Rheumatic diseases are more common in females in their reproductive years. Pregnancy is a significant factor that can influence and be influenced by rheumatic diseases, including systemic lupus erythematosus (SLE), antiphospholipid antibody syndrome (APS), rheumatoid arthritis (RA), and Sjogren’s syndrome (SS) (El Miedany and Palmer, 2020). Pregnancy can potentially jeopardize both the health of the mother and the unborn child by worsening whatever rheumatic ailment the woman currently has as well as by causing fetal adverse events. Examples include recurrent spontaneous abortion in the first trimester, fetal death in the last trimester, fetal growth restriction, thrombocytopenia, preeclampsia, and eclampsia. Both the European League Against Rheumatism and the American College of Rheumatology concur that ensuring appropriate utilization of pregnancy-compatible antirheumatic drugs is imperative for attaining a satisfactory pregnancy outcome in women with rheumatic diseases (Götestam Skorpen et al., 2016; Sammaritano et al., 2020). Therefore, it is critical to continue taking rheumatic diseases medications and to understand the variety of medications that can be used to treat rheumatic diseases while pregnant (Pacini et al., 2020). At present, recommendations for safe therapeutic medications for rheumatic diseases during pregnancy have been given by guidelines from both China and abroad (Birru Talabi and Clowse, 2020; Zhang et al., 2021). Some drugs such as glucocorticoids, immunosuppressive agents, low molecular weight heparins (LMWHs), non-steroidal anti-inflammatory drugs (NSAIDs), tumor necrosis factor inhibitors (TNFi), and intravenous immunoglobulin (IVIG) can be appropriate for use during pregnancy complicated by rheumatic diseases.

The medication’s effectiveness is impacted by many factors during pregnancy, including early-pregnancy nausea and vomiting, late-pregnancy frequent urination, and changes in the body’s hormone levels. Furthermore, pregnant women are also psychologically more likely to experience negative feelings including stress, worry, sensitivity, and despair. Patients frequently have worries about the safety of medications and have poor compliance due to the specific physiological and psychological characteristics of women during pregnancy. Clinical pharmacists in hospitals should increase patient medication adherence by logical drug use promotion and enhance drug efficacy and safety monitoring. At the same time, they need to keep an eye on adverse drug reactions and drug-drug interactions, provide timely pharmacological advice to physicians and patients, and improve the level of rational drug use (Zhang et al., 2019). For example, the risk of miscarriage increases with the use of NSAIDs in the first trimester, and they should be avoided in the last stages of pregnancy because they may result in the premature closure of the fetal ductus arteriosus (Koren et al., 2006; Brouwer et al., 2015). Relatively low doses of glucocorticoids (e.g., prednisone less than 10 mg or equivalent) administered orally, intra-articularly, or intramuscularly have a better safety profile during pregnancy. However, taking more than 20 mg of prednisone per day may result in premature birth and fetal orofacial clefts (Birru Talabi and Clowse, 2020).

In this study, we statistically analyzed the use of therapeutic drugs for rheumatic diseases during pregnancy in nine Chinese cities from 2016 to 2021. We aimed to comprehensively describe the real-world prescription patterns among patients with rheumatic diseases during pregnancy by using national multi-center data sources, with a focus on comprehending patient characteristics and the trends in therapeutic drug use, in order to provide a reference for the development of rational use of clinical drugs, monitoring techniques and scientific diffusion.

The incidence of rheumatic diseases is relatively high during pregnancy, and pregnancy and rheumatic diseases affect each other. Rheumatic diseases can easily lead to infertility, miscarriage, premature birth, and other adverse pregnancy outcomes, and pregnancy also aggravates rheumatic diseases. Therefore, long-term drug therapy to maintain disease stability is particularly important for improving the quality of life for pregnant women (Østensen et al., 2015; Giles et al., 2019). Based on statistical data, we analyzed real-world trends in medication for pregnancy complicated by rheumatic diseases in nine cities from China over the 6 years.

