Skip to main content

Advertisement

SpringerLink
Log in

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

  • Review
  • Published:
Journal of Assisted Reproduction and Genetics Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10

Similar content being viewed by others

References

  1. Wyns C, Bergh C, Calhaz-Jorge C, De Geyter C, Kupka MS, Motrenko T, et al. ART in Europe, 2016: results generated from European registries by ESHRE. Hum Reprod Open. 2020;31(3):hoaa032. https://doi.org/10.1093/hropen/hoaa032.

    Article  Google Scholar 

  2. Mackens S, Santos-Ribeiro S, van de Vijver A, Racca A, Van Landuyt L, Tournaye H, et al. Frozen embryo transfer: a review on the optimal endometrial preparation and timing. Hum Reprod. 2017;32(11):2234–42. https://doi.org/10.1093/humrep/dex285.

    Article  CAS  PubMed  Google Scholar 

  3. Groenewoud ER, Cantineau AEP, Kollen BJ, Macklon NS, Cohlen B. What is the optimal means of preparing the endometrium in frozen-thawed embryo transfer cycles? A systematic review and meta-analysis. Hum Reprod Update. 2013;19(5):458–70. https://doi.org/10.1093/humupd/dmt030.

    Article  PubMed  Google Scholar 

  4. Ghobara T, Gelbaya TA, Ayeleke RO. Cycle regimens for frozen-thawed embryo transfer. Cochrane Database Syst Rev. 2017;7:CD003414. https://doi.org/10.1002/14651858.CD003414.pub3.

    Article  PubMed  Google Scholar 

  5. Yarali H, Polat M, Mumusoglu S, Yarali I, Bozdag G. Preparation of endometrium for frozen embryo replacement cycles: a systematic review and meta-analysis. J Assist Reprod Genet. 2016;33(10):1287–304. https://doi.org/10.1007/s10815-016-0787-0.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Benson K, Hartz AJ. A comparison of observational studies and randomized controlled trials. N Engl J Med. 2000;342:1878–86. https://doi.org/10.1056/NEJM200006223422506.

    Article  CAS  PubMed  Google Scholar 

  7. Concato J, Shah N, Horwitz RI. Randomized controlled trials observational studies and the hierarchy of research designs. N Engl J Med. 2000;342:1887–92. https://doi.org/10.1056/NEJM200006223422507.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Anglemyer A, Horvath HT, Bero L. Healthcare outcomes assessed with observational study designs compared with those assessed in randomized trials. Cochrane Database Syst Rev. 2014;4:MR000034. https://doi.org/10.1002/14651858.MR000034.pub2.

    Article  Google Scholar 

  9. Abraham NS, Byrne CJ, Young JM, Solomon MJ. Meta-analysis of well-designed nonrandomized comparative studies of surgical procedures is as good as randomized controlled trials. J Clin Epidemiol. 2010;63(3):238–45. https://doi.org/10.1016/j.jclinepi.2009.04.005.

    Article  PubMed  Google Scholar 

  10. Arditi C, Burnand B, Peytremann-Bridevaux I. Adding non-randomised studies to a Cochrane review brings complementary information for healthcare stakeholders: an augmented systematic review and meta-analysis. BMC Health Serv Res. 2016;16(1):598. https://doi.org/10.1186/s12913-016-1816-5.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Frieden TR. Evidence for health decision making – beyond randomized, controlled trials. N Engl J Med. 2017;377:465–75. https://doi.org/10.1056/NEJMra1614394.

    Article  PubMed  Google Scholar 

  12. Wang Z, Liu H, Song H, Li X, Jiang J, Sheng Y, et al. Increased risk of pre-eclampsia after frozen-thawed embryo transfer in programming cycles. Front Med. 2020;8(7):104. https://doi.org/10.3389/fmed.2020.00104 eCollection 2020.

    Article  Google Scholar 

  13. Saito K, Kuwahara A, Ishikawa T, Morisaki N, Miyado M, Miyado K, et al. Endometrial preparation methods for frozen-thawed embryo transfer are associated with altered risks of hypertensive disorders of pregnancy, placenta accreta, and gestational diabetes mellitus. Hum Reprod. 2019;34(8):1567–75. https://doi.org/10.1093/humrep/dez079.

