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Number of embryos for transfer following in vitro fertilisation or intra-cytoplasmic sperm injection

  1. Zabeena Pandian1,*,
  2. Jane Marjoribanks2,
  3. Ozkan Ozturk3,
  4. Gamal Serour4,
  5. Siladitya Bhattacharya1

Editorial Group: Cochrane Menstrual Disorders and Subfertility Group

Published Online: 29 JUL 2013

Assessed as up-to-date: 17 JUL 2013

DOI: 10.1002/14651858.CD003416.pub4


How to Cite

Pandian Z, Marjoribanks J, Ozturk O, Serour G, Bhattacharya S. Number of embryos for transfer following in vitro fertilisation or intra-cytoplasmic sperm injection. Cochrane Database of Systematic Reviews 2013, Issue 7. Art. No.: CD003416. DOI: 10.1002/14651858.CD003416.pub4.

Author Information

  1. 1

    Aberdeen Maternity Hospital, Obstetrics and Gynaecology, Aberdeen, UK

  2. 2

    University of Auckland, Department of Obstetrics and Gynaecology, Auckland, New Zealand

  3. 3

    University College London Hospitals, Academic Department of Obstetrics and Gynaecology, London, UK

  4. 4

    Al Azhar University, The Egyptian IVF-ET Center, Cairo, Egypt

*Zabeena Pandian, Obstetrics and Gynaecology, Aberdeen Maternity Hospital, Foresterhill, Aberdeen, AB25 2ZD, UK. pandianzl@aol.com. ogy211@abdn.ac.uk.

Publication History

  1. Publication Status: Edited (no change to conclusions)
  2. Published Online: 29 JUL 2013

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Summary of findings    [Explanations]

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms

 
Summary of findings for the main comparison. Repeated single embryo transfer compared to double embryo transfer

Repeated single compared to mixed policies for transfer following in vitro fertilisation or intra-cytoplasmic sperm injection

Population: women having embryo transfer following in vitro fertilisation or intra-cytoplasmic sperm injection
Settings: Assisted reproduction
Intervention: Repeated single embryo transfer (in one or more cycles)
Comparison: Double embryo transfer

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

Double ETRepeated single ET

Cumulative live birth

Repeated single embryo transfer versus double embryo transfer
420 per 1000373 per 1000
(310 to 441)
OR 0.82 (0.62 to 1.09 )811
(3 Studies)
⊕⊕⊝⊝
LOW 1,2

Cumulative live birth - Single embryo transfer plus one cycle of frozen embryo transfer versus one cycle of double embryo transfer422 per 1000377 per 1000
(308 to 450)
OR 0.83 (0.61 to 1.12 )703
(2 Studies)
⊕⊕⊝⊝
LOW 1,2

Cumulative live birth - Two cycles of single embryo transfer SET (x2) versus one cycle of double embryo transfer407 per 1000352 per 1000
(198 to 542)
OR 0.79 (0.36 to 1.72 )108
(1 Studies)
⊕⊝⊝⊝
VERY LOW 1,2,3

Multiple pregnancy

Repeated single embryo transfer versus double embryo transfer
133 per 10005 per 1000
(2 to 19)
OR 0.03 (0.01 to 0.13 )811
(3 Studies)
⊕⊕⊝⊝
LOW 1,2

Multiple pregnancy

Single embryo transfer plus one cycle of frozen embryo transfer versus one cycle of double embryo transfer
136 per 10005 per 1000
(2 to 22)
OR 0.03 (0.01 to 0.14 )703
(2 Studies)
⊕⊕⊝⊝
LOW 1,2

Multiple pregnancy

Two cycles of single embryo transfer SET (x2) versus one cycle of double embryo transfer
111 per 10009 per 1000
(0 to 135)
OR 0.07 (0.00 to 1.25 )108
(1 Studies)
⊕⊝⊝⊝
VERY LOW 1,2,3

*The basis for the assumed risk is the median control group risk across studies. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; OR: Odds ratio

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

 1Methods of allocation concealment not described in enough detail
2Wide confidence intervals
3One small study

 Summary of findings 2 Single embryo transfer compared to double embryo transfer (in a single cycle)

 

Background

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms
 

Description of the condition

Historically, in an effort to achieve 'acceptable' pregnancy rates, most women undergoing in vitro fertilisation (IVF) have received transfer of multiple embryos. However, this practice is being reassessed due to the high rates of multiple pregnancy that result from multiple embryo transfer and which commonly lead to poor clinical outcomes for the mother or her children, or both (ASRM 2012).

In the 1990s it was calculated that women undergoing IVF had an approximately 20-fold increased risk of twins and 400-fold increased risk of higher order pregnancies (Martin 1998). In 2006, twins accounted for nearly 20% of all live births resulting from IVF in Europe (De Mouzon 2010). Widespread concern about the medical, social and economic consequences of multiple pregnancy has prompted the development of strategies aimed at promoting birth of a single healthy baby following IVF.

Compared with singleton births, twins have a four-fold increased risk of mortality, and for triplets the risk is increased six-fold (ESHRE 2000). A recent study (ESHRE 2012) of 50,258 births following IVF and intra-cytoplasmic sperm injection (ICSI) pregnancies reported that twins accounted for half the total neonatal deaths and one-third of the perinatal deaths. Twins had a significantly higher perinatal mortality rate than singletons (27.8 per 1000 births and 12.4 per 1000 births, respectively). The relatively high congenital malformation rates observed in babies born after IVF and intracytoplasmic sperm injection (ICSI) are attributed to the high proportion of multiple births in this population compared to the general population (Sebire 2000; Wennerholm 2000). In babies with very low birth weight, twin gestation is an independent risk factor for neurodevelopmental impairment including cerebral palsy, severe bilateral hearing loss and bilateral blindness (Wadhawan 2009).

Twin pregnancy also increases the risk of obstetric complications, with a high incidence of miscarriage, pregnancy-induced hypertension, gestational diabetes, premature labour and abnormal delivery (FIVNAT 1995; ESHRE 2000). After the initial sense of achievement of parenthood, the care of children from a multiple gestation is often associated with practical difficulties and high stress levels (Garel 1992; Doyle 1996; Garel 1997). More hours per week are required to care for six-month old triplets and to carry out the necessary household tasks. Even in families with material resources and plenty of help, emotional stress is not uncommon and may necessitate psychiatric help (Garel 1997).

The economic impact of multiple pregnancies on health services is another consideration. In an Australian study, the average cost of an ART twin delivery was almost three times as high as for an ART singleton, while for higher order multiple births the cost was up to 11 times greater (Chambers 2007). It has been suggested that redeployment of money saved by reduction of multiple pregnancies could allow for increased provision of IVF treatment in the UK at no extra cost (Ledger 2006).

 

Description of the intervention

IVF or ICSI is followed by the transfer of one, two, three or four fresh or frozen and thawed embryos. Unused embryos can be frozen and transferred in a subsequent natural or hormone stimulated transfer cycle. Reduction of the number of embryos transferred is a strategy used to reduce rates of multiple pregnancy associated with ART.

There is a worldwide trend for an increase in the rates of elective single embryo transfer, defined as the transfer of a single embryo at cleavage or blastocyst stage, which is chosen from a larger number of available embryos. In Europe, in 2005, about 20% of all embryo transfers were of single embryos but much higher rates are reported in some countries (69% in Sweden in 2005, and 57% in Australia and New Zealand in 2006) (ASRM 2012).

Embryos are often transferred after culture for two or three days, when they comprise two to eight cells (cleavage stage). The rationale for cleavage-stage transfer is that the uterus is the best environment for the survival of the embryo (Laverge 2001). Over the past decade there has been a steady shift in practice to the transfer of embryos on day five or six, when they have developed into blastocysts with 64 cells. Blastocyst transfer has been shown to be successful (Papanikolaou 2006; Khalaf 2008) but requires laboratory expertise and experience in extended embryo culture. An advantage of blastocyst transfer is that embryos surviving five days are more likely to be viable than embryos at two or three days, and so the likelihood of implantation is higher. Disadvantages of blastocyst transfer include a higher risk of cycles being cancelled (Marek 1999) and fewer embryos being available for cryopreservation due to failed embryo development.

