Antioxidants for male subfertility.

BACKGROUND: The inability to have children affects 10% to 15% of couples worldwide. A male factor is estimated to account for up to half of the infertility cases with between 25% to 87% of male subfertility considered to be due to the effect of oxidative stress. Oral supplementation with antioxidants is thought to improve sperm quality by reducing oxidative damage. Antioxidants are widely available and inexpensive when compared to other fertility treatments, however most antioxidants are uncontrolled by regulation and the evidence for their effectiveness is uncertain. We compared the benefits and risks of different antioxidants used for male subfertility. OBJECTIVES: To evaluate the effectiveness and safety of supplementary oral antioxidants in subfertile men. SEARCH METHODS: The Cochrane Gynaecology and Fertility (CGF) Group trials register, CENTRAL, MEDLINE, Embase, PsycINFO, AMED, and two trial registers were searched on 15 February 2021, together with reference checking and contact with experts in the field to identify additional trials. SELECTION CRITERIA: We included randomised controlled trials (RCTs) that compared any type, dose or combination of oral antioxidant supplement with placebo, no treatment, or treatment with another antioxidant, among subfertile men of a couple attending a reproductive clinic. We excluded studies comparing antioxidants with fertility drugs alone and studies that included men with idiopathic infertility and normal semen parameters or fertile men attending a fertility clinic because of female partner infertility. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures recommended by Cochrane. The primary review outcome was live birth. Clinical pregnancy, adverse events and sperm parameters were secondary outcomes. MAIN RESULTS: We included 90 studies with a total population of 10,303 subfertile men, aged between 18 and 65 years, part of a couple who had been referred to a fertility clinic and some of whom were undergoing medically assisted reproduction (MAR). Investigators compared and combined 20 different oral antioxidants. The evidence was of 'low' to 'very low' certainty: the main limitation was that out of the 67 included studies in the meta-analysis only 20 studies reported clinical pregnancy, and of those 12 reported on live birth. The evidence is current up to February 2021. Live birth: antioxidants may lead to increased live birth rates (odds ratio (OR) 1.43, 95% confidence interval (CI) 1.07 to 1.91, P = 0.02, 12 RCTs, 1283 men, I2 = 44%, very low-certainty evidence). Results in the studies contributing to the analysis of live birth rate suggest that if the baseline chance of live birth following placebo or no treatment is assumed to be 16%, the chance following the use of antioxidants is estimated to be between 17% and 27%. However, this result was based on only 246 live births from 1283 couples in 12 small or medium-sized studies. When studies at high risk of bias were removed from the analysis, there was no evidence of increased live birth (Peto OR 1.22, 95% CI 0.85 to 1.75, 827 men, 8 RCTs, P = 0.27, I2 = 32%). Clinical pregnancy rate: antioxidants may lead to increased clinical pregnancy rates (OR 1.89, 95% CI 1.45 to 2.47, P < 0.00001, 20 RCTs, 1706 men, I2 = 3%, low-certainty evidence) compared with placebo or no treatment. This suggests that, in the studies contributing to the analysis of clinical pregnancy, if the baseline chance of clinical pregnancy following placebo or no treatment is assumed to be 15%, the chance following the use of antioxidants is estimated to be between 20% and 30%. This result was based on 327 clinical pregnancies from 1706 couples in 20 small studies. Adverse events Miscarriage: only six studies reported on this outcome and the event rate was very low. No evidence of a difference in miscarriage rate was found between the antioxidant and placebo or no treatment group (OR 1.46, 95% CI 0.75 to 2.83, P = 0.27, 6 RCTs, 664 men, I2 = 35%, very low-certainty evidence). The findings suggest that in a population of subfertile couples, with male factor infertility, with an expected miscarriage rate of 5%, the risk of miscarriage following the use of an antioxidant would be between 4% and 13%. Gastrointestinal: antioxidants may lead to an increase in mild gastrointestinal discomfort when compared with placebo or no treatment (OR 2.70, 95% CI 1.46 to 4.99, P = 0.002, 16 RCTs, 1355 men, I2 = 40%, low-certainty evidence). This suggests that if the chance of gastrointestinal discomfort following placebo or no treatment is assumed to be 2%, the chance following the use of antioxidants is estimated to be between 2% and 7%. However, this result was based on a low event rate of 46 out of 1355 men in 16 small or medium-sized studies, and the certainty of the evidence was rated low and heterogeneity was high. We were unable to draw conclusions from the antioxidant versus antioxidant comparison as insufficient studies compared the same interventions. AUTHORS' CONCLUSIONS: In this review, there is very low-certainty evidence from 12 small or medium-sized randomised controlled trials suggesting that antioxidant supplementation in subfertile males may improve live birth rates for couples attending fertility clinics. Low-certainty evidence suggests that clinical pregnancy rates may increase. There is no evidence of increased risk of miscarriage, however antioxidants may give more mild gastrointestinal discomfort, based on very low-certainty evidence. Subfertile couples should be advised that overall, the current evidence is inconclusive based on serious risk of bias due to poor reporting of methods of randomisation, failure to report on the clinical outcomes live birth rate and clinical pregnancy, often unclear or even high attrition, and also imprecision due to often low event rates and small overall sample sizes. Further large well-designed randomised placebo-controlled trials studying infertile men and reporting on pregnancy and live births are still required to clarify the exact role of antioxidants.

Antioxidants for female subfertility.

