Reproductive Factors and Risk of Systemic Lupus Erythematosus: Nationwide Cohort Study in Denmark

Objective. The female predominance in systemic lupus erythematosus (SLE) suggests the possible involvement of reproductive factors in its etiology. We evaluated the relationship between parity and pregnancy losses and subsequent risk of SLE in a population-based cohort study. Methods. We followed 4.4 million Danes aged 15–69 years for first inpatient hospitalizations for SLE between 1977 and 2004. As measures of relative risk, we used Poisson regression-derived hospitalization rate ratios (RR) with 95% confidence intervals (CI) for cohort members with different reproductive histories. Results. Overall, 1614 women and 274 men were hospitalized with SLE during 88.9 million person-years of followup. Number of children was unrelated to SLE risk in men, but women with at least one liveborn child were at lower risk than nulliparous women (RR 0.74; 95% CI 0.64–0.86), and women with 2 or more children were at lower risk than 1-child mothers. Recurrent idiopathic pregnancy losses, including spontaneous abortions, missed abortions, and stillbirths, were associated with markedly increased SLE risk (RR 3.50; 95% CI 2.38–4.96, for 2+ vs none; p < 0.001). Conclusion. Nulliparous women, 1-child mothers, and women who experience spontaneous abortions, missed abortions, or stillbirths are at increased SLE risk. Theoretically, immunological processes involved in subfertility or idiopathic pregnancy losses might act as initiating or contributing factors in some cases of SLE. However, considering the well established excess of pregnancy complications in women with established SLE, the observed associations more likely reflect the effect of subclinical immunological processes in women destined to develop SLE.