In order to promote clinicians to understand the latest advances in rheumatology and immunology and apply them to clinical practice and scientific research, the Department of Rheumatology and Immunology has launched a series of columns called "Rheumatology Forum". This column aims to report the latest research results of outstanding professors in the field of rheumatology and immunology in mainland China, so that clinicians and researchers can understand the frontiers of rheumatological diseases, and help transform the latest research results into clinical practice.
本期医脉通有幸邀请到北京大学第三医院风湿免疫科穆荣教授，分享其在国际权威期刊《Rheumatology（OXFORD）》上发表的一项研究——《Reproductive health in female patients with systemic sclerosis：a cross-sectional study》1。
Expert Profile
Professor Mu Rong
Professor, Department of Rheumatology and Immunology, Peking University Third Hospital, Ph.D. supervisor
Vice Chairman of the Rheumatology and Immunology Branch of the Chinese Women Physicians Association
Vice Chairman of the Rheumatology Committee of the Beijing Association of Integrative Medicine
Member of the Standing Committee of the Rheumatology Branch of the Cross-Strait Special Committee
Executive Director of Beijing Society of Immunology
Co-chair of the Education Committee of the Asia-Pacific Rheumatism Alliance
Background:
Systemic sclerosis (SSc) is a systemic autoimmune disease characterized by skin thickening and hardening, which was included in the first batch of rare diseases in China in 2018. SSc is more common in women and occurs in about 50% of patients of childbearing age. As a systemic disease, SSc can affect internal organs, such as the reproductive system, in addition to affecting the skin. Reproductive health refers to the health status of the reproductive system and its normal physiological functions and processes, and is the core element of human health and an important cornerstone of women's health.
With the aging of the population, it is particularly important to ensure the reproductive rights of women of childbearing age, and the impact of SSc on women's reproductive health is an issue worthy of study. Previous studies have shown secondary hypogonadism in patients with SSc and a poor prognosis in pregnancy outcomes in patients with SSc. However, due to the small sample size of the studies involved and the inconsistent conclusions of the studies, the effects of SSc on reproductive health and related factors need to be further studied.
Objectives:
To explore the effects of SSc on the reproductive health of female patients and related factors.
Research Methods:
A cross-sectional study of female patients with scleroderma in China was conducted by questionnaire survey. Collect data on reproductive health status, including menstruation and fertility. Premature menopause refers to the cessation of menstruation before the age of 40, and premature menopause refers to the last menstrual period between the ages of 40-45. For post-onset pregnancies, each pregnancy was matched to healthy pregnant women of similar age. To analyze the relationship between clinical features and reproductive health status.
Findings:
➤ Baseline characteristics
A total of 342 women with SSc were included in the study, with a mean age of 46 (35,54) years and a median duration of 7 (4, 13) years. Raynaud's phenomenon (296/342, 86.6%), dryness (158/342, 46.2%) and digital ulcers (124/342, 36.2%) were the most common symptoms. Gastrointestinal involvement (220/342, 64.3%) and interstitial lung disease (ILD) (217/342, 63.5%) were the most common visceral lesions. Of the 342 women with SSc, 31.8% (108/342, 95% CI 26.9%-36.7%) had reproductive health problems.
➤ Premature menopause and early menopause are common in patients with SSc
Among the included patients, 164 patients were postmenopausal, and they were divided into premenopausal onset group (n=99, 60.4%) and postmenopausal onset group (n=65, 39.6%) according to the time relationship between onset and menopause.
- Compared with the mean age of menopause in Chinese women,2 the age of menopause was younger in premenopausal onset (45.2±6.1 vs. 48.2±4.4, P<0.001). Among patients with premenopausal onset, the incidence of premature menopause (17/99, 17.2% vs. 4.2%, P<0.001) and early menopause (28/99, 27.3% vs. 11.7%, P<0.001) was higher than in the general population (Figure 1A).
