Kunyan Zhou1,2, Jing Zhang1,2, Liangzhi Xu1,2, Chi Eung Danforn Lim3. 1. Department of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University, Chengdu, China. 2. Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, China. 3. Faculty of Science, University of Technology Sydney, Earlwood, Australia.
Abstract
BACKGROUND: Polycystic ovarian syndrome (PCOS) is characterised by both metabolic and reproductive disorders, and affects 5% to 15% of women of reproductive age. Different western medicines have been proposed for PCOS-related subfertility, such as oral contraceptives, insulin sensitisers and laparoscopic ovarian drilling (LOD). Chinese herbal medicines (CHM) have also been used for subfertility caused by PCOS for decades, and are expected to become an alternative treatment for subfertile women with PCOS. OBJECTIVES: To assess the efficacy and safety of Chinese herbal medicine (CHM) for subfertile women with polycystic ovarian syndrome (PCOS). SEARCH METHODS: We searched the Cochrane Gynaecology and Fertility Group Specialised Register, CENTRAL, MEDLINE, Embase and six other databases, from inception to 2 June 2020. In addition, we searched three trials registries, the reference lists of included trials and contacted experts in the field to locate trials. SELECTION CRITERIA: We included randomised controlled trials (RCTs) comparing CHM versus placebo, no treatment or conventional (western) therapies for the treatment of subfertile women with PCOS. DATA COLLECTION AND ANALYSIS: Two review authors independently screened trials for inclusion, assessed the risk of bias in included studies and extracted data. We contacted primary study authors for additional information. We conducted meta-analyses. We used the odds ratios (ORs) to report dichotomous data, with 95% confidence intervals (CIs). We assessed the certainty of the evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methods. MAIN RESULTS: We included eight RCTs with 609 participants. The comparisons in the included trials were as follows: CHM versus clomiphene, CHM plus clomiphene versus clomiphene (with or without ethinyloestradiol cyproterone acetate (EE/CPA)), CHM plus follicle aspiration plus ovulation induction versus follicle aspiration plus ovulation induction alone, and CHM plus laparoscopic ovarian drilling (LOD) versus LOD alone. The overall certainty of the evidence for most comparisons was very low. None of the included studies reported the primary outcome, live birth rate. Most studies reported the secondary outcomes, and only one study reported data on adverse events. In trials that compared CHM to clomiphene (with or without LOD in both study arms), we are uncertain of the effect of CHM on pregnancy rates (odds ratio (OR) 1.41, 95% confidence interval (CI) 0.63 to 3.19; I2 = 28%; 3 studies, 140 participants; very low certainty evidence). Results suggest that if the chance of pregnancy following clomiphene is assumed to be 21.5%, the chance following CHM would vary between 14.7% and 46.7%. No study reported data on adverse events. When CHM plus clomiphene was compared to clomiphene (with or without EE/CPA), there was low certainty evidence of a higher pregnancy rate in the CHM plus clomiphene group (OR 3.06, 95% CI 2.05 to 4.55; I2 = 10%; 6 studies, 470 participants; low certainty evidence). Results suggest that if the chance of pregnancy following clomiphene is assumed to be 31.5%, the chance following CHM plus clomiphene would vary between 48.5% and 67.7%. No data were reported on adverse events. In trials that compared CHM plus follicle aspiration and ovulation induction to follicle aspiration and ovulation induction alone, we are uncertain of the effect of CHM on pregnancy rates (OR 1.62, 95% CI 0.46 to 5.68; 1 study, 44 women; very low certainty evidence). Results suggest that if the chance of pregnancy following follicle aspiration and ovulation induction is assumed to be 29.2%, the chance following CHM with follicle aspiration and ovulation induction would vary between 15.9% and 70%. Reported adverse events included severe luteinised unruptured follicle syndrome (LUFS) (Peto OR 0.60, 95% CI 0.06 to 6.14; 1 study, 44 women; very low certainty evidence), ovarian hyperstimulation syndrome (OHSS) (Peto OR 0.16, 95% CI 0.00 to 8.19; 1 study, 44 women; very low certainty evidence) or multiple pregnancy (Peto OR 0.60, 95% CI 0.06 to 6.14; 1 study, 44 women; very low certainty evidence). These results suggest that if the chances of LUFS, OHSS, and multiple pregnancy following follicle aspiration and ovulation induction are assumed to be 8.3%, 4.2%, and 8.3% respectively, the chances following CHM with follicle aspiration and ovulation induction would be 0.5% to 35.8%, 0% to 26.3% and 0.5% to 35.8% respectively. In trials that compared CHM plus LOD to LOD alone, we are uncertain if CHM improves pregnancy rates (OR 3.50, 95% CI 0.72 to 17.09; 1 study, 30 women; very low certainty evidence). Results suggest that if the chance of pregnancy following LOD is assumed to be 40%, the chance following CHM with LOD would vary between 32.4% and 91.9%. No data were reported on adverse events. We are uncertain of the results in the comparison groups for all outcomes. The certainty of the evidence for all other comparisons and outcomes was very low. The main limitations in the evidence were failure to report live birth or adverse events, failure to describe study methods in adequate detail and imprecision due to very low event rates and wide CIs. AUTHORS' CONCLUSIONS: There is insufficient evidence to support the use of CHM for subfertile women with PCOS. No data are available on live birth. We are uncertain of the effect of CHM on pregnancy rates for there is no consistent evidence to indicate that CHM influences fertility outcomes. However, we find that the addition of CHM to clomiphene may improve pregnancy rates, but there is very limited, low certainty evidence for this outcome. Furthermore, there is insufficient evidence on adverse effects to indicate whether CHM is safe. In the future, well-designed, carefully conducted RCTs are needed, with a particular focus on the live birth rate and other safety indexes.