The prevalence of rheumatic diseases is higher between the ages of 15 and 50, and to investigate the relationship between age and disease in demographic characteristics, we divided the age of patients in the prescription data into five groups: 20 to < 25, 25 to < 30, 30 to <35, 35 to < 40, and ≥ 40 years (Borchers et al., 2010). Notably, the proportion of patients aged 35 to <40 years gradually increased to more than double during the study period from 2016 to 2021. This phenomenon was likely to be related to the comprehensive “two child policy” issued by China in October 2015 and to the fact that the number of older pregnant women has also been increasing annually (Li et al., 2019). In addition, SLE and APS are the two prevalent rheumatic diseases observed in pregnant women, which is consistent with the epidemiological studies (Mekinian et al., 2015; Pons-Estel et al., 2017). Our analysis results showed that the number of prescriptions for pregnancy complicated by rheumatic diseases increased yearly. This may imply that the prevalence or visiting rates of pregnant patients with rheumatic diseases increased over time. In terms of drug therapy, traditional antirheumatic drugs such as glucocorticoids, LMWHs, and immunosuppressive agents were the most popular drugs.

LMWHs can reduce the risk of pregnancy complications, including unexplained recurrent pregnancy loss, fetal death, and intrauterine growth restriction (Satta and Biondi, 2019; Schreiber and Hunt, 2019). Dalteparin sodium, enoxaparin sodium, and nadroparin calcium are regarded as basic therapeutic drugs that meet the health requirement of patients. In particular, there are clear beneficial effects of LMWHs combined with low-dose aspirin for rheumatic diseases during pregnancy (Fernandes et al., 2020). Low-dose aspirin, which is a classic representative drug of NSAIDs, can not only be used in patients with APS but also protects SLE patients from hypertensive diseases during pregnancy (Hoffman et al., 2020). Interestingly, a retrospective study revealed that NSAIDs use in the first trimester may raise the incidence of abortion and malformations (Li et al., 2018), with the exception of low-dose aspirin. Aspirin is being used more frequently in clinic, and our analysis of the data indicated that its DDDs climbed to second place in 2021.

Glucocorticoids are classic antirheumatic drugs that have been used clinically for a long time. A number of management standards and practices for pregnancy complicated by rheumatic diseases from China and abroad recommend glucocorticoids as a class of major antirheumatic drugs (Flint et al., 2016a; Flint et al., 2016b; Götestam Skorpen et al., 2016; Zhang et al., 2021). Pregnancy may be considered in women with rheumatic diseases who use no more than 10 mg of prednisone daily to maintain the stability of the disease. If disease activity increases during pregnancy, we can consider appropriately increasing the dosage of glucocorticoids or combining them with relatively safe immunosuppressive agents (Zhang et al., 2021). Recently, hydroxychloroquine has been explored as a widely used immunosuppressive agents that stabilizes the endothelium and has antithrombotic effects (Misra et al., 2020). Its continuous use is generally advised during pregnancy to enhance disease protection and improve pregnancy outcomes (Sammaritano et al., 2020). Sulfasalazine and azathioprine are also widely used for rheumatic diseases during pregnancy (Viktil et al., 2012; Flint et al., 2016a). These drugs are considered relatively safe when used as directed. For example, sulfasalazine may be used at a dosage of less than 2 g/d together with folic acid (5 mg/d) supplementation throughout the whole period of pregnancy (2019). In addition, the lowest effective dose of tacrolimus or ciclosporin can be used during pregnancy and has not been associated with fetal malformation. However, it is necessary to perform increased monitoring of the patient’s own indicators, such as blood pressure, kidney function, and blood drug concentration (Zhang et al., 2021).

