Antioxidants for female subfertility

Showell et al., 2020 | Cochrane Database Syst Rev | Meta Analysis

Citation

Showell Marian G, Mackenzie-Proctor Rebecca, ... Hart Roger J. Antioxidants for female subfertility. Cochrane Database Syst Rev. 2020-Aug-27;8(8):CD007807. doi:10.1002/14651858.CD007807.pub4

Abstract

EDITORIAL NOTE: This editorial note has been published online on March 5th, 2026, by the editors of the Cochrane Database of Systematic Reviews, in agreement with the authors, due to concerns discovered by Cochrane and the Managing Editor of the Cochrane Gynaecology and Fertility Group regarding nine of the studies included in the systematic review ‘Antioxidants for female subfertility’ (https://doi.org/10.1002/14651858.CD007807.pub4). It replaces an editorial note previously published on August 27, 2020 that highlighted concerns regarding eight of these studies included in the systematic review. Since publication of the systematic review, retractions have been published for seven of the included studies and expressions of concern have been published on a further two. Following an investigation using the Cochrane framework for determining the impact of removing studies with retractions from a systematic review, editors have determined that removing these studies from the systematic review leads to no meaningful impact on the review’s findings, and therefore the editors retain confidence in its conclusions. In the next update of this Cochrane review, these nine studies will be excluded from the analyses. The studies with retractions will be moved to the excluded studies table and the studies with expressions of concern will be moved to studies awaiting classification. Summary of the assessment of impact For the comparison of antioxidant(s) compared to placebo or no treatment/standard treatment for female subfertility, the studies with retractions and expressions of concern do not have a meaningful impact on the findings or conclusions reported in the review (summary of findings table 1). This is based on an assessment of the scale of the contribution of the studies to the analyses, and the effect of the studies on the quantitative assessments and certainty of the evidence. For the comparison of head‐to‐head antioxidants for female subfertility, the studies with retractions and expressions of concern have some impact on the findings but do not have an meaningful impact on the conclusions(summary of findings table 2). El Sharkwy 2019a was the only study included in the review to contribute results for two outcomes (clinical pregnancy and miscarriage in the ‘N‐acetylcysteine versus L‐carnitine’ comparison). Exclusion of this study changes the certainty of the evidence for these outcomes from no evidence of a difference (for clinical pregnancy) and very low certainty (for miscarriage) to no studies measured this outcomes (for both clinical pregnancy and miscarriage). BACKGROUND: A couple may be considered to have fertility problems if they have been trying to conceive for over a year with no success. This may affect up to a quarter of all couples planning a child. It is estimated that for 40% to 50% of couples, subfertility may result from factors affecting women. Antioxidants are thought to reduce the oxidative stress brought on by these conditions. Currently, limited evidence suggests that antioxidants improve fertility, and trials have explored this area with varied results. This review assesses the evidence for the effectiveness of different antioxidants in female subfertility. OBJECTIVES: To determine whether supplementary oral antioxidants compared with placebo, no treatment/standard treatment or another antioxidant improve fertility outcomes for subfertile women. SEARCH METHODS: We searched the following databases (from their inception to September 2019), with no language or date restriction: Cochrane Gynaecology and Fertility Group (CGFG) specialised register, CENTRAL, MEDLINE, Embase, PsycINFO, CINAHL and AMED. We checked reference lists of relevant studies and searched the trial registers. SELECTION CRITERIA: 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 women attending a reproductive clinic. We excluded trials comparing antioxidants with fertility drugs alone and trials that only included fertile women attending a fertility clinic because of male partner infertility. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. The primary review outcome was live birth; secondary outcomes included clinical pregnancy rates and adverse events. MAIN RESULTS: We included 63 trials involving 7760 women. Investigators compared oral antioxidants, including: combinations of antioxidants, N-acetylcysteine, melatonin, L-arginine, myo-inositol, carnitine, selenium, vitamin E, vitamin B complex, vitamin C, vitamin D+calcium, CoQ10, and omega-3-polyunsaturated fatty acids versus placebo, no treatment/standard treatment or another antioxidant. Only 27 of the 63 included trials reported funding sources. Due to the very low-quality of the evidence we are uncertain whether antioxidants improve live birth rate compared with placebo or no treatment/standard treatment (odds ratio (OR) 1.81, 95% confidence interval (CI) 1.36 to 2.43; P < 0.001, I2 = 29%; 13 RCTs, 1227 women). This suggests that among subfertile women with an expected live birth rate of 19%, the rate among women using antioxidants would be between 24% and 36%. Low-quality evidence suggests that antioxidants may improve clinical pregnancy rate compared with placebo or no treatment/standard treatment (OR 1.65, 95% CI 1.43 to 1.89; P < 0.001, I2 = 63%; 35 RCTs, 5165 women). This suggests that among subfertile women with an expected clinical pregnancy rate of 19%, the rate among women using antioxidants would be between 25% and 30%. Heterogeneity was moderately high. Overall 28 trials reported on various adverse events in the meta-analysis. The evidence suggests that the use of antioxidants makes no difference between the groups in rates of miscarriage (OR 1.13, 95% CI 0.82 to 1.55; P = 0.46, I2 = 0%; 24 RCTs, 3229 women; low-quality evidence). There was also no evidence of a difference between the groups in rates of multiple pregnancy (OR 1.00, 95% CI 0.63 to 1.56; P = 0.99, I2 = 0%; 9 RCTs, 1886 women; low-quality evidence). There was also no evidence of a difference between the groups in rates of gastrointestinal disturbances (OR 1.55, 95% CI 0.47 to 5.10; P = 0.47, I2 = 0%; 3 RCTs, 343 women; low-quality evidence). Low-quality evidence showed that there was also no difference between the groups in rates of ectopic pregnancy (OR 1.40, 95% CI 0.27 to 7.20; P = 0.69, I2 = 0%; 4 RCTs, 404 women). In the antioxidant versus antioxidant comparison, low-quality evidence shows no difference in a lower dose of melatonin being associated with an increased live-birth rate compared with higher-dose melatonin (OR 0.94, 95% CI 0.41 to 2.15; P = 0.89, I2 = 0%; 2 RCTs, 140 women). This suggests that among subfertile women with an expected live-birth rate of 24%, the rate among women using a lower dose of melatonin compared to a higher dose would be between 12% and 40%. Similarly with clinical pregnancy, there was no evidence of a difference between the groups in rates between a lower and a higher dose of melatonin (OR 0.94, 95% CI 0.41 to 2.15; P = 0.89, I2 = 0%; 2 RCTs, 140 women). Three trials reported on miscarriage in the antioxidant versus antioxidant comparison (two used doses of melatonin and one compared N-acetylcysteine versus L-carnitine). There were no miscarriages in either melatonin trial. Multiple pregnancy and gastrointestinal disturbances were not reported, and ectopic pregnancy was reported by only one trial, with no events. The study comparing N-acetylcysteine with L-carnitine did not report live birth rate. Very low-quality evidence shows no evidence of a difference in clinical pregnancy (OR 0.81, 95% CI 0.33 to 2.00; 1 RCT, 164 women; low-quality evidence). Low quality evidence shows no difference in miscarriage (OR 1.54, 95% CI 0.42 to 5.67; 1 RCT, 164 women; low-quality evidence). The study did not report multiple pregnancy, gastrointestinal disturbances or ectopic pregnancy. The overall quality of evidence was limited by serious risk of bias associated with poor reporting of methods, imprecision and inconsistency. AUTHORS' CONCLUSIONS: In this review, there was low- to very low-quality evidence to show that taking an antioxidant may benefit subfertile women. Overall, there is no evidence of increased risk of miscarriage, multiple births, gastrointestinal effects or ectopic pregnancies, but evidence was of very low quality. At this time, there is limited evidence in support of supplemental oral antioxidants for subfertile women.