A Cochrane review comparing cleavage-stage versus blastocyst transfer (Glujovsky 2012) had mixed findings. There was evidence that blastocyst transfer was associated with a small but significant benefit in the live birth rate per couple but that cleavage-stage transfers were associated with higher cumulative clinical pregnancy rates. This finding was attributed to higher rates of frozen embryos and lower failure-to-transfer rates obtained from cleavage-stage protocols. Multiple birth rates did not differ between the two groups.

 

How the intervention might work

A strategy of reducing the risk of multiple pregnancy by limiting the number of embryos transferred needs to be balanced against the risk of jeopardising the overall pregnancy rate. An obvious solution is to consider an individualised embryo transfer policy based on identification of key clinical and laboratory parameters associated with a higher implantation rate. The above-mentioned ESHRE study (ESHRE 2012) of 50,258 births following IVF and ICSI pregnancies reported that double embryo transfer was associated with a 53% higher risk of perinatal mortality than single embryo transfer (19 per 1000 births compared with 13 per 1000 births). This difference was especially apparent when fresh (unfrozen) embryos were used. Births following the transfer of two fresh embryos had a 74% higher risk of perinatal mortality than those following fresh single embryo transfer.

Use of elective single embryo transfer at the cleavage stage (day two or three) has been limited in clinical practice for fear that the overall success rates of IVF would decline. This assumption has been supported by the published results of single embryo transfer where only one embryo was available. Because no opportunity for selection of more suitable embryos exists, the implantation potential of the only available embryo is usually poor, with clinical pregnancy rates of around 10% (FIVNAT 1995; Giorgetti 1995; Preutthipan 1996; Yaron 1997; Lieberman 1998; Westergaard 2000). In a situation where the transferred embryos are the only available embryos, pregnancy rates are unfavourable even for multiple embryo transfer (Ludwig 2000).

A study from Finland reported a 20.2% pregnancy rate in 94 women who had only one embryo available for transfer compared with a rate of 29.7% in women who had multiple embryos available and from which a single high quality embryo was selected for transfer. The cumulative pregnancy rate after frozen and thawed embryo transfers in the elective single embryo transfer group was 47.3% per oocyte retrieval. By comparison, the pregnancy rate for double embryo transfers was 29.4% per transfer, of which 23.9% were twin pregnancies (Vilska 1999).

Another strategy for reducing multiple pregnancy is multifetal pregnancy reduction. However, this procedure is invasive, can have long term adverse psychological consequences for the potential parents (Berkowits 1996; McKinney 1996) and may be unacceptable to some couples given the attendant ethical and legal issues. Clinicians in Europe have generally accepted the desirability of reducing multiple births by limiting the number of embryos transferred, especially if this can be achieved without unduly reducing live birth rates (Roberts 2011).

 

Why it is important to do this review

It is important to find ways to limit the risk of multiple pregnancy without reducing the chance of achieving live birth in couples undergoing ART cycles. This systematic review evaluates the effectiveness and safety of different policies for the number of embryos transferred in couples who undergo assisted reproductive technology (ART).

 

Objectives

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms

To evaluate the effectiveness and safety of different policies for the number of embryos transferred in couples undergoing assisted reproductive technology (ART) cycles.

 

Methods

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms
 

Criteria for considering studies for this review

 

Types of studies

Published and unpublished randomised controlled trials (RCTs) were eligible for inclusion. We excluded non-randomised studies (for example studies with evidence of inadequate sequence generation such as alternate days, chart numbers) as they are associated with a high risk of bias. Cross-over trials were eligible but it was planned that only data from the first phase would be included in the meta-analysis as the cross-over design is not valid in this context.

 

Types of participants

Trials of subfertile women who underwent embryo transfer following in vitro fertilisation or intra-cytoplasmic sperm injection treatment with their own gametes or as oocyte or embryo donation recipients were eligible for inclusion.

 

Types of interventions

We compared the following interventions.

  1. Repeated single embryo transfer versus repeated multiple transfer.
  2. Repeated single embryo transfer versus mixed policies
  3. Single versus multiple embryo transfer in a single cycle.
  4. Other fresh cycle comparisons.

It was required that elective transfer of embryos followed an initial fresh IVF or ICSI treatment using standard protocols for controlled ovarian stimulation, oocyte retrieval under ultrasound guidance, insemination, embryo culture, and transcervical replacement of embryos (cleavage stage or blastocyst) using standard culture medium and catheters for the culture and transfer of embryos respectively.

Studies could (in addition) transfer one or more frozen thawed embryos in one or both arms using standard procedures in a natural or hormone-stimulated cycle.

Studies comparing cleavage-stage transfer versus blastocyst-stage transfer were excluded.

 

Types of outcome measures

 
Primary outcome

(1) Live birth rate per woman or couple, or cumulative live birth rate per woman or couple (in trials with multiple transfers or multiple cycles).

Live birth was defined as the delivery of one or more living infants. Cumulative live birth rate reflects the number of live births following fresh and frozen embryo transfers after a single IVF treatment leading to the harvesting of eggs, or (where stated) after multiple IVF cycles. It is calculated by dividing the total number of live births in each group by the total number of women randomised in each group. One IVF cycle is defined as a single treatment leading to the harvesting of eggs.

(2) Multiple pregnancy rate per woman or couple. The demonstration of more than one sac with a fetal pole on ultrasound scan defines a multiple pregnancy.

Secondary outcomes

(1) Pregnancy rate per woman or couple.

Pregnancy was defined as the presence of a gestational sac on ultrasound scan or confirmation of products of conception by pathological examination in the event of spontaneous abortion or ectopic pregnancy.

(2) Miscarriage rate per woman.

 

Search methods for identification of studies

We searched for all relevant published and unpublished RCTs without language restriction and in consultation with the Menstrual Disorders and Subfertility Group (MDSG) Trials Search Co-ordinator. For the search strategies, please see Appendix 1, Appendix 2, Appendix 3, Appendix 4, Appendix 5, Appendix 6.

 

Electronic searches

We searched the following electronic databases: the Menstrual Disorders and Subfertility Group (MDSG) Specialised Register of controlled trials, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, PsycINFO and CINAHL. The last search date was July 17th 2013.

Other electronic sources of trials included the following.

  • Trials registers for ongoing and registered trials:
    • www.clinicaltrials.gov/;
    • www.who.int/trialsearch/Default.aspx.
  • OpenGrey for unpublished literature from Europe at www.opengrey.eu/.
  • Citation index: Web of Science.

 

Searching other resources

We handsearched other resources as follows:

  • conference proceedings - International Federation of Fertility Societies (IFFS), American Society for Reproductive Medicine (ASRM), British Fertility Society (BFS), European Society for Human Reproduction and Embryology (ESHRE) between 1997 and 2013;
  • the bibliographies of the identified studies.

We personally communicated with experts and investigators in the field.

 

Data collection and analysis

 

Selection of studies

The selection of trials for inclusion in the review from those identified employing the search strategy was performed independently by at least two review authors. Disagreements about study eligibility were resolved by discussion.

 

Data extraction and management

Quality assessment and data extraction were independently performed by two review authors. Any discrepancies were resolved by discussion with senior review authors (GS, SB). Additional information on trial methodology or trial data was sought from the principal authors of trials which appeared to meet the eligibility criteria but were unclear in aspects of methodology, or where the data were in a form unsuitable for meta-analysis.

 

Assessment of risk of bias in included studies

The included studies were assessed for risk of bias using the Cochrane risk of bias tool to evaluate the following: random sequence generation; allocation concealment; blinding of participants, providers and outcome assessors; completeness of outcome data; selective outcome reporting; and other potential sources of bias (see Figure 1). At least two authors (ZP, SB, JM) assessed these six domains. Any disagreements were resolved by consensus or by discussion with another author. The assessments are presented in the 'Risk of bias' table (see Characteristics of included studies, Figure 1 and Figure 2).

 FigureFigure 1. Methodological quality graph: review authors' judgements about each methodological quality item presented as percentages across all included studies.
 FigureFigure 2. Methodological quality summary: review authors' judgements about each methodological quality item for each included study.

 

Measures of treatment effect

All data were dichotomous. The numbers of events in the control and intervention groups of each study were used to calculate the Mantel-Haenszel odds ratios (ORs) with 95% confidence intervals (CIs).

Where outcome data were reported as a percentage of the total number of participants, they were included in the analyses by multiplying the percentage by the total number of participants (n) in that group and dividing by 100.

