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Comparative effectiveness and safety of 36 therapies or interventions for pregnancy outcomes with recurrent implantation failure: a systematic review and network meta-analysis

  • Assisted Reproduction Technologies
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Abstract

Purpose

To investigate the effectiveness and safety of 36 different therapies for recurrent implantation failure (RIF) patients.

Methods

We searched PubMed, Embase, the Cochrane Library (CENTRAL), Web of Science, and China National Knowledge Internet (CNKI) from inception to August 24, 2022, with language in both English and Chinese. Randomized controlled trials (RCTs) and observational studies that provided data with one of pregnancy outcomes on RIF patients were included in the network meta-analysis (NMA). The odds ratios (OR) and 95% credible interval (CrI) on pregnancy outcomes were summarized by NMA with a random-effects model. We also analyzed data from only RCTs and compared whether the optimal treatment is the same for different failed embryo transfer attempts.

Results

The total of 29,906 RIF patients from 154 clinical studies (74 RCTs and 80 non-RCTs) were included in the NMA. In terms of implantation rate (IR), growth hormone (GH) (OR: 3.32, 95% CrI: 1.95–5.67) is the best treatment in all included studies; IVIG+PBMC (5.84, 2.44–14.1) is the best for clinical pregnancy rate (CPR); hyaluronic acid (HA) (12.9, 2.37–112.0) for live birth rate (LBR); and aspirin combined with glucocorticoids (0.208, 0.0494–0.777) for miscarriage rate (MR). The two-dimensional graphs showed that GH could maximize IR and CPR simultaneously; HA and GH could simultaneously increase IR and LBR to a large extent; HA could maximize IR and minimize MR.

Conclusion

IVIG+PBMC, GH, and embryo medium enriched with HA could significantly improve pregnancy outcomes in patients with RIF. It appears that combination therapy is a potential administration strategy.

Trial registration

This study has been registered on PROSPERO (CRD42022353423).

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Data availability

The data are derived from published studies, and all raw data used in the study are available in the supplementary files.

Abbreviations

AECC:

autologous embryo-cumulus cells co-culture

AH:

assisted hatching

BET:

blastocyst-stage embryo transfer

cGMP:

cyclic guanosine monophosphate

CPR:

clinical pregnancy rate

CrI:

credible interval

EI:

endometrial injury

EPR:

ectopic pregnancy rate

ERA:

endometrial receptivity array

ET:

embryos transfers

GC:

glucocorticoids

G-CSF:

granulocyte-colony stimulating factor

GH:

growth hormone

HA:

hyaluronic acid

hCG:

human chorionic gonadotropin

HCQ:

hydroxychloroquine

HP:

hysteroscopy

ICSI:

intracytoplasmic sperm injection

IGF-1:

insulin-like growth factor 1

IL:

interleukin

IMSI:

intracytoplasmic morphologically selected sperm injection

IR:

implantation rate

ITGB3:

integrin beta 3

IUD:

intra uterine device

IVF:

in vitro fertilization

IVIG:

intravenous immunoglobulins

LBR:

live birth rate

LIF:

leukemia inhibitory factor

LIT:

lymphocyte immunotherapy

LMWH:

low molecular weight heparin

MR:

miscarriage rate

mTOR:

mechanistic target of rapamycin

NMA:

network meta-analysis

OR:

odds ratios

PBMC:

peripheral blood mononuclear cell

PGT-A:

preimplantation genetic testing aneuploidy

PRISMA:

Preferred Reporting Items for Systematic Reviews and Meta-Analyses

PRP:

platelet-rich plasma

RCT:

randomized controlled trials

r-hLIF:

recombinant human leukemia inhibitory factor

RIF:

recurrent implantation failure

ROBINS-I:

Risk of Bias in Non-Randomized Studies of Interventions

RSA:

recurrent spontaneous abortion

SET:

sequential embryo transfer

SUCRA:

surface under the cumulative ranking curve

TNF-α:

tumor necrosis factor-alpha

Tregs:

regulatory T cells

VEGF:

vascular endothelial growth factor

ZIFT:

zygote intrafallopian tube transfer

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Acknowledgements

We would like to thank the RIF patients participated in the included studies and all researchers.

Funding

This study was supported by Major Clinical Research Projects of the Second Affiliated Hospital, Air Force Medical University (2021LCYJ004), and was also supported by National Natural Science Foundation of China (82204152). The funders had no influence on the data collection, analyses or conclusions of the study, and the views expressed in the study were from all the authors themselves and not related to the funders. All authors declared that there were no conflicts of interests in the study.

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Author notes

  1. Yunan He and Ruonan Tang contributed equally to this work.

Authors and Affiliations

  1. Reproductive Medicine Center, Department of Gynecology and Obstetrics, Tangdu Hospital, Air Force Medical University, Xi’an, Shaanxi, China

    Yunan He, Ruonan Tang, Haikun Yu, Hui Mu, Jie Dong, Lu Wang, Shuqiang Chen & Xiaohong Wang

  2. Clinical Research Center for Reproductive Medicine and Gynecological Endocrine Diseases of Shaanxi Province, No.1 Xinsi Road, Baqiao District, Xi’an City, 710038, Shaanxi Province, China

    Yunan He, Ruonan Tang, Haikun Yu, Hui Mu, Jie Dong, Lu Wang, Shuqiang Chen & Xiaohong Wang

  3. Xi’an Medical University, Xi’an, Shaanxi, China

    Ruonan Tang

  4. Australian Regenerative Medicine Institute, Monash University, Clayton, Victoria, Australia

    Hongbin Jin

  5. Department of Statistics, Military Prevention Medicine, Air Force Medical University, Xi’an, Shaanxi, China

    Wenwen Wang

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  1. Yunan He
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Contributions

XHW and YNH conceived and designed the study. YNH, RNT, and HKY selected articles and extracted the data. RNT, YNH, HM, and WWW analyzed the data. YNH, RNT, HBJ, HM, and HKY wrote the manuscript. JD, LW, SQC, and XHW contributed to the writing of final version of the manuscript. All authors agreed and reviewed the final version of the manuscript.

Corresponding author

Correspondence to Xiaohong Wang.

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He, Y., Tang, R., Yu, H. et al. Comparative effectiveness and safety of 36 therapies or interventions for pregnancy outcomes with recurrent implantation failure: a systematic review and network meta-analysis. J Assist Reprod Genet 40, 2343–2356 (2023). https://doi.org/10.1007/s10815-023-02923-8

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