BACKGROUND: A couple may be considered to have fertility problems if they have been trying to conceive for over a year with no success. This may affect up to a quarter of all couples planning a child. It is estimated that for 40% to 50% of couples, subfertility may result from factors affecting women. Antioxidants are thought to reduce the oxidative stress brought on by these conditions. Currently, limited evidence suggests that antioxidants improve fertility, and trials have explored this area with varied results. This review assesses the evidence for the effectiveness of different antioxidants in female subfertility. OBJECTIVES: To determine whether supplementary oral antioxidants compared with placebo, no treatment/standard treatment or another antioxidant improve fertility outcomes for subfertile women. SEARCH METHODS: We searched the following databases (from their inception to September 2019), with no language or date restriction: Cochrane Gynaecology and Fertility Group (CGFG) specialised register, CENTRAL, MEDLINE, Embase, PsycINFO, CINAHL and AMED. We checked reference lists of relevant studies and searched the trial registers. SELECTION CRITERIA: We included randomised controlled trials (RCTs) that compared any type, dose or combination of oral antioxidant supplement with placebo, no treatment or treatment with another antioxidant, among women attending a reproductive clinic. We excluded trials comparing antioxidants with fertility drugs alone and trials that only included fertile women attending a fertility clinic because of male partner infertility. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. The primary review outcome was live birth; secondary outcomes included clinical pregnancy rates and adverse events. MAIN RESULTS: We included 63 trials involving 7760 women. Investigators compared oral antioxidants, including: combinations of antioxidants, N-acetylcysteine, melatonin, L-arginine, myo-inositol, carnitine, selenium, vitamin E, vitamin B complex, vitamin C, vitamin D+calcium, CoQ10, and omega-3-polyunsaturated fatty acids versus placebo, no treatment/standard treatment or another antioxidant. Only 27 of the 63 included trials reported funding sources. Due to the very low-quality of the evidence we are uncertain whether antioxidants improve live birth rate compared with placebo or no treatment/standard treatment (odds ratio (OR) 1.81, 95% confidence interval (CI) 1.36 to 2.43; P < 0.001, I2 = 29%; 13 RCTs, 1227 women). This suggests that among subfertile women with an expected live birth rate of 19%, the rate among women using antioxidants would be between 24% and 36%. Low-quality evidence suggests that antioxidants may improve clinical pregnancy rate compared with placebo or no treatment/standard treatment (OR 1.65, 95% CI 1.43 to 1.89; P < 0.001, I2 = 63%; 35 RCTs, 5165 women). This suggests that among subfertile women with an expected clinical pregnancy rate of 19%, the rate among women using antioxidants would be between 25% and 30%. Heterogeneity was moderately high. Overall 28 trials reported on various adverse events in the meta-analysis. The evidence suggests that the use of antioxidants makes no difference between the groups in rates of miscarriage (OR 1.13, 95% CI 0.82 to 1.55; P = 0.46, I2 = 0%; 24 RCTs, 3229 women; low-quality evidence). There was also no evidence of a difference between the groups in rates of multiple pregnancy (OR 1.00, 95% CI 0.63 to 1.56; P = 0.99, I2 = 0%; 9 RCTs, 1886 women; low-quality evidence). There was also no evidence of a difference between the groups in rates of gastrointestinal disturbances (OR 1.55, 95% CI 0.47 to 5.10; P = 0.47, I2 = 0%; 3 RCTs, 343 women; low-quality evidence). Low-quality evidence showed that there was also no difference between the groups in rates of ectopic pregnancy (OR 1.40, 95% CI 0.27 to 7.20; P = 0.69, I2 = 0%; 4 RCTs, 404 women). In the antioxidant versus antioxidant comparison, low-quality evidence shows no difference in a lower dose of melatonin being associated with an increased live-birth rate compared with higher-dose melatonin (OR 0.94, 95% CI 0.41 to 2.15; P = 0.89, I2 = 0%; 2 RCTs, 140 women). This suggests that among subfertile women with an expected live-birth rate of 24%, the rate among women using a lower dose of melatonin compared to a higher dose would be between 12% and 40%. Similarly with clinical pregnancy, there was no evidence of a difference between the groups in rates between a lower and a higher dose of melatonin (OR 0.94, 95% CI 0.41 to 2.15; P = 0.89, I2 = 0%; 2 RCTs, 140 women). Three trials reported on miscarriage in the antioxidant versus antioxidant comparison (two used doses of melatonin and one compared N-acetylcysteine versus L-carnitine). There were no miscarriages in either melatonin trial. Multiple pregnancy and gastrointestinal disturbances were not reported, and ectopic pregnancy was reported by only one trial, with no events. The study comparing N-acetylcysteine with L-carnitine did not report live birth rate. Very low-quality evidence shows no evidence of a difference in clinical pregnancy (OR 0.81, 95% CI 0.33 to 2.00; 1 RCT, 164 women; low-quality evidence). Low quality evidence shows no difference in miscarriage (OR 1.54, 95% CI 0.42 to 5.67; 1 RCT, 164 women; low-quality evidence). The study did not report multiple pregnancy, gastrointestinal disturbances or ectopic pregnancy. The overall quality of evidence was limited by serious risk of bias associated with poor reporting of methods, imprecision and inconsistency. AUTHORS' CONCLUSIONS: In this review, there was low- to very low-quality evidence to show that taking an antioxidant may benefit subfertile women. Overall, there is no evidence of increased risk of miscarriage, multiple births, gastrointestinal effects or ectopic pregnancies, but evidence was of very low quality. At this time, there is limited evidence in support of supplemental oral antioxidants for subfertile women.

Antioxidants for male subfertility.