 

Unit of analysis issues

Multiple live births (for example twins or triplets) were counted as one live birth event. It was planned to include only first-phase data from cross-over trials. Per cycle data were not included in tables of comparison but were reported descriptively.

 

Dealing with missing data

The data were analysed on an intention-to-treat basis as far as possible and attempts were made to obtain missing data from the original investigators.  

 

Assessment of heterogeneity

The authors considered whether the clinical and methodological characteristics of the included studies were sufficiently similar for meta-analysis to provide a meaningful summary. Clinical heterogeneity in subfertility (such as variations in entry criteria, subtle differences in the treatment used and that are important from a clinical aspect) cannot be avoided because most centres use their own protocols which can vary in some aspects. When trials met the inclusion criteria and had performed the same intervention we considered it appropriate to pool their results. Statistical heterogeneity was assessed by inspecting the scatter in the data points and the overlap in their CIs and, more formally by checking the results of the I2 statistic. An I2 measurement greater than 50% was taken to indicate substantial heterogeneity (Higgins 2011). If substantial heterogeneity was detected, possible explanations were explored in sensitivity analyses. Even when included trials in a comparison group were statistically homogeneous, there were potentially considerable differences in clinical features (clinical heterogeneity). These differences were taken into account when analysing and interpreting the pooled results.

 

Assessment of reporting biases

In view of the difficulty of detecting and correcting for publication bias and other reporting biases, we aimed to minimise their potential impact by ensuring a comprehensive search for eligible studies and by being alert for duplication of data. If there were sufficient studies (preferably more than 10) for the primary outcomes, we planned to use a funnel plot to explore the possibility of small study effects (a tendency for estimates of the intervention effect to be more beneficial in smaller studies).

 

Data synthesis

The data from primary studies were combined with RevMan software to calculate pooled Mantel-Haenszel ORs and 95% CIs, using a fixed-effect model, with the following comparisons.

  1. Repeated single versus repeated multiple transfer.
  2. Repeated single embryo transfer versus mixed policies
  3. Single versus multiple embryo transfer in a single cycle
  4. Other fresh cycle comparisons
  5. Other fresh or frozen cycle comparisons

Data were stratified by the stage of embryo transfer (cleavage or blastocyst).

For the 2012 update, we reformatted the comparisons of interest, as above. The choice of repeated single versus repeated multiple embryo transfer as the first comparison of interest reflects the view that a policy of repeated SET may optimise the chance of live birth while minimising the risk of multiple pregnancy (Roberts 2011).

An increase in the odds of a particular outcome, which may be beneficial (for example live birth) or detrimental (for example multiple pregnancy), is displayed graphically in the meta-analyses to the right of the centre-line and a decrease in the odds of an outcome to the left of the centre-line.

 

Subgroup analysis and investigation of heterogeneity

If data were available, we planned to conduct subgroup analyses to determine the separate evidence within groups with different prognostic characteristics.

If we detected substantial heterogeneity, we planned to explore possible explanations in sensitivity analyses. We planned to take any statistical heterogeneity into account when interpreting the results.

 

Sensitivity analysis

We conducted sensitivity analyses for the primary outcomes to determine whether the conclusions were robust to arbitrary decisions made regarding study eligibility and statistical methods. We considered whether the review conclusions would have differed if:  

  1. eligibility was restricted to studies at lower risk of bias (i.e. with clearly reported methods of randomisation and allocation concealment and not at high risk of bias in any of the domains assessed);
  2. a random-effects model had been adopted;
  3. the summary effect measure had been relative risk rather than odds ratio (OR).

 

Overall quality of the body of evidence: 'Summary of findings' table

A 'Summary of findings' table was generated using the GRADEPro software. This table evaluated the overall quality of the body of evidence for the primary review outcomes for selected comparisons. Items assessed were study limitations (that is risk of bias), consistency of effect, imprecision, indirectness and publication bias. Judgements about evidence quality (high, moderate or low) were incorporated into the reporting of results.

 

Results

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms
 

Description of studies

 

Results of the search

The search for the 2013 update identified 640 articles (including duplicates) of which 14 full text articles or online abstracts were retained for detailed appraisal. Five of the 14 were included in the review (ASSETT 2003; Gardner 2004; Thurin 2005; ECOSSE 2006; Fernandez-Sanchez 2012), six were excluded (Motta 1998 A & B; Livingstone 2001; Bowman 2004; Elgindy 2011; Guerif 2011; Forman 2012), one is awaiting assessment (Obrado 2012) and two are ongoing (Abuzeid 2012; Scott 2013). In addition, two studies excluded from the previous version of the review were included (Komori 2004; Mostajeran 2006). For details, see Figure 3.

 FigureFigure 3. Study flow diagram.

 

Included studies

For this update, seven studies were added to the seven included in the original review, making a total of 14 included studies. Five new studies (ASSETT 2003; Gardner 2004; Thurin 2005; ECOSSE 2006; Fernandez-Sanchez 2012) were added. Two previously excluded studies (Komori 2004; Mostajeran 2006) were also added. These two studies had been excluded from the previous version of the review for failure to report full details of randomisation and allocation concealment. They were added to this update after discussion between the review authors, who noted that poor reporting was not a review exclusion criterion. Additional information was sought from authors of all the new trials and replies were received from four (ASSETT 2003; Thurin 2005; ECOSSE 2006; Fernandez-Sanchez 2012). See the 'Characteristics of included studies' table.

 

Study design and setting

Fourteen studies with a total of 2165 participants were included in the review (Vauthier-Brouzes 1994; Gerris 1999; Martikainen 2001; ASSETT 2003; Gardner 2004; Komori 2004; Thurin 2004; Lukassen 2005; Thurin 2005; ECOSSE 2006; Heijnen 2006; Mostajeran 2006; van Montfoort 2006; Fernandez-Sanchez 2012). All were randomised parallel-group trials. Six were multicentred (Martikainen 2001; ASSETT 2003; Thurin 2004; Thurin 2005; ECOSSE 2006; Heijnen 2006). Sample sizes ranged from 23 to 661 women.

Of the four unpublished studies that have been added to this update, one was a pilot trial published as part of a PhD dissertation (Thurin 2005). Another, the 'Australian study of single embryo transfer' (ASSETT 2003) was stopped early because its implementation immediately and substantially altered consumer decision making. This had the effect of more than tripling rates of elective single embryo transfer during the study period and reducing study participation rates (M Davies, University of Adelaide, personal communication). A UK trial, known as the 'Efficacy and cost effectiveness of selective single embryo transfer' (ECOSSE) study, was also stopped early due to poor recruitment (ECOSSE 2006). The fourth unpublished study (Fernandez-Sanchez 2012) was in press.

Nine studies reported their funding sources. Six reported non-commercial funding (Gerris 1999; ASSETT 2003; ECOSSE 2006; Mostajeran 2006; van Montfoort 2006; Fernandez-Sanchez 2012) and three reported pharmaceutical company funding (Gardner 2004; Thurin 2004; Thurin 2005).

 

Participants

Study inclusion criteria differed with regard to participant age. Most studies had a maximum age threshold. This varied across studies and included 34 years (Gerris 1999), 35 years (Vauthier-Brouzes 1994; Lukassen 2005), 36 years (Thurin 2004), 38 years (ECOSSE 2006; Fernandez-Sanchez 2012), and 40 years (ASSETT 2003). One study included women aged between 38 and 45 years (Heijnen 2006) while another required them to be at least 36 years old (Thurin 2005). Other studies used a variety of age limits (Martikainen 2001; van Montfoort 2006).

Two studies only included women in their first treatment cycle (Gerris 1999; van Montfoort 2006) while three included women with an indication for IVF or ICSI either for the first time or after a previous successful treatment (Vauthier-Brouzes 1994; Lukassen 2005; Heijnen 2006). Three studies included women in their first or second IVF or ICSI treatment cycle (ASSETT 2003; Thurin 2004; Thurin 2005). In a multicentre study, one centre included women in their first treatment cycle only and another centre included women in their first or second cycle (Martikainen 2001). One study included all women undergoing IVF and embryo transfer (Gardner 2004) who agreed to participate.

