Melatonin Supplementation and Outcomes After Assisted Reproductive Technology: A Systematic Review and Meta-analyses
Authors: Zhao Jing , Hao Jie , Xu Bin , Wang Yonggang , Li Yanping 
Published: October 2020

Abstract
Melatonin (MT) regulates a variety of important actions related to reproduction. Many studies have investigated the effect of MT application on the outcome after assisted reproductive technology (ART), with controversial results. The aim of this systematic review was to synthesize evidence from clinical studies that examine the effect of MT on the main outcomes of ART. PubMed, Embase, Web of Science, and Google scholar were searched. Clinical trials, which studied the effect of MT supplementation on outcome after 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. Eleven studies performed 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 oocyte retrieved, MII oocyte, top-quality embryo were 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 No. of MII oocyte (MD, 1.39; 95% CI, 0.74, 2.04), the No. of top-quality embryo (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), No. of oocyte 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 interventions, no matter the control group is MI+FA or placebo/none, MT supplementation increased No. of MII oocyte (MT+MI+FA vs. MI+FA MD, 0.91; 95% CI, 0.40, 1.41; MT vs. Placebo/none MD, 2.06; 95% CI, 0.73, 3.39) and No. of top embryo (MT+MI+FA vs. MI+FA MD, 0.70; 95% CI, 0.24, 1.16; MT vs. Placebo/none MD, 0.33; 95% CI, 0.11, 0.54), whereas showed similar CPR (MT+MI+FA vs. MI+FA RR, 1.22; 95% CI, 0.96, 1.54; MT vs. Placebo/None RR, 1.26; 95% CI, 0.97, 1.62). When studies were sub-grouped according to women’s characteristic, MT supplementation showed no significant beneficial effect on CPR in women with PCOS (RR, 1.18; 95% CI, 0.92, 1.52), with normal ovary function (RR, 1.15; 95% CI, 0.87, 1.53), and women with previous low fertilization or poor-quality embryo (RR, 1.71; 95% CI, 0.95, 3.07). However, MT supplementation increased the No of MII in women with PCOS (MD, 0.97; 95% CI, 0.22, 1.73), but did not show such benefit in women with normal ovary function (MD, 1.49; 95% CI, -0.33, 3.31). In conclusion, MT supplementation may not improve the clinical pregnancy and live birth of ART. But MT seems to be beneficial to the quality of oocyte and embryo, especially for women with PCOS and DOR, at least to some extent. Further well-designed studies are needed before recommendation of its use in clinical practice.