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Meta-Analysis
. 2021 Jan 18;11(1):1747.
doi: 10.1038/s41598-021-81439-6.

Efficacy of therapies and interventions for repeated embryo implantation failure: a systematic review and meta-analysis

Andrea Busnelli  1   2 , Edgardo Somigliana  3   4 , Federico Cirillo  5 , Annamaria Baggiani  5 , Paolo Emanuele Levi-Setti  5
Affiliations
Meta-Analysis

Efficacy of therapies and interventions for repeated embryo implantation failure: a systematic review and meta-analysis

Andrea Busnelli et al. Sci Rep. .

Abstract

The aim of the present systematic review and meta-analysis was to assess the effect of the different therapeutic options for repeated embryo implantation failure (RIF) on a subsequent IVF cycle outcome. Twenty-two RCTs and nineteen observational studies were included. Pooling of results showed a beneficial effect of intrauterine PBMC infusion on both CPR (RR 2.18; 95% CI 1.58-3.00; p < 0.00001; OR 2.03; 95% CI 1.22-3.36; p = 0.006) and LBR (RR 2.41; 95% CI 1.40-4.16; p = 0.002; OR 3.73; 95% CI 1.13-12.29; p = 0.03), of subcutaneous G-CSF administration on CPR (RR 2.29; 95% CI 1.58-3.31; p < 0.0001) and of intrauterine PRP infusion on CPR (RR 2.45; 95% CI 1.55-3.86; p = 0.0001). Observational studies also demonstrated a positive effect of IVIG and intrauterine hCG infusion on both CPR and LBR and of atosiban on CPR. Studies investigating intrauterine G-CSF infusion, LMWH, intravenous intralipid, hysteroscopy, blastocyst-stage ET, ZIFT, PGT-A and AH failed to observe an impact on IVF outcome. The quality of the evidence that emerged from RCTs focused on intrauterine PBMC infusion and subcutaneous G-CSF administration was moderate. For all other therapies/interventions it varied from low to very low. In conclusion, intrauterine PBMC infusion and subcutaneous G-CSF administration are the most promising therapeutic options for RIF. However, further well conducted RCTs are necessary before their introduction into clinical practice.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Figure 1
Figure 1
Study selection.
Figure 2
Figure 2
Risk of bias summary: review authors' judgements about each risk of bias item for each included randomized controlled trial (RCT).
Figure 3
Figure 3
(A) Effect of subcutaneous G-CSF administration on CPR in women with RIF (RCTs). (B) Effect of intrauterine G-CSF infusion on CPR in women with RIF (RCTs). (C) Effect of subcutaneous G-CSF administration on LBR in women with RIF (RCT). (D) Effect of intrauterine PBMC infusion on CPR in women with RIF (RCTs). (E) Effect of intrauterine PBMC infusion on LBR in women with RIF (RCT). (F) Effect of intrauterine PBMC infusion on CPR in women with RIF (observational studies). (G) Effect of intrauterine PBMC infusion on LBR in women with RIF (observational studies). RIF repeated implantation failure, G-CSF granulocyte-colony stimulating factor, PBMC peripheral blood mononuclear cells, RCT randomized clinical trial, CPR clinical pregnancy rate, LBR live birth rate.
Figure 3
Figure 3
(A) Effect of subcutaneous G-CSF administration on CPR in women with RIF (RCTs). (B) Effect of intrauterine G-CSF infusion on CPR in women with RIF (RCTs). (C) Effect of subcutaneous G-CSF administration on LBR in women with RIF (RCT). (D) Effect of intrauterine PBMC infusion on CPR in women with RIF (RCTs). (E) Effect of intrauterine PBMC infusion on LBR in women with RIF (RCT). (F) Effect of intrauterine PBMC infusion on CPR in women with RIF (observational studies). (G) Effect of intrauterine PBMC infusion on LBR in women with RIF (observational studies). RIF repeated implantation failure, G-CSF granulocyte-colony stimulating factor, PBMC peripheral blood mononuclear cells, RCT randomized clinical trial, CPR clinical pregnancy rate, LBR live birth rate.
