Antioxidants for male subfertility

Marian G Showell; Rebecca Mackenzie‐Proctor; Julie Brown; Anusch Yazdani; Marcin T Stankiewicz; Roger J Hart

doi:10.1002/14651858.CD007411.pub3

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Figure 1

Study flow diagram.

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Figure 2

Methodological quality graph: review authors' judgements about each methodological quality item presented as percentages across all included studies.

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Figure 3

Methodological quality summary: review authors' judgements about each methodological quality item for each included study.

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Figure 4

Forest plot of comparison: 1 Antioxidant(s) versus placebo or no treatment, outcome: 1.1 Live birth; type of antioxidant.

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Figure 5

Forest plot of comparison: 1 Antioxidant(s) versus placebo or no treatment, outcome: 1.3 Clinical pregnancy; type of antioxidant.

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Figure 6

Forest plot of comparison: 1 Antioxidant(s) versus placebo or no treatment, outcome: 1.5 Adverse events.

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Figure 7

Forest plot of comparison: 1 Antioxidant(s) versus placebo or no treatment, outcome: 1.6 Sperm DNA fragmentation; type of antioxidant.

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Figure 8

Forest plot of comparison: 1 Antioxidant(s) versus placebo or no treatment, outcome: 1.7 Total sperm motility at 3 months or less; type of antioxidant.

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Figure 9

Forest plot of comparison: 1 Antioxidant(s) versus placebo or no treatment, outcome: 1.12 Total sperm motility over time.

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Figure 10

Forest plot of comparison: 1 Antioxidant(s) versus placebo or no treatment, outcome: 1.13 Sperm concentration at 3 months or less; type of antioxidant.

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Figure 11

Forest plot of comparison: 1 Antioxidant(s) versus placebo or no treatment, outcome: 1.18 Sperm concentration over time.

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Analysis 1.1

Comparison 1 Antioxidant(s) versus placebo or no treatment, Outcome 1 Live birth; type of antioxidant.

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Analysis 1.2

Comparison 1 Antioxidant(s) versus placebo or no treatment, Outcome 2 Live birth; IVF/ICSI.

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Analysis 1.3

Comparison 1 Antioxidant(s) versus placebo or no treatment, Outcome 3 Clinical pregnancy; type of antioxidant.

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Analysis 1.4

Comparison 1 Antioxidant(s) versus placebo or no treatment, Outcome 4 Clinical pregnancy; IVF/ICSI.

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Analysis 1.5

Comparison 1 Antioxidant(s) versus placebo or no treatment, Outcome 5 Adverse events.

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Analysis 1.6

Comparison 1 Antioxidant(s) versus placebo or no treatment, Outcome 6 Sperm DNA fragmentation; type of antioxidant.

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Analysis 1.7

Comparison 1 Antioxidant(s) versus placebo or no treatment, Outcome 7 Total sperm motility at 3 months or less; type of antioxidant.

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Study	Intervention	Control	P value
L‐carnitine + Acetyl‐carnitine versus placebo (median and interquartile range)
Cavallini 2004	L‐carnitine + Acetyl‐carnitine Median=22.3 (n=39) Interquartile range =28.4‐15.2	Placebo Median= 14.0 (n=47) Interquartile range=17.4‐5.1	Not provided
Combined antioxidants versus no treatment
Galatioto 2008	Combined antioxidants % of motile sperm =58% (n=20)	No treatment % of motile sperm =51% (n=22)	P=0.847
Vitamin E versus placebo
Kessopoulou 1995	Vitamin E Median=7 (n=15) min/max= ‐27‐34	Placebo Median=7 (n=15) min/max= ‐33‐36	Not provided
L‐carnitine versus placebo
Lenzi 2003	L‐carnitine Mean=11(n=43) no sd given	Placebo Mean=8.8 (n=43) no sd given	P=.04
Selenium + Zinc versus placebo
Sivkov 2011	Selenium + Zinc Mean =38.3 (n=15) no sd given	Placebo Mean =38 (n=15) no sd given	Not provided

Analysis 1.8

Comparison 1 Antioxidant(s) versus placebo or no treatment, Outcome 8 Total sperm motility at 3 months or less (data not suitable for meta analysis).

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Analysis 1.9

Comparison 1 Antioxidant(s) versus placebo or no treatment, Outcome 9 Total sperm motility at 6 months; type of antioxidant.

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Study	Intervention	Control	P value
L‐carnitine + Acetyl‐carnitine versus placebo (median and interquartile range)
Cavallini 2004	L‐carnitine + acetyl‐carnitine Median=23.6 (n=39) Interquartile range=28.9‐16.0	Placebo Median=13.2 (n=47) Interquartile range=18.6‐9.0	Not provided
Folic acid versus placebo
Wong 2002	Folic acid Median=35 (n=22) Range=5‐65	Placebo Median=30 (n=25) Range=5‐80
Zinc versus placebo
Wong 2002	Zinc Median=35 (n=23) Range=10‐65	Placebo Median=30 (n=25) Range=5‐80
Zinc + folic acid versus placebo
Wong 2002	Zinc + folic acid Median=35 (n=24) Range 5‐70	Placebo Median=30 (n=25) Range=5‐80

Analysis 1.10

Comparison 1 Antioxidant(s) versus placebo or no treatment, Outcome 10 Total sperm motility at 6 months(data not suitable for meta analysis).

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Analysis 1.11

Comparison 1 Antioxidant(s) versus placebo or no treatment, Outcome 11 Total sperm motility at 9 months or more; type of antioxidant.

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Analysis 1.12

Comparison 1 Antioxidant(s) versus placebo or no treatment, Outcome 12 Total sperm motility over time.

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Analysis 1.13

Comparison 1 Antioxidant(s) versus placebo or no treatment, Outcome 13 Sperm concentration at 3 months or less; type of antioxidant.

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Study	Intervention	Control	P value
L‐carnitine + Acetyl‐carnitine versus placebo (median and interquartile range)
Cavallini 2004	L‐carnitine + acetyl‐carnitine Median=20.9 (n=39) Interquartile range=25.6‐14.8	Placebo Median=12.3 (n=47) Interquartile range=16.0‐9.1	Not provided
Vitamin E versus placebo
Kessopoulou 1995	Vitamin E Median= ‐15 (n=15) min/max= ‐58‐59	Placebo Median=0 (n=15) min/max= ‐37‐160	Not provided
L‐carnitine versus placebo
Lenzi 2003	L‐carnitine Mean= 9 (1st phase data) (n=43) no sd given	Placebo Mean=5.3 (n=43) no sd given	P=0.03

Analysis 1.14

Comparison 1 Antioxidant(s) versus placebo or no treatment, Outcome 14 Sperm concentration at 3 months or less (data not suitable for meta analysis).

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Analysis 1.15

Comparison 1 Antioxidant(s) versus placebo or no treatment, Outcome 15 Sperm concentration at 6 months; type of antioxidant.