    Article  PubMed  Google Scholar 

  14. Zong L, Liu P, Zhou L, Wei D, Ding L, Qin YY. Increased risk of maternal and neonatal complications in hormone replacement therapy cycles in frozen embryo transfer. Reprod Biol Endocrinol. 2020;18(1):36. https://doi.org/10.1186/s12958-020-00601-3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Makhijani R, Bartels C, Godiwala P, Bartolucci A, Nulsen J, Grow D, et al. Maternal and perinatal outcomes in programmed versus natural vitrified-warmed blastocyst transfer cycles. Reprod Biomed Online. 2020;41(2):300–8. https://doi.org/10.1016/j.rbmo.2020.03.009.

    Article  PubMed  Google Scholar 

  16. Hutton B, Salanti G, Caldwell DM, Chaimani A, Schmid CH, Cameron C, et al. The PRISMA extension statement for reporting of systematic reviews incorporating network meta-analyses of health care interventions: checklist and explanations. Ann Intern Med. 2015;162(11):777–84. https://doi.org/10.7326/M14-2385.

    Article  PubMed  Google Scholar 

  17. Higgins JP, Altman DG, Gøtzsche PC, Jüni P, Moher D, Oxman AD, et al. Cochrane Statistical Methods Group. The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. BMJ. 2011;343:d5928. https://doi.org/10.1136/bmj.d5928.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Wells G, Shea B, O’Connell D, Peterson J, Welch V, Losos M, et al. Quality assessment scales for observational studies. Ottawa Health Res Inst. 2004; http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp.

  19. Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ. 2003;327(7414):557–60. https://doi.org/10.1136/bmj.327.7414.557.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Begg CB, Mazumdar M. Operating characteristics of a rank correlation test for publication bias. Biometrics. 1994;50(4):1088–101.

    Article  CAS  PubMed  Google Scholar 

  21. Chaimani A, Higgins JP, Mavridis D, Spyridonos P, Salanti G. Graphical tools for network meta-analysis in STATA. PLoS One. 2013;8(10):e76654. https://doi.org/10.1371/journal.pone.0076654.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Salanti G. Indirect and mixed-treatment comparison, network, or multiple-treatments meta-analysis: many names, many benefits, many concerns for the next generation evidence synthesis tool. Res Synth Methods. 2012;3(2):80–97. https://doi.org/10.1002/jrsm.1037 Epub 2012 Jun 11.

    Article  PubMed  Google Scholar 

  23. Salanti G, Del Giovane C, Chaimani A, Caldwell DM, Higgins JP. Evaluating the quality of evidence from a network meta-analysis. PLoS One. 2014;9(7):e99682. https://doi.org/10.1371/journal.pone.0099682.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. White IR. Network meta-analysis. Stata J. 2015;15:951–85.

    Article  Google Scholar 

  25. Guyatt GH, Oxman AD, Schunemann HJ, Tugwell P, Knottnerus A. GRADE guidelines: a new series of articles in the Journal of Clinical Epidemiology. J Clin Epidemiol. 2011;64(4):380–2. https://doi.org/10.1016/j.jclinepi.2010.09.011.

    Article  PubMed  Google Scholar 

  26. Nikolakopoulou A, Higgins JPT, Papakonstantinou T, Chaimani A, Del Giovane C, Egger M, et al. CINeMA: an approach for assessing confidence in the results of a network meta-analysis. PLoS Med. 2020;17(4):e1003082. https://doi.org/10.1371/journal.pmed.1003082 eCollection 2020 Apr.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Sathanandan M, Macnamee MC, Rainsbury P, Wick K, Brinsden P, Edwards RG. Replacement of frozen - thawed embryos in artificial and natural cycles: a prospective semi-randomized study. Hum Reprod. 1991;6(5):685–7. https://doi.org/10.1093/oxfordjournals.humrep.a137407.

    Article  CAS  PubMed  Google Scholar 

  28. Mackens S, Stubbe A, Santos-Ribeiro S, Van Landuyt L, Racca A, Roelens C, et al. To trigger or not to trigger ovulation in a natural cycle for frozen embryo transfer: a randomized controlled trial. Hum Reprod. 2020;35(5):1073–81. https://doi.org/10.1093/humrep/deaa026.

