Impact of Antioxidant Therapy on Natural Pregnancy Outcomes and Semen Parameters in Infertile Men: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Ashok Agarwal 1, Rossella Cannarella 2 3, Ramadan Saleh 4 5, Ahmed M Harraz 6 7 8, Hussein Kandil 9, Gianmaria Salvio 10, Florence Boitrelle 11 12, Shinnosuke Kuroda 3, Ala'a Farkouh 13, Amarnath Rambhatla 14, Armand Zini 15, Giovanni Colpi 16, Murat Gül 17, Parviz Kavoussi 18, Taha Abo-Almagd Abdel-Meguid Hamoda 19 20, Edmund Ko 21, Gokhan Calik 22, Tuncay Toprak 23, Germar-Michael Pinggera 24, Hyun Jun Park 25 26, Ramy Abou Ghayda 27, Suks Minhas 28, Gian Maria Busetto 29, Mustafa Emre Bakırcıoğlu 30, Ates Kadioglu 31, Eric Chung 32, Giorgio Ivan Russo 33, Aldo E Calogero 2, Rafael F Ambar 34 35, Channa N Jayasena 36 37, Rupin Shah 38

Affiliations

01 January 2023

-

doi: 10.5534/wjmh.220067

Abstract

Purpose: Seminal oxidative stress (OS) is a recognized factor potentially associated with male infertility, but the efficacy of antioxidant (AOX) therapy is controversial and there is no consensus on its utility. Primary outcomes of this study were to investigate the effect of AOX on spontaneous clinical pregnancy, live birth and miscarriage rates in male infertile patients. Secondary outcomes were conventional semen parameters, sperm DNA fragmentation (SDF) and seminal OS.

Materials and methods: Literature search was performed using Scopus, PubMed, Ovid, Embase, and Cochrane databases. Only randomized controlled trials (RCTs) were included and the meta-analysis was conducted according to PRISMA guidelines.

Results: We assessed for eligibility 1,307 abstracts, and 45 RCTs were finally included, for a total of 4,332 infertile patients. We found a significantly higher pregnancy rate in patients treated with AOX compared to placebo-treated or untreated controls, without significant inter-study heterogeneity. No effects on live-birth or miscarriage rates were observed in four studies. A significantly higher sperm concentration, sperm progressive motility, sperm total motility, and normal sperm morphology was found in patients compared to controls. We found no effect on SDF in analysis of three eligible studies. Seminal levels of total antioxidant capacity were significantly higher, while seminal malondialdehyde acid was significantly lower in patients than controls. These results did not change after exclusion of studies performed following varicocele repair.

Conclusions: The present analysis upgrades the level of evidence favoring a recommendation for using AOX in male infertility to improve the spontaneous pregnancy rate and the conventional sperm parameters. The failure to demonstrate an increase in live-birth rate, despite an increase in pregnancy rates, is due to the very few RCTs specifically assessing the impact of AOX on live-birth rate. Therefore, further RCTs assessing the impact of AOX on live-birth rate and miscarriage rate, and SDF will be helpful.

Keywords: Antioxidants; Male infertility; Meta-analysis; Pregnancy; Semen parameters; Sperm DNA fragmentation.

Conflict of interest statement

The authors have nothing to disclose.

Figures

Fig. 1. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow chart of the included studies. RCT: randomized controlled trial.

Fig. 1. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow chart of the included studies. RCT: randomized controlled trial.

Fig. 2. Forest plot of the spontaneous pregnancy rate in infertile patients treated with antioxidants (AOXs) compared to placebo or untreated infertile controls.

Fig. 2. Forest plot of the spontaneous pregnancy rate in infertile patients treated with antioxidants (AOXs) compared to placebo or untreated infertile controls.

Fig. 3. Funnel plot of the spontaneous pregnancy rate in infertile patients treated with antioxidants compared to placebo or untreated infertile controls.

Fig. 3. Funnel plot of the spontaneous pregnancy rate in infertile patients treated with antioxidants compared to placebo or untreated infertile controls.

Fig. 4. Forest plot of the spontaneous pregnancy rate in infertile patients treated with antioxidants (AOXs) compared to placebo or untreated infertile controls, after the removal of studies including patients with varicocele undergoing varicocele repair.

Fig. 4. Forest plot of the spontaneous pregnancy rate in infertile patients treated with antioxidants (AOXs) compared to placebo or untreated infertile controls, after the removal of studies including patients with varicocele undergoing varicocele repair.

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