and mortality data became sufficiently comprehensive for population-based analyses. It would also help to add the start date at which these registries were generally representative of the full population- for example line 127 shows that only 2.4% were diagnosed in or before 2000. I’m guessing this means the registry wasn’t fully functional or operational or complete until just before 2000.

3. Trend testing is mentioned in line 154; please specify in the Methods how trends were tested.

4. Lines 189–191 and line 208 require citation. In addition, lines 189–191 should acknowledge prior U.S. findings of especially low livebirth after gastrointestinal cancers (e.g., Betts et al. 2024), if relevant.

Reviewer #3: The study is methodologically sound, clearly presented, and the conclusions are well supported by the data. I have only a few minor suggestions.

1. Please briefly acknowledge that the association between chemotherapy and reduced childbirth may reflect both treatment-related gonadotoxicity and confounding by indication, as women receiving chemotherapy are more likely to have advanced or aggressive disease. In addition, because the registry only captures broad treatment categories, the lack of information on specific agents, treatment intensity, and cumulative doses should be acknowledged when interpreting these findings.

2. Please clarify that the lower childbirth rate among women diagnosed at older reproductive ages may reflect both biological aging and pre-existing reproductive choices (e.g., completed family size). Because parity before diagnosis was unavailable, this distinction would help readers interpret the findings appropriately.

3. Please clarify that the lower SBR observed among women diagnosed in the most recent calendar period is likely influenced by the shorter duration of follow-up, and therefore their reproductive outcomes may be underestimated.

Overall, I believe this manuscript is suitable for publication after minor revision.

Reviewer #4: Major Revision

Introduction

1. The description of Taiwan's recently implemented fertility preservation subsidy program would benefit from greater specificity. As fertility preservation methods and subsidy policies vary across countries, the authors should clarify the specific procedures covered by the Taiwanese program (i.e., oocyte cryopreservation for eligible female patients and sperm cryopreservation for eligible male patients) and briefly distinguish this cancer-specific fertility preservation program from the general IVF subsidy available to infertile couples in Taiwan. This clarification is particularly important for international readers and would strengthen the policy context and relevance of the present study.

2. The Introduction could be more focused and lead readers more directly to the central research question. In particular, the discussion of the ASCO fertility preservation guideline does not appear to be closely relevant to the specific objective of this study, which examines livebirth after cancer. The authors may consider removing this portion from the Introduction or, if relevant to the interpretation of the findings, moving it to the Discussion. This would improve the flow and help readers more readily identify the knowledge gap and central research question.

Methods

1. In the first paragraph of the Methods section, the description of the data sources and study period could be clarified. The current paragraph appears to mix the date of data acquisition, the available date ranges of the respective registries, and the actual study inclusion period. Please consider presenting these separately and clearly specify the calendar period during which cancer diagnoses were eligible for inclusion. For example:

September 1, 2025: date on which the researchers obtained the data.

1979–2022: availability period of the Taiwan Cancer Registry.

2001–2023: availability period of the Birth Reporting Registry.

Up to 2023: availability period of the Taiwan Death Registry.

Actual cancer diagnosis inclusion period: currently unclear.

Clearly distinguishing these different time periods would make the study population and follow-up framework easier to understand and improve reproducibility.

2. In the second paragraph, for readers who are not familiar with cancer registry classification systems, the reference to the ICD-O-3/WHO 2008 definitions may appear outdated, particularly given the long study period and substantial changes in cancer classification over time. A brief clarification of how cancer diagnoses across different calendar periods were harmonized would help reassure readers regarding complete case ascertainment and consistent classification. For example, the original sentence could be revised to:

“Cancer types were classified into mutually exclusive categories according to the ICD-O-3/WHO 2008 definitions, with cancer diagnoses across different calendar periods harmonized to this common classification system.”

3. The authors excluded livebirths occurring within one year after cancer diagnosis. A brief justification for this methodological choice, for example by citing the previous study protocol on which this approach was based, would improve clarity and reproducibility.

Results and Discussion

1. The terms “fertility” and “reproductive potential” appear to be used interchangeably with post-diagnosis livebirth throughout the Results and Discussion, although these are not equivalent outcomes. This study directly assessed post-diagnosis livebirth rather than biological fertility, ovarian reserve, pregnancy attempts, or reproductive intentions.