The duration of infertility was mentioned in six studies (Gerris 1999; Thurin 2004; Lukassen 2005; Thurin 2005; Heijnen 2006; van Montfoort 2006) and seven mentioned the indication(s) for treatment (Martikainen 2001; Thurin 2004; Lukassen 2005; Thurin 2005; Heijnen 2006; Mostajeran 2006; van Montfoort 2006). See 'Prognostic factors' in  Table 1.

Two studies did not provide details of participant characteristics (Komori 2004; Mostajeran 2006).

 

Interventions

All the studies included embryo transfer after fresh IVF or ICSI cycles and two studies included frozen cycles administered to one or both groups (Thurin 2004; Thurin 2005). Several other studies also administered frozen cycles during follow-up but not as part of the randomised comparison (Vauthier-Brouzes 1994; Martikainen 2001; ECOSSE 2006; Fernandez-Sanchez 2012).

Interventions in the included studies were as follows:

  • one fresh single embryo transfer (SET) plus one frozen embryo transfer (1FZET) in a natural or hormone-stimulated cycle compared with one fresh cycle of double embryo transfer (DET) (Thurin 2004; Thurin 2005);
  • two fresh cycles of SET compared with one fresh cycle of DET (Lukassen 2005);
  • one fresh cycle of SET plus multiple cycles of frozen DET compared with one cycle of fresh DET plus multiple cycles of frozen DET (ECOSSE 2006)
  • one fresh cycle of SET compared with one fresh cycle of DET (Gerris 1999; Martikainen 2001; Gardner 2004; ASSETT 2003; van Montfoort 2006; Fernandez-Sanchez 2012);
  • one fresh cycle of DET compared with one fresh cycle of triple embryo transfer (TET) (Heijnen 2006);
  • fresh or frozen DET compared with fresh or frozen TET, multiple cycles (Komori 2004)
  • two fresh cycles of DET compared to two fresh cycles of TET (Heijnen 2006);
  • three fresh cycles of DET compared to three fresh cycles of TET (Heijnen 2006);
  • fresh DET compared with fresh TET where the number of cycles used was unclear (Mostajeran 2006);
  • one fresh cycle of DET compared with one fresh cycle of four embryo transfer (FET) (Vauthier-Brouzes 1994).

One study (Komori 2004) reported only per-cycle data. There a large disparity between the number of women (169) and the number of cycles (212), and it was unclear how many women were included in each group. The data from this study were therefore unusable.

Four studies that randomised women to more than one embryo transfer cycle reported interim data after the first fresh cycle of SET versus DET (Thurin 2004; Thurin 2005; Lukassen 2005; ECOSSE 2006). In the case of ECOSSE 2006, these were the only data available, as the trial was stopped due to poor recruitment and data were only available for the first cycle (i.e. fresh DET versus fresh SET).

Protocols for ovarian stimulation, oocyte recovery and embryo transfer were clearly described in nine studies (Vauthier-Brouzes 1994; Gerris 1999; Martikainen 2001; Thurin 2004; Lukassen 2005; Thurin 2005; Heijnen 2006; van Montfoort 2006; Fernandez-Sanchez 2012). Good quality embryos were transferred in all studies, usually at cleavage stage. However, in four studies all or some women had embryos transferred at blastocyst rather than cleavage stage; this applied to a small number of women in two studies (Thurin 2004; Thurin 2005), half the women in one study (Fernandez-Sanchez 2012) and all women in another study (Gardner 2004). The stage of embryo transfer was not mentioned in one study (Mostajeran 2006).

Natural progesterone was used for luteal phase support in most cases (Gerris 1999; Martikainen 2001; Gardner 2004; Thurin 2004; Lukassen 2005; Thurin 2005; Heijnen 2006; van Montfoort 2006; Fernandez-Sanchez 2012). One study used both human chorionic gonadotropin (HCG) and natural progesterone for luteal phase support (Vauthier-Brouzes 1994).

 

Outcomes

 
Primary outcomes
 
1. Live birth rate and cumulative live birth rate

Eleven studies reported live birth rate per couple (Vauthier-Brouzes 1994; Gerris 1999; Martikainen 2001; ASSETT 2003; Thurin 2004; Lukassen 2005; Thurin 2005; ECOSSE 2006; Heijnen 2006; van Montfoort 2006; Fernandez-Sanchez 2012). One reported 'take home baby' per cycle only (Komori 2004).

Five studies reported cumulative live birth rates (ASSETT 2003; Thurin 2004; Lukassen 2005; Thurin 2005; Heijnen 2006).

 
2. Multiple pregnancy rate per woman or couple

All but one study reported multiple pregnancy rate per couple. One reported multiple pregnancy per cycle only (Komori 2004).

 
Secondary outcomes
 
1. Clinical pregnancy rate

Ten studies reported pregnancy rate per couple (Vauthier-Brouzes 1994; Gerris 1999; Martikainen 2001; Gardner 2004; Thurin 2004; Lukassen 2005; Heijnen 2006; Mostajeran 2006; van Montfoort 2006; Fernandez-Sanchez 2012).

 
2. Miscarriage rate per woman

Three studies reported miscarriage rate (Martikainen 2001; Lukassen 2005; van Montfoort 2006).

 

Excluded studies

See Characteristics of excluded studies.

Fourteen studies were excluded from the review for the following reasons:

 

Risk of bias in included studies

See Characteristics of included studies; Figure 1; Figure 2.

 

Allocation

 
Generation of random sequence

Ten studies were at low risk of bias related to random sequence generation as they used computer-generated methods. Four studies did not describe their randomisation methods and were therefore at unclear risk of this bias.

 
Allocation concealment

Four studies were at low risk of bias related to allocation concealment. They used sealed opaque envelopes (ASSETT 2003) or remote allocation (ECOSSE 2006; Heijnen 2006; Fernandez-Sanchez 2012). In the other ten studies a satisfactory method of allocation concealment was not described clearly enough or no information was given, and the risk of this bias was therefore rated as unclear.

 

Blinding

Five trials were rated as at low risk of bias related to blinding (ASSETT 2003; Thurin 2004; Thurin 2005; ECOSSE 2006; van Montfoort 2006) as neither the patient nor physician knew whether one embryo or two embryos had been transferred. Two studies were unblinded (Lukassen 2005; Fernandez-Sanchez 2012) and the others did not mention blinding. These nine studies were rated as at unclear risk of bias as it was unclear whether lack of blinding would be likely to influence the outcomes of this review.

 

Incomplete outcome data

Ten studies were rated as at low risk of this bias as they included all randomised women in the analysis. Three studies were rated as at unclear risk of this bias because it was unclear how many women were included in the analysis (Gardner 2004; Komori 2004; Vauthier-Brouzes 1994). One study (Mostajeran 2006) was rated as at high risk of this bias because it was unclear how many women were randomised: women non-compliant with the drug regimen or who had ovarian hyperstimulation syndrome (numbers not stated) were excluded and three women with ectopic pregnancy were also excluded from the analysis.

 

Selective reporting

Eleven studies were deemed to be at low risk of this bias. Two studies (Gardner 2004; Mostajeran 2006) that did not report live birth and one study which only reported per cycle data (Komori 2004) were deemed to be at unclear risk of this bias.

 

Other potential sources of bias

Two studies were judged to be at low risk of other potential biases and 11 were at unclear risk. One study (Fernandez-Sanchez 2012) gave women the option of changing the number of embryos transferred or the day of transfer if they were unhappy with the group to which they were randomised. A large number of participants (21%) chose to change, including 36% of women in the SET groups who changed to DET. Although the study was analysed by intention to treat, the results were deemed to be at high risk of bias due to the high level of non-compliance and the fact that nearly all the changes were in the same direction.

 

Effects of interventions

See:  Summary of findings for the main comparison Repeated single embryo transfer compared to double embryo transfer;  Summary of findings 2 Single embryo transfer compared to double embryo transfer (in a single cycle)

The results below are formatted by type of comparison, as follows.

  1. Repeated single embryo transfer versus repeated multiple transfer
  2. Repeated single embryo transfer versus mixed policies
  3. Single versus multiple embryo transfer in a single cycle
  4. Other fresh cycle comparisons.

 

1. Repeated single embryo transfer versus repeated multiple transfer.

No studies compared repeated single embryo transfer versus repeated multiple transfer.

 

2. Repeated single embryo embryo transfer versus mixed policies

Three studies, all of cleavage-stage transfer, made this comparison (Thurin 2004; Lukassen 2005; Thurin 2005).