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Study	Intervention	Control	P value
L‐carnitine + acetyl‐carnitine versus placebo
Cavallini 2004	L‐carnitine + acetyl‐carniitne Median=20.6 (n=39) Interquartile range=24.9‐15.1	Placebo Median=10.9 (n=47) Interquartile range=15.1‐9.0	Not provided
Folic acid versus Placebo
Wong 2002	Folic acid Median=14 (n=22) Range=0.9‐130	Placebo Median=9 (n=25) Range=0.8‐80	Not provided
Zinc versus Placebo
Wong 2002	Zinc Median=16 (n= 23) Range=0.6‐80	Placebo Median=9 (n= 25) Range=0.8‐80	Not provided
Zinc + folic acid versus placebo
Wong 2002	Zinc + folic acid Median= 12 (n=24) Range= 0.5‐180	Placebo Median=9 (n= 25) Range=0.8‐80	Not provided

Analysis 1.16

Comparison 1 Antioxidant(s) versus placebo or no treatment, Outcome 16 Sperm concentration at 6 months(data not suitable for meta analysis).

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Analysis 1.17

Comparison 1 Antioxidant(s) versus placebo or no treatment, Outcome 17 Sperm concentration at 9 months; type of antioxidant.

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Analysis 1.18

Comparison 1 Antioxidant(s) versus placebo or no treatment, Outcome 18 Sperm concentration over time.

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Analysis 2.1

Comparison 2 Head to head antioxidant(s), Outcome 1 Total sperm motility at 3 months or less; type of antioxidant.

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Analysis 2.2

Comparison 2 Head to head antioxidant(s), Outcome 2 Total sperm motility at 6 months; type of antioxidant.

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Study	Antioxidant a	Antioxidant b	P value
Zinc versus Folic acid
Wong 2002	Zinc Median=35 Range=10‐65	Folic acid Median=35 Range=5‐65	Not provided
Zinc versus Zinc + folic acid
Wong 2002	Zinc Median=35 Range=10‐65	Zinc + folic acid Median=35 Range=5‐70	Not provided
Folic acid versus Zinc + folic acid
Wong 2002	Folic acid Median=35 Range=5‐65	Zinc + folic acid Median=35 Range=5‐70	Not provided

Analysis 2.3

Comparison 2 Head to head antioxidant(s), Outcome 3 Total sperm motility at 6 months.

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Analysis 2.4

Comparison 2 Head to head antioxidant(s), Outcome 4 Total sperm motility at 9 months or more; type of antioxidant.

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Analysis 2.5

Comparison 2 Head to head antioxidant(s), Outcome 5 Sperm concentration at 3 months or less; type of antioxidant.

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Analysis 2.6

Comparison 2 Head to head antioxidant(s), Outcome 6 Sperm concentration at 6 months; type of antioxidant.

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Study	Antioxidant a	Antioxidant b	P value
Zinc versus Folic acid
Wong 2002	Zinc Median=16 Range=0.6‐80	Folic acid Median=14 Range=0.9‐130	Not provided
Zinc versus Zinc + Folic acid
Wong 2002	Zinc Median= 16 Range=0.6‐80	Zinc + Folic acid Median=12 Range=0.5‐180	Not provided
Folic acid versus Zinc + folic acid
Wong 2002	Folic acid Folic acid Median=14 Range=0.9‐130	Zinc + Folic acid Median=12 Range=0.5‐180	Not provided

Analysis 2.7

Comparison 2 Head to head antioxidant(s), Outcome 7 Sperm concentration at 6 months.

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Analysis 2.8

Comparison 2 Head to head antioxidant(s), Outcome 8 Sperm concentration at 9 months or more; type of antioxidant.

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Analysis 3.1

Comparison 3 Pentoxifylline versus placebo or no treatment, Outcome 1 Total sperm motility at 3 months or less; pentoxifylline versus placebo or no treatment.

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Study	Antioxidant	Placebo	P value
Pentoxifylline versus placebo
Merino 1997	Pentoxifylline Median=35.5 (n=25) Range=31.5‐39.5	Placebo Median=33.5 (n=22) Range=28.5‐37.5	P<0.01

Analysis 3.2

Comparison 3 Pentoxifylline versus placebo or no treatment, Outcome 2 Total sperm motility at 3 months or less (data not suitable for meta analysis).

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Analysis 3.3

Comparison 3 Pentoxifylline versus placebo or no treatment, Outcome 3 Total sperm motility at 6 months; pentoxifylline versus placebo or no treatment.

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Study	Antioxidant	Control	P value
Pentoxifylline versus placebo
Merino 1997	Pentoxifylline Median=42 (n=25) Range=38‐46	Placebo Median=31.5 (22) Range=28‐35	P<0.00001

Analysis 3.4

Comparison 3 Pentoxifylline versus placebo or no treatment, Outcome 4 Total sperm motility at 6 months (data not suitable for meta analysis).

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Analysis 3.5

Comparison 3 Pentoxifylline versus placebo or no treatment, Outcome 5 Total sperm motility at 9 months; pentoxifylline versus placebo or no treatment.

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Analysis 3.6

Comparison 3 Pentoxifylline versus placebo or no treatment, Outcome 6 Total sperm motility over time.

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Analysis 3.7

Comparison 3 Pentoxifylline versus placebo or no treatment, Outcome 7 Sperm concentration at 3 months or less; pentoxifylline versus placebo or no treatment.

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Analysis 3.8

Comparison 3 Pentoxifylline versus placebo or no treatment, Outcome 8 Sperm concentration at 6 months; pentoxifylline versus placebo.

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Analysis 3.9

Comparison 3 Pentoxifylline versus placebo or no treatment, Outcome 9 Sperm concentration at 9 months; pentoxifylline versus placebo.

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Analysis 3.10

Comparison 3 Pentoxifylline versus placebo or no treatment, Outcome 10 Sperm concentration over time.

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Analysis 3.11

Comparison 3 Pentoxifylline versus placebo or no treatment, Outcome 11 Adverse events.

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Summary of findings for the main comparison. Antioxidants versus placebo or no treatment for male subfertility

Antioxidants versus placebo or no treatment for male subfertility
Patient or population: patients with male subfertility Settings: Intervention: Antioxidants versus placebo or no treatment
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Control	Antioxidants versus placebo or no treatment
Live Birth per couple randomised Follow‐up: 3 ‐ 24 months	50 per 1000	181 per 1000 (99 to 309)	OR 4.21 (2.08 to 8.51)	277 (4 studies)	⊕⊕⊝⊝ low^1,2
Clinical Pregnancy rate per couple randomised Follow‐up: 3‐24 months	59 per 1000	177 per 1000 (108 to 277)	OR 3.43 (1.92 to 6.11)	522 (7 studies)	⊕⊕⊝⊝ low^1,3
Adverse event: Miscarriage rate per couple randomised Follow‐up: 3‐18 months	19 per 1000	33 per 1000 (8 to 129)	OR 1.74 (0.40 to 7.60)	247 (3 studies)	⊕⊝⊝⊝ very low^1,4
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; OR: Odds ratio;
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
¹ Inadequate explanations of methodology and large unexplained dropouts in one study ² Confidence limits of one study crosses the line of no effect ³ Wide confidence intervals. Six of the nine analyses (one trial has 3 arms) cross the line of no effect. ⁴ Low event rate

