Recurrent spontaneous abortion (RSA), which is classically defined as the occurrence of two or more clinically consecutive pregnancy losses before 20 gestational weeks in fertile couples [
In recent years, Chinese medicines have been accepted as a mainstream of medical care and have become a popular complement to western medicines in the treatment of unexplained recurrent spontaneous abortion patients, with satisfied effect and high safety and reliability [
We reported this systematic review and meta-analysis following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [
All of the random controlled trials (RCTs) examining the effect of Shoutai Pill combined with western medicine for the treatment of unexplained recurrent spontaneous abortion with no limitations on language and publication status were included. Non-RCTs or animal experiments were excluded.
Patients who had been confirmed pregnant by serum human chorionic gonadotropin (HCG) or ultrasound in the first trimester of pregnancy with a diagnosis history of URSA, defined as two or more spontaneous abortions that had ruled out the following four definite etiologies: infections, abnormal parental karyotypes, endocrine disorders, and anatomic abnormality, regardless of maternal age, gestational age, ethnicity, nationality, education, or economic status. The inclusion criteria also stipulated that there had been no treatment given before pregnancy or the entry into the trials. Trials involving recurrent spontaneous abortion with definite etiologies and URSA participants without pregnancy were excluded.
We included studies using the common prescription of Shoutai Pill as a basic formula and modified according to syndrome differentiation meanwhile, regardless of the dose, method of dosing, or duration of administration, in combination with western medicine compared with western medicine excluding bed rest and psychological supports. The western medicine should remain the same in the control group in the same RCT. All the treatments were initiated after the patients were confirmed to be pregnant. If trials included other cointerventions such as acupuncture, acupoint application, and moxibustion, they were excluded.
Primary outcome is the incidence of early pregnancy loss, as defined by the authors. Second outcomes included the incidence of live birth, as defined by the authors, TCM syndromes and symptoms, serum D-dimer level, and incidence of maternal and perinatal adverse events during treatment. Studies without pregnancy outcome reported were excluded.
We systematically conducted electronic searches in the following clinical studies databases: PubMed, Embase, Cochrane Library, Web of Science, China National Knowledge Infrastructure (CNKI), the Chinese BioMedical database (CBM), Chinese Scientific Journals Database (VIP), and the Wanfang database with no limitations on language and publication status for RCTs examining the effect of Shoutai Pill combined with western medicine for the treatment of URSA from inception of each databases through to 31 December 2019. We made the retrieval formula according to the PICOS strategy. The search terms for literature searching were as follows: (“recurrent spontaneous abortion” OR “recurrent miscarriage” OR “habitual abortion” OR “recurrent pregnancy loss” OR “hua tai”) AND (“shou tai pill” OR “shoutai pill” OR “shoutai wan” OR “shou tai wan”) AND (“clinical research” OR “randomized controlled trial” OR “randomization” OR “RCT” OR “random grouping”). We also manually searched the reference lists of all identified articles for possible related studies to supplement the relevant literature.
Two researchers (Hui-fang Li, Qi-hong Shen) extracted the general information of the eligible studies by a predesigned and standardized data extraction form: first author, year of published, TCM syndrome differentiation, sample size, age, gestational age, times of abortions, definition of miscarriage and live birth, intervention time, treatment interventions and control groups, treatment duration, and outcomes. Any conflict was resolved by a third author (Wei-min Chen). The methodologic quality of each individual study was independently evaluated by two researchers (Li Shen, Yi Yang) in reference to the Cochrane Handbook for Systematic Reviews of Interventions. We evaluated using the following criteria: random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessments, incomplete outcome data, selective reporting, and other bias. Each study was classified into low risk, high risk, or unclear. If there was a disagreement, we referred to the views of the third researcher (Wei-min Chen).
The quality of outcome was evaluated by GRADE (Grading of Recommendations Assessment, Development, and Evaluation) according to the following criteria: study design, risk of bias, rating inconsistency in results, rating indirectness of evidence, and others. The quality of evidence was classified as high, moderate, low, or very low.
We conducted this meta-analysis by using Review Manager (RevMan) (computer program) (Version 5.3. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014). Regarding the study outcomes, relative risk (RR) with 95% confidence interval (CI) was used for binary variables, while the weighted mean difference (WMD) and 95% CI were presented for continuous variables. Cochrane’s
Funnel plots and the Egger regression test were performed to examine potential publish bias. In addition, sensitivity analysis was performed by sequentially deleting trials to check the stability of the primary outcomes.