BACKGROUND: The inability to have children affects 10% to 15% of couples worldwide. A male factor is estimated to account for up to half of the infertility cases with between 25% to 87% of male subfertility considered to be due to the effect of oxidative stress. Oral supplementation with antioxidants is thought to improve sperm quality by reducing oxidative damage. Antioxidants are widely available and inexpensive when compared to other fertility treatments, however most antioxidants are uncontrolled by regulation and the evidence for their effectiveness is uncertain. We compared the benefits and risks of different antioxidants used for male subfertility. This review did not examine the use of antioxidants in normospermic men. OBJECTIVES: To evaluate the effectiveness and safety of supplementary oral antioxidants in subfertile men. SEARCH METHODS: The Cochrane Gynaecology and Fertility (CGF) Group trials register, CENTRAL, MEDLINE, Embase, PsycINFO, CINAHL, and two trials registers were searched on 1 February 2018, together with reference checking and contact with study authors and experts in the field to identify additional trials. SELECTION CRITERIA: We included randomised controlled trials (RCTs) that compared any type, dose or combination of oral antioxidant supplement with placebo, no treatment or treatment with another antioxidant, among subfertile men of a couple attending a reproductive clinic. We excluded studies comparing antioxidants with fertility drugs alone and studies that included fertile men attending a fertility clinic because of female partner infertility. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures recommended by Cochrane. The primary review outcome was live birth. Clinical pregnancy, adverse events and sperm parameters were secondary outcomes. MAIN RESULTS: We included 61 studies with a total population of 6264 subfertile men, aged between 18 and 65 years, part of a couple who had been referred to a fertility clinic and some of whom were undergoing assisted reproductive techniques (ART). Investigators compared and combined 18 different oral antioxidants. The evidence was of 'low' to 'very low' quality: the main limitation was that out of the 44 included studies in the meta-analysis only 12 studies reported on live birth or clinical pregnancy. The evidence is current up to February 2018.Live birth: antioxidants may lead to increased live birth rates (OR 1.79, 95% CI 1.20 to 2.67, P = 0.005, 7 RCTs, 750 men, I2 = 40%, low-quality evidence). Results suggest that if in the studies contributing to the analysis of live birth rate, the baseline chance of live birth following placebo or no treatment is assumed to be 12%, the chance following the use of antioxidants is estimated to be between 14% and 26%. However, this result was based on only 124 live births from 750 couples in seven relatively small studies. When studies at high risk of bias were removed from the analysis, there was no evidence of increased live birth (Peto OR 1.38, 95% CI 0.89 to 2.16; participants = 540 men, 5 RCTs, P = 0.15, I2 = 0%).Clinical pregnancy rate: antioxidants may lead to increased clinical pregnancy rates (OR 2.97, 95% CI 1.91 to 4.63, P < 0.0001, 11 RCTs, 786 men, I2 = 0%, low-quality evidence) compared to placebo or no treatment. This suggests that if in the studies contributing to the analysis of clinical pregnancy, the baseline chance of clinical pregnancy following placebo or no treatment is assumed to be 7%, the chance following the use of antioxidants is estimated to be between 12% and 26%. This result was based on 105 clinical pregnancies from 786 couples in 11 small studies.Adverse eventsMiscarriage: only three studies reported on this outcome and the event rate was very low. There was no difference in miscarriage rate between the antioxidant and placebo or no treatment group (OR 1.74, 95% CI 0.40 to 7.60, P = 0.46, 3 RCTs, 247 men, I2 = 0%, very low-quality evidence). The findings suggest that in a population of subfertile men with an expected miscarriage rate of 2%, the chance following the use of an antioxidant would result in the risk of a miscarriage between 1% and 13%.Gastrointestinal: antioxidants may lead to an increase in mild gastrointestinal upsets when compared to placebo or no treatment (OR 2.51, 95% CI 1.25 to 5.03, P = 0.010, 11 RCTs, 948 men, I2 = 50%, very low-quality evidence). This suggests that if the chance of gastrointestinal upsets following placebo or no treatment is assumed to be 2%, the chance following the use of antioxidants is estimated to be between 2% and 9%. However, this result was based on a low event rate of 35 out of 948 men in 10 small or medium-sized studies, and the quality of the evidence was rated very low and was high in heterogeneity.We were unable to draw any conclusions from the antioxidant versus antioxidant comparison as insufficient studies compared the same interventions. AUTHORS' CONCLUSIONS: In this review, there is low-quality evidence from seven small randomised controlled trials suggesting that antioxidant supplementation in subfertile males may improve live birth rates for couples attending fertility clinics. Low-quality evidence suggests that clinical pregnancy rates may also increase. Overall, there is no evidence of increased risk of miscarriage, however antioxidants may give more mild gastrointestinal upsets but the evidence is of very low quality. Subfertilte couples should be advised that overall, the current evidence is inconclusive based on serious risk of bias due to poor reporting of methods of randomisation, failure to report on the clinical outcomes live birth rate and clinical pregnancy, often unclear or even high attrition, and also imprecision due to often low event rates and small overall sample sizes. Further large well-designed randomised placebo-controlled trials reporting on pregnancy and live births are still required to clarify the exact role of antioxidants.

Inositol for subfertile women with polycystic ovary syndrome.

BACKGROUND: Subfertile women are highly motivated to try different adjunctive therapies to have a baby, and the widespread perception is that dietary supplements such as myo-inositol (MI) and D-chiro-insoitol (DCI) are associated with only benefit, and not with harm. Many fertility clinicians currently prescribe MI for subfertile women with polycystic ovary syndrome (PCOS) as pre-treatment to in vitro fertilisation (IVF) or for ovulation induction; however no high-quality evidence is available to support this practice. This review assessed the evidence for the effectiveness of inositol in subfertile women with a diagnosis of PCOS. OBJECTIVES: To evaluate the effectiveness and safety of oral supplementation of inositol for reproductive outcomes among subfertile women with PCOS who are trying to conceive. SEARCH METHODS: We searched the following databases (to July 2018): Cochrane Gynaecology and Fertility Group (CGFG) Specialised Register, CENTRAL, MEDLINE, Embase, PsycINFO, CINAHL, and AMED. We also checked reference lists and searched the clinical trials registries. SELECTION CRITERIA: We included randomised controlled trials (RCTs) that compared any type, dose, or combination of oral inositol versus placebo, no treatment/standard treatment, or treatment with another antioxidant, or with a fertility agent, or with another type of inositol, among subfertile women with PCOS. DATA COLLECTION AND ANALYSIS: Two review authors independently selected eligible studies, extracted data, and assessed risk of bias. The primary outcomes were live birth and adverse effects; secondary outcomes included clinical pregnancy rates and ovulation rates. We pooled studies using a fixed-effect model, and we calculated odds ratios (ORs) with 95% confidence intervals (CIs). We assessed the overall quality of the evidence by applying GRADE criteria. MAIN RESULTS: We included 13 trials involving 1472 subfertile women with PCOS who were receiving myo-inositol as pre-treatment to IVF (11 trials), or during ovulation induction (two trials). These studies compared MI versus placebo, no treatment/standard, melatonin, metformin, clomiphene citrate, or DCI. The evidence was of 'low' to 'very low' quality. The main limitations were serious risk of bias due to poor reporting of methods, inconsistency, and lack of reporting of clinically relevant outcomes such as live birth and adverse events.We are uncertain whether MI improves live birth rates when compared to standard treatment among women undergoing IVF (OR 2.42, 95% CI 0.75 to 7.83; P = 0.14; 2 RCTs; 84 women; I² = 0%). Very low-quality evidence suggests that for subfertile women with PCOS undergoing pre-treatment to IVF who have an expected live birth rate of 12%, the rate among women using MI would be between 9% and 51%.We are uncertain whether MI may be associated with a decrease in miscarriage rate when compared to standard treatment (OR 0.40, 95% CI 0.19 to 0.86; P = 0.02; 4 RCTs; 535 women; I² = 66%; very low-quality evidence). This suggests that among subfertile women with PCOS with an expected miscarriage rate of 9% who are undergoing pre-treatment to IVF, the rate among women using MI would be between 2% and 8%; however this meta-analysis is based primarily on one study, which reported an unusually high miscarriage rate in the control group, and this has resulted in very high heterogeneity. When we removed this trial from the sensitivity analysis, we no longer saw the effect, and we noted no conclusive differences between MI and standard treatment.Low-quality evidence suggests that MI may be associated with little or no difference in multiple pregnancy rates when compared with standard treatment (OR 1.04, 95% CI 0.63 to 1.71; P = 0.89; 2 RCTs; 425 women). This suggests that among subfertile women with PCOS who are undergoing pre-treatment to IVF, with an expected multiple pregnancy rate of 18%, the rate among women using inositol would be between 12% and 27%.We are uncertain whether MI may be associated with an increased clinical pregnancy rate when compared to standard treatment (OR 1.27, 95% CI 0.87 to 1.85; P = 0.22; 4 RCTs; 535 women; I² = 0%; very low-quality evidence). This suggests that among subfertile women with PCOS who are undergoing pre-treatment to IVF, with an expected clinical pregnancy rate of 26%, the rate among women using MI would be between 24% and 40%. Ovulation rates were not reported for this comparison.Other comparisons included only one trial in each, so for the comparisons MI versus antioxidant, MI versus an insulin-sensitising agent, MI versus an ovulation induction agent, and MI versus another DCI, meta-analysis was not possible.No pooled evidence was available for women with PCOS undergoing ovulation induction, as only single trials performed comparison of the insulin-sensitising agent and the ovulation induction agent. AUTHORS' CONCLUSIONS: In light of available evidence of very low quality, we are uncertain whether MI improves live birth rate or clinical pregnancy rate in subfertile women with PCOS undergoing IVF pre-treatment taking MI compared to standard treatment. We are also uncertain whether MI decreases miscarriage rates or multiple pregnancy rates for these same women taking MI compared to standard treatment. No pooled evidence is available for use of MI versus placebo, another antioxidant, insulin-sensitising agents, ovulation induction agents, or another type of inositol for women with PCOS undergoing pre-treatment to IVF. No pooled evidence is available for use of MI in women undergoing ovulation induction.