Summary of findings for the main comparison. Antioxidants versus placebo or no treatment for male subfertility

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Table 1. Data for undefined or biochemical pregnancy

Undefined or biochemical pregnancy	Events Intervention	Total 1	Events Control	Total 2	Effect Estimate	CI
Antioxidant(s) versus placebo or no treatment
Combined antioxidants
Galatioto 2008	1	20	0	22
Arginine versus placebo
Pryor 1978	2	35	2	29	0.82	0.82 [0.11, 6.16]
Carnitines versus placebo or no treatment	25	154	3	145	5.33
Sigman 2006	1	12	1	9	0.74	0.74 [0.04, 13.02]
Peivandi 2010	3	15	0	15	8.57	8.57 [0.82, 89.45]
Lenzi 2004	4	30	0	26	7.20	7.20 [0.95, 54.34]
Lenzi 2003	6	43	0	43	8.37	8.37 [1.61, 43.58]
Cavallini 2004	9	39	1	47	7.50	7.50 [2.01, 27.98]
Balercia 2005	2	15	1	5	0.61	0.61 [0.04, 9.64]
Coenzyme Q10 versus placebo	6	136	3	136	2.16
Safarinejad 2009a	0	106	0	106	0	Not estimable
Balercia 2009	6	30	3	30	2.16	2.16 [0.53, 8.82]
Pentoxifylline versus placebo
Wang 1983	0	11	0	7	0	Not estimable
Vitamin C plus vitamin E versus placebo
Rolf 1999	0	15	0	16	0	Not estimable

Head to head antioxidant(s)						CI Start	CI End
L‐acetyl carnitine + L‐carnitine versus L‐acetyl carnitine
Balercia 2005	2	7	2	15	2.66	0.27	25.80
L‐acetyl carnitine + L‐carnitine versus L‐carnitine
Balercia 2005	3	8	2	15	3.89	0.51	29.76
L‐acetyl carnitine + L‐carnitine versus vitamin E + vitamin C
Li 2005	10	85	2	53	2.72	0.81	9.14
L‐carnitine plus vitamin E versus vitamin E
Wang 2010	21	68	3	67	6.01	2.49	14.47

Table 1. Data for undefined or biochemical pregnancy

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Table 2. Outcomes and conclusions from all included trials

