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, I 2 = 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, I 2 = 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, I 2
= 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 events
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, I
2 = 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, I 2 = 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. 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. Antioxidants for male subfertility Review
question
Do supplementary oral antioxidants compared with placebo, no treatment or another
antioxidant improve fertility outcomes for subfertile men? Background
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. Study characteristics
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.
Main results
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.