Review question: do supplementary oral antioxidants improve fertility outcomes for subfertile men when compared with placebo, no treatment or another antioxidant?
Background: many subfertile men who are part of a couple undergoing fertility treatment are also taking dietary supplements in the hope of improving their fertility. It is important that these men have access to high quality evidence that informs them on the benefits and risks of taking an antioxidant. This review aimed to assess whether oral antioxidants would increase the chances of a couple with a subfertile male partner achieving a clinical pregnancy and ultimately a live birth. This review did not examine the use of antioxidants in men with normal sperm.
Study characteristics: the Cochrane review authors included in this updated review 48 randomised controlled trials 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 (surgical removal of an engorged vein in the scrotum), one enrolled men with a varicocoele (an engorged vein in the scrotum) and one recruited men with chronic prostatitis (infection of the prostate gland). 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). The data were current to 31 January 2014.
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 sources or university grants. Thirty-three trials did not report any funding sources.
Key results: antioxidants may have been effective in treating subfertile men but the reporting of studies was too inconsistent to be confident in these findings. The live birth results suggest that we would expect a live birth of a baby for 5 out of 100 subfertile men who did not take any antioxidants, compared to between 10 and 31 out of 100 men who were taking antioxidants. The results for the clinical pregnancy rate showed an expected clinical pregnancy for 6 out of 100 subfertile men who did not take any antioxidants, compared to between 11 and 28 out of 100 men who were taking antioxidants. Adverse events were poorly reported and we could not make conclusions on any harmful effects. More high quality, larger placebo-controlled trials reporting on these outcomes and adverse events are needed to draw definite conclusions.
Quality of the evidence: the quality of the evidence for live birth and clinical pregnancy was deemed 'low' while adverse events was assessed as 'very low'. These 'low' and 'very low' assessments were due to the lack of a clear description of trial methods and inconsistent, inadequate reporting of live births and clinical pregnancies. Not enough trials compared the same interventions to make any conclusions about whether one intervention worked better than the other.
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.
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.
This Cochrane review aimed to evaluate the effectiveness and safety of oral supplementation with antioxidants for subfertile male partners in couples seeking fertility assistance.
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'.
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.
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 I2 statistic. We assessed the overall quality of the evidence for the main outcomes using GRADE methods.
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, I2 = 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, I2 = 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, I2 = 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, I2 = 0%).
We were unable to draw any conclusions from the antioxidant versus antioxidant comparison as not enough trials compared the same interventions.