Study ID	Population, design	Outcomes described in methods section	Outcomes reported on in results	In meta‐analysis Y or N	Results	Conclusions + = positive effect ‐ = negative or no effect
Akiyama 1999	Infertile men ‐ high ROS levels N = 10 Crossover Head to head Japanese	Sperm parameters	Sperm parameters	Y	Sperm density and motility did not improve but "sperm function" increased and ROS levels decreased	+ Ethylcysteine shown to be effective when compared to vitamin E for ROS associated infertility
Attallah 2013	Idiopathic athenozospermia IUI N = 30 parallel, no treatment conference abstract	Chemical and clinical pregnancy sperm parameters	Clinical pregnancy Sperm parameters	Y	NAC increased sperm concentration and motility Clinical pregnancy was not significantly different between the groups	+ NAC improves semen quality and improves pregnancy rates prior to IUI
Azizollahi 2013	Men post‐varicocelectomy N = 160 4‐armed trial	Sperm parameters	Sperm parameters	Y sperm parameters reported but clinical pregnancy from correspondence with author ‐ men were asked at their last semen assessment session about pregnancy if yes ultrasound was used to confirm	Mild improvement in sperm parameters with the use of antioxidants	+ Co‐administration of zinc and folic acid improved sperm parameters and increased varicocelectomy outcomes
Balercia 2005	Infertile men or unexplained infertility N = 60 Placebo and head to head	Sperm parameters	Sperm parameters Spontaneous pregnancies 5 LC + LAC 2 LC 2 LAC 3 placebo	Y ‐ sperm N ‐ pregnancy	Improvement in motility in LAC group. 12 spontaneous pregnancies (unknown if biochemical or clinical)	+ Long term carnitine is effective in increasing sperm motility
Balercia 2009	Infertile and unexplained N = 60	Sperm parameters	Sperm parameters Spontaneous pregnancies 6 Q10 3 placebo	Y ‐ sperm N ‐ pregnancy	Co enzyme Q10 increased sperm motility. 9 spontaneous pregnancies (unknown if biochemical or clinical)	+ Q10 effective in improving sperm kinetic features in asthenospermia
Biagiotti 2003	Severe idiopathic oligoasthenospermia conference abstract N = 42	Sperm parameters	Sperm	N ‐ no data available	A significant improvement in morphology concentration, motility in the carnitine group No side effects	+ Quality of semen is positively associated with fertilisation and implantation rates in assisted reproduction
Cavallini 2004	Idiopathic and varicocoele associated infertility N = 325	Sperm parameters pregnancies side effects	Sperm parameters pregnancies at 6 months post‐treatment and assumed to be clinical	N Medians only given for sperm parameters in full paper Analysis 1.8 , .Analysis 1.10; Analysis 1.13; Analysis 1.14; Analysis 1.16. Means in conference abstract but no data given for placebo group and data for group 3 (carnitine + cinoxacin) versus group 2 (carnitines) unable to be used as 3 includes cinoxacin an antiinflammatory drug Y clinical pregnancy	Significant increase in sperm parameters for carnitines when compared to placebo. Carnitine groups had a significantly higher pregnancy rate than placebo group	+ The antioxidant plus antiinflammatory group was more effective in improving sperm parameters and pregnancy than those of carnitines alone or placebo however carnitines alone were more effective than placebo
Ciftci 2009	Idiopathic infertility N = 120	Sperm parameters	Sperm parameters	Y sperm parameters	NAC showed significant improvement in sperm parameters when compared with placebo	+ Sperm parameters improved after the use of NAC
Conquer 2000	Asthenozoospermic men N = 28	Sperm parameters	Sperm parameters	Y sperm parameters (SEs converted to SDs)	DHA showed no effect on sperm motility or concentration	± DHA supplementation increased DHA levels in the sperm but not motility or concentration
Dawson 1990	Agglutination associated infertility N = 30	Sperm parameters	Sperm parameters	Y sperm parameters (SEs converted to SDs)	The group receiving 1000 mg of AA showed more improvement in parameters than the 200mg group and the placebo	+
Dimitriadis 2010	Oligoasthenospermia N = 75 4 arm trial only 2 arms able to be used	Sperm parameters	Sperm parameters	Y sperm parameters	An improvement in sperm concentration with carnitine versus no treatment	+ Enhancement of Leydig cell secretory function may increase sperm concentration and motility
Eslamian 2012	Asthenoszoospermic men N = 50	Sperm parameters	sperm parameters ‐ sperm membrane and serum fatty acids	N outcomes not included in this review	Sperm parameters improved with DHA + vitamin E supplementation	+
Galatioto 2008	Oligospermia post‐embolisation of varicocoele N = 42	Sperm parameters Pregnancy Adverse events	Sperm parameters Pregnancy Adverse events	N medians only given for sperm parameters Analysis 1.8 Y pregnancy at 12 months post‐treatment assumed to be clinical Adverse events	Significant difference in sperm count in combined antioxidant group but not in motility. One pregnancy in the NAC group No significant adverse effects	±
Greco 2005	Male infertility ‐ high DNA fragmentation N = 64	Sperm parameters	Sperm parameters	Y sperm parameters	No significant difference in concentration or motility however DNA fragmentation was significantly reduced in the vitamin C + E when compared to placebo	+ A short oral treatment of VitC + E can reduce DNA fragmentation
Keskes‐Ammar 2003	Men with high levels of ROS in semen N = 78 Head to head	Sperm parameters	Sperm parameters	Y sperm parameters	Treatment with Vit E and selenium increased sperm motility when compared to vitamin B	+
Kessopoulou 1995	Male infertility Crossover N = 30	Sperm parameters	Sperm parameters Live birth Clinical pregnancy	N medians only given for sperm parameters Analysis 1.8; Analysis 1.14 Y Pregnancy	No differences in sperm outcomes were seen between the groups. 1 pregnancy in the vitamin E group and nil in the placebo (first phase data)	‐ No difference in semen parameters
Kumamoto 1988	Male patients with abnormal sperm count and motility 3‐armed trial N = 396	Sperm parameters	Sperm parameters	N scales given	No statistical difference in sperm outcomes in vitamin B 12 groups or placebo	‐
Lenzi 2003	Male factor infertility N = 100 Crossover	Sperm parameters Pregnancy rates	Sperm parameters Pregnancy rates	N no SDs given for sperm parameters Analysis 1.8; Analysis 1.14 N no definition of pregnancy given see Table 1	The patient groups showed no differences in sperm outcomes between therapy (carnitine) and placebo groups. Six pregnancies in the carnitine group and nil in the placebo (first phase)	+ The pregnancies obtained during the carnitine therapy period could suggest that carnitines may also lead to improvement in sperm function and fertilisation
Lenzi 2004	Infertile males ‐ oligoasthenoteratozoospermia N = 60	Sperm parameters Adverse events	Sperm parameters Pregnancy rates	Y sperm parameters N no definition of pregnancy given see analysis for biochemical pregnancy Table 1 N adverse events	Four participants taking carnitine induced a pregnancy in their partner and nil in the placebo	+
Li 2005	Infertile males ‐ oligoasthenoteratozoospermia (150) Head to head	Sperm parameters Pregnancy rates Adverse events	Sperm parameters Pregnancy rates	Y sperm parameters N no definition of pregnancy given see analysis for biochemical pregnancy Table 1	Y 10 pregnancies in the carnitine group and 2 in the vitamin E + C group	+ Lcarnitine and acetyl carnitine more effective than vitamin E + vitamin C for pregnancy, sperm parameters and no evidence of adverse events
Li 2005a	Infertile males ‐ oligoasthenoteratozoospermia (80) Head to head	Sperm parameters	Sperm parameters	Y		+ Staistical significance for carnitines over vitamin E + C
Lombardo 2002	Infertile males Conference abstract Crossover (N = 100)	Sperm parameters	Sperm parameters	N no data		+ Sperm parameters (concentration, motility) carnitines versus placebo
Martinez‐Soto 2010	Infertile males (N = 50) Conference abstract + communication with author	Sperm parameters	Sperm parameters	Y		+ DNA fragmentation
Merino 1997	Idiopathic asthenospermia (N = 47)	Sperm parameters		N medians only given for sperm parameters Analysis 3.2; Analysis 3.4		+
Micic 1988	Idiopathic asthenospermia (N = 90)	Sperm parameters		Y		+ Significant improvement in sperm motility in pentoxifylline versus no treatment
Morgante 2010	Idiopathic asthenospermia (N = 180)	Sperm parameters		Y		+ Sexual satisfaction Significant improvement in sperm motility
Nadjarzadeh 2011	Idiopathic oligoasthenospermia (N = 60)	Sperm parameters		Y		‐
Nozha 2001	Oligoasthenospermia head to head (N = 20)	Sperm parameters		N no data available		+ Vitamin E + selenium associated with improved sperm motility when compared with vitamin B
Omu 1998	Asthenospermia (N = 100)	Sperm parameters	Sperm parameters pregnancy and live birth	Y pregnancy and live birth only N sperm parameters not appropriate for review		+ Pregnancy or live birth and sperm parameters
Omu 2008	Asthenospermia (N = 100)	Sperm parameters		Y		+
Peivandi 2010	Infertile men (N = 30) (crossover)	Sperm parameters		Y Y biochemical pregnancies Table 1		+ Sperm outcomes + biochemical pregnancies
Poveda 2013	Infertile men (N = 60) conference abstract	Sperm parameters		N		+ Sperm concentration and motility with L‐carnitine and spermotrend
Pryor 1978	Oligozoospermia (N = 64) crossover	Sperm parameters Pregnancy rates		N bar graph of % patients showing an increase in motility and density Y pregnancy data included in biochemical analysis Table 1		‐ Arginine was no more effective than placebo for sperm parameters and biochemical pregnancy rates
Rolf 1999	Asthenospermia (N = 33)	Sperm parameters Pregnancy rates		Y	No adverse events or pregnancies in either group	‐ No difference vitamin E + C versus placebo
Safarinejad 2009	Idiopathic oligozoospermia (N = 468)	Sperm parameters		Y		+ N acetylcysteine, selenium
Safarinejad 2009a	Idiopathic oligozoospermia (N = 212)	Sperm parameters		Y		+ Coenzyme Q10
Safarinejad 2011	Idiopathic infertility (N = 254)	Sperm parameters		Y	Adverse events, sperm concentration and motility	+ Pentoxifylline
Safarinejad 2012	Idiopathic infertility (N=228)	Sperm parameters		Y		+ Coenzyme Q10
Scott 1998	Reduced sperm motility (N = 69)	Sperm parameters Pregnancy		Y N due to pregnancy data pooled in the two intervention groups		+ Sperm motility and pregnancy, combined antioxidants and selenium
Sigman 2006	Low sperm motility (N = 26)	Sperm parameters Pregnancy		Y		_ Carnitine
Sivkov 2011	Subnormal spermatogenesis ‐ prostatitis (N = 30) Russian	Sperm parameters		N no sd given see Analysis 1.8		+ Selenium + zinc
Suleiman 1996	Asthenospermia (N = 110)	Sperm parameters	Sperm parameters Pregnancy Live birth Miscarriage	Y Y Y Y		+ Vit E
Tremellen 2007	Male factor infertility (N = 60)	Pregnancy Side effects	Pregnancy Side effects	Y		+ Menevit
Wang 1983	Idiopathic oligozoospermia (N = 46)	Sperm parameters Pregnancy		Y no data on motility available		‐ Pentoxifylline
Wang 2010	Asthenospermia (N = 135) Chinese	Sperm parameters Pregnancy	Sperm parameters pregnancy	Y		+ Sperm motility, pregnancy ‐ Sperm density and normal morphology
Wong 2002	Subfertile males (N = 103)	Sperm parameters		N Medians only see Analysis 1.10;and Analysis 1.16		+ Folic acid + zinc
Zalata 1998	Men attending andrology clinic (N = 22) conference abstract	Sperm parameters including DNA fragmentation		N only before and after median data given		+ DNA fragmentation but ‐ Other sperm parameters Combined antioxidants and fatty acids (DHA)
Zavaczki 2003	Idiopathic infertility (N = 20)	Sperm parameters Clinical pregnancy		Y		‐ Magnesium

