Do supplementary oral antioxidants compared with placebo, no treatment or another antioxidant improve fertility outcomes for subfertile men?
A couple may be considered to have fertility problems if they have been trying to conceive for over a year with no success. Many subfertile men undergoing fertility treatment also take dietary supplements in the hope of improving their fertility. Fertility treatment can be a very stressful time for men and their partners. It is important that these couples have access to high-quality evidence that will allow them to make informed decisions on whether to take a supplemental antioxidant. This is especially important, as most antioxidant supplements are uncontrolled by regulation. This review aimed to assess whether supplements with oral antioxidants, taken by the subfertile men, would increase the chances of a couple to achieve a (clinical) pregnancy confirmed by ultrasound and ultimately the birth of a baby (live birth). This review did not examine the use of antioxidants in men with normal sperm.
Cochrane authors conducted a review including 61 randomised controlled trials comparing 18 different antioxidants with placebo, no treatment or another antioxidant in a total population of 6264 subfertile men. The age range of the participants was 18 to 65 years; they were part of a couple who had been referred to a fertility clinic and some were undergoing fertility treatment. The evidence is current to February 2018.
Antioxidants may be associated with an increased live birth and clinical pregnancy rate. Based on the studied population for live birth, we would expect that out of 100 subfertile men not taking antioxidants, 12 couples would have a baby, compared with between 14 and 26 couples per 100 who would have a baby if taking antioxidants. If studies with high risk were removed from the analysis, there was no evidence of increased live birth. In the people who were studied for clinical pregnancy, we would expect that out of 100 subfertile men not taking antioxidants, seven couples would have a clinical pregnancy, compared with between 12 and 26 couples per 100 who would have a clinical pregnancy if taking antioxidants. Adverse events were poorly reported. However based on three studies, we could conclude that miscarriage did not occur more often if taking antioxidants. The use of antioxidants could give more gastrointestinal upsets, meaning that we expect that out of 100 subfertile men not taking antioxidants, two would have gastrointestinal upsets compared to between two and nine men if taking antioxidants.
Authors' conclusion and quality of the evidence
Antioxidant supplementation taken by subfertile males of a couple attending a fertility clinic may increase the chance of a live birth, however the overall quality of evidence was low from only seven small randomised controlled trials. Low-quality evidence also suggests that clinical pregnancy rates may increase. Overall, there is no evidence of increased risk of miscarriage, however evidence of very low quality suggest that antioxidants may give more mild gastrointestinal upsets. Subfertile couples should be advised that overall the current evidence is inconclusive due to the poor reporting of methods, failure to report on the clinical outcomes live birth rate and clinical pregnancy, and furthermore imprecision due to often low event rates, high number of dropouts and small study group 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.
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.
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.
To evaluate the effectiveness and safety of supplementary oral antioxidants in subfertile men.
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.
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.
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.
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.
Miscarriage: 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.