Chinese herbal medicine for subfertile women with polycystic ovarian syndrome.

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.

Interventions for leg cramps in pregnancy.

BACKGROUND: Leg cramps are a common problem in pregnancy. Various interventions have been used to treat them, including drug, electrolyte and vitamin therapies, and non-drug therapies. This Cochrane Review is an update of a review first published in 2015. OBJECTIVES: To assess the effectiveness and safety of different interventions for treating leg cramps in pregnancy. SEARCH METHODS: We searched Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP) (25 September 2019), and reference lists of retrieved studies. SELECTION CRITERIA: Randomised controlled trials (RCTs) of any intervention for the treatment of leg cramps in pregnancy compared with placebo, no treatment or other treatments. Quinine was excluded for its known adverse effects. Cluster-RCTS were eligible for inclusion. Quasi-RCTs and cross-over studies were excluded. DATA COLLECTION AND ANALYSIS: Three review authors independently assessed trials for inclusion and risk of bias, extracted data and checked them for accuracy. The certainty of the evidence was assessed using the GRADE approach. MAIN RESULTS: We included eight small studies (576 women). Frequency of leg cramps was our primary outcome and secondary outcomes included intensity and duration of leg cramps, adverse outcomes for mother and baby and health-related quality of life. Overall, the studies were at low or unclear risk of bias. Outcomes were reported in different ways, precluding the use of meta-analysis and thus data were limited to single trials. Certainty of evidence was assessed as either low or very-low due to serious limitations in study design and imprecision. Oral magnesium versus placebo/no treatment The results for frequency of leg cramps were inconsistent. In one study, results indicated that women may be more likely to report never having any leg cramps after treatment (risk ratio (RR) 5.66, 95% confidence interval (CI) 1.35 to 23.68, 1 trial, 69 women, low-certainty evidence); whilst fewer women may report having twice-weekly leg cramps (RR 0.29, 95% CI 0.11 to 0.80, 1 trial, 69 women); and more women may report a 50% reduction in number of leg cramps after treatment (RR 1.42, 95% CI 1.09 to 1.86, 1 trial, 86 women, low-certainty evidence). However, other findings indicated that magnesium may make little to no difference in the frequency of leg cramps during differing periods of treatment. For pain intensity, again results were inconsistent. Findings indicated that magnesium may make little or no difference: mean total pain score (MD 1.80, 95% CI -3.10 to 6.70, 1 trial, 38 women, low-certainty evidence). In another study the evidence was very uncertain about the effects of magnesium on pain intensity as measured in terms of a 50% reduction in pain. Findings from another study indicated that magnesium may reduce pain intensity according to a visual analogue scale (MD -17.50, 95% CI -34.68 to -0.32,1 trial, 69 women, low-certainty evidence). For all other outcomes examined there may be little or no difference: duration of leg cramps (low to very-low certainty); composite outcome - symptoms of leg cramps (very-low certainty); and for any side effects, including nausea and diarrhoea (low certainty). Oral calcium versus placebo/no treatment The evidence is unclear about the effect of calcium supplements on frequency of leg cramps because the certainty was found to be very low: no leg cramps after treatment (RR 8.59, 95% CI 1.19 to 62.07, 1 study, 43 women, very low-certainty evidence). In another small study, the findings indicated that the mean frequency of leg cramps may be slightly lower with oral calcium (MD -0.53, 95% CI -0.72 to -0.34; 1 study, 60 women; low certainty). Oral vitamin B versus no treatment One small trial, did not report on frequency of leg cramps individually, but showed that oral vitamin B supplements may reduce the frequency and intensity (composite outcome) of leg cramps (RR 0.29, 95% CI 0.11 to 0.73; 1 study, 42 women). There were no data on side effects. Oral calcium versus oral vitamin C The evidence is very uncertain about the effect of calcium on frequency of leg cramps after treatment compared with vitamin C (RR 1.33, 95% CI 0.53 to 3.38, 1 study, 60 women, very low-certainty evidence). Oral vitamin D versus placebo One trial (84 women) found vitamin D may make little or no difference to frequency of leg cramps compared with placebo at three weeks (MD 2.06, 95% CI 0.58 to 3.54); or six weeks after treatment (MD 1.53, 95% CI 0.12 to 2.94). Oral calcium-vitamin D versus placebo One trial (84 women) found oral calcium-vitamin D may make little or no difference to frequency of leg cramps compared with placebo after treatment at three weeks (MD -0.30, 95% CI -1.55 to 0.95); and six weeks (MD 0.03, 95% CI -1.3 to 1.36). Oral calcium-vitamin D versus vitamin D One trial (84 women) found oral calcium-vitamin D may make little or no difference to frequency of leg cramps compared with vitamin D after treatment at three weeks (MD -1.35, 95% CI -2.84 to 0.14); and six weeks after treatment (MD -1.10, 95% CI -2.69 to 0.49). AUTHORS' CONCLUSIONS: It is unclear from the evidence reviewed whether any of the interventions provide an effective treatment for leg cramps. This is primarily due to outcomes being measured and reported in different, incomparable ways so that data could not be pooled. The certainty of evidence was found to be low or very-low due to design limitations and trials being too small to address the question satisfactorily. Adverse outcomes were not reported, other than side effects for magnesium versus placebo/no treatment. It is therefore not possible to assess the safety of these interventions. The inconsistency in the measurement and reporting of outcomes meant that meta-analyses could not be carried out. The development of a core outcome set for measuring the frequency, intensity and duration of leg cramps would address these inconsistencies and mean these outcomes could be investigated effectively in the future.