Table 2. Outcomes and conclusions from all included trials

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Comparison 1. Antioxidant(s) versus placebo or no treatment

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Live birth; type of antioxidant Show forest plot	4	277	Peto Odds Ratio (Peto, Fixed, 95% CI)	4.21 [2.08, 8.51]

1.1 Vitamin E versus placebo	2	117	Peto Odds Ratio (Peto, Fixed, 95% CI)	6.44 [1.72, 24.04]
1.2 Zinc versus no treatment	1	100	Peto Odds Ratio (Peto, Fixed, 95% CI)	3.74 [1.02, 13.74]
1.3 Combined antioxidants versus placebo	1	60	Peto Odds Ratio (Peto, Fixed, 95% CI)	3.42 [1.15, 10.13]
2 Live birth; IVF/ICSI Show forest plot	2	90	Peto Odds Ratio (Peto, Fixed, 95% CI)	3.61 [1.27, 10.29]

3 Clinical pregnancy; type of antioxidant Show forest plot	7	522	Peto Odds Ratio (Peto, Fixed, 95% CI)	3.43 [1.92, 6.11]

3.1 Combined antioxidants versus placebo	1	60	Peto Odds Ratio (Peto, Fixed, 95% CI)	2.44 [0.84, 7.13]
3.2 Magnesium versus placebo	1	26	Peto Odds Ratio (Peto, Fixed, 95% CI)	8.73 [0.17, 445.08]
3.3 Vitamin E versus placebo	2	117	Peto Odds Ratio (Peto, Fixed, 95% CI)	6.71 [1.98, 22.69]
3.4 Zinc versus placebo or no treatment	2	153	Peto Odds Ratio (Peto, Fixed, 95% CI)	4.43 [1.39, 14.14]
3.5 N‐acetylcysteine versus no treatment	1	60	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.60 [0.42, 6.16]
3.6 Zinc plus folic acid versus placebo	1	53	Peto Odds Ratio (Peto, Fixed, 95% CI)	3.86 [0.15, 99.84]
3.7 Folic acid versus placebo	1	53	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.0 [0.0, 0.0]
4 Clinical pregnancy; IVF/ICSI Show forest plot	2	90	Peto Odds Ratio (Peto, Fixed, 95% CI)	2.64 [0.94, 7.41]

5 Adverse events Show forest plot	8		Peto Odds Ratio (Peto, Fixed, 95% CI)	Subtotals only

5.1 Miscarriage	3	247	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.74 [0.40, 7.60]
5.2 Gastrointestinal	6	429	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.60 [0.47, 5.50]
5.3 Euphoria	1	86	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.21 [0.16, 9.01]
5.4 Ectopic pregnancy	1	60	Peto Odds Ratio (Peto, Fixed, 95% CI)	4.48 [0.07, 286.49]
6 Sperm DNA fragmentation; type of antioxidant Show forest plot	2	100	Mean Difference (IV, Fixed, 95% CI)	‐13.85 [‐17.28, ‐10.41]

6.1 Vitamin C + vitamin E versus placebo at 2 months	1	64	Mean Difference (IV, Fixed, 95% CI)	‐13.80 [‐17.50, ‐10.10]
6.2 Docosahexaenoic acid (DHA) 1000mg/day versus placebo at 10 weeks	1	36	Mean Difference (IV, Fixed, 95% CI)	‐14.12 [‐23.23, ‐5.01]
7 Total sperm motility at 3 months or less; type of antioxidant Show forest plot	16	1039	Mean Difference (IV, Random, 95% CI)	10.02 [3.79, 16.25]

7.1 Docosahexaenoic acid (DHA) 400mg/day versus placebo	1	18	Mean Difference (IV, Random, 95% CI)	‐7.80 [‐27.79, 12.19]
7.2 Docosahexaenoic acid (DHA) 800mg/day vs placebo	1	19	Mean Difference (IV, Random, 95% CI)	‐15.20 [‐30.92, 0.52]
7.3 Docosahexaenoic acid (DHA) 1000mg/day versus placebo at 10 weeks	1	36	Mean Difference (IV, Random, 95% CI)	‐6.45 [‐17.64, 4.74]
7.4 Vitamin C acid 200mg/day versus placebo	1	20	Mean Difference (IV, Random, 95% CI)	2.0 [‐18.82, 22.82]
7.5 Vitamin C 1000mg/day versus placebo	1	20	Mean Difference (IV, Random, 95% CI)	45.0 [19.72, 70.28]
7.6 Vitamin C + Vitamin E versus placebo at 2 months	2	95	Mean Difference (IV, Random, 95% CI)	1.46 [‐5.82, 8.74]
7.7 Carnitines versus placebo or no treatment at 3 months	3	99	Mean Difference (IV, Random, 95% CI)	15.32 [‐3.70, 34.35]
7.8 Selenium versus placebo at 3 months	1	34	Mean Difference (IV, Random, 95% CI)	14.9 [1.14, 28.66]
7.9 Combined antioxidants versus placebo or no treatment at 3 months	2	228	Mean Difference (IV, Random, 95% CI)	15.13 [13.56, 16.69]
7.10 N‐acetylcysteine versus placebo/no treatment at 3 months	2	180	Mean Difference (IV, Random, 95% CI)	7.65 [0.68, 14.62]
7.11 Magnesium versus placebo at 90 days	1	20	Mean Difference (IV, Random, 95% CI)	14.5 [‐6.01, 35.01]
7.12 Zinc versus no treatment or placebo at 3 months	2	76	Mean Difference (IV, Random, 95% CI)	14.66 [‐5.91, 35.24]
7.13 Zinc + Vitamin E versus no treatment at 3 months	1	20	Mean Difference (IV, Random, 95% CI)	26.0 [12.85, 39.15]
7.14 Zinc + Vitamin E + Vitamin C versus no treatment at 3 months	1	22	Mean Difference (IV, Random, 95% CI)	26.0 [12.62, 39.38]
7.15 Coenzyme Q10 versus placebo	1	47	Mean Difference (IV, Random, 95% CI)	3.58 [‐6.16, 13.32]
7.16 Zinc plus folic acid versus placebo	1	54	Mean Difference (IV, Random, 95% CI)	6.80 [‐2.84, 16.44]
7.17 Folic acid versus placebo	1	51	Mean Difference (IV, Random, 95% CI)	8.40 [‐0.99, 17.79]
8 Total sperm motility at 3 months or less (data not suitable for meta analysis) Show forest plot			Other data	No numeric data

8.1 L‐carnitine + Acetyl‐carnitine versus placebo (median and interquartile range)			Other data	No numeric data
8.2 Combined antioxidants versus no treatment			Other data	No numeric data
8.3 Vitamin E versus placebo			Other data	No numeric data
8.4 L‐carnitine versus placebo			Other data	No numeric data
8.5 Selenium + Zinc versus placebo			Other data	No numeric data
9 Total sperm motility at 6 months; type of antioxidant Show forest plot	9		Mean Difference (IV, Random, 95% CI)	Subtotals only

