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Clinical effectiveness of elective single versus double embryo transfer: meta-analysis of individual patient data from randomised trials

BMJ 2010; 341 doi: https://doi.org/10.1136/bmj.c6945 (Published 22 December 2010) Cite this as: BMJ 2010;341:c6945
  1. D J McLernon, research fellow1,
  2. K Harrild, research fellow1,
  3. C Bergh, professor2,
  4. M J Davies, associate professor3,
  5. D de Neubourg, medical director4,
  6. J C M Dumoulin, head of IVF laboratory5,
  7. J Gerris, sector manager6,
  8. J A M Kremer, professor in reproductive medicine7,
  9. H Martikainen, chief physician8,
  10. B W Mol, professor of obstetrics and gynaecology9,
  11. R J Norman, professor10,
  12. A Thurin-Kjellberg, senior consultant2,
  13. A Tiitinen, professor of reproductive medicine11,
  14. A P A van Montfoort, research fellow12,
  15. A M van Peperstraten, resident in obstetrics and gynaecology7,
  16. E Van Royen, scientific director4,
  17. S Bhattacharya, professor of reproductive medicine 13
  1. 1Medical Statistics Team, Section of Population Health, University of Aberdeen, Aberdeen AB25 2ZD, UK
  2. 2Department of Obstetrics and Gynaecology, Institute of Clinical Sciences, Sahlgrenska University Hospital, Gothenburg, Sweden
  3. 3Robinson Institute, Discipline of Obstetrics and Gynaecology, University of Adelaide, South Australia 5005, Australia
  4. 4Centre for Reproductive Medicine, ZNA Middelheim Hospital, Antwerp, Belgium
  5. 5Department of Obstetrics and Gynaecology, Maastricht University Medical Centre, Maastricht, Netherlands
  6. 6Sector Man, Women and Child, Centre for Reproductive Medicine, Department of Obstetrics and Gynaecology, University Hospital Ghent, Ghent, Belgium
  7. 7Radboud University Nijmegen Medical Centre, 791 Obstetrics and Gynaecology, Nijmegen, Netherlands
  8. 8Department of Obstetrics and Gynaecology, Division of Reproductive Endocrinology and Infertility, University of Oulu, Oulu, Finland
  9. 9Department of Obstetrics and Gynaecology, Academic Medical Centre, Amsterdam, Netherlands
  10. 10Discipline of Obstetrics and Gynaecology, University of Adelaide, South Australia
  11. 11Helsinki University, Department of Obstetrics and Gynaecology, Helsinki University Central Hospital, Helsinki, Finland
  12. 12IVF Laboratory, Department of Obstetrics and Gynaecology, Maastricht University Medical Centre, Maastricht
  13. 13Applied Clinical Sciences, Division of Applied Health Sciences, School of Medicine and Dentistry, University of Aberdeen, Aberdeen Maternity Hospital, Aberdeen
  1. Correspondence to: D J McLernon d.mclernon{at}abdn.ac.uk
  • Accepted 29 October 2010

Abstract

Objective To compare the effectiveness of elective single embryo transfer versus double embryo transfer on the outcomes of live birth, multiple live birth, miscarriage, preterm birth, term singleton birth, and low birth weight after fresh embryo transfer, and on the outcomes of cumulative live birth and multiple live birth after fresh and frozen embryo transfers.

Design One stage meta-analysis of individual patient data.

Data sources A systematic review of English and non-English articles from Medline, Embase, and the Cochrane Central Register of Controlled Trials (up to 2008). Additional studies were identified by contact with clinical experts and searches of bibliographies of all relevant primary articles. Search terms included embryo transfer, randomised controlled trial, controlled clinical trial, single embryo transfer, and double embryo transfer.

Review methods Comparisons of the clinical effectiveness of cleavage stage (day 2 or 3) elective single versus double embryo transfer after fresh or frozen in vitro fertilisation (IVF) or intracytoplasmic sperm injection (ICSI) treatments were included. Trials were included if the intervention differed only in terms of the intended number of embryos to be transferred. Trials that involved only blastocyst (day five) transfers were excluded.

