Menstrual irregularity, pregnancy outcomes, and birth outcomes in patients with systemic lupus erythematosus of childbearing age in China: a multicenter cross-sectional study

To the Editor: Systemic lupus erythematosus (SLE) is an autoimmune disease that tends to affect females of childbearing age. There are nearly 4 million people in China currently suffering from SLE, which can cause multiple organ damage in its early stages and seriously affect patients’ quality of life.[1,2] Menstrual disorders are common in SLE patients and vary from heavy menstrual bleeding to amenorrhea. The etiology of menstrual irregularities includes the disease activity itself, glucocorticoids (GCs) treatment, and the use of some immunosuppressants.[3] This multicenter, cross-sectional, web-based observational study investigated menstrual irregularity, pregnancy outcomes, and birth outcomes on SLE patients across China. The research was approved by the Ethics Committee of Peking University People's Hospital, China (No. 2019PHB253-01). The patients were informed that consent was implied with completion of the questionnaire, and the process was anonymous and voluntary. A total of 3964 SLE female patients ranging in age between 15 years and 49 years were recruited from 157 hospitals across China [Supplementary Figure 1, https://links.lww.com/CM9/B404]. The patients answered the standardized questionnaire via email or text message under the guidance of a rheumatologist over the phone. Clinical data were collected through questionnaires [Supplementary Materials, https://links.lww.com/CM9/B404], including basic features, menstruation after diagnosis, medications, marriage and fertility status, reproductive history, adverse pregnancy outcomes (APO), and adverse birth outcomes (ABO). The categorized variables were shown as frequency or percentage, and continuous variables were demonstrated as mean ± standard deviation. The Mann–Whitney and chi-squared tests were used to determine any statistical difference between the means and proportions of the two groups. The variables were tested for normality and homogeneity of variance before the Mann–Whitney and chi-squared tests were carried out. Univariate and multivariate logistic regression analyses were used to assess associations between clinical characteristics and menstruation, pregnancy, and neonatal outcomes. A 95% confidence interval (CI) was calculated to identify the independent variable in the binary logistic regression analysis. Differences were considered statistically significant when P < 0.05. Statistical Package for Social Sciences (SPSS 26.0, IBM Corp, Armonk, NY, USA) was used to analyze all data. The mean age of the participants was 30.42 ± 7.40 years. Of these patients, 75.55% experienced menstrual disorders, including light menstrual bleeding (48.99%), shortened menstrual bleeding (23.31%), prolonged menstrual bleeding (13.65%), amenorrhea (10.85%), and heavy menstrual bleeding (7.11%). The proportions of GCs, cyclophosphamide (CYC), and mycophenolate mofetil (MMF) in these patients were 55.17%, 27.22%, and 28.58%, respectively. The percentage of CYC in combination with GC and GC with MMF was 24.09% and 20.51%, respectively. Compared with patients who experienced normal menstruation, patients experiencing abnormal menstruation were older (31.17 ± 7.59 vs. 28.12 ± 6.25 years, P < 0.001), had a higher average body mass index (BMI) (21.69 ± 3.32 vs. 21.32 ± 3.46 kg/m2, P = 0.003), and experienced a longer disease duration (6.28 ± 5.49 vs. 5.38 ± 4.72 year, P < 0.001). The treatment of CYC (37.67% vs. 21.88%, P < 0.001), GCs (75.84% vs. 51.56%, P < 0.001), and MMF (39.67% vs. 21.35%, P < 0.001) were all significantly higher in patients with abnormal menstruation [Supplementary Table 1, https://links.lww.com/CM9/B404]. Binary logistic regression demonstrated that older patients (Odds ratio [OR]: 1.039, 95% CI: 1.016–1.062, P = 0.001), longer disease duration (OR: 1.041, 95% CI: 1.004–1.079, P = 0.029), CYC treatment (OR: 1.830, 95% CI: 1.273–2.630, P = 0.001), and GCs treatment (OR: 2.721, 95% CI: 2.008–3.686, P < 0.001) were independently related to menstrual disorders [Figure 1].Figure 1: Risk factors of menstrual disorders. ∗P < 0.05. BMI: Body Mass Index; CI: Confidence