9.1 Carnitines versus placebo at 6 months	3	107	Mean Difference (IV, Random, 95% CI)	7.28 [‐9.47, 24.02]
9.2 Selenium versus placebo at 26 weeks (6 months)	1	140	Mean Difference (IV, Random, 95% CI)	3.20 [2.28, 4.12]
9.3 N‐acetyl‐cysteine versus placebo at 26 weeks (6months)	1	140	Mean Difference (IV, Random, 95% CI)	1.90 [0.98, 2.82]
9.4 Selenium plus N‐acetyl‐cysteine versus placebo at 26 weeks (6months)	1	139	Mean Difference (IV, Random, 95% CI)	6.30 [5.38, 7.22]
9.5 Coenzyme Q10 versus placebo at 6 months	3	479	Mean Difference (IV, Random, 95% CI)	6.58 [1.80, 11.37]
9.6 Vitamin E versus placebo at 6 months	1	87	Mean Difference (IV, Random, 95% CI)	13.0 [7.02, 18.98]
9.7 Zinc versus placebo	1	40	Mean Difference (IV, Random, 95% CI)	0.0 [‐10.19, 10.19]
9.8 Zinc plus folic acid versus placebo	1	37	Mean Difference (IV, Random, 95% CI)	2.60 [‐8.82, 14.02]
9.9 Folic acid versus placebo	1	34	Mean Difference (IV, Random, 95% CI)	1.70 [‐8.49, 11.89]
10 Total sperm motility at 6 months(data not suitable for meta analysis) Show forest plot			Other data	No numeric data

10.1 L‐carnitine + Acetyl‐carnitine versus placebo (median and interquartile range)			Other data	No numeric data
10.2 Folic acid versus placebo			Other data	No numeric data
10.3 Zinc versus placebo			Other data	No numeric data
10.4 Zinc + folic acid versus placebo			Other data	No numeric data
11 Total sperm motility at 9 months or more; type of antioxidant Show forest plot	4		Mean Difference (IV, Random, 95% CI)	Subtotals only

11.1 L‐carnitine versus placebo at 9 months	1	20	Mean Difference (IV, Random, 95% CI)	11.54 [1.66, 21.42]
11.2 L‐acetyl carnitine versus placebo at 9 months	1	20	Mean Difference (IV, Random, 95% CI)	7.84 [‐1.41, 17.09]
11.3 L‐carnitine + L‐acetyl carnitine versus placebo at 9 months	1	20	Mean Difference (IV, Random, 95% CI)	6.27 [‐3.36, 15.90]
11.4 Coenzyme Q10 versus placebo at 9 months	3	479	Mean Difference (IV, Random, 95% CI)	1.88 [‐1.58, 5.34]
12 Total sperm motility over time Show forest plot	23		Mean Difference (IV, Random, 95% CI)	Subtotals only

12.1 Total sperm motility at 3 months or less	16	832	Mean Difference (IV, Random, 95% CI)	9.55 [2.12, 16.97]
12.2 Total sperm motility at 6 months	9	964	Mean Difference (IV, Random, 95% CI)	6.86 [3.78, 9.94]
12.3 Total sperm motility at 9 months or more	4	509	Mean Difference (IV, Random, 95% CI)	3.17 [‐0.10, 6.45]
13 Sperm concentration at 3 months or less; type of antioxidant Show forest plot	13		Mean Difference (IV, Random, 95% CI)	Subtotals only

13.1 Docosahexaenoic acid (DHA) 400g/day versus placebo	1	18	Mean Difference (IV, Random, 95% CI)	‐5.30 [‐41.09, 30.49]
13.2 Docosahexaenoic acid (DHA) 800g/day versus placebo	1	19	Mean Difference (IV, Random, 95% CI)	1.50 [‐35.23, 38.23]
13.3 Docosahexaenoic acid (DHA) 1000mg/day versus placebo at 10 weeks	1	36	Mean Difference (IV, Random, 95% CI)	‐1.38 [‐18.78, 16.02]
13.4 Magnesium versus placebo at 90 days	1	20	Mean Difference (IV, Random, 95% CI)	5.20 [‐2.61, 13.01]
13.5 Vitamin C + Vitamin E versus placebo at 2 months	2	95	Mean Difference (IV, Random, 95% CI)	1.36 [‐10.01, 12.72]
13.6 N‐acetylcysteine versus placebo at 3 months	1	120	Mean Difference (IV, Random, 95% CI)	‐0.47 [‐6.70, 5.76]
13.7 Carnitines versus placebo	2	78	Mean Difference (IV, Random, 95% CI)	14.29 [‐15.50, 44.08]
13.8 Coenzyme Q10 versus placebo	1	47	Mean Difference (IV, Random, 95% CI)	‐0.12 [‐12.39, 12.15]
13.9 N‐acetylcysteine versus no treatment	1	60	Mean Difference (IV, Random, 95% CI)	4.72 [‐0.31, 9.75]
13.10 Combined antioxidants versus placebo or no treatment	2	219	Mean Difference (IV, Random, 95% CI)	‐0.89 [‐1.84, 0.06]
13.11 Zinc plus folic acid versus placebo	1	37	Mean Difference (IV, Random, 95% CI)	18.0 [1.13, 34.87]
13.12 Folic acid versus placebo	1	34	Mean Difference (IV, Random, 95% CI)	22.20 [3.79, 40.61]
13.13 Zinc versus placebo	1	40	Mean Difference (IV, Random, 95% CI)	16.9 [0.53, 33.27]
13.14 Selenium versus placebo	1	25	Mean Difference (IV, Random, 95% CI)	21.20 [‐11.45, 53.85]
14 Sperm concentration at 3 months or less (data not suitable for meta analysis) Show forest plot			Other data	No numeric data

14.1 L‐carnitine + Acetyl‐carnitine versus placebo (median and interquartile range)			Other data	No numeric data
14.2 Vitamin E versus placebo			Other data	No numeric data
14.3 L‐carnitine versus placebo			Other data	No numeric data
15 Sperm concentration at 6 months; type of antioxidant Show forest plot	7		Mean Difference (IV, Random, 95% CI)	Subtotals only

15.1 Carnitines versus placebo at 6 months	2	116	Mean Difference (IV, Random, 95% CI)	2.59 [‐3.11, 8.30]
15.2 Selenium versus placebo at 26 weeks (6 months)	1	140	Mean Difference (IV, Random, 95% CI)	4.10 [1.82, 6.38]
15.3 N‐acetyl‐cysteine versus placebo at 26 weeks (6months)	1	140	Mean Difference (IV, Random, 95% CI)	3.30 [1.13, 5.47]
15.4 Selenium plus N‐acetyl‐cysteine versus placebo at 26 weeks (6months)	1	139	Mean Difference (IV, Random, 95% CI)	8.60 [6.28, 10.92]
15.5 Coenzyme Q10 versus placebo at 6 months	3	479	Mean Difference (IV, Random, 95% CI)	6.88 [1.20, 12.56]
15.6 Zinc plus folic acid versus placebo	1	37	Mean Difference (IV, Random, 95% CI)	17.70 [‐1.88, 37.28]
15.7 Folic acid versus placebo	1	34	Mean Difference (IV, Random, 95% CI)	19.20 [4.74, 33.66]
15.8 Zinc versus placebo	1	40	Mean Difference (IV, Random, 95% CI)	9.70 [‐7.01, 26.41]
16 Sperm concentration at 6 months(data not suitable for meta analysis) Show forest plot			Other data	No numeric data