Chinese herbal medicine for subfertile women with polycystic ovarian syndrome.

BACKGROUND: Polycystic ovarian syndrome (PCOS) is one of the most common reproductive endocrinology abnormalities, and affects 5% to 10% of women of reproductive age. Western medicines, such as oral contraceptives, insulin sensitizers and laparoscopic ovarian drilling (LOD), have been used to treat PCOS. Recently, many studies have been published that consider Chinese herbal medicine (CHM) as an alternative treatment for women with PCOS. OBJECTIVES: To assess the efficacy and safety of CHM for subfertile women with PCOS. SEARCH METHODS: We searched sources, including the following databases, from inception to 9 June 2016: the Cochrane Gynaecology and Fertility Group Specialized Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, Allied and Complementary Medicine (AMED), PsycINFO, Chinese National Knowledge Infrastructure (CNKI), VIP, Wanfang and trial registries. In addition, we searched the reference lists of included trials and contacted experts in the field to locate trials. SELECTION CRITERIA: Randomized controlled trials (RCTs) that considered the use of CHM for the treatment of subfertile women with PCOS. DATA COLLECTION AND ANALYSIS: Two review authors independently screened appropriate 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 (CI). We assessed the quality of the evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methods. MAIN RESULTS: We included five RCTs with 414 participants. The comparisons in the included trials were as follows: CHM versus clomiphene, CHM plus clomiphene versus clomiphene (with or without ethinyloestradiol cyproterone acetate (CEA)), 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 quality of the evidence for most comparisons was very low.None of the included studies reported live birth rate, and only one study reported data on adverse events.When CHM was compared with clomiphene (with or without LOD in both arms), there was no evidence of a difference between the groups in pregnancy rates (odds ratio (OR) 1.98, 95% confidence interval (CI) 0.78 to 5.06; two studies, 90 participants, I² statistic = 0%, very low quality evidence). No study reported data on adverse events. When CHM plus clomiphene was compared with clomiphene (with or without CEA), there was low quality evidence of a higher pregnancy rate in the CHM plus clomiphene group (OR 2.62, 95% CI 1.65 to 4.14; three RCTs, 300 women, I² statistic = 0%,low quality evidence). No data were reported on adverse events.When CHM with follicle aspiration and ovulation induction was compared with follicle aspiration and ovulation induction alone, there was no evidence of a difference between the groups in pregnancy rates (OR 1.60, 95% CI 0.46 to 5.52; one study, 44 women, very low quality evidence), severe luteinized unruptured follicle syndrome (LUFS) (OR 0.60, 95% CI 0.06 to 6.14; one study, 44 women, very low quality evidence), ovarian hyperstimulation syndrome (OHSS) (OR 0.16, 95% CI 0.00 to 8.19; one study, 44 women, very low quality evidence) or multiple pregnancy (OR 0.60, 95% CI 0.06 to 6.14; one study, 44 women, very low quality evidence).When CHM with LOD was compared with LOD alone, there was no evidence of a difference between the groups in rates of pregnancy (OR 3.50, 95% CI 0.72 to 17.09; one study, 30 women, very low quality evidence), No data were reported on adverse events.There was no evidence of a difference between any of the comparison groups for any other outcomes. The quality 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 women with PCOS and subfertility. No data are available on live birth, and there is no consistent evidence to indicate that CHM influences fertility outcomes. However there is very limited low quality evidence to suggest that the addition of CHM to clomiphene may improve pregnancy rates. There is insufficient evidence on adverse effects to indicate whether CHM is safe.

Interventions for leg cramps in pregnancy.