BACKGROUND: Polycystic ovarian syndrome (PCOS) is characterised by both metabolic and reproductive disorders, and affects 5% to 15% of women of reproductive age. Different western medicines have been proposed for PCOS-related subfertility, such as oral contraceptives, insulin sensitisers and laparoscopic ovarian drilling (LOD). Chinese herbal medicines (CHM) have also been used for subfertility caused by PCOS for decades, and are expected to become an alternative treatment for subfertile women with PCOS. OBJECTIVES: To assess the efficacy and safety of Chinese herbal medicine (CHM) for subfertile women with polycystic ovarian syndrome (PCOS). SEARCH METHODS: We searched the Cochrane Gynaecology and Fertility Group Specialised Register, CENTRAL, MEDLINE, Embase and six other databases, from inception to 2 June 2020. In addition, we searched three trials registries, the reference lists of included trials and contacted experts in the field to locate trials. SELECTION CRITERIA: We included randomised controlled trials (RCTs) comparing CHM versus placebo, no treatment or conventional (western) therapies for the treatment of subfertile women with PCOS. DATA COLLECTION AND ANALYSIS: Two review authors independently screened trials for inclusion, assessed the risk of bias in included studies and extracted data. We contacted primary study authors for additional information. We conducted meta-analyses. We used the odds ratios (ORs) to report dichotomous data, with 95% confidence intervals (CIs). We assessed the certainty of the evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methods. MAIN RESULTS: We included eight RCTs with 609 participants. The comparisons in the included trials were as follows: CHM versus clomiphene, CHM plus clomiphene versus clomiphene (with or without ethinyloestradiol cyproterone acetate (EE/CPA)), CHM plus follicle aspiration plus ovulation induction versus follicle aspiration plus ovulation induction alone, and CHM plus laparoscopic ovarian drilling (LOD) versus LOD alone. The overall certainty of the evidence for most comparisons was very low. None of the included studies reported the primary outcome, live birth rate. Most studies reported the secondary outcomes, and only one study reported data on adverse events. In trials that compared CHM to clomiphene (with or without LOD in both study arms), we are uncertain of the effect of CHM on pregnancy rates (odds ratio (OR) 1.41, 95% confidence interval (CI) 0.63 to 3.19; I2 = 28%; 3 studies, 140 participants; very low certainty evidence). Results suggest that if the chance of pregnancy following clomiphene is assumed to be 21.5%, the chance following CHM would vary between 14.7% and 46.7%. No study reported data on adverse events. When CHM plus clomiphene was compared to clomiphene (with or without EE/CPA), there was low certainty evidence of a higher pregnancy rate in the CHM plus clomiphene group (OR 3.06, 95% CI 2.05 to 4.55; I2 = 10%; 6 studies, 470 participants; low certainty evidence). Results suggest that if the chance of pregnancy following clomiphene is assumed to be 31.5%, the chance following CHM plus clomiphene would vary between 48.5% and 67.7%. No data were reported on adverse events. In trials that compared CHM plus follicle aspiration and ovulation induction to follicle aspiration and ovulation induction alone, we are uncertain of the effect of CHM on pregnancy rates (OR 1.62, 95% CI 0.46 to 5.68; 1 study, 44 women; very low certainty evidence). Results suggest that if the chance of pregnancy following follicle aspiration and ovulation induction is assumed to be 29.2%, the chance following CHM with follicle aspiration and ovulation induction would vary between 15.9% and 70%. Reported adverse events included severe luteinised unruptured follicle syndrome (LUFS) (Peto OR 0.60, 95% CI 0.06 to 6.14; 1 study, 44 women; very low certainty evidence), ovarian hyperstimulation syndrome (OHSS) (Peto OR 0.16, 95% CI 0.00 to 8.19; 1 study, 44 women; very low certainty evidence) or multiple pregnancy (Peto OR 0.60, 95% CI 0.06 to 6.14; 1 study, 44 women; very low certainty evidence). These results suggest that if the chances of LUFS, OHSS, and multiple pregnancy following follicle aspiration and ovulation induction are assumed to be 8.3%, 4.2%, and 8.3% respectively, the chances following CHM with follicle aspiration and ovulation induction would be 0.5% to 35.8%, 0% to 26.3% and 0.5% to 35.8% respectively. In trials that compared CHM plus LOD to LOD alone, we are uncertain if CHM improves pregnancy rates (OR 3.50, 95% CI 0.72 to 17.09; 1 study, 30 women; very low certainty evidence). Results suggest that if the chance of pregnancy following LOD is assumed to be 40%, the chance following CHM with LOD would vary between 32.4% and 91.9%. No data were reported on adverse events. We are uncertain of the results in the comparison groups for all outcomes. The certainty of the evidence for all other comparisons and outcomes was very low. The main limitations in the evidence were failure to report live birth or adverse events, failure to describe study methods in adequate detail and imprecision due to very low event rates and wide CIs. AUTHORS' CONCLUSIONS: There is insufficient evidence to support the use of CHM for subfertile women with PCOS. No data are available on live birth. We are uncertain of the effect of CHM on pregnancy rates for there is no consistent evidence to indicate that CHM influences fertility outcomes. However, we find that the addition of CHM to clomiphene may improve pregnancy rates, but there is very limited, low certainty evidence for this outcome. Furthermore, there is insufficient evidence on adverse effects to indicate whether CHM is safe. In the future, well-designed, carefully conducted RCTs are needed, with a particular focus on the live birth rate and other safety indexes.
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