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-certainty 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 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 90 randomised controlled trials comparing 18 different antioxidants with placebo, no treatment or another antioxidant in a total population of 10,303 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 2021.
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, 16 couples would have a baby. In subfertile men taking antioxidants, between 17 and 27 per 100 couples would have a baby. If studies with high risk of bias were removed from the analysis, there was no evidence of increased live birth in the population taking antioxidants. In the people who were studied for clinical pregnancy, we would expect that out of 100 subfertile men not taking antioxidants, 15 couples would have a clinical pregnancy. In subfertile men taking antioxidants, between 20 and 30 per 100 couples would have a clinical pregnancy. Adverse events were poorly reported. Only six studies reported miscarriage. In these studies, miscarriage did not occur more often in the group using antioxidants when compared with the group with placebo or no treatment. However, there is insufficient evidence to draw conclusions about antioxidant use and the risk of miscarriage. The use of antioxidants may be associated with more mild stomach discomfort, with a frequency of 2% in subfertile men not taking antioxidants, and between 2% and 7% in men taking antioxidants. The oral supplements may cause discomforts such as nausea or stomach ache.
Authors' conclusion and certainty 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 certainty of evidence was very low from only 12 small to medium-sized randomised controlled trials. Low-certainty evidence suggests that clinical pregnancy rates may increase. Overall, there is no evidence of increased risk of miscarriage. Evidence of low certainty suggests that antioxidants may be associated with more gastrointestinal discomfort. Subfertile couples should be advised that overall the current evidence is inconclusive due to the poor reporting of methods, failure to report on live birth and clinical pregnancy rate, imprecision due to low event rates, high number of dropouts and small study group sizes. 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.
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.
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.
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, 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.
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.
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 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.
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.