Melatonin supplementation and outcomes of assisted reproductive technology: a systematic review and meta-analysis

Melatonin (MT) is involved in the regulation of various important biological processes related to reproduction. Many studies have investigated the effects of MT supplementation on outcomes following assisted reproductive technology (ART), yielding conflicting results. The aim of this systematic review was to synthesize evidence from clinical studies regarding the impact of MT on the key outcomes of ART.

PubMed, Embase, Web of Science, and Google scholar were searched. Clinical trials that studied the effect of MT supplementation on outcomes following ART and published in English from inception to April 2020, were included. One author assessed the risk of bias in the studies using the Cochrane Collaboration checklist. Dichotomous outcomes were analyzed as risk ratios (RR) using the Mantel-Haenszel statistical method and a random/fixed effect model. Continuous outcomes were analyzed as Mean Difference (MD) using the Inverse Variance statistical method. The funnel plot was used to assess the publication bias.

Eleven studies conducted between 2008 and 2019 were included in this meta-analysis. Clinical pregnancy rate (CPR), live birth rate (LBR), Miscarriage rate (MR), fertilization rate (FR), Number of oocytes retrieved, MII oocytes, top-quality embryos was reported in 10, 3, 6, 7, 9, 8, and 6 studies, respectively. MT supplementation significantly increased the CPR (RR, 1.24; 95% confidence interval [CI], 1.04, 1.47), the number of MII oocytes (MD, 1.39; 95% CI, 0.74, 2.04), the number of top-quality embryos (MD, 0.56; 95% CI, 0.24, 0.88), and the FR (4 studies with RR, 1.10; 95% CI, 1.03, 1.17; 3 studies with MD, 0.13; 95% CI, 0.01, 0.24). However, there was no significant difference in LBR (RR, 1.23; 95% CI, 0.85, 1.80), the number of oocytes retrieved (MD, 0.58; 95% CI, -0.12, 1.27), and the MR (RR, 0.96; 95% CI, 0.50, 1.82). When studies were sub-grouped by the control interventions, either myoinositol(MI) plus folic acid (FA) or placebo/no treatment, MT supplementation increased number of MII oocytes (MT + MI + FA vs. MI + FA, MD, 0.91; 95% CI, 0.40, 1.41; MT vs. Placebo/no treatment, MD, 2.06; 95% CI, 0.73, 3.39) and number of top-quality embryos (MT + MI + FA vs. MI + FA, MD, 0.70; 95% CI, 0.24, 1.16; MT vs. Placebo/no treatment, MD, 0.33; 95% CI, 0.11, 0.54), while the CPR remained comparable between groups(MT + MI + FA vs. MI + FA, RR, 1.22; 95% CI, 0.96, 1.54; MT vs. Placebo/No treatment, RR, 1.26; 95% CI, 0.97, 1.62). When sub-group analysis was performed basing on women's characteristics, MT supplementation showed no significant beneficial effect on CPR in women with polycystic ovary syndrome (PCOS) (RR, 1.18; 95% CI, 0.92, 1.52), normal ovarian function (RR, 1.15; 95% CI, 0.87, 1.53), or a history of low fertilization rates or poor-quality embryos (RR, 1.71; 95% CI, 0.95, 3.07). However, MT supplementation increased the number of MII oocytes in women with PCOS (MD, 0.97; 95% CI, 0.22, 1.73), but this benefit was not observed in women with normal ovarian function (MD, 1.49; 95% CI, -0.33, 3.31).

As the outcomes of ART were influenced by multiple factors, MT supplementation may not significantly improve clinical pregnancy or live birth rate. However, MT appears to have a positive effect on oocyte and embryo quality, particularly in women with PCOS or decreased ovarian reserve (DOR), at least to some extent. Nevertheless, further well-designed, large-scale studies are needed before MT can be recommended for routine use in clinical practice.