Objective: To explore the contribution of female hormonal factors occurring prior to the onset of rheumatoid arthritis (RA), such as age at menarche, parity, age at first birth, breast-feeding, use of oral contraceptives (OCs), irregular menstrual cycles, and postmenopausal hormone (PMH) use, to the subsequent development of RA in a large female cohort.
Methods: We studied female reproductive and hormonal risk factors for RA in a cohort of 121,700 women enrolled in the longitudinal Nurses' Health Study. The diagnosis of incident RA (between 1976 and 2002) in 674 women was confirmed by a connective tissue disease screening questionnaire and blinded medical record review for American College of Rheumatology criteria. Sixty percent of the patients with RA were rheumatoid factor positive. The relationship between potential risk factors, including age, age at menarche, parity, age at first birth, total lifetime history of breast-feeding, use of OCs, and irregular menstrual cycles and the multivariate-adjusted risk of RA was estimated using Cox proportional hazards models.
Results: Using a multivariate model that adjusted for age, body mass index, smoking, parity, and other hormonal factors, we observed a strong trend for decreasing risk of RA with increasing duration of breast-feeding (P for trend = 0.001). For women who breast-fed (compared with parous women who did not breast-feed), the risk ratios (RRs) and 95% confidence intervals (95% CIs) were as follows: breast-feeding for < or =3 total months, RR 1.0 (95% confidence interval [95% CI] 0.8-1.2); for 4-11 total months, RR 0.9 (95% CI 0.7-1.1); for 12-23 total months, RR 0.8 (95% CI 0.6-1.0); and for > or =24 total months, RR 0.5 (95% CI 0.3-0.8). Very irregular menstrual cycles were associated with an increased risk of RA (RR 1.4, 95% CI 1.0-2.0). Age at menarche < or =10 years was associated with an increased risk of seropositive RA (RR 1.6, 95% CI 1.1-2.4) but not significantly associated with risk of RA. Parity, total number of children, age at first birth, and OC use were not associated with an increased risk of RA in this cohort.
Conclusion: In this large cohort, breast-feeding for >12 months was inversely related to the development of RA. This apparent effect was dose-dependent, with a significant trend toward lower risk with longer duration of breast-feeding. Irregular menstrual cycles and earlier age at menarche increased the risk of RA. Other reproductive hormonal factors were not associated with RA risk.