    Article  CAS  PubMed  Google Scholar 

  29. Montagut M, Santos-Ribeiro S, De Vos M, Polyzos NP, Drakopoulos P, Mackens S, et al. Frozen-thawed embryo transfers in natural cycles with spontaneous or induced ovulation: the search for the best protocol continues. Hum Reprod. 2016;31(12):2803–10. https://doi.org/10.1093/humrep/dew263.

    Article  CAS  PubMed  Google Scholar 

  30. Bjuresten K, Landgren BM, Hovatta O, Stavreus-Evers A. Luteal phase progesterone increases live birth rate after frozen embryo transfer. Fertil Steril. 2011;95(2):534–7. https://doi.org/10.1016/j.fertnstert.2010.05.019.

    Article  CAS  PubMed  Google Scholar 

  31. Lee VC, Li RH, Ng EH, Yeung WS, Ho PC. Luteal phase support does not improve the clinical pregnancy rate of natural cycle frozen-thawed embryo transfer: a retrospective analysis. Eur J Obstet Gynecol Reprod Biol. 2013;169(1):50–3. https://doi.org/10.1016/j.ejogrb.2013.02.005.

    Article  PubMed  Google Scholar 

  32. Groenewoud ER, Cohlen BJ, Al-Oraiby A, Brinkhuis EA, Broekmans FJ, de Bruin JP, et al. A randomized controlled, non-inferiority trial of modified natural versus artificial cycle for cryo-thawed embryo transfer. Hum Reprod. 2016;31(7):1483–92. https://doi.org/10.1093/humrep/dew120.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Ginström Ernstad E, Wennerholm UB, Khatibi A, Petzold M, Bergh C. Neonatal and maternal outcome after frozen embryo transfer: increased risks in programmed cycles. Am J Obstet Gynecol. 2019;221(2):126.e1–126.e18. https://doi.org/10.1016/j.ajog.2019.03.010.

    Article  Google Scholar 

  34. von Versen-Höynck F, Narasimhan P, Selamet Tierney ES, Martinez N, Conrad KP, Baker VL, et al. Absent or excessive corpus luteum number is associated with altered maternal vascular health in early pregnancy. Hypertension. 2019;73(3):680–90. https://doi.org/10.1161/HYPERTENSIONAHA.118.12046.

    Article  CAS  Google Scholar 

  35. Wang B, Zhang J, Zhu Q, Yang X, Wang Y. Effects of different cycle regimens for frozen embryo transfer on perinatal outcomes of singletons. Hum Reprod. 2020;35(7):1612–22. https://doi.org/10.1093/humrep/deaa093.

    Article  CAS  PubMed  Google Scholar 

  36. Patel S, Kilburn B, Imudia A, Armant DR, Skafar DF. Estradiol elicits proapoptotic and antiproliferative effects in human trophoblast cells. Biol Reprod. 2015;93(3):74. https://doi.org/10.1095/biolreprod.115.129114.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Hancke K, More S, Kreienberg R, Weiss JM. Patients undergoing frozen-thawed embryo transfer have similar live birth rates in spontaneous and artificial cycles. J Assist Reprod Genet. 2012;29(5):403–7. https://doi.org/10.1007/s10815-012-9724-z.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Morozov V, Ruman J, Kenigsberg D, Moodie G, Brenner S. Natural cycle cryothaw transfer may improve pregnancy outcome. J Assist Reprod Genet. 2007;24(4):119–23. https://doi.org/10.1007/s10815-006-9100-y.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Levron J, Yerushalmi GM, Brengauz M, Gat I, Katorza E. Comparison between two protocols for thawed embryo transfer: natural cycle versus exogenous hormone replacement. Gynecol Endocrinol. 2014;30(7):494–7. https://doi.org/10.3109/09513590.2014.900032.

    Article  CAS  PubMed  Google Scholar 

  40. Johnson MR, Abdalla H, Allman AC, Wren ME, Kirkland A, Lightman SL. Relaxin levels in ovum donation pregnancies. Fertil Steril. 1991;56(1):59–61.

