Endometrial preparation for frozen-thawed embryo transfer cycles: a systematic review and network meta-analysis

Abstract

Purpose: To compare the effects of different endometrial preparation protocols for frozen-thawed embryo transfer (FET) cycles and present treatment hierarchy.

Methods: Systematic review with meta-analysis was performed by electronic searching of MEDLINE, the Cochrane Library, Embase, ClinicalTrials.gov and Google Scholar up to Dec 26, 2020. Randomised controlled trials (RCTs) or observational studies comparing 7 treatment options (natural cycle with or without human chorionic gonadotrophin trigger (mNC or tNC), artificial cycle with or without gonadotropin-releasing hormone agonist suppression (AC+GnRH or AC), aromatase inhibitor, clomiphene citrate, gonadotropin or follicle stimulating hormone) in FET cycles were included. Meta-analyses were performed within random effects models. Primary outcome was live birth presented as odds ratio (OR) with 95% confidence intervals (CIs).

Results: Twenty-six RCTs and 113 cohort studies were included in the meta-analyses. In a network meta-analysis, AC ranked last in effectiveness, with lower live birth rates when compared with other endometrial preparation protocols. In pairwise meta-analyses of observational studies, AC was associated with significant lower live birth rates compared with tNC (OR 0.81, 0.70 to 0.93) and mNC (OR 0.85, 0.77 to 0.93). Women who achieved pregnancy after AC were at an increased risk of pregnancy-induced hypertension (OR 1.82, 1.37 to 2.38), postpartum haemorrhage (OR 2.08, 1.61 to 2.78) and very preterm birth (OR 2.08, 1.45 to 2.94) compared with those after tNC.

Conclusion: Natural cycle treatment has a higher chance of live birth and lower risks of PIH, PPH and VPTB than AC for endometrial preparation in women receiving FET cycles.

Keywords: Endometrial preparation; Frozen–thawed embryo transfer; Maternal and perinatal outcomes; Meta-analysis; Pregnancy rate.

Conflict of interest statement

The authors declare no competing interests.

© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.

Figures

Fig. 1

Article retrieval and screening

Fig. 2

Network plots of network meta-analyses of randomised controlled trials: a live births, b ongoing pregnancy, c clinical pregnancy, d miscarriage. The size of the nodes corresponds to the number of trials evaluating the comparison. The thickness of the lines corresponds to the number of trials evaluating the comparison. The colours of nodes refer to the risk of bias: low (green), moderate (yellow) and high (red). tNC, true natural cycle; mNC, modified natural cycle; AC, artificial cycle without suppression; AC+GnRH, artificial cycle with gonadotropin-releasing hormone cycle; Gn/FSH, ovarian stimulation with gonadotropin or follicle stimulating hormone; AI, aromatase inhibitor; CC, clomiphene citrate

Fig. 3

Live birth league table. Results of the network meta-analysis are presented in the left lower half and results from pairwise meta-analysis in the upper right half, if available. Comparisons between treatments should be read from left to right and the estimate is in the cell in common between the column-defining treatment and the row-defining treatment. Effect sizes represent summary odds ratios and 95% confidence intervals. In the left lower half, values greater than 1 favour the column-defining treatment and in the upper right half, those values greater than 1 favour the row-defining treatment. Cells in bold print indicate significant results. The evidence is graded using CINeMA system approach for network meta-analysis. Colours in the cells indicate the confidence in the evidence: grey, low; pink, very low. tNC, true natural cycle; mNC, modified natural cycle; AC, artificial cycle without suppression; AC+GnRH, artificial cycle with gonadotropin-releasing hormone cycle; Gn/FSH, ovarian stimulation with gonadotropin or follicle stimulating hormone; AI, aromatase inhibitor; CC, clomiphene citrate; NA, not applicable