Specific interventions were as follows (with the number of cycles in brackets).

  • Single embryo transfer (x 2) versus double embryo transfer (x 1) (SET (x2) versus DET (X1))(Lukassen 2005).
  • Single embryo transfer (x 1) plus transfer of one frozen thawed embryo in a natural or hormone-stimulated cycle versus double embryo transfer (x 1) (SET + 1 FZET versus DET (X1)) (Thurin 2004; Thurin 2005).

 

Primary outcomes

 
2.1 Cumulative live birth rate

When the three studies (Thurin 2004; Lukassen 2005; Thurin 2005) were pooled, the cumulative live birth rate after repeated single embryo transfer was not significantly different from the rate after one cycle of DET (OR 0.82, 95% CI 0.62, to 1.09, three studies, n=811, I2=0%). This suggests that for a woman with a 40% chance of live birth following a single cycle of DET, the chance following repeated SET would be between 31% and 44%.

 
2.1.1 SET + 1 FZET versus DET (x1)

Two studies reported cumulative live birth rates after SET followed by 1 FZET versus DET in a single cycle (Thurin 2004; Thurin 2005). The difference in cumulative live birth rate between SET + 1 FZET and DET was not statistically significant (OR 0.83, 95% CI 0.61 to 1.12, two studies, n = 703, I2 = 0%).

 
2.1.2 SET (x 2) versus DET (x1)

A single study compared cumulative live birth rate after two fresh cycles of SET versus a single fresh cycle of DET (Lukassen 2005). It did not find a significant difference between the two groups (OR 0.79, 95% CI 0.36 to 1.72, one study, n = 108).

See  Analysis 2.1; Figure 4

 FigureFigure 4. Forest plot of comparison: 2 Repeated single versus mixed policies, outcome: 2.1 Cumulative live birth.

 
2.2 Multiple pregnancy rate

When the three studies (Thurin 2004; Lukassen 2005; Thurin 2005) were pooled, the multiple pregnancy rate after repeated single embryo transfer was significantly lower than after a single cycle of DET (OR 0.03, 95% CI 0.01 to 0.13, three studies, n=811, I2 = 23%). This suggests that for a woman with a 13% risk of multiple pregnancy following a single cycle of DET, the risk following repeated SET would be between 0% and 2%.

 
2.2.1 SET + 1 FZET versus DET (x 1)

Two studies reported multiple pregnancy rates after SET plus 1 FZET versus DET in a single cycle (Thurin 2004; Thurin 2005). There was a significantly lower multiple pregnancy rate in the SET group, with substantial heterogeneity (OR 0.03, 95% CI 0.01 to 0.14, two studies, n = 703, I2 = 60%). There was no obvious explanation for the heterogeneity.

 
2.2.2 SET (x 2) versus DET (x 1)

A single study compared the multiple pregnancy rate after two fresh cycles of SET versus a single fresh cycle of DET (Lukassen 2005) and did not find a significant difference between the two groups (OR 0.07, 95% CI 0.00 to 1.25, one study, n = 108).

See  Analysis 2.2; Figure 5

 FigureFigure 5. Forest plot of comparison: 2 Repeated single versus mixed policies, outcome: 2.2 Multiple pregnancy.

 

Secondary outcomes

 
2.3 Clinical pregnancy rate

When two studies reporting this outcome (Lukassen 2005; Thurin 2004) were pooled, the clinical pregnancy rate after repeated single embryo transfer was not significantly different from the rate after one cycle of DET (OR 0.81, 95% CI 0.61 to 1.08, two studies, n=768, I2=0%)

 
2.3.1 SET + 1 FZET versus DET (x 1)

A single study reported the clinical pregnancy rate after SET followed by 1 FZET versus DET in a single cycle (Thurin 2004). No significant difference was found between the groups (OR 0.83 95% CI 0.61 to 1.12, one study, n = 661).

 
2.3.2 Fresh SET (x 2) versus DET (x 1)

A single study compared the clinical pregnancy rate after two fresh cycles of SET versus a single fresh cycle of DET (Lukassen 2005) and did not find a significant difference between the two groups (OR 0.71, 95% CI 0.33 to 1.53, one study, n= 107).

See  Analysis 2.3

 
2.4 Miscarriage rate

A single study reported the miscarriage rate after two fresh cycles of SET versus a single fresh cycle of DET (Lukassen 2005). No significant difference was found between the two groups (OR 0.60, 95% CI 0.18 to 1.97, one study, n = 107).

See  Analysis 2.4

 

3. Single versus multiple embryo transfer in a single cycle

Nine studies of cleavage-stage transfer (Gerris 1999; Martikainen 2001; ASSETT 2003; Thurin 2004; Lukassen 2005; Thurin 2005; ECOSSE 2006; van Montfoort 2006; Fernandez-Sanchez 2012) and two of blastocyst-stage transfer (Gardner 2004; Fernandez-Sanchez 2012) made this comparison. One reported both (Fernandez-Sanchez 2012).

All compared one cycle of single versus one cycle of double embryo transfer (SET (x 1) versus DET (x 1)). As noted above, for four of these studies (Thurin 2004; Thurin 2005; Lukassen 2005; ECOSSE 2006) the data for this comparison derive from an interim analysis, as women in one or both arms were randomised to undergo further transfer cycles if the first cycle did not result in pregnancy.

 

Primary outcomes

 
3.1 Live birth rate
 
3.1.1 SET (x 1) versus DET (x 1)

Nine studies of cleavage-stage transfer and one of blastocyst transfer reported this outcome. See  Analysis 3.1; Figure 6

 FigureFigure 6. Forest plot of comparison: 3 Single versus multiple (in a single cycle), outcome: 3.1 Live birth.

When all studies were pooled, the live birth rate per woman was significantly lower in women who had SET than those who had DET (OR 0.48, 95% CI 0.39 to 0.60, nine studies, n = 1564, I2 = 0%). This suggests that for a woman with a 45% chance of live birth following a single cycle of DET, the chance following a single cycle of SET would be between 24% and 33%.

These findings applied in comparisons of cleavage-stage transfer (OR 0.49, 95% CI 0.40 to 0.62, nine studies, n = 1464, I2 = 0%) and also in the single comparison of blastocyst transfer (OR 0.34, 95% CI 0.15 to 0.77, one study, n = 100).

A funnel plot for this outcome was not suggestive of publication bias. See Figure 7

 FigureFigure 7. Funnel plot of comparison: 3 Single versus multiple (in a single cycle), outcome: 3.1 Live birth.

 
3.2 Multiple pregnancy rate
 
3.2.1 SET (x 1) versus DET (x 1)

Nine studies of cleavage-stage transfer and two of blastocyst transfer reported this outcome. See  Analysis 3.2; Figure 8

 FigureFigure 8. Forest plot of comparison: 3 Single versus multiple (in a single cycle), outcome: 3.2 Multiple pregnancy.

When all studies were pooled, the multiple pregnancy rate per woman was significantly lower in those who had SET than those who had DET (OR 0.12, 95% CI 0.07 to 0.20, 10 studies, n = 1612, I2 = 45%). This suggests that for a woman with a 14% risk of multiple pregnancy following a single cycle of DET, the risk following a single cycle of SET would be between 1% and 3%

These findings applied in comparisons of cleavage-stage transfer (OR 0.10, 95% CI 0.05 to 0.18, nine studies, n = 1464, I2 = 0%) and also in comparisons of blastocyst transfer (OR 0.25, 95% CI0.08 to 0.72, two studies, n = 148, I2 = 67%). Heterogeneity in these analyses appeared to derive from a study at high risk of bias (Fernandez-Sanchez 2012). Treatment contamination (also known as ‘cross-over’) occurred in a high proportion of cases in this study and would be expected to attenuate any treatment difference. I2 reduced to 0% when this study was excluded from the analyses, without materially affecting the conclusion.

In a sensitivity analysis restricted to studies which clearly reported methods of randomisation and allocation concealment and did not appear to be at high risk of bias, there were only three studies (ASSETT 2003; Lukassen 2005; ECOSSE 2006) with a total of 157 participants. Findings for live births for SET versus DET were no longer statistically significant (OR 0.68, 95% CI 0.35 to 1.34) but the findings for multiple pregnancy still significantly favoured SET (OR 0.13, 95% CI 0.02 to 0.74).

