Reproductive Shifts and Ovarian Cancer Risk in Women Aged 40 Years or Older

Reproductive factors are associated with ovarian cancer risk, but their influence may differ across menopausal status and birth cohorts.

To examine the associations between reproductive factors and ovarian cancer risk stratified by menopausal status and birth cohort.

This nationwide population-based cohort study obtained data from the National Health Insurance Service (NHIS), a single-payer system covering 97% of the population in South Korea. Women aged 40 years or older who underwent NHIS health screening in 2009 and had reproductive, clinical, and other data were included and followed up until ovarian cancer diagnosis, death, or December 31, 2022. Data were analyzed in March 2025.

Age at menarche, parity, breastfeeding duration, oral contraceptive use, age at menopause, total reproductive span, and hormone replacement therapy use.

Incident ovarian cancer identified from NHIS claims with International Statistical Classification of Diseases and Related Health Problems, Tenth Revision codes C56, C57, and C48 and confirmed through the Rare/Intractable Disease Registry (code V193). Cox proportional hazards regression models estimated hazard ratios (HRs) and 95% CIs.

A total of 2 285 774 women (932 637 [40.8%] premenopausal, 1 353 137 [59.2%] postmenopausal; mean [SD] age, 54.9 [10.85] years) were included in the final analytic cohort. The mean (SD) follow-up duration overall was 10.7 (2.99) years, and 10 729 ovarian cancer cases were identified during follow-up. Early menarche (aged ≤12 vs >16 years) was associated with higher ovarian cancer risk in both premenopausal women (HR, 1.37; 95% CI, 1.16-1.61) and postmenopausal women (HR, 1.24; 95% CI, 1.00-1.54). Parity of 2 or more births was associated with lower risk in both groups (HR, 0.68 [95% CI, 0.58-0.79] and 0.71 [95% CI, 0.60-0.85]). Breastfeeding for 12 months or longer and oral contraceptive use for 1 year or longer were associated with lower risk in premenopausal women but not postmenopausal women (HR, 0.86 [95% CI, 0.77-0.96] and 0.75 [95% CI, 0.61-0.93]). Among postmenopausal women, later menopause (at age ≥55 years; HR, 1.36 [95% CI, 1.11-1.66]), longer reproductive span (≥40 years; HR, 1.21 [95% CI, 1.09-1.34]), and hormone replacement therapy use for 2 to 5 years (HR, 1.20 [95% CI, 1.07-1.34]) were associated with higher risk. Parity-related risk reduction was attenuated in the 1960s birth cohort (HR, 1.07; 95% CI, 0.52-2.19; P for interaction = .36).

This cohort study found that reproductive factors were associated with ovarian cancer risk, with distinct patterns across menopausal status and birth cohorts. These findings highlight the need for tailored prevention strategies in aging, low-fertility populations.