https://orcid.org/0000-0001-8723-1044
Figures
Abstract
Introduction
Endometrial cancer, an adenocarcinoma originating from the uterine lining, is the most prevalent cancer of the female genital tract globally.Identifying early risk factors for endometrial cancer is crucial for prevention.Prior research suggests that pregnancy may lower endometrial cancer risk by reducing estrogen exposure.This meta-analysis aims to delve into the existing population-based longitudinal studies to evaluate the association between the time elapsed since the last birth and the risk of endometrial cancer.
Methods and analysis
We searched PubMed, Cochrane Library, Embase, and Web of Science for cohort studies published up to June 21, 2024, using relevant medical subject headings (MeSH) and keywords. Statistical analyses were conducted using Stata version 14.0. A fixed-effects model was applied if P > 0.1 and I2 ≤ 50%; otherwise, a random-effects model was used to account for significant heterogeneity Publication bias was assessed using funnel plots and Egger’s test. Our meta-analysis included 3 cohort studies and 5 case-control studies with a total of 3,310,734 participants, published between 1994 and 2024. The analysis revealed that time since last birth is associated with endometrial cancer risk. Specifically, a period of 0–10 years since the last birth was linked to a reduced risk of endometrial cancer (OR= 0.431; 95% CI: 0.351–0.530). A period of 10–20 years since the last birth also showed a decreased risk (OR=0.867; 95% CI:0.747–1.007), whereas more than 20 years since the last birth was associated with an increased risk (OR = 1.304; 95% CI: 1.111–1.530).
Conclusions
Our meta-analysis indicates that a shorter time since the last birth is protective against endometrial cancer, whereas a longer interval increases risk. Further research is needed to clarify the underlying mechanisms of this association. These findings are crucial for developing new strategies for endometrial cancer prevention and treatment.
Citation: Gu J, Lai Y, Shou H, Wang L (2025) Time since last birth and the risk of endometrial cancer: A meta-analysis of observational studies. PLoS One 20(7): e0325907. https://doi.org/10.1371/journal.pone.0325907
Editor: Nishel Mohan Shah, Imperial College London, UNITED KINGDOM OF GREAT BRITAIN AND NORTHERN IRELAND
Received: September 11, 2024; Accepted: May 21, 2025; Published: July 8, 2025
Copyright: © 2025 Gu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: All relevant data are within the manuscript and its Supporting Information files
Funding: This study was supported by the following sources: Zhejiang Provincial Health Department clinical research project (2022KY510) awarded to J.G. and Zhejiang Province Chinese Medicine scientific research fund project (2022ZB029) awarded to J.G.
Competing interests: The authors have declared that no competing interests exist.
Prospero registration number
International Prospective Register of Systematic Reviews (PROSPERO)
CRD42025644114.
Introduction
Endometrial cancer, an adenocarcinoma originating from the uterine lining, is the most prevalent cancer of the female genital tract globally, with its incidence rising steadily [1,2]. Despite significant advances in disease prevention research, progress in therapeutic interventions remains limited, and clinicians are still awaiting effective disease-modifying treatments. Identifying early risk factors for endometrial cancer is crucial for prevention. Although several risk factors such as polycystic ovarian syndrome (PCOS), anovulatory infertility, age, family history, tamoxifen use, high BMI, and diabetes have been well-studied, pregnancy-related factors have received less attention [3–5].
Pregnancy impacts the endometrium through notable changes, including an increase in glandular and vascular development to form the placenta, which supplies the embryo and fetus with essential nutrients [6]. Prior research suggests that pregnancy may lower endometrial cancer risk by reducing estrogen exposure [7]. However, it is important to note that other pregnancy-related variables, such as whether a woman has ever been pregnant, the number of pregnancies (parity), and the patient’s age during pregnancies or at the time of diagnosis, may also influence endometrial cancer risk and serve as potential confounders. While this study focuses on time since last birth, further investigation of these variables is warranted [7,8].Some pregnancy-related factors, like placental growth factor (PlGF) and placenta-specific protein 1 (PLAC-1), have been linked to endometrial cancer [9–13], and associations with pregnancy-related Wnt signaling or Homeobox (HOX) genes have also been observed [2,14,15].