Figure 4
Figure 4
(A) Effect of intentional endometrial injury on CPR in women with RIF (RCTs). (B) Effect of intentional endometrial injury on LBR in women with RIF (RCTs). (C) Effect of intentional endometrial injury on CPR in women with RIF (observational studies). (D) Effect of hysteroscopy on LBR in women with RIF (RCT). (E) Effect of atosiban on CPR in women with RIF (observational study). (F) Effect of sequential ET on CPR in women with RIF (RCT). (G) Effect of sequential ET on CPR in women with RIF (observational studies). (H) Effect of PGT-A on CPR in women with RIF (RCTs). (I) Effect of PGT-A on LBR in women with RIF (RCTs). (J) Effect of PGT-A on CPR in women with RIF (observational studies). (K) Effect of PGT-A on LBR in women with RIF (observational studies). (L) Effect of ZIFT on CPR in women with RIF (observational studies). (M) Effect of ZIFT on LBR in women with RIF (observational studies). (N) Effect of AH on CPR in women with RIF (RCT). (O) Effect of AH on LBR in women with RIF (observational study). (P) Effect of intravenous intralipid on CPR (RCT). (Q) Effect of intravenous intralipid on LBR in women with RIF (RCT). (R) Effect of LMWH on CPR in women with RIF (RCTs). (S) Effect of LMWH on LBR in women with RIF (RCT). (T) Effect of LMWH on CPR in women with RIF (observational study). (U) Effect of LMWH on LBR in women with RIF (observational study). (V) Effect of IVIG on CPR in women with RIF (observational study). (W) Effect of IVIG on LBR in women with RIF (observational study). (X) Effect of intrauterine hCG infusion on CPR in women with RIF (observational studies). (Y) Effect of intrauterine hCG infusion on LBR in women with RIF (observational study). (Z) Effect of intrauterine PRP infusion on CPR in women with RIF (RCT). ET embryo transfer, RIF repeated implantation failure, RCT randomized clinical trial, CPR clinical pregnancy rate, LBR live birth rate, LMWH low molecular weight heparin, PGT-A preimplantation genetic testing for aneuploidy, IVIG intravenous immunoglobulin, hCG human chorionic gonadotropin, ZIFT zygote intrafallopian transfer, AH assisted hatching, PRP platelet rich plasma.
Figure 4
Figure 4
(A) Effect of intentional endometrial injury on CPR in women with RIF (RCTs). (B) Effect of intentional endometrial injury on LBR in women with RIF (RCTs). (C) Effect of intentional endometrial injury on CPR in women with RIF (observational studies). (D) Effect of hysteroscopy on LBR in women with RIF (RCT). (E) Effect of atosiban on CPR in women with RIF (observational study). (F) Effect of sequential ET on CPR in women with RIF (RCT). (G) Effect of sequential ET on CPR in women with RIF (observational studies). (H) Effect of PGT-A on CPR in women with RIF (RCTs). (I) Effect of PGT-A on LBR in women with RIF (RCTs). (J) Effect of PGT-A on CPR in women with RIF (observational studies). (K) Effect of PGT-A on LBR in women with RIF (observational studies). (L) Effect of ZIFT on CPR in women with RIF (observational studies). (M) Effect of ZIFT on LBR in women with RIF (observational studies). (N) Effect of AH on CPR in women with RIF (RCT). (O) Effect of AH on LBR in women with RIF (observational study). (P) Effect of intravenous intralipid on CPR (RCT). (Q) Effect of intravenous intralipid on LBR in women with RIF (RCT). (R) Effect of LMWH on CPR in women with RIF (RCTs). (S) Effect of LMWH on LBR in women with RIF (RCT). (T) Effect of LMWH on CPR in women with RIF (observational study). (U) Effect of LMWH on LBR in women with RIF (observational study). (V) Effect of IVIG on CPR in women with RIF (observational study). (W) Effect of IVIG on LBR in women with RIF (observational study). (X) Effect of intrauterine hCG infusion on CPR in women with RIF (observational studies). (Y) Effect of intrauterine hCG infusion on LBR in women with RIF (observational study). (Z) Effect of intrauterine PRP infusion on CPR in women with RIF (RCT). ET embryo transfer, RIF repeated implantation failure, RCT randomized clinical trial, CPR clinical pregnancy rate, LBR live birth rate, LMWH low molecular weight heparin, PGT-A preimplantation genetic testing for aneuploidy, IVIG intravenous immunoglobulin, hCG human chorionic gonadotropin, ZIFT zygote intrafallopian transfer, AH assisted hatching, PRP platelet rich plasma.