Initially, a total of 794 relevant studies were collected. After excluding duplicate studies, we scanned 562 studies based on their abstracts and titles. Then, 41 articles were evaluated by full text. And 29 trials were eliminated for the following reasons: seventeen non-URSA studies, one study was not RCT, one trial without pregnancy outcome reported, one study included URSA women without pregnancy, one article with mixed interventions, two articles were lacking data, and six studies giving intervention before pregnancy. Eventually, 12 studies were included in our system review. The search process is displayed in Figure
The inclusion process of literature.
The basic information of the included RCTs is summarized in Table
The basic characteristics of the included studies.
First author and year | Sample size ( | Age (y) | Gestational age (d) | TCM syndrome differentiation | Times of abortions ( | Definition of miscarriage | Definition of live birth | Intervention time | Intervention measures | Duration of intervention | Main outcomes |
---|---|---|---|---|---|---|---|---|---|---|---|
Guo 2018 | T: 54 | T: | T: NR | NR | T: | Pregnancy loss before 16 weeks | Delivery of a live infant after 28 weeks | NR | T: modified STP (1/dose/day) + C | Until miscarriage or the 16th weeks | ①②③ |
He 2018 | T: 30 | T: | T: | Kidney deficiency and blood stasis | T: | Pregnancy loss before 12 weeks | Delivery of a live infant after 37 weeks | Pregnancy confirmed by | T: modified STP (1/dose/day) + C | 3 months | ①②③ |
Huang 2016 | T: 31 | T: | T: | Spleen and kidney deficiency | T: | Pregnancy loss before 12 weeks | NR | Pregnancy confirmed by ultrasound | T: modified STP (1/dose/day) + C | 14 days | ① |
Li 2017 | T: 42 | T: | T: | NR | T: | Pregnancy loss before 12 weeks | NR | Pregnancy confirmed by | T: modified STP (1/dose/day) + C | NR | ①③④ |
Lu 2016 | T: 39 | T: | T: | NR | T: | Pregnancy loss before 20 weeks | NR | Pregnancy confirmed by ultrasound | T: modified STP (1/dose/day) + C | Until miscarriage or the 16th weeks | ①⑤ |
Mo 2018 | T: 20 | T: | T: NR | Kidney deficiency and blood stasis | T: | NR | Delivery of a live infant after 37 weeks | Pregnancy confirmed by | T: modified STP (1/dose/day) + C | 7 days for a course of treatment | ②③④ |
Tian 2019 | T: 40 | T: | T: NR | NR | T: | Pregnancy loss before 12 weeks | NR | Pregnancy confirmed by ultrasound | T: STP (1/dose/day) + C | Until miscarriage or more than the 12th weeks | ①③ |
Wang 2016 | T: 75 | T: | T: | NR | T: NR | Pregnancy loss before 12 weeks | NR | Pregnancy confirmed by ultrasound | T: STP (1/dose/day) + C | Until miscarriage or the 12th weeks | ① |
Wei 2017 | T: 30 | T: | T: | Kidney deficiency and blood stasis | T: | Pregnancy loss before 12 weeks | Delivery of a live infant after 37 weeks | Pregnancy confirmed by | T: modified STP (1/dose/day) + C | NR | ①②③④ |
Xie 2016 | T: 36 | T: | T: | Kidney deficiency and blood stasis | T: | Pregnancy loss before 12 weeks | NR | NR | T: modified STP (1/dose/day) + C | 28 days | ①③④⑤ |
Yuan 2015 | T: 40 | T: | T: NR | Kidney deficiency and blood stasis | T: | Pregnancy loss before 12 weeks | NR | Pregnancy confirmed by ultrasound | T: modified STP (1/dose/day) + C | Until miscarriage or the 12th weeks | ①⑤ |
Zheng 2019 | T: 23 | T: | T: NR | NR | T: | Pregnancy loss before 28 weeks | Delivery of a live infant after 28 weeks | NR | T: STP (1/dose/day) + C | Until miscarriage or the 20th weeks | ①②③ |
T: trial group; C: control group; NR: not reported; ①: the incidence of early pregnancy loss; ②: the incidence of live birth; ③: TCM syndromes and symptoms; ④: serum D-dimer level; ⑤: adverse events.