    Article  CAS  PubMed  Google Scholar 

  41. von Versen-Höynck F, Strauch NK, Liu J, Chi YY, Keller-Woods M, Conrad KP, et al. Effect of mode of conception on maternal serum relaxin, creatinine, and sodium concentrations in an infertile population. Reprod Sci. 2019;26(3):412–9. https://doi.org/10.1177/1933719118776792.

    Article  CAS  Google Scholar 

  42. Khalil A, Garcia-Mandujano R, Maiz N, Elkhouli M, Nicolaides KH. Longitudinal changes in maternal hemodynamics in a population at risk for pre-eclampsia. Ultrasound Obstet Gynecol. 2014;44(2):197–204. https://doi.org/10.1002/uog.13367.

    Article  CAS  PubMed  Google Scholar 

  43. Katsipi I, Stylianou K, Petrakis I, Passam A, Vardaki E, Parthenakis F, et al. The use of pulse wave velocity in predicting pre-eclampsia in high-risk women. Hypertens Res. 2014;37(8):733–40. https://doi.org/10.1038/hr.2014.62.

    Article  CAS  PubMed  Google Scholar 

  44. Khaw A, Kametas NA, Turan OM, Bamfo JE, Nicolaides KH. Maternal cardiac function and uterine artery Doppler at 11–14 weeks in the prediction of preeclampsia in nulliparous women. BJOG. 2008;115(3):369–76. https://doi.org/10.1111/j.1471-0528.2007.01577.x.

    Article  CAS  PubMed  Google Scholar 

  45. Weissgerber TL, Milic NM, Milin-Lazovic JS, Garovic VD. Impaired flow mediated dilation before, during, and after preeclampsia: a systematic review and meta-analysis. Hypertension. 2016;67(2):415–23. https://doi.org/10.1161/HYPERTENSIONAHA.115.06554.

    Article  CAS  PubMed  Google Scholar 

  46. Imudia AN, Awonuga AO, Doyle JO, Kaimal AJ, Wright DL, Toth TL, et al. Peak serum estradiol level during controlled ovarian hyperstimulation is associated with increased risk of small for gestational age and preeclampsia in singleton pregnancies after in vitro fertilization. Fertil Steril. 2012;97(6):1374–9. https://doi.org/10.1016/j.fertnstert.2012.03.028.

    Article  CAS  PubMed  Google Scholar 

Download references

Availability of data and material

Not applicable

Code availability

Not applicable

Funding

This work was supported by the National Natural Science Foundation of China grant (81671435 to S. Z).

Author information

Authors and Affiliations

  1. Department of Obstetrics and Gynaecology, Hangzhou Women’s Hospital, No. 369 Kun Peng Road, Zhejiang, 310008, Hangzhou, China

    Hanglin Wu

  2. Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, No. 3 Qingchun East Road, Zhejiang, 310016, Hangzhou, China

    Ping Zhou, Xiaona Lin, Shasha Wang & Songying Zhang

Authors
  1. Hanglin Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ping Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Xiaona Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Shasha Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Songying Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

S.Y.Z. conceived and designed the study. H.L.W. selected articles for inclusion, extracted data, performed the statistical analyses and drafted the first version of the manuscript. P. Z. conducted literature searches, and selected articles for inclusion. S.S.W. and X.N.L. extracted data and assessed study quality. All the authors contributed to the revision of the first draft of the manuscript, critically checked its content and approved its final version.

Corresponding author

Correspondence to Songying Zhang.

Ethics declarations

Conflict of interest

The authors declare no competing interests.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Ping Zhou and Hanglin Wu should be considered similar in author order.

Supplementary Information

ESM 1

(PDF 1243 kb)

ESM 2

(XLSX 28 kb)

ESM 3

(PDF 391 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wu, H., Zhou, P., Lin, X. et al. Endometrial preparation for frozen–thawed embryo transfer cycles: a systematic review and network meta-analysis. J Assist Reprod Genet 38, 1913–1926 (2021). https://doi.org/10.1007/s10815-021-02125-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10815-021-02125-0

Keywords

Search

Navigation