Factors associated with fertility abnormalities in women with systemic lupus erythematosus: a systematic review and meta-analysis

Background: Fertility is thought to be not affected in women with systemic lupus erythematosus (SLE), however disease-related factors, psychosocial effects of chronic disease, as well as medications exposure might impair gonadal function. Objective: This systematic literature review (SLR) aimed to explore clinical, hormonal, serological and treatment factors associated with fertility outcomes in women of childbearing age with SLE. Methods: This SLR was conducted following the Preferred Reporting Items for systematic reviews and Meta analysis (PRISMA) statement. All articles available in English (1972 30th April 2021) in Pubmed, EMBASE, Scopus and Cochrane Library were screened. Studies selection and data collection were performed by two independent reviewers. All data were extracted using a standardized template. The risk of bias of the included studies was assessed using the NIH risk-of-bias tool. Results: Of 789 abstracts evaluated, we included in this review 46 studies, of which 1 SLR, 16 cross-sectional studies, 18 cohort studies, 10 observational studies and 1 case-series, with data pertaining to 4704 patients (mean age 31.5 +/- 3.7 years, disease duration 83.27 +/- 38.3 months). Definitions of premature ovarian failure (POF) adopted in the studies varied in terms of the number of months of amenorrhea considered and the age of onset of amenorrhea. Clinical factors associated with the development of POF were older age at the time of initiation of therapy, and older age at the onset of SLE disease. Cyclophosphamide exposure (CYC) and its cumulative dose influenced gonadal function in SLE women, leading to amenorrhoea and POF, as reported in 19 studies. Mycophenolate, azathioprine, calcineurin inhibitors and steroids associated with a lower risk of POF compared to CYC. POF was less frequent in patients co-treated with CYC and gonadotropin-releasing hormone analogues (GnRH-a) compared with patients not receiving GnRH-a (risk ratio 0.28, 95%-CI [0.14; 0.55]). 11 studies evaluated the impact of damage accrual and disease activity on ovarian reserve with conflicting evidence. Finally, 18 studies investigated exposure to hormonal and serological factors and, among others, neither antiMullerian Hormone nor anti-corpus luteum antibodies were associated with POF. Conclusion: The strongest evidence regarding management factors associated with fertility in SLE women of childbearing age remains the treatment with CYC, as well as its cumulative dosage. Hormonal and serological factors appeared not to impact fertility outcomes, but they might be used as a surrogate of fertility, especially during the treatment with disease-specific drugs.