Results Individual patient data were received for every patient recruited to all eight eligible trials (n=1367). A total of 683 and 684 women randomised to the single and double embryo transfer arms, respectively, were included in the analysis. Baseline characteristics in the two groups were comparable. The overall live birth rate in a fresh IVF cycle was lower after single (181/683, 27%) than double embryo transfer (285/683, 42%) (adjusted odds ratio 0.50, 95% confidence interval 0.39 to 0.63), as was the multiple birth rate (3/181 (2%) v 84/285 (29%)) (0.04, 0.01 to 0.12). An additional frozen single embryo transfer, however, resulted in a cumulative live birth rate not significantly lower than the rate after one fresh double embryo transfer (132/350 (38%) v 149/353 (42%) (0.85, 0.62 to 1.15), with a minimal cumulative risk of multiple birth (1/132 (1%) v 47/149 (32%)). The odds of a term singleton birth (that is, over 37 weeks) after elective single embryo transfer was almost five times higher than the odds after double embryo transfer (4.93, 2.98 to 8.18).

Conclusions Elective single embryo transfer results in a higher chance of delivering a term singleton live birth compared with double embryo transfer. Although this strategy yields a lower pregnancy rate than a double embryo transfer in a fresh IVF cycle, this difference is almost completely overcome by an additional frozen single embryo transfer cycle. The multiple pregnancy rate after elective single embryo transfer is comparable with that observed in spontaneous pregnancies.

Footnotes

  • We thank all authors of the original published trials. Gerris trial: Jan Gerris, Diane de Neubourg, Kathelijne Mangelschots, Eric Van Royen, Muriel Van de Meerssche, and Marion Valkenburg; Lukassen trial: H G M Lukassen, D D Braat, Alex M M Wetzels, Gerhard A Zielhuis, Eddy M M Adang, Eduard Scheenjes, and Jan A M Kremer; Martikainen trial: Hannu Martikainen, Aila Tiitinen, Candido Tomás, Juha Tapanainen, Mauri Orava, Leena Tuomivaara, Sirpa Vilska, Christel Hydén-Granskog, Outi Hovatta, and the Finnish ET Study Group; Thurin trial: Ann Thurin, Jon Hausken, Torbjörn Hillensjö, Barbara Jablonowska, Anja Pinborg, Annika Strandell, and Christina Bergh; Van Montfoort trial: Aafke PA van Montfoort, Audrey A A Fiddelers, J Marij Janssen, Josien G Derhaag, Carmen D Dirksen, Gerard A J Dunselman, Jolande A Land, Joep P M Geraedts, Johannes L H Evers, and John CM Dumoulin.

  • We also thank J Wang (ASSET trial) and S Keay, R Gazvani, Y Sajjad, H Lyall, M Jamieson, V Sandison, and P Braude (ECOSSE trial), Maureen Porter for her significant contribution to the ECOSSE trial, and all participants of the original trials that provided the data for this systematic review.

  • Contributors: SB and BWM conceived the idea for the review. KH with SB and BWM developed the protocol with input from all the authors. KH and SB carried out literature searches and retrieved the identified papers. BWM acted as the third reviewer if consensus could not be reached between KH and SB. KH developed the master database and performed the initial statistical analysis. DJMcL developed the master database, performed the statistical analysis, and wrote the initial draft of the manuscript and all subsequent drafts with input from all coauthors. DJMcL is guarantor. All authors had full access to all of the data and can take responsibility for the integrity of the data and the accuracy of the data analysis.

  • Funding: This review was funded by the Wellcome Trust (Research Leave award for SB). The study funder did not participate in study design; in the collection, analysis or interpretation of data; in the writing of the report; or in the decision to submit the paper for publication. All researchers were independent from the funder.

  • Competing interests: All authors have completed the Unified Competing Interest form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare: no support from any organisation for the submitted work apart from the funding from the Wellcome Trust (mentioned above); MJD received a research grant from the National Health and Medical Research Council, DdeN is secretary of the VWRG (Reproductive Medicine subgroup of the Flemish Gynaecological society) and received travel and accommodation sponsored by Schering-Plough for the 6th world congress on ovulation induction; with the exception of DJM, KH, BWM, and AMvanP, all authors were involved in the conduct of the primary randomised trials included in this systematic review.

  • Ethical approval: Advice regarding ethical approval to conduct this meta-analysis was sought from the local ethics committee of the centre (Aberdeen) where IPD analysis of anonymised data was performed. The North of Scotland Research Ethics Service deemed that a formal ethics application was unnecessary. Where necessary, local ethics approval to share anonymised trial data was obtained by participating trial groups.

  • Data sharing: No additional data available.

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