Despite evidence indicating pregnancy’s protective effect against endometrial cancer, the specifics of this protection, particularly the influence of the time since last birth, remain unclear. This meta-analysis aims to delve into the existing population-based longitudinal studies to elucidate the relationship between time since last birth and the risk of endometrial cancer, with the ultimate goal of clarifying how this factor may contribute to cancer risk.
Methods
This meta-analysis adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [16]. The study protocol was pre-registered with the International Prospective Register of Systematic Reviews (PROSPERO)(CRD42025644114).
Data sources
We conducted a systematic search of PubMed, Cochrane Library, Embase, and Web of Science from their inception to May 15, 2024. The search was not restricted by language. For non-English studies, initial translations were performed using professional translation software, followed by verification and review by bilingual members of the research team to ensure accuracy. We employed a search strategy that combined both medical subject headings (MeSH) and keywords related to the topic. The search terms included “Birth,” “Pregnancy,” “Gestation,” “Endometrial Neoplasms,” “Cancer of the Endometrium,” “Carcinoma of Endometrium,” and “Cancer of Endometrium.” The detailed search strategy is provided in S1 File. Additionally, we examined reference lists of the included studies and relevant meta-analyses to identify any further relevant trials.
Eligibility criteria
We included studies based on the following criteria:
- 1) Cohort studies or case-control studies that explored the association between the time since last birth and the risk of endometrial cancer. These study designs were selected because they allow for a clearer understanding of temporal and causal relationships, whereas cross-sectional studies were excluded due to their inability to establish temporality.
- 2) Studies that reported odds ratios (ORs) with corresponding 95% confidence intervals (CIs). Studies that did not report these measures were excluded from the meta-analysis but were reviewed to ensure no critical information was missed for the systematic review.
We excluded conference abstracts, study protocols, duplicate publications, and studies without relevant outcome data. When multiple reports from the same cohort were identified, we prioritized studies with the longest follow-up or the largest sample size.
Study selection
Two reviewers (GJ and WLP) independently screened the literature according to the predefined eligibility and exclusion criteria. Initially, articles were screened for relevance based on titles and abstracts, resulting in the exclusion of duplicates and irrelevant studies. Subsequently, full texts of potentially eligible articles were retrieved and assessed to determine their suitability for inclusion. Any disagreements were resolved through consultation with a third reviewer (LYC), who acted as an arbiter.
Data extraction
Data extraction was carried out independently by reviewers GJ and WLP using pre-designed forms. The extracted information included the first author, publication year, study design, sample size, participant demographics (such as age), diagnosis of endometrial cancer, and adjusted confounders. While most studies adjusted for key confounders such as age and BMI, not all studies included these adjustments, which could introduce residual confounding. Discrepancies in data extraction were resolved through discussion with LYC to reach consensus.
Risk of bias
The quality of the included cohort or case-control studies was evaluated using the Newcastle-Ottawa Scale (NOS). The NOS assigns a maximum of 9 stars, distributed as follows: four stars for selection and exposure measurement, two stars for comparability, and three stars for outcome assessment and follow-up. Studies were categorized as low, moderate, or high quality based on their total scores of 0–3, 4–6, and 7–9 stars, respectively. Studies with a high risk of bias were not excluded but were assessed in sensitivity analyses to determine their impact on the overall results. The Newcastle-Ottawa Scale scores indicated that all included studies were of moderate to high quality, with a mean score of 7.5.
Statistical analysis
Adjusted odds ratios (ORs) and their corresponding 95% confidence intervals (CIs) were used to assess the relationship between the time since last birth and endometrial cancer risk. Heterogeneity among studies was evaluated using the χ² test and the I² statistic. A fixed-effects model was applied when P > 0.1 and I² ≤ 50%; otherwise, a random-effects model was used if I² > 50%, indicating substantial heterogeneity. Sensitivity analyses were performed by sequentially excluding individual studies to test the robustness of the overall results. Publication bias was assessed both visually using funnel plots and statistically with Egger’s regression test. Subgroup analyses were carried out based on study type and gender. All statistical analyses were performed using Stata statistical software version 14.0 (Stata Corp, College Station, Texas) [17,18].
Results
Literature search
The systematic search of cohort studies published before June 21st, 2024, identified 4086 results. After title and abstract screening, 8 articles were considered potentially relevant. Eight studies [19–26] were included after full text review, of which 8 reported the incidence of endometrial cancer on follow-up. The inclusion process explicitly excluded studies focusing solely on nulliparous women, as the research primarily examines the effect of time since last birth rather than parity status. The selection process is presented in Fig 1.