- 单因素分析中，发病年龄早、mRSS评分高、合并钙质沉着（43±8 vs. 46±6，P<0.015）、雷诺现象（RP）（45±6.7 vs. 50.7±7.3，P<0.035）、指端溃疡（DU）（42.3±7.6 vs. 47.3±5，P<0.007）和抗Scl-70抗体阳性（43.1±5.9 vs. 47.9±5.7，P<0.001）的患者绝经年龄较小（图1B-G）。
- Multiple linear regression analysis (F=3.153, P=0.007, adjusted R2=0.252) confirmed that age of onset (P=0.018) and DU (P=0.020) were the influencing factors of menopausal age in SSc patients.
Fig.1 Analysis of menopausal age in patients with SSc
Notes: (A) Incidence of premenopause and premenopause in SSc patients vs. general population, (B-G) Analysis of the relationship between clinical features of SSc and reproductive status, DU, digital ulcers, mRSS, modified Rodnan skin score, RP, Raynaud's phenomenon
➤ The overall reproductive behavior of patients with SSc is affected by the disease
There were significant differences in the proportion of patients with fertility intention (238/298, 79.9% vs. 91/298, 30.5%, P<0.001) and attempted pregnancy (238/238, 100% vs. 69/91, 75.8%, P<0.001).
- Before the onset of the disease, 79.9% (238/298) of the patients had the desire to have children and tried to conceive, 96.2% (229/238) had successful pregnancy, and 3.8% (9/238) were infertile.
- After the onset of the disease, only 30.5% (91/298) of the patients had the desire to have children, and 75.8% (69/91) of the patients had attempted pregnancy. Of these, 88.4% (61/69) had successful pregnancies. 11.6% (8/69) were infertile.
➤ The infertility rate of SSc patients did not increase, and the rate of spontaneous abortion increased
The success rates of 31 patients were 74.2% (23/31) and 70% (22/31) before and after the onset of the disease, respectively, and the difference was not statistically significant (P=0.776). There was no increase in infertility rates in patients in this study compared to previously reported overall infertility rates3 (26/342, 7.6% vs. 15.5%).
In terms of pregnancy outcomes, 61 patients had a total of 84 pregnancies after the onset of the disease, including 10 induced abortions and 9 spontaneous abortions. Compared with national data,4 spontaneous abortion rates were higher in patients with SSc (9/74, 12.2% vs. 4.3%, P<0.001). There was no significant difference in the incidence of gestational hypertension and preeclampsia compared with national data5.
➤ Neonates with SSc have increased rates of preterm birth, low body weight, and cesarean section
All fetal outcomes after the onset of the disease were analysed, and each pregnancy was matched to the control group in a 1:2 ratio. Among the 49 patients with SSc, there were a total of 84 pregnancies, of which 55 were live births. The preterm birth rate in the SSc group (12/55, 21.8% vs. 7/110, 6.4%, P<0.003) and low body weight (15/55, 27.3% vs. 6/110, 5.5%, P<0.001) was significantly higher than that of the control group (Fig. 2A). The risk of low birth weight infants was higher in patients with DU than in patients without DU (11/27, 40.7% vs. 3/22, 13.6%, P=0.037, Figure 2B). Compared with the control group, the cesarean section rate was significantly increased in the SSc group (27/55, 49.1% vs. 21/110, 19.1%, P<0.001, Fig. 2A).
Fig.2 Analysis of neonatal preterm birth, low body weight (LBW) and cesarean section rates in patients with SSc
Conclusions of the study
Impaired reproductive health of women with SSc is common, involving multiple clinical departments, especially in maternal health, and further action should be taken to improve the reproductive health status of SSc patients.
Expert commentary
Autoimmune diseases are more common in women, and it is especially important to pay attention to reproductive health for women with autoimmune diseases. From the perspective of SSc, this study explored the reproductive health status (menopause, fertility) and related factors of women with SSc. The results showed that patients with SSc had a reduced desire to have children, an increased age of menopause, and an increased risk of pregnancy and neonatal complications (including spontaneous abortion, preterm birth, and low birth weight), suggesting that patients with SSc may face additional challenges and risks in terms of reproductive health. However, the infertility rate of patients with SSc did not increase compared with the general population, indicating that these patients can have successful pregnancies.