 

Secondary outcomes

 
3.3 Clinical pregnancy rate
 
3.3.1 SET (x 1) versus DET (x 1)

Six studies of cleavage-stage transfer and two of blastocyst transfer reported this outcome. See  Analysis 3.3

When all studies were pooled, the clinical pregnancy rate per woman was significantly lower in those who had SET than those who had DET (OR 0.46, 95% CI 0.37 to 0.57, seven studies, n = 1521, I2 = 0%).

These findings applied in comparisons of cleavage-stage transfer (OR 0.46, 95% CI 0.37 to 0.57, six studies, n = 1357, I2 = 0%) and also in comparisons of blastocyst transfer (OR 0.37, 95% CI 0.18 to 0.76, two studies, n = 148, I2 = 0%).

 
Miscarriage rate

Three studies of cleavage-stage transfer reported this outcome (Martikainen 2001; Thurin 2004; van Montfoort 2006). No significant difference was found between the two groups (OR 0.85, 95% CI 0.54 to 1.34, three studies, n = 1113, I2 = 61%), see  Analysis 3.4

 

4. Other fresh cycle comparisons

Three studies tested other fresh cycle comparisons. Two were of cleavage-stage transfer (Vauthier-Brouzes 1994; Heijnen 2006). The day of transfer of the third study (Mostajeran 2006) was not reported. Specific interventions were as follows (with the number of cycles in brackets):

 

Primary outcomes

 
4.1 Live birth rate or cumulative live birth rate across single or repeated IVF cycles
 
4.1.1 DET (x 1) versus TET (x 1)

No significant difference was found between the groups in the live birth rate (OR 0.40, 95% CI 0.09 to 1.85, one study, n = 45) (Heijnen 2006).

 
4.1.2 DET (x 1) versus FET (x 1)

No significant difference was found between the groups in the live birth rate (OR 0.35, 95% CI 0.11 to 1.05, one study, n = 56) (Vauthier-Brouzes 1994).

 
4.1.3 DET (x 2) versus TET (x 2)

No significant difference was found between the groups in the cumulative live birth rate after two cycles of SET versus two cycles of TET (OR 0.77, 95% CI 0.22 to 2.65, one study, n = 45) (Heijnen 2006).

 
4.1.4 DET (x 3) versus TET (x 3)

No significant difference was found between the groups in the cumulative live birth rate after three cycles of SET versus three cycles of TET (OR 0.77, 95% CI 0.24 to 2.52, one study, n = 45) (Heijnen 2006).

See  Analysis 4.1.

 
4.2 Multiple pregnancy rate
 
4.2.1 DET (x 1) versus TET (x 1)

There was a significantly lower multiple pregnancy rate in the DET group than in the TET group (OR 0.36, 95% CI 0.13 to 0.99, two studies, n = 343) (Heijnen 2006; Mostajeran 2006).

 
4.2.2 DET (x 1) versus FET (x 1)

No significant difference was found between the groups in the multiple pregnancy rate (OR 0.44, 95% CI 0.10 to 1.97, one study, n = 56) (Vauthier-Brouzes 1994).

See analysis  Analysis 4.3.

 

Secondary outcomes

 
4.3 Clinical pregnancy rate
 
4.3.1 DET (x 1) versus TET (x 1)

There was no significant difference between the groups in the clinical pregnancy rate (OR 0.67, 95% CI 0.42 to 1.08, one study, n = 343) (Heijnen 2006).

 
4.3.2 DET versus FET

No significant difference was found between the groups in the clinical pregnancy rate (OR 0.56, 95% CI 0.19 to 1.62, one study, n = 56) (Vauthier-Brouzes 1994).

 
4.4 Miscarriage rate

No studies reported this outcome.

 

5. Other fresh or frozen cycle comparisons

One study (Komori 2004) of cleavage-stage transfer compared DET versus TET among 169 participants. A total of 106 cycles of fresh or frozen embryos were apparently administered in each group, but study reporting was unclear and, moreover, outcomes were reported per cycle rather than per woman. Attempts to contact the authors were unsuccessful. Study findings were reported descriptively below.

 

Primary outcomes

 
5.1 Cumulative live birth rate
 
5.1.1 DET versus TET, apparently using fresh or frozen embryos for multiple cycles

No significant difference was found between the groups for this outcome using per cycle data (30 versus 26 live births resulting from 106 cycles in each group) (Komori 2004).

 
5.2 Multiple pregnancy rate
 
5.2.1 DET versus TET, apparently using fresh or frozen embryos for multiple cycles

There was a significantly lower incidence of multiple births per pregnancy in the DET group (6/40 pregnancies versus 14/29 pregnancies) (Komori 2004).

 

Secondary outcomes

 
5.3 Clinical pregnancy rate
 
5.3.1 DET versus TET, apparently using fresh or frozen embryos for multiple cycles

No significant difference was found between the groups for this outcome using per cycle data (40 versus 29 pregnancies resulting from 106 cycles in each group) (Komori 2004).

 
5.4 Miscarriage rate

This outcome was not reported.

 

Subgroup and sensitivity analyses

We did not perform our planned subgroup analyses to assess the efficacy of embryo replacement protocols in participant groups with differing prognostic characteristics because most studies did not identify such subgroups.

There were insufficient studies which clearly reported methods of randomisation and allocation concealment to conduct sensitivity analyses by study quality, other than for analysis 3.1. The overall findings did not materially change with the use of a random-effects model rather than a fixed-effect model or with use of risk ratios rather than odds ratios.

 

Discussion

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms
 

Summary of main results

Our findings indicate, as one would expect, that live birth and pregnancy rates following single embryo transfer (SET) are lower than those following double embryo transfer (DET) in a single fresh IVF cycle but that the risk of multiple pregnancy is much higher in the DET group. However, pooling of three studies of cleavage-stage transfer found no evidence of a significant difference in the cumulative live birth rate when a single cycle of DET was compared with repeated SET (either SET followed by transfer of a single frozen embryo in a natural or hormone-stimulated cycle (Thurin 2004; Thurin 2005), or two fresh cycles of SET (Lukassen 2005)). Confidence intervals for this finding were wide, and suggested that for a woman with a 42% chance of live birth following a single cycle of DET, the chance following repeated SET would be between 31% and 44%.

Thus, although DET achieves higher live birth rates per fresh cycle, the evidence suggests that the difference in effectiveness may be substantially offset when elective SET is followed by a further single fresh or frozen cycle, at least among women with a good prognosis.

Eleven studies compared one fresh cycle of SET versus one fresh cycle of DET. The live birth rate was 60% higher in the DET group but the risk of multiple pregnancy was eight times as high. One of this group of studies included a high proportion of women who chose not to comply with their randomised treatment, and inclusion of this study was associated with substantial heterogeneity for the outcome of multiple pregnancy. Otherwise there was little evidence of statistical heterogeneity in the review, suggesting that clinical differences between studies had little effect on overall findings.

Three studies of cleavage-stage transfer tested fresh cycle comparisons of DET versus transfer of three or four embryos. Live birth rates did not differ significantly, but there was a significantly lower multiple pregnancy rate in the DET group than in the three embryo transfer (TET) group.

 

Overall completeness and applicability of evidence

No studies compared repeated single versus repeated multiple embryo transfer within the same IVF cycle. This comparison was planned in one study (ECOSSE 2006) but the study was closed due to poor enrolment, with only 23 participants. This comparison would be a useful way to structure future trials in order to determine the safety and effectiveness of different embryo transfer policies, given that a number of embryos have been produced. Policy in this context means the strategy for using up the available embryos until success is achieved or the supply of embryos is exhausted. A comparison of repeated multiple versus repeated single embryo transfer would address the policy question by determining ‘cumulative’ success rates.

The vast majority of participants in the included studies had a good prognosis (aged under 36 years and with sufficient good quality embryos). Only two small studies (Thurin 2005; Heijnen 2006) focused on older women. As one of the studies (Gardner 2004) noted, there was a strong potential for self-selection bias, as only a small proportion of eligible women volunteered for the trial, probably due to the belief that single ET could result in lower pregnancy rates and that twin pregnancy is a desirable outcome: they commented that most volunteers were younger women. Future studies should include older women and those with previously failed IVF cycles or lack of good quality embryos

Per cycle, DET appears to be more expensive than SET (Tiitinen 2001; Gerris 2004; Thurin 2006; Chambers 2007; Fiddelers 2007). The higher cost is mainly due to the increased rate of multiple births and premature births in the DET group, and fewer pregnancies in the SET group. Long term costs related to multiple births and prematurity in the DET group have not yet been adequately assessed. However the additional costs of cryopreservation with SET + 1 FZET have not been evaluated. In order to implement a policy of multiple single embryo transfers per woman, providers require either an efficient cryopreservation service or the ability to provide multiple fresh IVF cycles. The former is likely to be a safer and less invasive option for the women concerned.