Study characteristics
This meta-analysis included 5 case-control studies and 3 cohort studies covering 3,310,734 individuals, which were published between 1995 and 2024. The adjusted estimates were available for almost all studies even though the adjusted confounders are slightly different. The main characteristics of the included trials are shown in Table 1.
Quality assessment
According to NOS criteria, the average score was 7.5 of all included studies, and the score for each trail was 7 or above, indicating that all studies were of high quality in this meta-analysis. The scores of the included studies are shown in Table 1 and S1 Table.
0-10 years since last birth and risk of endometrial cancer.
Seven included study states [19–22,24–26] assessed the association between 0–10 years since last birth and the risk of endometrial cancer. Overall, the history of 0–10 years since last birth was associated with a decreased risk of endometrial cancer (OR = 0.431; 95% CI: 0.351–0.530; I2 = 69.5%, P = 0.003; Fig 2). Sensitivity analysis showed that none of the individual studies reversed the pooled-effect size, which means that the results are robust (S1 Fig). Egger’s regression test (P = 0.000) likewise indicated no publication bias in our meta-analysis.
10-20 years since last birth and Risk of endometrial cancer.
Seven included studies [19–21,23–26] assessed the association between 10–20 years since last birth and the risk of endometrial cancer. Overall, the history of 10–20 years since last birth was associated with a decreased risk of endometrial cancer (OR = 0.867; 95% CI: 0.747–1.007; I² = 78.03%, P = 0.000; Fig 3). Sensitivity analysis showed that none of the individual studies reversed the pooled-effect size, indicating robust results (S2 Fig). A visual inspection of the funnel plot showed no evidence of significant publication bias for the included studies on this outcome (Fig 5). Egger’s regression test (P = 0.062) similarly indicated no publication bias in our meta-analysis.
Above 20 years since last birth and Risk of endometrial cancer.
Ten included study states [19–22,24–26] assessed the association between above 20 years since last birth and the risk of endometrial cancer. Overall, the history of above 20 years since last birth was associated with an increased risk of endometrial cancer (OR = 1.304; 95% CI: 1.111–1.530; I2 = 92.10%, P = 0.000; Fig 4). Sensitivity analysis showed that none of the individual studies had reversed the pooled-effect size, which means that the results are robust (S3 Fig).
Publication bias.
Visual examination of the funnel plot revealed no evidence of significant publication bias for the studies included in this meta-analysis (Fig 5). Additionally, Egger’s regression test (P = 0.062) confirmed the absence of publication bias.
Discussion
Main findings
This meta-analysis, encompassing 5 case-control studies and 3 cohort studies with a total of 3,310,734 participants, provides a comprehensive assessment of the relationship between time since last birth and endometrial cancer risk. We observed a significant reduction in endometrial cancer risk with 0–10 years and 10–20 years since the last birth, showing a 0.431-fold and 0.867-fold decrease in risk, respectively, compared to controls. Conversely, a time since last birth of over 20 years was associated with a 1.304-fold increase in risk. These findings suggest that time since last birth may be an independent risk factor for endometrial cancer.
Interpretation of findings
Our analysis, which integrates data from both case-control and cohort studies, underscores the independent effect of time since last birth on endometrial cancer risk. Shorter intervals since the last birth appear to offer protective benefits to the endometrial lining, while longer intervals in multiparous women significantly elevate risk. To ensure the reliability of our conclusions, all included studies controlled for key confounding factors, which could potentially influence the association between reproductive history and endometrial cancer risk. Specifically:
Age: As a well-established risk factor, age was consistently adjusted for across all studies. Older age is associated with cumulative estrogen exposure and higher endometrial cancer risk, and thus adjusting for it reduces potential bias.
Parity (number of births): Multiparity may reduce the lifetime risk of endometrial cancer through cumulative hormonal and immune changes during pregnancy. By controlling for parity, our results specifically isolate the effect of time since last birth.
Metabolic comorbidities: Conditions such as obesity, diabetes, and hypertension are major risk factors for endometrial cancer, often mediated by increased estrogen levels. All studies adjusted for these variables to minimize their confounding effects.