For example, the statement that “fertility was most preserved among survivors of skin and thyroid cancers” may not be fully supported by the data. The higher livebirth rate observed among thyroid cancer survivors could reflect multiple factors, including favorable prognosis, longer survival, less gonadotoxic treatment, age distribution, or reproductive choices, rather than preserved biological fertility alone.

Similarly, the conclusion that the findings “underscore the combined contributions of treatment-related gonadotoxicity, age at diagnosis, and non-biologic factors to reduced fertility after cancer” appears stronger than what can be directly inferred from the study, as neither biological fertility nor gonadotoxicity was directly assessed.

The authors may consider using more precise terms such as “post-diagnosis livebirth,” “childbearing,” or “likelihood of livebirth” throughout the manuscript and revising the conclusion to more closely reflect the measured outcome. For example:

“Together with international evidence, our findings suggest that reduced post-diagnosis childbearing may reflect the combined influence of treatment-related gonadotoxicity, age at diagnosis, and non-biologic factors.”

2. The interpretation of the association between chemotherapy and subsequent childbirth should be more cautious. The manuscript reports that chemotherapy was associated with a 48% reduction in subsequent childbirth compared with surgery alone; however, the reported HR of 0.52 is unadjusted. Patients receiving chemotherapy may differ substantially from those receiving surgery alone with respect to cancer type, age, disease characteristics, prognosis, and other factors. In addition, treatment information was available only in broad categories without details regarding specific agents, cumulative doses, conditioning regimens, or other gonadotoxic exposures. Therefore, the observed association should not be interpreted as directly demonstrating chemotherapy-related gonadotoxicity, and the authors should consider acknowledging the potential for confounding more explicitly.

3. The Discussion could be shortened and made more focused. Several paragraphs provide overlapping explanations for reduced post-diagnosis childbearing, including disease prognosis, treatment-related gonadotoxicity, age-related biological constraints, reproductive intentions, and psychosocial factors. Consolidating these overlapping sections would improve conciseness and allow the principal findings of the study to remain more prominent.

Minor Revision

Introduction

1. The opening sentence, “Cancer is sometimes diagnosed at a young age,” is overly general and does not effectively engage the reader or introduce the central focus of the study. Given that the study examines livebirth after cancer among young females, the authors may consider opening more directly with the growing importance of reproductive outcomes among young cancer survivors in the context of improving cancer survival.

Methods

1. Line 94: The first sentence of this subsection is redundant, as the availability of birth records from 2001 to 2023 has already been described in the Data source section, and may be deleted for conciseness.

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what does this mean?). If published, this will include your full peer review and any attached files.

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Reviewer #1: No

Reviewer #2: No

Reviewer #3: Yes: Ya-Yun Cheng

Reviewer #4: No

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Rates of childbirth in female cancer survivors: a population-based study in Taiwan

PONE-D-26-17199R1

Dear Dr. Yu,

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.

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Kind regards,

Chong-Chi Chiu

Academic Editor

PLOS One

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

Reviewer #3: All comments have been addressed

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

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

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

Reviewer #1: Yes

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

Reviewer #1: Yes

Reviewer #2: No

Reviewer #3: Yes

**********

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

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

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Reviewer #1: The authors have adequately addressed my comments raised in a previous round of review and this manuscript is now acceptable for publication.

Reviewer #2: extremely minor- but one response to the review created a little confusion for me. The manuscript mentions testing for ordinal trends across age and period of cancer onset (127-129) but only one trend test is presented (by time); they did not include p-trend for age results in the paper. If they had they done test for trend by age group, using the median of each group would have been more appropriate than using sequential integers. I think they can likely delete mention of age group in that area of the manuscript, and then it would be ready for acceptance.

Reviewer #3: The authors have adequately addressed all of my previous comments, particularly regarding the interpretation of chemotherapy-related findings, reproductive outcomes among women diagnosed at older ages, and the shorter follow-up duration in the most recent diagnostic cohort. The revised manuscript is clearer and appropriately acknowledges these limitations. I have no further comments and support publication.

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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: No

Reviewer #3: Yes: Ya-Yun Cheng

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