Figure 4
Figure 4
(A) Effect of intentional endometrial injury on CPR in women with RIF (RCTs). (B) Effect of intentional endometrial injury on LBR in women with RIF (RCTs). (C) Effect of intentional endometrial injury on CPR in women with RIF (observational studies). (D) Effect of hysteroscopy on LBR in women with RIF (RCT). (E) Effect of atosiban on CPR in women with RIF (observational study). (F) Effect of sequential ET on CPR in women with RIF (RCT). (G) Effect of sequential ET on CPR in women with RIF (observational studies). (H) Effect of PGT-A on CPR in women with RIF (RCTs). (I) Effect of PGT-A on LBR in women with RIF (RCTs). (J) Effect of PGT-A on CPR in women with RIF (observational studies). (K) Effect of PGT-A on LBR in women with RIF (observational studies). (L) Effect of ZIFT on CPR in women with RIF (observational studies). (M) Effect of ZIFT on LBR in women with RIF (observational studies). (N) Effect of AH on CPR in women with RIF (RCT). (O) Effect of AH on LBR in women with RIF (observational study). (P) Effect of intravenous intralipid on CPR (RCT). (Q) Effect of intravenous intralipid on LBR in women with RIF (RCT). (R) Effect of LMWH on CPR in women with RIF (RCTs). (S) Effect of LMWH on LBR in women with RIF (RCT). (T) Effect of LMWH on CPR in women with RIF (observational study). (U) Effect of LMWH on LBR in women with RIF (observational study). (V) Effect of IVIG on CPR in women with RIF (observational study). (W) Effect of IVIG on LBR in women with RIF (observational study). (X) Effect of intrauterine hCG infusion on CPR in women with RIF (observational studies). (Y) Effect of intrauterine hCG infusion on LBR in women with RIF (observational study). (Z) Effect of intrauterine PRP infusion on CPR in women with RIF (RCT). ET embryo transfer, RIF repeated implantation failure, RCT randomized clinical trial, CPR clinical pregnancy rate, LBR live birth rate, LMWH low molecular weight heparin, PGT-A preimplantation genetic testing for aneuploidy, IVIG intravenous immunoglobulin, hCG human chorionic gonadotropin, ZIFT zygote intrafallopian transfer, AH assisted hatching, PRP platelet rich plasma.