Hormonal factors: Long-term estrogen use, hormone replacement therapy, and oral contraceptive use were also considered in most studies, as they can independently modify endometrial cancer risk.
Despite these adjustments, it is possible that some residual confounding exists, particularly from unmeasured factors such as genetic predisposition, lifestyle behaviors (diet, exercise), or environmental exposures. Future studies should aim to incorporate these variables for a more comprehensive risk assessment. Several pathophysiological mechanisms could explain the observed associations between time since last birth and endometrial cancer risk:
Progesterone’s Protective Effect: High levels of progesterone during pregnancy may help remove premalignant lesions or abnormal endometrial cells, reducing the risk of malignant transformation [27].
Mechanical Clearance: Childbirth and uterine involution may mechanically clear abnormal cells, offering protection against endometrial cancer in the years immediately following delivery.
Immunological and Hormonal Shifts: Pregnancy induces immune modulation and hormonal changes (e.g., increased placental hormones) that may influence endometrial health. However, the long-term implications of these changes remain underexplored [28].
Unopposed Estrogen Hypothesis: Prolonged exposure to high levels of estrogen without progesterone opposition can promote endometrial cell proliferation, increasing cancer risk [29]. Conversely, pregnancies closer to the time of diagnosis may limit this exposure through shorter intervals of unopposed estrogen [30].
Our findings suggest that shorter intervals since last pregnancy might be protective due to high progesterone levels during pregnancy clearing malignant cells. Conversely, longer intervals in multiparous women were associated with higher endometrial cancer risk, potentially due to prolonged unopposed estrogen exposure. Women who are older at their final birth may have reduced endometrial cancer risk, as sustaining pregnancy later in life may indicate a healthier endometrial environment or fewer anovulatory cycles.
Implications and limitations
This meta-analysis highlights the importance of reproductive history as a factor in assessing endometrial cancer risk. Clinicians should consider time since last birth as part of a comprehensive risk evaluation, especially in multiparous women with extended intervals since their last delivery. Women in this category should be counseled on their increased risk and may benefit from regular gynecological examinations and screenings, including endometrial biopsy or transvaginal ultrasound, as part of a personalized prevention strategy.
While our analysis is based on robust data, several limitations should be acknowledged. The inclusion of both cohort and case-control studies introduces methodological heterogeneity, which, despite statistical adjustments, may still leave residual variability affecting the results. Additionally, unmeasured confounding variables, such as genetic predisposition, lifestyle factors (e.g., smoking, diet), and socioeconomic status, were not consistently reported or adjusted for across studies. Cross-sectional studies were excluded to strengthen causal inference, but this decision may have narrowed the scope of data and limited the breadth of our findings.
Future research should incorporate a broader range of study designs, including cross-sectional studies, to validate findings across diverse populations. Greater exploration of additional covariates, such as genetic and lifestyle factors, is necessary to fully elucidate the complex relationship between reproductive history and endometrial cancer risk. Investigating the biological mechanisms underlying the protective effects of pregnancy and the increased risk associated with prolonged intervals since last birth will provide more comprehensive insights into preventive strategies.
Supporting information
S1 Fig. Sensitivity analysis of the risk of endometrial cancer of 0–10 years since last birth.
https://doi.org/10.1371/journal.pone.0325907.s001
(DOCX)
S2 Fig. Sensitivity analysis of the risk of endometrial cancer of 10–20 years since last birth.
https://doi.org/10.1371/journal.pone.0325907.s002
(DOCX)
S3 Fig. Sensitivity analysis of the risk of endometrial cancer of above 20 years since last birth.
https://doi.org/10.1371/journal.pone.0325907.s003
(DOCX)
S1 Table. The quality assessment of cohort and case-control studies.
https://doi.org/10.1371/journal.pone.0325907.s004
(DOCX)
S2 Table. The numble table of all studies identified in the literature search.
https://doi.org/10.1371/journal.pone.0325907.s005
(DOCX)
S3 Table. All data extracted from the primary research sources.
https://doi.org/10.1371/journal.pone.0325907.s006
(DOCX)
S1 File. Search strategy in different databases.
https://doi.org/10.1371/journal.pone.0325907.s007
(DOCX)
Acknowledgments
The datasets presented in this study can be found in the article and supplementary. GJ and WLP conceived the study.
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