interval; CYC: Cyclophosphamide; GCs: Glucocorticoids; MMF: Mycophenolate Mofetil; SLE: Systemic lupus erythematosus.Among subjects with pregnancy history, the incidence of preterm delivery, miscarriage, fetal growth restriction, placental abruption, and hypertensive disease of pregnancy was 14.05%, 9.95%, 7.87%, 4.40%, and 2.26%, respectively [Supplementary Table 2, https://links.lww.com/CM9/B404]. There were no significant differences in age (34.83 ± 6.71 vs. 34.50 ± 6.61 years, P = 0.326), BMI (22.11 ± 3.18 vs. 22.21 ± 3.40 kg/m2, P = 0.558), disease duration (6.43 ± 5.37 vs. 6.06 ± 5.03 years, P = 0.146), history of CYC treatment (39.46% vs. 40.27%, P = 0.770), GCs treatment (73.70% vs. 72.86%, P = 0.739), or history of MMF treatment (38.00% vs. 35.15%, P = 0.295) between patients with and without APO [Supplementary Table 3, https://links.lww.com/CM9/B404]. Of the 1250 births in women, 70.48% were full-term normal births, 19.44% were born prematurely, 8.96% were small for gestational age neonates, 7.76% had neonatal pathological jaundice, and 1.44% had neonatal lupus. Patients in the ABO group were younger (32.59 ± 5.57 vs. 34.73 ± 6.52 years, P < 0.001) and experienced longer disease duration (7.53 ± 5.66 vs. 6.18 ± 5.02 years, P < 0.001) than patients without ABO. History of CYC treatment (24.39% vs. 48.03%, P < 0.001), GCs treatment (48.79% vs. 100%, P < 0.001), and MMF treatment (16.80% vs. 52.49%, P < 0.001) were significantly lower in the ABO group [Supplementary Table 4, https://links.lww.com/CM9/B404]. Binary logistic regression demonstrated that age (OR: 0.951, 95% CI: 0.912–0.991, P = 0.017) might be a protective factor associated with ABO. We conducted a large, cross-sectional study that investigated menstrual irregularity, pregnancy outcomes, and birth outcomes in SLE patients in China, and the results revealed that >75% of SLE patients experienced menstruation irregularity. Risk factors for menstrual irregularity included age, CYC treatment, and GCs treatment. This study found that age, BMI, disease duration, and treatment were not significantly associated with APO. The CYC, MMF, and GCs treatment may be associated with a low prevalence of ABO. Menstrual irregularity is common in SLE patients. In this study, nearly 50% of the patients experienced light menstrual bleeding, >20% of patients experienced shortened menstrual bleeding, and 10% experienced amenorrhea. This is consistent with previous studies.[4,5] Additionally, premature ovarian failure is associated with specific SLE-related autoantibodies (anti-Sm, anti-RNP, anti-cardiolipin, and lupus anticoagulant) and the use of immunosuppressants, particularly the use of CYC.[6,7] This study indicates that CYC treatment might be a risk factor for menstrual irregularity. Women with SLE have poorer maternal-fetal outcome compared with healthy individuals.[8] The rate of fetal loss has ranged from 3% to 43%. The rate of fetal loss in SLE pregnancies has decreased from an average of 43% to 17% over the past 40 years.[9] Disease flares, pregnancy loss, preeclampsia, preterm delivery, and intrauterine growth restrictions remain the primary complications during pregnancy.[10] This study has some limitations. It is a cross-sectional observational study that is unable to identify a clear cause–effect relationship. Additionally, the questionnaire could result in time, selection, recall, and reporting bias. At the same time, the timing of medication administration was unclear, which was a limitation of our study. However, this study included a large number of multicenter SLE patients, which helped avoid selection bias. Despite these limitations, the results of our study represent the current status of SLE patients in China. In conclusion, female SLE patients of childbearing age have a high proportion of menstrual abnormalities, APO, and ABO. Acknowledgements We would like to thank all the rheumatologists, gynecologists, and patients that participated in this study. We were especially grateful to an out-of-hospital patient management platform called “MIJIAN.” Funding This study was supported by grants from the research project from the Beijing Natural Science Foundation (No. 7192211) and China International Medical Foundation (No. Z-2018-40-2101).