Clinical trial registration in fertility trials - a case for improvement?

STUDY QUESTION: What is the prevalence and source of prospectively and retrospectively registered and unregistered trials in fertility treatments? SUMMARY ANSWER: Trial registration is low and does not appear to be changing over the 5 years studied. WHAT IS KNOWN ALREADY: Trial registration is associated with lower risk of bias than in unregistered trials. STUDY DESIGN, SIZE, DURATION: The Cochrane Gynaecology and Fertility Group's specialised register was searched on 5 November 2015 for randomised controlled trials (RCTs) published from January 2010 to December 2014. PARTICIPANTS/MATERIALS, SETTING, METHODS: Eligible trials included randomised women or men for fertility treatments, were published in full text, and written in English. Two reviewers independently assessed trial registration status for each trial, by searching the publication, trial registries, and by contacting the original authors. MAIN RESULTS AND ROLE OF CHANCE: Of 693 eligible RCTS, only 44% were registered trials. Of 309 registered trials, 21.7% were prospectively registered, 15.8% were registered within 6 months of first patient enrolment and 62.5% were retrospectively registered trials. Prospective trial registration by country varied from 0% to 100%. The highest frequency of prospective trial registration amongst the top 10 publishing countries was 31% in the Netherlands. LIMITATIONS, REASONS FOR CAUTION: Only English language trials were included in this review. WIDER IMPLICATIONS OF THE FINDINGS: Prospective trial registration is still low. Journals, funders and ethics committees could have a greater role to increase trial registration. STUDY FUNDING/COMPETING INTERESTS: University of Auckland. No competing interests.

Antioxidants for female subfertility.