Key Findings

We included 63 trials involving 7760 women. Investigators compared oral antioxidants, including: combinations of antioxidants, N-acetylcysteine, melatonin, L-arginine, myo-inositol, carnitine, selenium, vitamin E, vitamin B complex, vitamin C, vitamin D+calcium, CoQ10, and omega-3-polyunsaturated fatty acids versus placebo, no treatment/standard treatment or another antioxidant. Only 27 of the 63 included trials reported funding sources. Due to the very low-quality of the evidence we are uncerta

Outcomes Measured

• Requires manual extraction

Population

MeSH Terms

• Abortion, Spontaneous
• Administration, Oral
• Antioxidants
• Female
• Humans
• Infertility, Female
• Live Birth
• Minerals
• Oxidative Stress
• Pentoxifylline
• Placebos
• Pregnancy
• Pregnancy Rate
• Pregnancy, Multiple
• Randomized Controlled Trials as Topic
• Vitamins

Evidence Classification

• Level: Meta Analysis
• Publication Types: Journal Article, Meta-Analysis, Systematic Review
• Vertical: vitamin-c

Provenance

• PMID: 32851663
• DOI: 10.1002/14651858.CD007807.pub4
• PMCID: PMC8094745
• Verified: 2026-04-09 via PubMed E-utilities API

Source extracted via PubMed E-utilities API on 2026-04-09