In terms of menopause in patients with SSc, this study showed that the age of menopause in patients with premenopausal onset was about 2 years earlier than that of the general population, suggesting that SSc may affect gonadal function and make women with SSc experience menopause earlier. Previous studies have also revealed that patients with SSc have decreased ovarian reserve, an increase in the proportion of early menopausal age, and a long course of disease, cyclophosphamide, and prednisone are associated with menopausal age6. According to the results of this study, the early onset of SSc and the earlier correlation between the age of menopause and the early age of menopause in SSc patients with premenopausal onset further support the potential impact of SSc disease itself on gonadal function, and the early onset and severe disease have great damage to gonadal function. At present, the pathological mechanism of early menopause in SSc patients is still unclear and needs to be further explored.
In terms of fertility in women with SSc, this study suggests that SSc may not have a significant effect on fertility in most patients, and it is important to note that disease-related factors are the main reason for the decrease in the number of planned pregnancies after the onset of illness, and more than half of these patients do not receive professional counseling, suggesting that many patients do not receive reproductive health-related education and support. Based on this, health care providers should provide comprehensive reproductive health care and health counselling to all women with SSc and encourage patients to uphold their reproductive rights.
In terms of pregnancy outcomes, women with SSc had higher rates of spontaneous abortion, preterm birth, and low birth weight; Low birth weight infants are at higher risk in patients with DU. Combined with the results of previous clinical studies in women with primary Raynaud syndrome,7 preterm birth and low birth weight infants are associated with vascular pathology, suggesting that more attention needs to be paid to the potential risk of adverse neonatal outcomes and appropriate measures to improve pregnancy outcomes in women with SSc, especially those with DU.
With the increasing demand for fertility from patients and society, reproductive health has attracted more and more attention, and for women of childbearing age with rheumatic diseases, optimizing pregnancy planning, pregnancy and postpartum medical care can help improve the quality of pregnancy and reduce adverse pregnancy outcomes. Rheumatologists and clinicians from other relevant departments should collaborate to enhance reproductive health education and management for patients with rheumatology and musculoskeletal disorders. In addition, clinicians need to share the decision-making process with patients when dealing with reproductive health issues, taking into account the patient's values, preferences, and complications.
Bibliography:
[1] Dai L, Xu D, Li X, et al. Reproductive health in female patients with systemic sclerosis: a cross-sectional study. Rheumatology (Oxford). 2024 Jul 1; 63(7):1911-1916.
[2] Wang M, Gan W, Kartsonaki C et al. Menopausal status, age at natural menopause and risk of diabetes in China: a 10-year prospective study of 300,000 women. Nutr Metab 2022;19:7.
[3] Zhou Z, Zheng D, Wu H et al. Epidemiology of infertility in China: a population-based study. BJOG 2018; 125:432–41.
[4] Liu B, Gao ES. Risk factors for spontaneous abortion of chinese
married women at reproductive age. Chin J Public Health 2002; 18:890–2.
[5] Yang Y, Le Ray I, Zhu J et al. Preeclampsia prevalence, risk factors, and pregnancy outcomes in Sweden and China. JAMA Netw Open 2021; 4:e218401.
[6] Jutiviboonsuk A, Salang L, Eamudomkarn N et al. Prevalence and clinical associations with premature ovarian insufficiency, early menopause, and low ovarian reserve in systemic sclerosis. Clinical Rheumatol 2021; 40:2267–75.
[7] Kahl LE, Blair C, Ramsey-Goldman R, Steen VD. Pregnancy outcomes in women with primary Raynaud’s phenomenon. Arthritis Rheum 1990; 33:1249–55.
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Review: Professor Mu Rong
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