TNFi and IVIG were gradually more widely used in the clinic in 2019–2021. Owing to the high economic cost of these drugs, as evidenced by their DDC being significantly higher than that of glucocorticoids, LMWHs, immunosuppressive agents, and NSAIDs, their DDDs were much lower than those of traditional antirheumatic drugs and had lower acceptance from patients. A clinical study showed that there was no increase in adverse events during pregnancy after IVIG administration (Flint et al., 2016a), suggesting that it can be safely used to treat rheumatic diseases during pregnancy. However, the correlation between TNFi and adverse events during pregnancy has been inconsistent among different reports. On one hand, previous studies have shown that TNFi can be used during early pregnancy without increasing the incidence of adverse pregnancy events and neonatal infections (Diav-Citrin et al., 2014). Etanercept and pexelizumabare, characterized by low placental transport rates, are also considered to be safe throughout pregnancy (Götestam Skorpen et al., 2016). Current evidence suggests that exacerbations in RA patients during pregnancy is significantly associated with refraining from TNFi treatment upon positive pregnancy tests. Therefore, considering the risk of disease onset and adverse pregnancy outcomes, it is recommended to continue TNFi treatment during pregnancy (Gerardi et al., 2022). On the other hand, it has also been reported that the use of TNFi during pregnancy is likely to carry some risks, and it has been recommended that the use of TNFi be stopped for at least 12 weeks before pregnancy (Carter et al., 2009). Notably, a growing number of plant drugs have gradually become the choice for the treatment of pregnancy complicated by rheumatic diseases; these include total glucosides of paeony and the compound glycyrrhizin. Some individual patients who were diagnosed with pregnancy complicated by rheumatic diseases did not choose ongoing pregnancy owing to special circumstances, and they were eventually exposed to drugs classified as category X by the United States Food and Drug Administration, such as methotrexate and mycophenolate mofetil. To summarize, the types of prescription drugs we extracted from the prescription data conform to the selection scope of drugs for the treatment of pregnancy complicated by rheumatic diseases recommended by guidelines from China and abroad.

As the number of prescriptions for pregnancy complicated by rheumatic diseases increased annually from 2016 to 2021, the total sample prescription costs also increased. However, the average prescription cost decreased from 2016 to 2018, reaching the lowest level in 2018, and this may be related to the update of the medical insurance catalogue and the implementation of canceling the drug price addition in China (National Health Commission of the People’s Republic of China, 2017).

There were a few limitations in our study. Firstly, the research prescription data were randomly chosen within 10 business days of each quarter, and given that the prescriptions we analyzed were from municipalities or provincial capitals in China, some economically depressed regions may have varied prescription patterns due to varying medical and economic issues. As a result, our study might not accurately represent the state of medication use among pregnant Chinese women with rheumatic diseases as a whole. Secondly, our analysis was conducted based on prescription data which only mentioning “pregnancy” and “systemic lupus erythematosus” or “antiphospholipid antibody syndrome” or “Sjogren’s syndrome” or “rheumatoid arthritis” in the diagnostic information. Consequently, some prescriptions of outpatients with rheumatic diseases of pregnancy might be excluded due to their diagnostic information not matching the above search terms. Thirdly, limited information on prescription data and lack of patient medical history limited the evaluation of rationality. Finally, our study was based on outpatient sampling prescriptions, and pregnancy outcomes and neonatal follow-up of pregnant women with rheumatic diseases were lacking. In the future, further collecting prescription samples with more complete information and wider geographical coverage is necessary, and further investigations are indispensable to analyze the correlation between the efficacy of drugs and their possible adverse side effects. In addition, the specific usage and dosage information of each patient should be accurate, as well as the safety and rationality of medication should be evaluated in combination with the pregnancy outcome of pregnant patients and relevant guidelines.

Our results revealed firstly the prescription patterns of pregnant women with rheumatic diseases over the last 6 years in China. The number and total cost of prescriptions for pregnancy complicated by rheumatic diseases in nine cities increased yearly from 2016 to 2021. Traditional drugs such as glucocorticoids, LMWHs, and hydroxychloroquine are the most frequently choices for pregnant patients with rheumatic diseases in China due to their apparent efficacy and cost-effectiveness. Significantly, the high cost of IVIG and TNFi may be one factor in the lower use of them compared with conventional therapeutic drugs, but they also play a role in treating rheumatic diseases of pregnancy that cannot be substituted by other drugs. In order to maximize therapeutic effect of IVIG and TNFi, we should always pay attention to the patient’s condition, although the current experimental data suggest that these drugs are deemed safe for pregnant women.