BACKGROUND: Leg cramps are a common problem in pregnancy. Various interventions have been used to treat them, including drug, electrolyte and vitamin therapies, and non-drug therapies. OBJECTIVES: To assess the effectiveness and safety of different interventions for treating leg cramps in pregnancy. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Register (31 March 2015) and reference lists of retrieved studies. SELECTION CRITERIA: Randomised controlled trials (RCTs) of any intervention (drug, electrolyte, vitamin or non-drug therapies) for treatment of leg cramps in pregnancy compared with placebo, no treatment or other treatment. Quinine was excluded for its known adverse effects (teratogenicity). Cluster-RCTS were considered for inclusion. Quasi-RCTs and cross-over studies were excluded. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion and risk of bias, extracted data and checked them for accuracy. MAIN RESULTS: We included six studies (390 women). Four trials compared oral magnesium with placebo/no treatment, two compared oral calcium with no treatment, one compared oral vitamin B versus no treatment, and one compared oral calcium with oral vitamin C. Two of the trials were well-conducted and reported, the other four had design limitations. The process of random allocation was sub-optimal in three studies, and blinding was not attempted in two. Outcomes were reported in different ways, precluding the use of meta-analysis and limiting the strength of our conclusions.The 'no treatment' group in one four-arm trial has been used as the comparison group for the composite outcome (intensity and frequency of leg cramps) in magnesium, calcium, and vitamin B versus no treatment. This gives it disproportionate weight in the overall analysis, thus interpretation of these results should be cautious. Oral magnesium versus placebo/no treatmentMagnesium (taken orally for two to four weeks) did not consistently reduce the frequency of leg cramps compared with placebo or no treatment. Outcomes that showed differences were: frequency of leg cramps after treatment: never, and twice a week (risk ratio (RR) 5.66, 95% confidence interval (CI) 1.35 to 23.68, one trial, 69 women, evidence graded low; RR 0.29, 95% CI 0.11 to 0.80, one trial, 69 women), and frequency of leg cramps: 50% reduction in number of leg cramps after treatment (RR 1.42, 95% CI 1.09 to 1.86, one trial, 86 women, evidence graded low). The outcomes that showed no difference were: frequency of leg cramps during two weeks of treatment (mean difference (MD) 1.80, 95% CI -1.32 to 4.92, one trial, 38 women, evidence graded low); frequency of leg cramps after treatment: daily, every other day, and once a week (RR 1.20, 95% CI 0.45 to 3.21, one trial, 69 women; RR 0.44, 95% CI 0.12 to 1.57, one trial, 69 women; RR 1.54, 95% CI 0.62 to 3.87, one trial, 69 women).Evidence about whether magnesium supplements reduced the intensity of pain was inconclusive, with two studies showing that it may slightly reduce pain, while one showed no difference. There were no differences in the experience of side effects (including nausea, flatulence, diarrhoea and intestinal air) between pregnant women receiving magnesium compared with placebo/no treatment. Oral calcium versus no treatmentA greater proportion of women receiving calcium supplements experienced no leg cramps after treatment than those receiving no treatment (frequency of leg cramps after treatment: never RR 8.59, 95% CI 1.19 to 62.07, one study, 43 women, evidence graded very low). There was no difference between groups for a composite outcome (intensity and frequency) for partial improvement (RR 0.64, 95% CI 0.36 to 1.15, one trial, 42 women); however, the same trial showed a greater proportion of women experiencing no leg cramps after treatment with calcium compared with no treatment (RR 5.50, 95% CI 1.38 to 21.86).Other secondary outcomes, including side effects, were not reported. Oral vitamin B versus no treatment Frequency of leg cramps was not reported in the one included trial. According to a composite outcome (frequency and intensity), more women receiving vitamin B fully recovered compared with those receiving no treatment (RR 7.50, 95% CI 1.95 to 28.81). Those women receiving no treatment were more likely to experience a partial improvement in the intensity and frequency of leg cramps than those taking vitamin B (RR 0.29, 95% CI 0.11 to 0.73, one trial, 42 women), or to see no change in their condition. However, these results are based on one small study with design limitations.Other secondary outcomes, including side effects, were not reported. Oral calcium versus oral vitamin CThere was no difference in the frequency of leg cramps after treatment with calcium versus vitamin C (RR 1.33, 95% CI 0.53 to 3.38, one study, 60 women, evidence graded very low). Other outcomes, includingside effects, were not reported. AUTHORS' CONCLUSIONS: It is unclear from the evidence reviewed whether any of the interventions (oral magnesium, oral calcium, oral vitamin B or oral vitamin C) provide an effective treatment for leg cramps. This is primarily due to outcomes being measured and reported in different, incomparable ways, and design limitations compromising the quality of the evidence (the level of evidence was graded low or very low). This was mainly due to poor study design and trials being too small to address the question satisfactorily.Adverse outcomes were not reported, other than side effects for magnesium versus placebo/no treatment. It is therefore not possible to assess the safety of these interventions.The inconsistency in the measurement and reporting of outcomes, meant that data could not be pooled, meta-analyses could not be carried out, and comparisons between studies are difficult.The review only identified trials of oral interventions (magnesium, calcium, vitamin B or vitamin C) to treat leg cramps in pregnancy. None of the trials considered non-drug therapies, for example, muscle stretching, massage, relaxation, heat therapy, and dorsiflexion of the foot. This limits the completeness and applicability of the evidence.Standardised measures for assessing the frequency, intensity and duration of leg cramps to be used in large well-conducted randomised controlled trials are needed to answer this question. Trials of non-drug therapies are also needed.