16.1 L‐carnitine + acetyl‐carnitine versus placebo			Other data	No numeric data
16.2 Folic acid versus Placebo			Other data	No numeric data
16.3 Zinc versus Placebo			Other data	No numeric data
16.4 Zinc + folic acid versus placebo			Other data	No numeric data
17 Sperm concentration at 9 months; type of antioxidant Show forest plot	4		Mean Difference (IV, Random, 95% CI)	Subtotals only

17.1 Carnitines versus placebo at 9 months	1	60	Mean Difference (IV, Random, 95% CI)	4.12 [‐1.74, 9.99]
17.2 Coenzyme Q10 versus placebo at 9 months or more	3	479	Mean Difference (IV, Random, 95% CI)	2.74 [‐1.56, 7.05]
18 Sperm concentration over time Show forest plot	20		Mean Difference (IV, Random, 95% CI)	Subtotals only

18.1 Sperm concentration at 3 months or less	13	746	Mean Difference (IV, Random, 95% CI)	5.32 [‐0.62, 11.26]
18.2 Sperm concentration 6 months	8	851	Mean Difference (IV, Random, 95% CI)	5.46 [1.81, 9.11]
18.3 Sperm concentration at 9 months or more	4	509	Mean Difference (IV, Random, 95% CI)	3.66 [‐0.31, 7.64]

Comparison 1. Antioxidant(s) versus placebo or no treatment

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Comparison 2. Head to head antioxidant(s)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Total sperm motility at 3 months or less; type of antioxidant Show forest plot	8		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

1.1 Ethylcysteine 600mg/day vs Vitamin E	1	10	Mean Difference (IV, Fixed, 95% CI)	‐1.90 [‐41.97, 38.17]
1.2 Docosahexaenoic acid (DHA) 400g/day vs Docosahexaenoic acid 800mg/day	1	19	Mean Difference (IV, Fixed, 95% CI)	7.40 [‐11.35, 26.15]
1.3 Vitamin C 200mg/day versus vitamin C 1000mg/day	1	20	Mean Difference (IV, Fixed, 95% CI)	‐43.0 [‐67.10, ‐18.90]
1.4 Vitamin E + Selenium versus Vitamin B at 3 months	1	54	Mean Difference (IV, Fixed, 95% CI)	0.0 [‐10.71, 10.71]
1.5 Zinc versus Zinc + Vitamin E at 3 months	1	18	Mean Difference (IV, Fixed, 95% CI)	‐1.0 [‐13.00, 13.00]
1.6 Zinc versus Zinc + Vitamin E + Vitamin C at 3 months	1	12	Mean Difference (IV, Fixed, 95% CI)	‐1.0 [‐19.66, 17.66]
1.7 Zinc + Vitamin E versus Zinc + Vitamin E + Vitamin C at 3 months	1	18	Mean Difference (IV, Fixed, 95% CI)	0.0 [‐18.97, 18.97]
1.8 Selenium versus combined antioxidants	1	46	Mean Difference (IV, Fixed, 95% CI)	3.20 [‐10.13, 16.53]
1.9 L acetyl carnitine + L carnitine versus Vitamin E + Vitamin C	1	138	Mean Difference (IV, Fixed, 95% CI)	23.05 [20.09, 26.01]
1.10 Zinc + folic acid versus folic acid	1	80	Mean Difference (IV, Fixed, 95% CI)	‐0.60 [‐7.74, 6.54]
1.11 Zinc versus zinc + folic acid	1	80	Mean Difference (IV, Fixed, 95% CI)	‐2.80 [‐12.91, 7.31]
1.12 Zinc versus folic acid	1	80	Mean Difference (IV, Fixed, 95% CI)	‐4.40 [‐14.21, 5.41]
2 Total sperm motility at 6 months; type of antioxidant Show forest plot	3		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

2.1 L‐acetyl carnitine + L‐carnitine versus L‐carnitine	1	30	Mean Difference (IV, Fixed, 95% CI)	‐3.46 [‐9.72, 2.80]
2.2 L‐acetyl carnitine + L‐carnitine versus L‐acetyl carnitine	1	30	Mean Difference (IV, Fixed, 95% CI)	0.64 [‐6.37, 7.65]
2.3 Selenium versus N‐acetyl‐cysteine	1	234	Mean Difference (IV, Fixed, 95% CI)	1.30 [0.56, 2.04]
2.4 Selenium versus selenium plus N‐acetyl‐cysteine	1	232	Mean Difference (IV, Fixed, 95% CI)	‐3.10 [‐3.85, ‐2.35]
2.5 N‐acetyl‐cysteine vs selenium plus N‐acetyl‐cysteine	1	234	Mean Difference (IV, Fixed, 95% CI)	‐4.40 [‐5.14, ‐3.66]
2.6 Zinc + folic acid versus folic acid	1	80	Mean Difference (IV, Fixed, 95% CI)	0.90 [‐5.45, 7.25]
2.7 Zinc versus zinc + folic acid	1	80	Mean Difference (IV, Fixed, 95% CI)	‐2.60 [‐9.13, 3.93]
2.8 Zinc versus folic acid	1	80	Mean Difference (IV, Fixed, 95% CI)	‐1.70 [‐6.42, 3.02]
3 Total sperm motility at 6 months Show forest plot			Other data	No numeric data

3.1 Zinc versus Folic acid			Other data	No numeric data
3.2 Zinc versus Zinc + folic acid			Other data	No numeric data
3.3 Folic acid versus Zinc + folic acid			Other data	No numeric data
4 Total sperm motility at 9 months or more; type of antioxidant Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

4.1 L‐aceytl carnitine + L‐carnitine versus L‐carnitine	1	30	Mean Difference (IV, Fixed, 95% CI)	‐5.27 [‐11.28, 0.74]
4.2 L‐acetyl carnitine + L‐carnitine versus L‐acetyl carnitine	1	30	Mean Difference (IV, Fixed, 95% CI)	‐1.57 [‐6.46, 3.32]
5 Sperm concentration at 3 months or less; type of antioxidant Show forest plot	6		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