Figure 4
Figure 4
(A) Effect of intentional endometrial injury on CPR in women with RIF (RCTs). (B) Effect of intentional endometrial injury on LBR in women with RIF (RCTs). (C) Effect of intentional endometrial injury on CPR in women with RIF (observational studies). (D) Effect of hysteroscopy on LBR in women with RIF (RCT). (E) Effect of atosiban on CPR in women with RIF (observational study). (F) Effect of sequential ET on CPR in women with RIF (RCT). (G) Effect of sequential ET on CPR in women with RIF (observational studies). (H) Effect of PGT-A on CPR in women with RIF (RCTs). (I) Effect of PGT-A on LBR in women with RIF (RCTs). (J) Effect of PGT-A on CPR in women with RIF (observational studies). (K) Effect of PGT-A on LBR in women with RIF (observational studies). (L) Effect of ZIFT on CPR in women with RIF (observational studies). (M) Effect of ZIFT on LBR in women with RIF (observational studies). (N) Effect of AH on CPR in women with RIF (RCT). (O) Effect of AH on LBR in women with RIF (observational study). (P) Effect of intravenous intralipid on CPR (RCT). (Q) Effect of intravenous intralipid on LBR in women with RIF (RCT). (R) Effect of LMWH on CPR in women with RIF (RCTs). (S) Effect of LMWH on LBR in women with RIF (RCT). (T) Effect of LMWH on CPR in women with RIF (observational study). (U) Effect of LMWH on LBR in women with RIF (observational study). (V) Effect of IVIG on CPR in women with RIF (observational study). (W) Effect of IVIG on LBR in women with RIF (observational study). (X) Effect of intrauterine hCG infusion on CPR in women with RIF (observational studies). (Y) Effect of intrauterine hCG infusion on LBR in women with RIF (observational study). (Z) Effect of intrauterine PRP infusion on CPR in women with RIF (RCT). ET embryo transfer, RIF repeated implantation failure, RCT randomized clinical trial, CPR clinical pregnancy rate, LBR live birth rate, LMWH low molecular weight heparin, PGT-A preimplantation genetic testing for aneuploidy, IVIG intravenous immunoglobulin, hCG human chorionic gonadotropin, ZIFT zygote intrafallopian transfer, AH assisted hatching, PRP platelet rich plasma.
Figure 4
Figure 4
(A) Effect of intentional endometrial injury on CPR in women with RIF (RCTs). (B) Effect of intentional endometrial injury on LBR in women with RIF (RCTs). (C) Effect of intentional endometrial injury on CPR in women with RIF (observational studies). (D) Effect of hysteroscopy on LBR in women with RIF (RCT). (E) Effect of atosiban on CPR in women with RIF (observational study). (F) Effect of sequential ET on CPR in women with RIF (RCT). (G) Effect of sequential ET on CPR in women with RIF (observational studies). (H) Effect of PGT-A on CPR in women with RIF (RCTs). (I) Effect of PGT-A on LBR in women with RIF (RCTs). (J) Effect of PGT-A on CPR in women with RIF (observational studies). (K) Effect of PGT-A on LBR in women with RIF (observational studies). (L) Effect of ZIFT on CPR in women with RIF (observational studies). (M) Effect of ZIFT on LBR in women with RIF (observational studies). (N) Effect of AH on CPR in women with RIF (RCT). (O) Effect of AH on LBR in women with RIF (observational study). (P) Effect of intravenous intralipid on CPR (RCT). (Q) Effect of intravenous intralipid on LBR in women with RIF (RCT). (R) Effect of LMWH on CPR in women with RIF (RCTs). (S) Effect of LMWH on LBR in women with RIF (RCT). (T) Effect of LMWH on CPR in women with RIF (observational study). (U) Effect of LMWH on LBR in women with RIF (observational study). (V) Effect of IVIG on CPR in women with RIF (observational study). (W) Effect of IVIG on LBR in women with RIF (observational study). (X) Effect of intrauterine hCG infusion on CPR in women with RIF (observational studies). (Y) Effect of intrauterine hCG infusion on LBR in women with RIF (observational study). (Z) Effect of intrauterine PRP infusion on CPR in women with RIF (RCT). ET embryo transfer, RIF repeated implantation failure, RCT randomized clinical trial, CPR clinical pregnancy rate, LBR live birth rate, LMWH low molecular weight heparin, PGT-A preimplantation genetic testing for aneuploidy, IVIG intravenous immunoglobulin, hCG human chorionic gonadotropin, ZIFT zygote intrafallopian transfer, AH assisted hatching, PRP platelet rich plasma.
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