Composition of prescription in the included studies.
References | Prescription | Composition of prescription |
---|---|---|
Guo et al. 2018, [ | Modified STP | Chinese Dodder Seed 15 g, Chinese Taxillus Twig 15 g, Himalayan Teasel Root 10 g, |
He et al. 2018, [ | Modified STP | Chinese Dodder Seed 30 g, Chinese Taxillus Twig 30 g, Himalayan Teasel Root 20 g, |
Huang et al. 2016, [ | Modified STP | Chinese Dodder Seed 20 g, Chinese Taxillus Twig 20 g, Himalayan Teasel Root 20 g, Donkey-hide Glue 10 g, |
Li et al. 2017, [ | Modified STP | Chinese Dodder Seed 30 g, Chinese Taxillus Twig 30 g, Himalayan Teasel Root 20 g, |
Lu 2016, [ | Modified STP | Chinese Dodder Seed 15 g, Chinese Taxillus Twig 15 g, Himalayan Teasel Root 9 g, Donkey-hide Glue 12 g, Chinese Wolfberry 15 g, |
Mo et al. 2018, [ | Modified STP | Chinese Dodder Seed 30 g, Chinese Taxillus Twig 30 g, Himalayan Teasel Root 20 g, Donkey-hide Glue 12 g, |
Tian et al. 2019, [ | STP | Chinese Dodder Seed 15 g, Chinese Taxillus Twig 15 g, Himalayan Teasel Root 10 g, and Donkey-hide Glue 12 g |
Wang et al. 2016, [ | STP | Chinese Dodder Seed 40 g, Chinese Taxillus Twig 20 g, Himalayan Teasel Root 20 g, and Donkey-hide Glue 20 g |
Wei et al. 2017, [ | Modified STP | Chinese Dodder Seed 30 g, Chinese Taxillus Twig 30 g, Himalayan Teasel Root 20 g, Donkey-hide Glue 12 g, |
Xie et al. 2016, [ | Modified STP | Chinese Dodder Seed 30 g, Chinese Taxillus Twig 30 g, Himalayan Teasel Root 20 g, Donkey-hide Glue 12 g, |
Yuan et al. 2015, [ | Modified STP | Chinese Dodder Seed 30 g, Chinese Taxillus Twig 30 g, Himalayan Teasel Root 20 g, Donkey-hide Glue 12 g, |
Zheng 2019, [ | STP | Chinese Dodder Seed 15 g, Chinese Taxillus Twig 15 g, Himalayan Teasel Root 15 g, and Root Donkey-hide Glue 15 g |
STP: Shoutai Pill.
In general, the methodological quality of the included trials was poor. All of the 12 included studies involved two-arm designs and declared as random controlled trials, and 8 trials reported proper generation methods (random number table or coin toss) with a low risk of bias [
The risk of bias about each included study.
Eleven studies reported the incidence of early pregnancy loss, and meta-analysis showed that patients in the combined group had a significantly lower occurrence (RR: 0.42; 95% CI: 0.34–0.52;
Forest plot for the incidence of early pregnancy loss between combined and western alone medicine group.
Subgroup analysis for early pregnancy loss rate based on the different types of TCM syndrome differentiation.
Eight studies assessed TCM syndromes and symptoms, five trials reported the incidence of live birth, and four trials evaluated serum D-dimer level. Compared with the western medicine alone group, patients treated with STP and western medicine had a lower TCM syndromes and symptoms (SMD: -2.39; 95% CI: -2.86, -1.93;
Forest plot for TCM syndromes and symptoms between combined and western alone medicine group.
Forest plot for serum D-dimer level between combined and western alone medicine group.
Forest plot for live birth rate between combined and western alone medicine group.
In the 12 included studies, only three trials reported on adverse events. No adverse effects of STP combined with western medicine group were identified in these trials, so there was insufficient data pooled to assess the safety of this intervention.
Although the funnel plot for the early pregnancy loss rate was asymmetrically distributed, Egger’s test showed no potential publish bias (
Sensitivity analysis for the early pregnancy loss rate.