BACKGROUND: A couple may be considered to have fertility problems if they have been trying to conceive for over a year with no success. This may affect up to a quarter of all couples planning a child. It is estimated that for 40% to 50% of couples, subfertility may result from factors affecting women. Antioxidants are thought to reduce the oxidative stress brought on by these conditions. Currently, limited evidence suggests that antioxidants improve fertility, and trials have explored this area with varied results. This review assesses the evidence for the effectiveness of different antioxidants in female subfertility. OBJECTIVES: To determine whether supplementary oral antioxidants compared with placebo, no treatment/standard treatment or another antioxidant improve fertility outcomes for subfertile women. SEARCH METHODS: We searched the following databases (from their inception to September 2016) with no language or date restriction: Cochrane Gynaecology and Fertility Group (CGFG) specialised register, the Cochrane Central Register of Studies (CENTRAL CRSO), MEDLINE, Embase, PsycINFO, CINAHL and AMED. We checked reference lists of appropriate studies and searched for ongoing trials in the clinical trials registers. SELECTION CRITERIA: We included randomised controlled trials (RCTs) that compared any type, dose or combination of oral antioxidant supplement with placebo, no treatment or treatment with another antioxidant, among women attending a reproductive clinic. We excluded trials comparing antioxidants with fertility drugs alone and trials that only included fertile women attending a fertility clinic because of male partner infertility. DATA COLLECTION AND ANALYSIS: Two review authors independently selected eligible studies, extracted the data and assessed the risk of bias of the included studies. The primary review outcome was live birth; secondary outcomes included clinical pregnancy rates and adverse events. We pooled studies using a fixed-effect model, and calculated odds ratios (ORs) with 95% confidence intervals (CIs) for the dichotomous outcomes of live birth, clinical pregnancy and adverse events. We assessed the overall quality of the evidence by applying GRADE criteria. MAIN RESULTS: We included 50 trials involving 6510 women. Investigators compared oral antioxidants, including combinations of antioxidants, N-acetyl-cysteine, melatonin, L-arginine, myo-inositol, D-chiro-inositol, carnitine, selenium, vitamin E, vitamin B complex, vitamin C, vitamin D+calcium, CoQ10, pentoxifylline and omega-3-polyunsaturated fatty acids versus placebo, no treatment/standard treatment or another antioxidant.Very low-quality evidence suggests that antioxidants may be associated with an increased live birth rate compared with placebo or no treatment/standard treatment (OR 2.13, 95% CI 1.45 to 3.12, P > 0.001, 8 RCTs, 651 women, I2 = 47%). This suggests that among subfertile women with an expected live birth rate of 20%, the rate among women using antioxidants would be between 26% and 43%.Very low-quality evidence suggests that antioxidants may be associated with an increased clinical pregnancy rate compared with placebo or no treatment/standard treatment (OR 1.52, 95% CI 1.31 to 1.76, P < 0.001, 26 RCTs, 4271 women, I2 = 66%). This suggests that among subfertile women with an expected clinical pregnancy rate of 22%, the rate among women using antioxidants would be between 27% and 33%. Heterogeneity was moderately high.There was insufficient evidence to determine whether there was a difference between the groups in rates of miscarriage (OR 0.79, 95% CI 0.58 to 1.08, P = 0.14, 18 RCTs, 2834 women, I2 = 23%, very low quality evidence). This suggests that, among subfertile women with an expected miscarriage rate of 7%, use of antioxidants would be expected to result in a miscarriage rate of between 4% and 7%. There was also insufficient evidence to determine whether there was a difference between the groups in rates of multiple pregnancy (OR 1.00, 95% CI 0.73 to 1.38, P = 0.98, 8 RCTs, 2163 women, I2 = 4%, very low quality evidence). This suggests that among subfertile women with an expected multiple pregnancy rate of 8%, use of antioxidants would be expected to result in a multiple pregnancy rate between 6% and 11%. Likewise, there was insufficient evidence to determine whether there was a difference between the groups in rates of gastrointestinal disturbances (OR 1.55, 95% CI 0.47 to 5.10, P = 0.47, 3 RCTs, 343 women, I2 = 0%, very low quality evidence). This suggests that among subfertile women with an expected gastrointestinal disturbance rate of 2%, use of antioxidants would be expected to result in a rate between 1% and 11%. Overall adverse events were reported by 35 trials in the meta-analysis, but there was insufficient evidence to draw any conclusions.Only one trial reported on live birth, clinical pregnancy or adverse effects in the antioxidant versus antioxidant comparison, and no conclusions could be drawn.Very low-quality evidence suggests that pentoxifylline may be associated with an increased clinical pregnancy rate compared with placebo or no treatment (OR 2.07, 95% CI 1.20 to 3.56, P = 0.009, 3 RCTs, 276 women, I2 = 0%). This suggests that among subfertile women with an expected clinical pregnancy rate of 25%, the rate among women using pentoxifylline would be between 28% and 53%.There was insufficient evidence to determine whether there was a difference between the groups in rates of miscarriage (OR 1.34, 95% CI 0.46 to 3.90, P = 0.58, 3 RCTs, 276 women, I2 = 0%) or multiple pregnancy (OR 0.78, 95% CI 0.20 to 3.09, one RCT, 112 women, very low quality evidence). This suggests that among subfertile women with an expected miscarriage rate of 4%, the rate among women using pentoxifylline would be between 2% and 15%. For multiple pregnancy, the data suggest that among subfertile women with an expected multiple pregnancy rate of 9%, the rate among women using pentoxifylline would be between 2% and 23%.The overall quality of evidence was limited by serious risk of bias associated with poor reporting of methods, imprecision and inconsistency. AUTHORS' CONCLUSIONS: In this review, there was very low-quality evidence to show that taking an antioxidant may provide benefit for subfertile women, but insufficient evidence to draw any conclusions about adverse events. At this time, there is limited evidence in support of supplemental oral antioxidants for subfertile women.

Intravenous in-line filters for preventing morbidity and mortality in neonates.

BACKGROUND: Venous access is an essential part of caring for the sick neonate. However, problems such as contamination of fluids with bacteria, endotoxins and particulates have been associated with intravenous infusion therapy. Intravenous in-line filters claim to be an effective strategy for the removal of bacteria, endotoxins and particulates associated with intravenous therapy in adults and are increasingly being recommended for use in neonates. OBJECTIVES: To determine the effect of intravenous in-line filters on morbidity and mortality in neonates. SEARCH METHODS: We used the standard search strategy of the Cochrane Neonatal Review Group. We searched the electronic databases MEDLINE (from 1966 to May, 2015), EMBASE (from 1980 to May, 2015), CINAHL (from 1982 to May 2015) and the Cochrane Central Register of Controlled Trials (CENTRAL; 2015, Issue 5). We did not impose any language restrictions. Further searching included cross references, abstracts, conferences, symposia proceedings, expert informants and journal handsearching. SELECTION CRITERIA: We included randomised controlled trials (RCTs) or quasi-RCTs that compared the use of intravenous in-line filters with placebo or nothing in neonates. DATA COLLECTION AND ANALYSIS: We followed the procedures of the Cochrane Neonatal Review Group throughout. We checked titles and abstracts identified from the search. We obtained the full text of all studies of possible relevance. We independently assessed the trials for their methodological quality and subsequent inclusion in the review. We contacted authors for further information as needed. Statistical analysis followed the procedures of the Cochrane Neonatal Review Group. MAIN RESULTS: There were four eligible studies that recruited a total of 704 neonates. This review of low to very low quality evidence found that the use of in-line filters compared with unfiltered fluids for intravenous infusion had no statistically significant difference in effectiveness on overall mortality (typical RR 0.87, 95% CI 0.52 to 1.47; typical RD -0.01, 95% CI -0.06 to 0.04; two studies, 530 infants), proven and suspect septicaemia (typical RR 0.86, 95% CI 0.59 to 1.27; typical RD -0.02, 95% CI -0.09 to 0.04; two studies, 530 infants), or other secondary outcomes (including local phlebitis and thrombus, necrotising enterocolitis, duration of cannula patency, length of stay in hospital, number of catheters inserted and financial costs). AUTHORS' CONCLUSIONS: There is insufficient evidence to recommend the use of intravenous in-line filters to prevent morbidity and mortality in neonates.

Antioxidants for male subfertility.