Only two studies (Gardner 2004; Fernandez-Sanchez 2012) specifically addressed blastocyst transfer.

 

Quality of the evidence

Many of the included studies were small, with half enrolling fewer than 60 participants. There was considerable clinical heterogeneity between the studies but little evidence of statistical heterogeneity for most analyses. The methodological quality of the studies was mixed. See Figure 2. Confidence intervals were wide for some analyses, and GRADEPro ratings for the primary outcomes ranged from high (for comparisons of DET versus SET in a single cycle) to low or very low (for comparisons of DET versus repeated SET). See Summary of findings table 3; Summary of findings table 4).

 

Potential biases in the review process

One of the review authors is primary investigator of one of the included studies (ECOSSE 2006).

Our comparison of one cycle of fresh SET versus one cycle of DET (Analysis 6.1) includes data from studies for which this was an interim analysis. This may be a potential source of bias, associated with placebo effects relating to participant anxiety. A post-hoc sensitivity analysis excluding these studies did not materially influence the live birth rate in this analysis.

We are unaware of any other potential biases in the review process.

 

Agreements and disagreements with other studies or reviews

Other studies and reviews are broadly in agreement with the current review.

A project commissioned by the UK National Institutes of Health Research Health Technology Assessment Programme (Roberts 2011) used statistical modelling, analysis of registry and cohort data, and exploration of consumer perspectives to explore options for increasing SET and reducing the incidence of multiple births. The analysis concluded that couples have approximately one-third less chance of a live birth if they have one fresh cycle of SET rather than DET, but that use of repeat cycles using cryopreservation might compensate for the lost potential in each individual transfer while reducing the likelihood of multiple births. However, the authors recognised that a policy of repeat SET (with use of cryopreserved eggs) would involve challenges including appropriate patient selection, optimisation of freezing techniques, and the emotional, financial and physical burden associated with additional treatment cycles.

Recent systematic reviews (Gelbaya 2010; McLernon 2010) and a report from the American Society for Reproductive Medicine (ASRM 2012) have reached similar conclusions.

A large Dutch cohort study is currently in progress, which aims to assess the long term costs and health outcomes of IVF singleton and twin children and the long term cost-effectiveness of SET versus DET strategies. Outcomes will be reported at one year, five years and 18-year follow-up (van Heesch 2010).

 

Authors' conclusions

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms

 

Implications for practice

This review indicates that in a single fresh IVF cycle, single embryo transfer is associated with a lower live birth rate than double embryo transfer. However, there is no evidence of a significant difference in the cumulative live birth rate when a single cycle of double embryo transfer is compared with repeated SET (either two cycles of fresh SET or one cycle of fresh SET followed by one cycle of frozen SET in a natural or hormone-stimulated cycle). Single embryo transfer is associated with much lower rates of multiple pregnancy than other embryo transfer policies. A policy of repeated SET may minimise the risk of multiple pregnancy in couples undergoing ART, without substantially reducing the likelihood of achieving a live birth. Most of the evidence currently available concerns younger women with a good prognosis.

 
Implications for research

More evidence is needed on policies for repeated embryo transfer, including the most safe and effective way to use available embryos within a single IVF cycle until success is achieved or the supply of embryos is exhausted. More research is needed to determine what characteristics of women and embryos are associated with multiple pregnancy and which, if present, should identify a need for single embryo transfer. As studies to date have been conducted largely among women with a good prognosis undergoing ART, future studies should include older women (above 36 years) and those with previously failed IVF cycles or lack of good quality embryos. Longer term cost-effectiveness analyses are also needed, which should take into account costs related to multiple births and also costs of cryopreservation in the various strategies. Finally, it is important to explore patient perspectives on multiple pregnancy and to increase consumer awareness that single embryo transfer is the best option for most women having IVF.

 

Acknowledgements

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms

Staff at the editorial base of the Cochrane Menstrual Disorders and Subfertility Review Group, in particular Trials Search Co-ordinator Marian Showell, for help with the literature searches. Statistician Andy Vail (University of Manchester University, UK) for methodological advice.

 

Data and analyses

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms
Download statistical data

 
Comparison 2. Repeated single versus mixed policies

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Cumulative live birth3811Odds Ratio (M-H, Fixed, 95% CI)0.82 [0.62, 1.09]

    1.1 SET + 1 FZET versus DET (x1) (cleavage stage)
2703Odds Ratio (M-H, Fixed, 95% CI)0.83 [0.61, 1.12]

    1.2 SET (x2) versus DET (x1) (cleavage stage)
1108Odds Ratio (M-H, Fixed, 95% CI)0.79 [0.36, 1.72]

 2 Multiple pregnancy3811Odds Ratio (M-H, Fixed, 95% CI)0.03 [0.01, 0.13]

    2.1 SET + 1 FZET versus DET (x1) (cleavage stage)
2703Odds Ratio (M-H, Fixed, 95% CI)0.03 [0.01, 0.14]

    2.2 SET (x2) versus DET (x1) (cleavage stage)
1108Odds Ratio (M-H, Fixed, 95% CI)0.07 [0.00, 1.25]

 3 Clinical pregnancy rate2768Odds Ratio (M-H, Fixed, 95% CI)0.81 [0.61, 1.08]

    3.1 SET + 1 FZET versus DET (x1) (cleavage stage)
1661Odds Ratio (M-H, Fixed, 95% CI)0.83 [0.61, 1.12]

    3.2 SET (x2) versus DET (x1) (cleavage stage)
1107Odds Ratio (M-H, Fixed, 95% CI)0.71 [0.33, 1.53]

 4 Miscarriage1Odds Ratio (M-H, Fixed, 95% CI)Subtotals only

    4.1 SET (x2) versus DET (x1) (cleavage stage)
1107Odds Ratio (M-H, Fixed, 95% CI)0.60 [0.18, 1.97]

 
Comparison 3. Single versus multiple (in a single cycle)

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Live birth91564Odds Ratio (M-H, Fixed, 95% CI)0.48 [0.39, 0.60]

    1.1 SET (x1) versus DET (x1) (cleavage stage)
91464Odds Ratio (M-H, Fixed, 95% CI)0.49 [0.40, 0.62]

    1.2 SET (x1) versus DET (x1) (blastocyst stage)
1100Odds Ratio (M-H, Fixed, 95% CI)0.34 [0.15, 0.77]

 2 Multiple pregnancy101612Odds Ratio (M-H, Fixed, 95% CI)0.12 [0.07, 0.20]

    2.1 SET (x1) versus DET (x1) (cleavage stage)
91464Odds Ratio (M-H, Fixed, 95% CI)0.10 [0.05, 0.18]

    2.2 SET (x1) versus DET (x1) (blastocyst stage)
2148Odds Ratio (M-H, Fixed, 95% CI)0.25 [0.08, 0.72]

 3 Clinical pregnancy rate71521Odds Ratio (M-H, Fixed, 95% CI)0.46 [0.37, 0.57]

    3.1 SET (x1) versus DET (x1) (cleavage stage)
61373Odds Ratio (M-H, Fixed, 95% CI)0.47 [0.37, 0.59]

    3.2 SET (x1) versus DET (x1) (blastocyst stage)
2148Odds Ratio (M-H, Fixed, 95% CI)0.37 [0.18, 0.76]

 4 Miscarriage3Odds Ratio (M-H, Fixed, 95% CI)Subtotals only

    4.1 SET (x1) versus DET (x1) (cleavage stage)
31113Odds Ratio (M-H, Fixed, 95% CI)0.85 [0.54, 1.34]

 
Comparison 4. Other fresh cycle comparisons

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Live or cumulative live birth2Odds Ratio (M-H, Fixed, 95% CI)Subtotals only

