Background
Global declines in fertility and widespread postponement of childbearing represent major demographic shifts with important implications for women’s cancer burden. Reproductive factors such as parous status, parity, and age at first birth have been associated with the risk of several cancers, yet existing evidence remains fragmented, largely cancer-site specific, and seldom evaluated within a unified dose–response framework across tumour subtypes. A comprehensive synthesis is needed to clarify the magnitude, direction, and shape of these associations to inform cancer prevention in the context of ongoing fertility transitions.
Objectives
To systematically evaluate the associations of parous status, parity, and age at first birth with the risk of female cancers across multiple cancer sites and tumour subtypes, and to characterise potential linear and non-linear dose–response relationships.
Methods
We conducted a systematic review and dose–response meta-analysis following PRISMA 2020 guidelines and a prespecified PROSPERO protocol. PubMed and Embase were searched from inception to 18 November 2024 for cohort and case–control studies examining associations between reproductive history (parous status, parity, or age at first birth) and incident cancers among adult women. Cancer outcomes were harmonised using the WHO Global Health Estimates 2021 classification. Random-effects models were used to pool relative effect estimates. Dose–response relationships were assessed using linear, quadratic, and restricted cubic spline models, with model selection guided by the Akaike Information Criterion. Study quality was evaluated using the Newcastle–Ottawa Scale, and certainty of evidence was assessed using the GRADE framework.
Results
A total of 123 studies involving approximately 18.75 million women were included, covering 17 cancer sites and seven tumour subtypes. Compared with nulliparous women, ever-parous women had a lower risk of breast cancer (effect size [ES] 0.79, 95% CI 0.68–0.91) and a higher risk of kidney cancer (ES 1.21, 95% CI 1.01–1.46), with no significant associations observed for corpus uteri, colorectal, ovarian, bladder, lymphoid, or thyroid cancers.
Dose–response analyses showed consistent protective associations with increasing parity. Each additional live birth was associated with reduced risks of breast cancer (ES per birth 0.93, 95% CI 0.88–0.98), ovarian cancer (ES 0.86, 95% CI 0.74–0.97), endometrial cancer (ES 0.71, 95% CI 0.58–0.86), and lung cancer (ES 0.79, 95% CI 0.68–0.93). No harmful dose–response associations with parity were identified for any cancer site.
Later age at first birth was linearly associated with increased risks of breast cancer (ES per year 1.03, 95% CI 1.02–1.04) and melanoma and other skin cancers (ES 1.03, 95% CI 1.01–1.04). Restricted cubic spline analyses identified significant non-linear associations for endometrial cancer (U-shaped; p for non-linearity = 0.045; highest risk at approximately age 21) and thyroid cancer (U-shaped; p = 0.034; lowest risk at approximately age 24). Subtype-specific analyses demonstrated a reduced risk of epithelial ovarian cancer among parous women (ES 0.54, 95% CI 0.35–0.83) and an increased risk of triple-negative breast cancer (ES 1.34, 95% CI 1.04–1.72).
?Conclusions
By integrating large-scale evidence synthesis with a life-course, dose–response approach, these findings support innovative and equitable cancer prevention strategies that can inform risk stratification across populations undergoing diverse fertility transitions.
Global declines in fertility and widespread postponement of childbearing represent major demographic shifts with important implications for women’s cancer burden. Reproductive factors such as parous status, parity, and age at first birth have been associated with the risk of several cancers, yet existing evidence remains fragmented, largely cancer-site specific, and seldom evaluated within a unified dose–response framework across tumour subtypes. A comprehensive synthesis is needed to clarify the magnitude, direction, and shape of these associations to inform cancer prevention in the context of ongoing fertility transitions.
Objectives
To systematically evaluate the associations of parous status, parity, and age at first birth with the risk of female cancers across multiple cancer sites and tumour subtypes, and to characterise potential linear and non-linear dose–response relationships.
Methods
We conducted a systematic review and dose–response meta-analysis following PRISMA 2020 guidelines and a prespecified PROSPERO protocol. PubMed and Embase were searched from inception to 18 November 2024 for cohort and case–control studies examining associations between reproductive history (parous status, parity, or age at first birth) and incident cancers among adult women. Cancer outcomes were harmonised using the WHO Global Health Estimates 2021 classification. Random-effects models were used to pool relative effect estimates. Dose–response relationships were assessed using linear, quadratic, and restricted cubic spline models, with model selection guided by the Akaike Information Criterion. Study quality was evaluated using the Newcastle–Ottawa Scale, and certainty of evidence was assessed using the GRADE framework.
Results
A total of 123 studies involving approximately 18.75 million women were included, covering 17 cancer sites and seven tumour subtypes. Compared with nulliparous women, ever-parous women had a lower risk of breast cancer (effect size [ES] 0.79, 95% CI 0.68–0.91) and a higher risk of kidney cancer (ES 1.21, 95% CI 1.01–1.46), with no significant associations observed for corpus uteri, colorectal, ovarian, bladder, lymphoid, or thyroid cancers.
Dose–response analyses showed consistent protective associations with increasing parity. Each additional live birth was associated with reduced risks of breast cancer (ES per birth 0.93, 95% CI 0.88–0.98), ovarian cancer (ES 0.86, 95% CI 0.74–0.97), endometrial cancer (ES 0.71, 95% CI 0.58–0.86), and lung cancer (ES 0.79, 95% CI 0.68–0.93). No harmful dose–response associations with parity were identified for any cancer site.
Later age at first birth was linearly associated with increased risks of breast cancer (ES per year 1.03, 95% CI 1.02–1.04) and melanoma and other skin cancers (ES 1.03, 95% CI 1.01–1.04). Restricted cubic spline analyses identified significant non-linear associations for endometrial cancer (U-shaped; p for non-linearity = 0.045; highest risk at approximately age 21) and thyroid cancer (U-shaped; p = 0.034; lowest risk at approximately age 24). Subtype-specific analyses demonstrated a reduced risk of epithelial ovarian cancer among parous women (ES 0.54, 95% CI 0.35–0.83) and an increased risk of triple-negative breast cancer (ES 1.34, 95% CI 1.04–1.72).
?Conclusions
By integrating large-scale evidence synthesis with a life-course, dose–response approach, these findings support innovative and equitable cancer prevention strategies that can inform risk stratification across populations undergoing diverse fertility transitions.
Main Result of Parity and Age at First Birth in Relation to Female Cancer Risk