5.1 Ethylcysteine 600mg/day vs Vitamin E	1	10	Mean Difference (IV, Fixed, 95% CI)	2.20 [‐16.65, 21.05]
5.2 Docosahexaenoic acid (DHA) 400g/day versus Docosahexaenoic acid (DHA) 800g/day	1	19	Mean Difference (IV, Fixed, 95% CI)	‐6.80 [‐41.87, 28.27]
5.3 L‐carnitine versus Vitamin E + Vitamin C	1	63	Mean Difference (IV, Fixed, 95% CI)	15.5 [12.49, 18.51]
5.4 L‐carnitine plus vitamin E versus vitamin E	1	113	Mean Difference (IV, Fixed, 95% CI)	1.90 [‐10.52, 14.32]
5.5 Selenium versus combined antioxidants	1	46	Mean Difference (IV, Fixed, 95% CI)	14.70 [‐6.51, 35.91]
5.6 Zinc + folic acid versus folic acid	1	80	Mean Difference (IV, Fixed, 95% CI)	‐4.20 [‐22.21, 13.81]
5.7 Zinc versus zinc + folic acid	1	80	Mean Difference (IV, Fixed, 95% CI)	‐1.10 [‐18.63, 16.43]
5.8 Zinc versus folic acid	1	80	Mean Difference (IV, Fixed, 95% CI)	‐5.30 [‐23.38, 12.78]
6 Sperm concentration at 6 months; type of antioxidant Show forest plot	3		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

6.1 L‐aceytl carnitine +L‐carnitine versus L‐carnitine at 6 months	1	30	Mean Difference (IV, Fixed, 95% CI)	‐8.13 [‐21.79, 5.53]
6.2 L‐acetyl carnitine + L‐carnitine versus L‐acetyl carnitine at 6 months	1	30	Mean Difference (IV, Fixed, 95% CI)	‐2.17 [‐15.26, 10.92]
6.3 Selenium versus N‐acetyl‐cysteine at 26 weeks (6 months)	1	234	Mean Difference (IV, Fixed, 95% CI)	0.80 [‐0.71, 2.31]
6.4 Selenium versus selenium plus N‐acetyl‐cysteine at 26 weeks (6 months)	1	232	Mean Difference (IV, Fixed, 95% CI)	‐4.5 [‐6.20, ‐2.80]
6.5 N‐acetyl‐cysteine vs selenium plus N‐acetyl‐cysteine at 26 weeks	1	234	Mean Difference (IV, Fixed, 95% CI)	‐5.30 [‐6.86, ‐3.74]
6.6 Zinc + folic acid versus folic acid	1	80	Mean Difference (IV, Fixed, 95% CI)	‐1.5 [‐15.06, 12.06]
6.7 Zinc versus zinc + folic acid	1	80	Mean Difference (IV, Fixed, 95% CI)	‐8.0 [‐23.69, 7.69]
6.8 Zinc versus folic acid	1	80	Mean Difference (IV, Fixed, 95% CI)	‐9.5 [‐20.31, 1.31]
7 Sperm concentration at 6 months Show forest plot			Other data	No numeric data

7.1 Zinc versus Folic acid			Other data	No numeric data
7.2 Zinc versus Zinc + Folic acid			Other data	No numeric data
7.3 Folic acid versus Zinc + folic acid			Other data	No numeric data
8 Sperm concentration at 9 months or more; type of antioxidant Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

8.1 L‐acetyl carnitine + L‐carnitine versus L‐carnitine at 9 months	1	30	Mean Difference (IV, Fixed, 95% CI)	‐6.13 [‐15.99, 3.73]
8.2 L‐acetyl carnitine + L‐carnitine versus L‐acetyl carnitine at 9 months	1	30	Mean Difference (IV, Fixed, 95% CI)	2.06 [‐6.09, 10.21]

Comparison 2. Head to head antioxidant(s)

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Comparison 3. Pentoxifylline versus placebo or no treatment

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Total sperm motility at 3 months or less; pentoxifylline versus placebo or no treatment Show forest plot	1	90	Mean Difference (IV, Fixed, 95% CI)	12.77 [9.23, 16.31]

2 Total sperm motility at 3 months or less (data not suitable for meta analysis) Show forest plot			Other data	No numeric data

2.1 Pentoxifylline versus placebo			Other data	No numeric data
3 Total sperm motility at 6 months; pentoxifylline versus placebo or no treatment Show forest plot	1	229	Mean Difference (IV, Fixed, 95% CI)	10.10 [9.09, 11.11]

4 Total sperm motility at 6 months (data not suitable for meta analysis) Show forest plot			Other data	No numeric data

4.1 Pentoxifylline versus placebo			Other data	No numeric data
5 Total sperm motility at 9 months; pentoxifylline versus placebo or no treatment Show forest plot	1	221	Mean Difference (IV, Random, 95% CI)	3.10 [1.93, 4.27]

6 Total sperm motility over time Show forest plot	2		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

6.1 Total sperm motility at 3 months or less	1	90	Mean Difference (IV, Fixed, 95% CI)	12.77 [9.23, 16.31]
6.2 Total sperm motility at 6 months	1	229	Mean Difference (IV, Fixed, 95% CI)	10.10 [9.09, 11.11]
6.3 Total sperm motility at 9 months or more	1	221	Mean Difference (IV, Fixed, 95% CI)	3.10 [1.93, 4.27]
7 Sperm concentration at 3 months or less; pentoxifylline versus placebo or no treatment Show forest plot	1	18	Mean Difference (IV, Fixed, 95% CI)	4.30 [‐0.69, 9.29]

8 Sperm concentration at 6 months; pentoxifylline versus placebo Show forest plot	2		Mean Difference (IV, Random, 95% CI)	Subtotals only

9 Sperm concentration at 9 months; pentoxifylline versus placebo Show forest plot	1	221	Mean Difference (IV, Fixed, 95% CI)	1.70 [0.62, 2.78]

10 Sperm concentration over time Show forest plot	2		Mean Difference (IV, Random, 95% CI)	Subtotals only

10.1 Sperm concentration at 3 months or less	1	18	Mean Difference (IV, Random, 95% CI)	4.30 [‐0.69, 9.29]
10.2 Sperm concentration at 6 months	2	247	Mean Difference (IV, Random, 95% CI)	6.90 [‐0.09, 13.89]
10.3 Sperm concentration at 9 months	1	221	Mean Difference (IV, Random, 95% CI)	1.70 [0.62, 2.78]
11 Adverse events Show forest plot	1		Peto Odds Ratio (Peto, Fixed, 95% CI)	Subtotals only

11.1 Vomiting	1	254	Peto Odds Ratio (Peto, Fixed, 95% CI)	4.98 [1.32, 18.81]
11.2 Dyspepsia	1	254	Peto Odds Ratio (Peto, Fixed, 95% CI)	4.68 [1.15, 19.07]
11.3 Headache	1	254	Peto Odds Ratio (Peto, Fixed, 95% CI)	2.41 [0.54, 10.78]
11.4 Diarrhoea	1	254	Peto Odds Ratio (Peto, Fixed, 95% CI)	7.63 [1.30, 44.67]
11.5 Tremor	1	254	Peto Odds Ratio (Peto, Fixed, 95% CI)	7.45 [0.46, 119.73]
11.6 Dizziness	1	254	Peto Odds Ratio (Peto, Fixed, 95% CI)	7.45 [0.46, 119.73]
11.7 Vertigo	1	254	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.96 [0.20, 18.99]

Comparison 3. Pentoxifylline versus placebo or no treatment

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