Studies selection and characteristics
This search strategy produced 160 citations. After reviewing the title and/or abstract, 103 irrelevant studies were excluded. Of the remaining 57 papers, 44 studies were excluded, as outcomes of IVF/ICSI were not reported or irrelevant to our subject. Two studies were system review and meta-analysis. The study flow diagram is shown as Supplemental Table 1.
The characteristics of the included studies are showed as in Table 1. 11 prospective studies were included in our meta-analysis. In these studies, there were 10 studies for clinical pregnancy, 3 studies for live birth rate, 6 studies for miscarriage rate, 7 studies for fertilization rate, 9 (8) studies for oocyte (MII) number, and 6 studies for top embryo. The control group used placebo or no-treatment in 7 studies, and used standard treatment with myoinositol + folic acid (MI+ FA) in 3 studies. One study did not report the treatment in control group. Among 11 studies, 1 study included infertile women with disturbed sleep, 2 studies included women with PCOS, 3 studies with normal ovarian function, 1 study with DOR, 3 studies with previous low fertilization rate or poor quality embryo, and 1 study did not reported the characteristic of participant.
Meta-analysis
Ten, three, six seven, nine, eight, six studies were obtained in our meta-analysis to assess the effect of MT supplementation on CPR, LBR, MR, FR, Number of oocyte, Number of MII, Number of top embryo after ART treatment, respectively.
When evaluated the effects of MT supplementation on the CPR, 10 studies were analyzed including 593 cycles with MT supplementation and 516 cycles without MT. The CPR was significantly increased in women with MT supplementation compared with control group. There was no heterogeneity across studies with P=0.96 (l2=0%). The fixed effects model was implied and the combined PR was 1.24 (95% CI, 1.04, 1.47; P=0.02) (Fig. 1).
Subsequently, we presented stratified results by the interventions. The MT supplementation with or without MI+FA did not bring beneficial effect on CPR with combined RR 1.22 (95% CI, 0.96, 1.54; P=0.10) compared with treatment with MI+FA and 1.26 (95% CI, 0.97, 1.62; P=0.08) compared with treatment with placebo/none. Included studies were subgrouped into 4 types by the characteristic of women: women with PCOS (2 studies), Normal ovarian function (3 studies), with previous poor oocyte quality of low fertilization rate (3 studies), and DOR (1 study). The pooled RRs in women with PCOS, Normal ovarian function, and with previous poor oocyte quality/ low fertilization rate, were 1.18 (95% CI, 0.92, 1.52; P=0.18), 1.15 (95% CI, 0.87, 1.53; P=0.32), 1.71 (95% CI, 0.95, 3.07; P=0.07), respectively, showed no significant difference with control group.
Three studies were included to evaluate the effects of MT supplementation on the LBR, including 190 cycles with MT supplementation and 101 cycles in control group. The LBR was similar between groups. The statistical heterogeneity was good with P=0.80 (l2=0%). The combined RR was 1.23 (95% CI, 0.85, 1.80; P=0.27) (Fig. 2).
Of 11 studies, six studies evaluated the effect of MT supplementation on MR. These results indicated that there was no beneficial effect in patients with MT supplementation. The pooled RR for MR was 0.96 (95% CI, 0.50, 1.82; P=0.89) with fixed effects model. There was no heterogeneity of the studies (l2=0%, P=0.91). (Sup Fig. 1)
As for the FR, three studies evaluated FR as mean ± SD, and the pooled MD was 0.13 (95% CI, 0.01, 0.24; P=0.03), with moderate statistical heterogeneity (l2=73%, P=0.01). In addition, four studies assessed FR as cases (events/ total), and the pooled RR was 1.10 (95% CI, 1.03, 1.17; P=0.007) with moderate statistical heterogeneity (l2=49%, P=0.12). (Sup Fig. 2)
We also evaluated the effect of MT supplementation on the Number of oocyte (Sup Fig. 3), MII (Sup Fig. 4) and top-quality embryo (Sup Fig. 5). The results showed MT supplementation increased number of MII (MD 1.39; 95% CI, 0.74, 2.04; P<0.0001) and top-quality embryo (MD 0.56; 95% CI, 0.24, 0.88; P=0.0005) compared with control group. However, there was no difference in number of oocyte (MD 0.58; 95% CI, -0.12, 1.27; P=0.10). Regardless of whether the intervention is with or without MI+FA, the supplementation of MT can significantly increase the number of MII (MI+MT+FA vs. MI+FA: MD 0.91; 95% CI 0.40, 1.41; P=0.004; MT vs. placebo/none: MD 2.06, 95% CI 0.73, 3.39; P=0.002), and top-quality embryo (MI+MT+FA vs. MI+FA: MD 0.70; 95% CI 0.24, 1.16; P=0.003; MT vs. placebo/none: MD 0.33, 95% CI 0.11, 0.54; P=0.003). However, MT supplementation only increased the No. of MII in women with PCOS (MD 0.97; 95% CI 0.22, 1.73; P=0.0004), and not in women with normal ovarian function (MD 1.49; 95% CI -0.33, 3.31; P=0.11) compared with control group.
These studies included were all have medium to high score via the Newcastle-Ottawa Quality Assessment Scale (not shown). There was no publication bias as a symmetrical shape was seen in the funnel plot in the evaluation the effect of MT supplementation on CPR, LBR, MR, Number of oocyte, MII, and top-quality embryo. However, the studies showed modest publication bias when assess the effect of MT supplementation on FR. (Sup Fig. 6-12)