BACKGROUND: Between 30% to 80% of male subfertility cases are considered to be due to the damaging effects of oxidative stress on sperm and 1 man in 20 will be affected by subfertility. Antioxidants are widely available and inexpensive when compared to other fertility treatments and many men are already using these to improve their fertility. It is thought that oral supplementation with antioxidants may improve sperm quality by reducing oxidative stress. Pentoxifylline, a drug that acts like an antioxidant, was also included in this review.   OBJECTIVES: This Cochrane review aimed to evaluate the effectiveness and safety of oral supplementation with antioxidants for subfertile male partners in couples seeking fertility assistance. SEARCH METHODS: We searched the Cochrane Menstrual Disorders and Subfertility Group Specialised Register, CENTRAL, MEDLINE, EMBASE, CINAHL, PsycINFO and AMED databases (from inception until January 2014); trial registers; sources of unpublished literature and reference lists. An updated search was run in August 2014 when potentially eligible studies were placed in 'Studies awaiting assessment'. SELECTION CRITERIA: We included randomised controlled trials (RCTs) comparing any type or dose of antioxidant supplement (single or combined) taken by the subfertile male partner of a couple seeking fertility assistance with a placebo, no treatment or another antioxidant. DATA COLLECTION AND ANALYSIS: Two review authors independently selected eligible studies, extracted the data and assessed the risk of bias of the included studies. The primary review outcome was live birth; secondary outcomes included clinical pregnancy rates, adverse events, sperm DNA fragmentation, sperm motility and concentration. Data were combined, where appropriate, to calculate pooled odds ratios (ORs) or mean differences (MD) and 95% confidence intervals (CIs). Statistical heterogeneity was assessed using the I(2) statistic. We assessed the overall quality of the evidence for the main outcomes using GRADE methods.   MAIN RESULTS: This updated review included 48 RCTs that compared single and combined antioxidants with placebo, no treatment or another antioxidant in a population of 4179 subfertile men. The duration of the trials ranged from 3 to 26 weeks with follow up ranging from 3 weeks to 2 years. The men were aged from 20 to 52 years. Most of the men enrolled in these trials had low total sperm motility and sperm concentration. One study enrolled men after varicocelectomy, one enrolled men with a varicocoele, and one recruited men with chronic prostatitis. Three trials enrolled men who, as a couple, were undergoing in vitro fertilisation (IVF) or intracytoplasmic sperm injection (ICSI) and one trial enrolled men who were part of a couple undergoing intrauterine insemination (IUI). Funding sources were stated by 15 trials. Four of these trials stated that funding was from a commercial source and the remaining 11 obtained funding through non-commercial avenues or university grants. Thirty-three trials did not report any funding sources.A limitation of this review was that in a sense we had included two different groups of trials, those that reported on the use of antioxidants and the effect on live birth and clinical pregnancy, and a second group that reported on sperm parameters as their primary outcome and had no intention of reporting the primary outcomes of this review. We included 25 trials reporting on sperm parameters and only three of these reported on live birth or clinical pregnancy. Other limitations included poor reporting of study methods, imprecision, the small number of trials providing usable data, the small sample size of many of the included studies and the lack of adverse events reporting. The evidence was graded as 'very low' to 'low'. The data were current to 31 January 2014.Live birth: antioxidants may have increased live birth rates (OR 4.21, 95% CI 2.08 to 8.51, P< 0.0001, 4 RCTs, 277 men, I(2) = 0%, low quality evidence). This suggests that if the chance of a live birth following placebo or no treatment is assumed to be 5%, the chance following the use of antioxidants is estimated to be between 10% and 31%. However, this result was based on only 44 live births from a total of 277 couples in four small studies.Clinical pregnancy rate: antioxidants may have increased clinical pregnancy rates (OR 3.43, 95% CI 1.92 to 6.11, P < 0.0001, 7 RCTs, 522 men, I(2) = 0%, low quality evidence). This suggests that if the chance of clinical pregnancy following placebo or no treatment is assumed to be 6%, the chance following the use of antioxidants is estimated at between 11% and 28%. However, there were only seven small studies in this analysis and the quality of the evidence was rated as low.Miscarriage: only three trials reported on this outcome and the event rate was very low. There was insufficient evidence to show whether there was a difference in miscarriage rates between the antioxidant and placebo or no treatment groups (OR 1.74, 95% CI 0.40 to 7.60, P = 0.46, 3 RCTs, 247 men, I(2) = 0%, very low quality evidence). The findings suggest that in a population of subfertile men with an expected miscarriage rate of 2%, use of an antioxidant would result in the risk of a miscarriage lying between 1% and 13%.Gastrointestinal upsets: there was insufficient evidence to show whether there was a difference in gastrointestinal upsets when antioxidants were compared to placebo or no treatment as the event rate was very low (OR 1.60, 95% CI 0.47 to 5.50, P = 0.46, 6 RCTs, 429 men, I(2) = 0%).We were unable to draw any conclusions from the antioxidant versus antioxidant comparison as not enough trials compared the same interventions. AUTHORS' CONCLUSIONS: There is low quality evidence from only four small randomised controlled trials suggesting that antioxidant supplementation in subfertile males may improve live birth rates for couples attending fertility clinics. Low quality evidence suggests that clinical pregnancy rates may increase. There is no evidence of increased risk of miscarriage but this is uncertain as the evidence is of very low quality. Data were lacking on other adverse effects. Further large well-designed randomised placebo-controlled trials are needed to clarify these results.

Antioxidants for female subfertility.