We assessed the quality for the outcomes by GRADE evaluation. The quality of included studies was really low, and the “Risk of bias” was downgraded to “serious.” The
The summary of GRADE evaluation.
Outcomes | Participants (studies) | RR/SMD (95% CI) | GRADE | Comments |
---|---|---|---|---|
The incidence of early pregnancy loss | 876 (11 RCTs) | 0.42 (0.34,0.52) | ⨁⨁⨁◯ Moderate | “Risk of bias” was downgraded to “serious” |
TCM syndromes and symptoms | 549 (8 RCTs) | -2.39 (-2.86, -10.93) | ⨁⨁◯◯ Low | “Risk of bias” was downgraded to “serious” |
Serum D-dimer level | 256 (4 RCTs) | -0.25 (-0.30, -0.20) | ⨁⨁⨁◯ Moderate | “Risk of bias” was downgraded to “serious” |
Live birth rate | 313 (5 RCTs) | 1.81 (1.46, 2.25) | ⨁⨁⨁◯ Moderate | “Risk of bias” was downgraded to “serious” |
RR: Risk Ratio; SMD: Standard Mean Difference; RCT: Random controlled trial.
This meta-analysis demonstrated a quantitative estimates of the clinical efficacy and safety of cotreatment with STP and western medicine for the treatment of URSA by integrating outcomes from the 12 RCTs of 916 patients. The baseline of each study was consistent. Results from the meta-analysis showed that STP combined with western medicine can significantly reduce the early pregnancy loss incidence in the first trimester of pregnancy in women with URSA compared to the control group. Our meta-analysis also indicated that, compared with control group, STP combined with western medicine has the more significant effect on the live birth rate, TCM syndromes and symptoms, and serum D-dimer level. The safety of STP for the treatment of URSA remains unclear. However, due to poor methodological quality, the conclusion about beneficial effect and safety of STP combined with western medicine needed to be further verified in future studies.
In recent years, the incidence of URSA has increased causing a considerable negative life occurrence and may cause notable physical and psychological damage to couples who attempt to have a child due to the multifactorial, complex, and poorly understood pathogenesis of URSA [
Whether progesterone as the major method used in most included studies, or immunologic intervention and anticoagulant therapy administrated in a few included studies, there tends to have controversy and limitations such as adverse reactions like dizziness, nausea, and vomiting; potential risks include allergies, infectious diseases, and bleeding along with increasing financial burden [
TCM has a unified medical theory for clinical diagnosis and treatment of URSA, which focuses on “Qi” and “blood” as the two basic elements of human physiology and believes that kidney-qi deficiency and blood stasis which can result in uterus pain and bleeding tendency are important in the pathology and mechanism of URSA [
Although, we have comprehensively analyzed and evaluated all studies, it still has limitations that should be acknowledged. First, the included studies had low quality due to an unclear allocation concealment, selective bias, attrition bias, and blinding methods. Second, although we conducted an unbiased literature search without language restriction, all trials included in this review were conducted in China and were published in Chinese without relevant foreign experiments, which likely lead to a potential bias and therefore limit their representativeness. Third, few studies included have mentioned the adverse reactions during and after treatment. Meanwhile, no trial reported long-term follow-up, so the long-term safety of the intervention is still not well known. Fourth, the criteria for the outcome of each study were inconsistent. As a result, the evaluation had certain subjectivity and difference, which affected the accuracy and stability of the test.
In summary, our results showed that Shoutai Pill in combination with western medicine might increase the chances of a successful pregnancy in the first trimester of pregnancy for unexplained recurrent spontaneous abortion and may be beneficial for women with URSA as adjunct therapies without obvious adverse event in the experimental group. However, due to the relatively low quality of the included studies, we should be more cautious to promote this result. Future well-designed, multicenter, and large-sample clinical studies on evaluating the efficacy and safety of STP are needed to ensure the scientific, objective, and reliable conclusions of the research so as to make the results more convincing and provide more valuable information.
The data set supporting the results of this article is included within the article.
The authors declare that there are no conflicts of interest regarding the publication of this paper.
This study was supported by grants from Jiaxing Key DISCIPLINE of Traditional Chinese Medicine–Integrated Chinese and Western Medicine Gynecology (2019-2021) and Jiaxing Key DISCIPLINE of Medicine–Anesthesiology (2019-zc-06).