Fig. 4

Ongoing pregnancy league table. Results of the network meta-analysis are presented in the left lower half and results from pairwise meta-analysis in the upper right half, if available. Comparisons between treatments should be read from left to right and the estimate is in the cell in common between the column-defining treatment and the row-defining treatment. Effect sizes represent summary odds ratios and 95% confidence intervals. In the left lower half, values greater than 1 favour the column-defining treatment and in the upper right half, those values greater than 1 favour the row-defining treatment. Cells in bold print indicate significant results. The evidence is graded using CINeMA system approach for network meta-analysis. Colours in the cells indicate the confidence in the evidence: grey, low; pink, very low. tNC, true natural cycle; mNC, modified natural cycle; AC, artificial cycle without suppression; AC+GnRH, artificial cycle with gonadotropin-releasing hormone cycle; Gn/FSH, ovarian stimulation with gonadotropin or follicle stimulating hormone; AI, aromatase inhibitor; CC, clomiphene citrate; NA, not applicable

Fig. 5

Clinical pregnancy league table. Results of the network meta-analysis are presented in the left lower half and results from pairwise meta-analysis in the upper right half, if available. Comparisons between treatments should be read from left to right and the estimate is in the cell in common between the column-defining treatment and the row-defining treatment. Effect sizes represent summary odds ratios and 95% confidence intervals. In the left lower half, values greater than 1 favour the column-defining treatment and in the upper right half, those values greater than 1 favour the row-defining treatment. Cells in bold print indicate significant results. The evidence is graded using CINeMA system approach for network meta-analysis. Colours in the cells indicate the confidence in the evidence: yellow, moderate; grey, low; pink, very low. tNC, true natural cycle; mNC, modified natural cycle; AC, artificial cycle without suppression; AC+GnRH, artificial cycle with gonadotropin-releasing hormone cycle; Gn/FSH, ovarian stimulation with gonadotropin or follicle stimulating hormone; AI, aromatase inhibitor; CC, clomiphene citrate; NA, not applicable

Fig. 6

Endometrial preparation by NC compared with AC on live birth in cohort studies. tNC, true natural cycle; mNC, modified natural cycle; AC, artificial cycle without suppression

Fig. 7

The effects of different endometrial preparation protocols on live birth in cohort studies. tNC, true natural cycle; mNC, modified natural cycle; AC, artificial cycle without suppression; AC+GnRH, artificial cycle with gonadotropin-releasing hormone cycle; Gn/FSH, ovarian stimulation with gonadotropin or follicle stimulating hormone; AI, aromatase inhibitor; CC, clomiphene citrate

Fig. 8

Sensitivity analyses of live birth in cohort studies. tNC, true natural cycle; mNC, modified natural cycle; AC, artificial cycle without suppression; AC+GnRH, artificial cycle with gonadotropin-releasing hormone cycle; Gn/FSH, ovarian stimulation with gonadotropin or follicle stimulating hormone; AI, aromatase inhibitor; CI, confidence interval; NA, not applicable. *Only studies with NOS scores of 8 or 9 points were included

Fig. 9

Endometrial preparation by tNC compared with AC on obstetric and neonatal outcomes. tNC, true natural cycle; AC, artificial cycle without suppression; PIH, pregnancy-induced hypertension; GDM, gestational diabetes mellitus; PP, placenta previa; PPH, postpartum haemorrhage; PTB, preterm birth; VPTB, very preterm birth; LBW, low birth weight; VLBW, very low birth weight; LGA, large for gestational age; SGA, small for gestational age; PM, perinatal mortality

Fig. 10

Endometrial preparation by mNC compared with AC on obstetric and neonatal outcomes. mNC, modified natural cycle; AC, artificial cycle without suppression; PIH, pregnancy-induced hypertension; GDM, gestational diabetes mellitus; PP, placenta previa; PTB, preterm birth; VPTB, very preterm birth; LBW, low birth weight; LGA, large for gestational age; SGA, small for gestational age; PM, perinatal mortality