BACKGROUND: A couple may be considered to have fertility problems if they have been trying to conceive for over a year with no success. This difficulty with conception may affect up to a quarter of all couples planning a child. The reported prevalence of subfertility has increased significantly over the past twenty years. It is estimated that for 40% to 50% of couples, subfertility may be a result of female problems, including ovulatory disorders, poor egg quality, fallopian tube damage and endometriosis. Antioxidants are thought to reduce the oxidative stress brought on by these conditions. Currently, limited evidence suggests that antioxidants improve fertility, and trials have explored this area with varied results. This review assessed the evidence for the effectiveness of different antioxidants in female subfertility. OBJECTIVES: To determine whether supplementary oral antioxidants compared with placebo, no treatment/standard treatment or another antioxidant improve fertility outcomes for subfertile women. SEARCH METHODS: We searched the following databases (from inception to April 2013) with no language restrictions applied: Cochrane Menstrual Disorders and Subfertility Group Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, PsycINFO, CINAHL, LILACS and OpenSIGLE. We also searched conference abstracts and citation lists in the ISI Web of Knowledge. Ongoing trials were searched in the Trials Registers. Reference lists were checked, and a search on Google was performed. SELECTION CRITERIA: We included randomised controlled trials (RCTs) that compared any type, dose or combination of oral antioxidant supplement with placebo, no treatment or treatment with another antioxidant, among women attending a reproductive clinic. Trials comparing antioxidants with fertility drugs alone and trials that exclusively included fertile women attending a fertility clinic because of male partner infertility were excluded. DATA COLLECTION AND ANALYSIS: Three review authors independently screened 2127 titles and abstracts, and 67 of these potentially eligible trials were appraised for inclusion and quality through review of full texts and contact with authors. Three review authors were involved in data extraction and assessment of risk of bias. Review authors also collected data on adverse events as reported from the trials. Studies were pooled using fixed-effect models; however, if high heterogeneity was found, a random-effects model was used. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated for the dichotomous outcomes of live birth, clinical pregnancy and adverse events. Analyses were stratified by type of antioxidant, by indications for subfertility and by those women also undergoing in vitro fertilisation (IVF) or intracytoplasmic sperm injection techniques (ICSIs). The overall quality of the evidence was assessed by applying GRADE criteria. MAIN RESULTS: A total of 28 trials involving 3548 women were included in this review. Investigators compared oral antioxidants, including combinations of antioxidants, pentoxifylline, N-acetyl-cysteine, melatonin, L-arginine, vitamin E, myo-inositol, vitamin C, vitamin D+calcium and omega-3-polyunsaturated fatty acids with placebo, with no treatment/standard treatment or another antioxidant.Antioxidants were not associated with an increased live birth rate compared with placebo or no treatment/standard treatment (OR 1.25, 95% CI 0.19 to 8.26, P = 0.82, 2 RCTs, 97 women, I(2) = 75%, very low-quality evidence). This suggests that among subfertile women with an expected live birth rate of 37%, the rate among women taking antioxidants would be between 10% and 83%.Antioxidants were not associated with an increased clinical pregnancy rate compared with placebo or no treatment/standard treatment (OR 1.30, 95% CI 0.92 to 1.85, P = 0.14, 13 RCTs, 2441 women, I(2)= 55%, very low-quality evidence). This suggests that among subfertile women with an expected clinical pregnancy rate of 23%, the rate among women taking antioxidants would be between 22% and 36%.Only one trial reported on live birth in the antioxidant versus antioxidant comparison, and two trials reported on clinical pregnancy in this comparison. Only subtotals were used in this analysis, and meta-analysis was not possible as each trial used a different antioxidant.Pentoxifylline was associated with an increased clinical pregnancy rate compared with placebo or no treatment (OR 2.03, 95% CI 1.19 to 3.44, P = 0.009, 3 RCTs, 276 women, I(2) = 0%).Adverse events were reported by 14 trials in the meta-analysis and included miscarriage, multiple pregnancy, ectopic pregnancy and gastrointestinal effects. No evidence revealed a difference in adverse effects between antioxidant groups and control groups, but these data were limited.The overall quality of evidence was 'very low' to 'low' because of poor reporting of outcomes, the number of small studies included, high risk of bias within studies and heterogeneity in the primary analysis. AUTHORS' CONCLUSIONS: The quality of the evidence in the 'antioxidant versus placebo/no treatment' and in the 'antioxidant versus antioxidant' comparisons was assessed to be 'very low'. Antioxidants were not associated with an increased live birth rate or clinical pregnancy rate. There was some evidence of an association of pentoxifylline with an increased clinical pregnancy rate; however, there were only three trials included in this comparison. Future trials may change this result. Variation in the types of antioxidants given meant that we could not assess whether one antioxidant was better than another. There did not appear to be any association of antioxidants with adverse effects for women, but data for these outcomes were limited.

New research questions identified for Cochrane reviews: a cross-sectional study of a specialized register: part two: fertility.

OBJECTIVES: The aim of this project was to identify gaps and research waste in the dissemination of fertility evidence in Cochrane systematic reviews (CSRs). STUDY DESIGN AND SETTING: A cross-sectional study of The Cochrane Gynecology and Fertility (CGF) Group's specialized register of randomized controlled trials (RCTs). We included trials on fertility problems published in 2010 and 2011. These trials were matched, by the condition and treatment, to existing CSRs. Unmatched trials were analyzed to prioritize new review titles. RESULTS: We exported 564 trials from the CGF specialized register and found that 115 (23%) of these could be included in an existing CSR if these were updated while 72 trials (14%) were not matched to any review topic, and from these, eight new Cochrane review titles were developed. The topic with the largest number of associated 'unused' trials was 'Traditional Chinese medicine for women undergoing assisted reproductive techniques'. CONCLUSION: This project found that 14% of fertility trials were 'unused' and from these we identified new review topics and identified those reviews that need to be updated, thereby identifying the gaps in evidence for people with infertility.

New research questions identified for Cochrane reviews: a cross-sectional study of a specialized register: part one: gynecology.

OBJECTIVES: The aim of this project was to identify gaps and research waste in the dissemination of gynecology evidence in Cochrane systematic reviews (CSRs). STUDY DESIGN AND SETTING: A cross-sectional study of the Cochrane Gynecology and Fertility (CGF) Group's specialized register of randomized controlled trials (RCTs). We included trials on benign gynecological conditions, published in 2010 and 2011. These trials were matched, by the condition and treatment, to existing Cochrane reviews. Unmatched trials were analysed to prioritize new review titles. RESULTS: After exporting 740 trials from the CGF specialized register, we found that 192 (26%) could be included in an existing CSR if it was updated, whereas 230 trials (32%) were not matched to any review title, and from these, we developed 21 new review titles. The topic with the largest number of associated 'unused' trials was 'Plant and herbal extracts for symptoms of menopause'. CONCLUSIONS: We found that a third of the benign gynecology trials published in 2010 and 2011 had no associated CSR. After identifying new topics from unmatched trials, we developed new CSR titles. This study identified the gaps in the evidence for women with gynecological problems.

Reporting of Cochrane systematic review protocols with network meta-analyses-A scoping review.

Publishing systematic review protocols is a fundamental part of systematic reviews to ensure transparency and reproducibility. In this scoping review, we aimed to evaluate reporting of Cochrane systematic review protocols with network meta-analyses (NMA). We searched all Cochrane NMA protocols published in 2018 and 2019, and assessed the characteristics and reporting of methodologies relevant to NMA. We reported frequencies for each reporting item. Forty-five protocols were assessed, including two for overviews and 43 for intervention reviews. Thirty-three (73%) were labelled as NMA protocols in the title. Forty-two (95%) justified the need of an NMA and 40 (89%) used appropriate search strategies to identify potential eligible studies. About half (24, 53%) considered the transitivity assumption when reporting inclusion criteria and 35 (78%) specified potential effect modifiers. Forty-three (96%) reported statistical software for NMA, 25 (56%) reported NMA model choice, 32 (71%) reported framework choice and 32 (71%) reported assumption about heterogeneity variances. Protocols varied in whether they reported methods for relative ranking (35, 78%), statistical inconsistency (40, 89%), reporting bias (44, 98%) and sources of heterogeneity (39, 87%). In conclusion, Cochrane NMA protocols reported multiple NMA-specific items well, but could be further improved, especially regarding transitivity assumptions. Our recommendations for NMA protocol reporting based on this scoping review could assist authors, reviewers, and editors to improve NMA protocols.

Individual participant data meta-analysis of trials comparing frozen versus fresh embryo transfer strategy (INFORM): a protocol.

INTRODUCTION: Existing randomised controlled trials (RCTs) comparing a freeze-all embryo transfer strategy and a fresh embryo transfer strategy have shown conflicting results. A freeze-all or a fresh transfer policy may be preferable for some couples undergoing in-vitro fertilisation (IVF), but it is unclear which couples would benefit most from each policy, how and under which protocols. Therefore, we plan a systematic review and individual participant data meta-analysis of RCTs comparing a freeze-all and a fresh transfer policy. METHODS AND ANALYSIS: We will search electronic databases (Medline, Embase, PsycINFO and CENTRAL) and trial registries (ClinicalTrials.gov and the International Clinical Trials Registry Platform) from their inception to present to identify eligible RCTs. We will also check reference lists of relevant papers. The search was performed on 23 September 2020 and will be updated. We will include RCTs comparing a freeze-all embryo transfer strategy and a fresh embryo transfer strategy in couples undergoing IVF. The primary outcome will be live birth resulting from the first embryo transfer. All outcomes listed in the core outcome set for infertility research will be reported. We will invite the lead investigators of eligible trials to join the Individual participant data meta-analysis of trials comparing frozen versus fresh embryo transfer strategy (INFORM) collaboration and share the deidentified individual participant data (IPD) of their trials. We will harmonise the IPD and perform a two-stage meta-analysis and examine treatment-covariate interactions for important baseline characteristics. ETHICS AND DISSEMINATION: The study ethics have been granted by the Monash University Human Research Ethics Committee (Project ID: 30391). The findings will be disseminated via presentations at international conferences and publication in peer-reviewed journals. PROSPERO REGISTRATION NUMBER: CRD42021296566.

Antioxidants for male subfertility.

BACKGROUND: Between 30% to 80% of male subfertility cases are considered to be due to the damaging effects of oxidative stress on sperm. Oral supplementation with antioxidants may improve sperm quality by reducing oxidative stress.   OBJECTIVES: This Cochrane review aimed to evaluate the effect of oral supplementation with antioxidants for male partners of couples undergoing assisted reproduction techniques (ART). SEARCH STRATEGY: We searched the Cochrane Menstrual Disorders and Subfertility Group Register, CENTRAL (The Cochrane Library), MEDLINE, EMBASE, CINAHL, PsycINFO and AMED databases (from their inception until Febuary 2010), trial registers, sources of unpublished literature, reference lists and we asked experts in the field. SELECTION CRITERIA: We included randomised controlled trials comparing any type or dose of antioxidant supplement (single or combined) taken by the male partner of a couple seeking fertility assistance with placebo, no treatment or another antioxidant. The outcomes were live birth, pregnancy, miscarriage, stillbirth, sperm DNA damage, sperm motility, sperm concentration and adverse effects. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed studies for inclusion and trial quality, and extracted data.   MAIN RESULTS: We included 34 trials with 2876 couples in total. Live birth: three trials reported live birth. Men taking oral antioxidants had an associated statistically significant increase in live birth rate (pooled odds ratio (OR) 4.85, 95% CI 1.92 to 12.24; P = 0.0008, I(2) = 0%) when compared with the men taking the control. This result was based on 20 live births from a total of 214 couples in only three studies.Pregnancy rate: there were 96 pregnancies in 15 trials including 964 couples. Antioxidant use was associated with a statistically significant increased pregnancy rate compared to control (pooled OR 4.18, 95% CI 2.65 to 6.59; P < 0.00001, I(2) = 0%).Side effects: no studies reported evidence of harmful side effects of the antioxidant therapy used. AUTHORS' CONCLUSIONS: The evidence suggests that antioxidant supplementation in subfertile males may improve the outcomes of live birth and pregnancy rate for subfertile couples undergoing ART cycles. Further head to head comparisons are necessary to identify the superiority of one antioxidant over another.

Antioxidants in fertility: impact on male and female reproductive outcomes.

A couple may be considered to have fertility problems if they have been trying to conceive for over 1 year with no success. Worldwide, the inability to have children affects 10% to 15% of all couples. Subfertility can be divided into either male or female factor, or both partners can be affected. However, for some couples the cause for subfertility cannot be identified, and this is called unexplained subfertility. It is thought that oxidative stress is involved in the pathophysiology of subfertility, and antioxidants are thought to reduce the damage caused by oxidative stress. Antioxidants are widely available and inexpensive. However, there is currently little high-quality evidence to show that taking antioxidants will provide any benefit or harm for infertile couples.

Clinical trial registration was not an indicator for low risk of bias.

OBJECTIVES: To determine the prevalence of registered trials and to evaluate the risk of bias between registered and unregistered clinical trials. STUDY DESIGN AND SETTING: The Cochrane Gynecology and Fertility Group's specialized register was searched on November 5, 2015, for randomized controlled trials published from 2010 to 2014. Studies were selected if they had randomized women or men for fertility treatments, were published in full text and written in English. Two reviewers then independently assessed trial registration status for each trial, by searching the publication, trial registries, and by contacting the original authors. RESULTS: Of 693 eligible randomized controlled trials, only 44% were found to be registered. Unregistered clinical trials had smaller sample sizes than registered trials (P < 0.001). A random subsample of 125 registered and 125 unregistered trials was assessed for risk of bias using five of the Cochrane Risk of Bias "domains." Registered and unregistered trials differed in their risk of bias for random sequence generation (P = 0.001), allocation concealment (P = 0.003), and selective reporting (P < 0.001) but not blinding or incomplete outcome data (P > 0.05) domains. Only 54 (43.2%) of the 125 registered trials were registered prospectively. This study has the following limitations. Only English language trials were included in this review. We were unable to obtain protocols for the unregistered trials and therefore were unable to assess the risk of bias in the selective reporting domain. CONCLUSIONS: All available trials should be included in systematic reviews and assessed for risk of bias as there are both registered trials with high risk of bias and unregistered trials with low risk of bias and by excluding unregistered trials more than half of the available evidence will be lost.