    1.1 DET (x1) versus TET (x1)
145Odds Ratio (M-H, Fixed, 95% CI)0.4 [0.09, 1.85]

    1.2 DET (x1) versus FET (x1)
156Odds Ratio (M-H, Fixed, 95% CI)0.35 [0.11, 1.05]

    1.3 DET (x2) versus TET (x2)
145Odds Ratio (M-H, Fixed, 95% CI)0.77 [0.22, 2.65]

    1.4 DET (x3) versus TET (x3)
145Odds Ratio (M-H, Fixed, 95% CI)0.77 [0.24, 2.52]

 2 Multiple pregnancy3Odds Ratio (M-H, Fixed, 95% CI)Subtotals only

    2.1 DET versus TET (cleavage stage)
2343Odds Ratio (M-H, Fixed, 95% CI)0.36 [0.13, 0.99]

    2.2 DET versus FET (cleavage stage)
156Odds Ratio (M-H, Fixed, 95% CI)0.44 [0.10, 1.97]

 3 Clinical pregnancy3Odds Ratio (M-H, Fixed, 95% CI)Subtotals only

    3.1 DET (x1) versus TET (x1) (cleavage stage)
2343Odds Ratio (M-H, Fixed, 95% CI)0.67 [0.42, 1.08]

    3.2 DET (x1) versus FET (x1) (cleavage stage)
156Odds Ratio (M-H, Fixed, 95% CI)0.56 [0.19, 1.62]

 

Appendices

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms
 

Appendix 1. MDSG search string

The following Medical Subject Headings (MeSH terms) and all combinations of these words were used: embryo transfer, multiple pregnancy, IVF, in vitro fertil$, ICSI, intra cytoplasmic sperm injection, infertility, subfertility, single/one embryo, two/double embryo, three/four/multiple embryos, effectiveness, ART, Assisted reprod$ techn$, randomised controlled trial, clinical trial.

 

Appendix 2. MEDLINE search

Database: Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations, Ovid MEDLINE(R) Daily and Ovid MEDLINE(R) <1946 to Nov 2012>

1 Embryo Transfer/ (11908)

2 (Embryo$ adj5 Transfer$).tw. (12767)

3 (blastocyst$ adj5 transfer$).tw. (1490)

4 exp embryo, mammalian/ or exp blastocyst/ (75947)

5 or/1-4 (89708)

6 (two adj2 embryo$).tw. (2775)

7 (double adj2 embryo$).tw. (431)

8 DET.tw. (591)

9 (three adj2 embryo$).tw. (1449)

10 (triple adj2 embryo$).tw. (32)

11 TET$.tw. (321295)

12 (two adj2 blastocyst$).tw. (168)

13 (double adj2 blastocyst$).tw. (13)

14 (three adj2 blastocyst$).tw. (77)

15 (triple adj2 blastocyst$).tw. (3)

16 DBT.tw. (1071)

17 TBT.tw. (1157)

18 (one adj2 embryo$).tw. (1781)

19 (single adj2 embryo$).tw. (1179)

20 SET.tw. (286512)

21 (one adj2 blastocyst$).tw. (141)

22 (single adj2 blastocyst$).tw. (170)

23 SBT.tw. (1139)

24 (four adj2 embryo$).tw. (727)

25 (four adj2 blastocyst$).tw. (55)

26 FET.tw. (1134)

27 FZET.tw. (0)

28 (multiple$ adj2 embryo$).tw. (448)

29 (multiple$ adj2 blastocyst$).tw. (9)

30 (quadruple adj2 embryo$).tw. (4)

31 (quadruple adj2 blastocyst$).tw. (1)

32 or/6-31 (614694)

33 5 and 32 (6467)

34 randomized controlled trial.pt. (342319)

35 controlled clinical trial.pt. (85680)

36 randomized.ab. (257751)

37 placebo.tw. (145527)

38 clinical trials as topic.sh. (163663)

39 randomly.ab. (187932)

40 trial.ti. (110917)

41 (crossover or cross-over or cross over).tw. (55492)

42 or/34-41 (838746)

43 exp animals/ not humans.sh. (3809972)

44 42 not 43 (773670)

45 33 and 44 (251)

 

Appendix 3. EMBASE search

Database: Embase <1980 to 2012 Week 45>

Search Strategy:

--------------------------------------------------------------------------------

1 Embryo Transfer/ (18351)

2 (Embryo$ adj5 Transfer$).tw. (16394)

3 (blastocyst$ adj5 transfer$).tw. (2079)

4 exp embryo, mammalian/ or exp blastocyst/ (49471)

5 or/1-4 (69463)

6 (two adj2 embryo$).tw. (3029)

7 (double adj2 embryo$).tw. (539)

8 DET.tw. (881)

9 (three adj2 embryo$).tw. (1624)

10 (triple adj2 embryo$).tw. (35)

11 TET$.tw. (351760)

12 (two adj2 blastocyst$).tw. (204)

13 (double adj2 blastocyst$).tw. (27)

14 (three adj2 blastocyst$).tw. (84)

15 (triple adj2 blastocyst$).tw. (4)

16 DBT.tw. (1414)

17 TBT.tw. (1560)

18 (one adj2 embryo$).tw. (2077)

19 (single adj2 embryo$).tw. (1717)

20 SET.tw. (332164)

21 (one adj2 blastocyst$).tw. (176)

22 (single adj2 blastocyst$).tw. (298)

23 SBT.tw. (1713)

24 (four adj2 embryo$).tw. (780)

25 (four adj2 blastocyst$).tw. (70)

26 FET.tw. (1399)

27 FZET.tw. (0)

28 (multiple$ adj2 embryo$).tw. (584)

29 (multiple$ adj2 blastocyst$).tw. (12)

30 (quadruple adj2 embryo$).tw. (6)

31 (quadruple adj2 blastocyst$).tw. (2)

32 or/6-31 (693129)

33 5 and 32 (6682)

34 Clinical trial/ (873896)

35 Randomized controlled trials/ (22276)

36 Random Allocation/ (59995)

37 Single-Blind Method/ (16629)

38 Double-Blind Method/ (111820)

39 Cross-Over Studies/ (35508)

40 Placebos/ (207982)

41 Randomi?ed controlled trial$.tw. (80804)

42 RCT.tw. (10393)

43 Random allocation.tw. (1194)

44 Randomly allocated.tw. (17927)

45 Allocated randomly.tw. (1847)

46 (allocated adj2 random).tw. (713)

47 Single blind$.tw. (12761)

48 Double blind$.tw. (132065)

49 ((treble or triple) adj blind$).tw. (288)

50 Placebo$.tw. (181564)

51 Prospective Studies/ (218579)

52 or/34-51 (1286058)

53 Case study/ (17669)

54 Case report.tw. (234557)

55 Abstract report/ or letter/ (850195)

56 or/53-55 (1097609)

57 52 not 56 (1249761)

58 animal/ (1801042)

59 human/ (13859436)

60 58 not 59 (1346252)

61 57 not 60 (1224281)

62 33 and 61 (498)

63 (2011$ or 2012$).em. (2193008)

64 62 and 63 (88)

 

Appendix 4. CENTRAL search

1 Embryo Transfer/ (736)

2 (Embryo$ adj5 Transfer$).tw. (1117)

3 (blastocyst$ adj5 transfer$).tw. (92)

4 exp embryo, mammalian/ or exp blastocyst/ (506)

5 or/1-4 (1702)

6 (two adj2 embryo$).tw. (96)

7 (double adj2 embryo$).tw. (21)

8 DET.tw. (46)

9 (three adj2 embryo$).tw. (62)

10 (triple adj2 embryo$).tw. (2)

11 TET$.tw. (4765)

12 (two adj2 blastocyst$).tw. (7)

13 (double adj2 blastocyst$).tw. (1)

14 (three adj2 blastocyst$).tw. (3)

15 (triple adj2 blastocyst$).tw. (0)

16 DBT.tw. (61)

17 TBT.tw. (17)

18 (one adj2 embryo$).tw. (44)

19 (single adj2 embryo$).tw. (52)

20 SET.tw. (6351)

21 (one adj2 blastocyst$).tw. (4)

22 (single adj2 blastocyst$).tw. (17)

23 SBT.tw. (81)

24 (four adj2 embryo$).tw. (23)

25 (four adj2 blastocyst$).tw. (1)

26 FET.tw. (72)

27 FZET.tw. (0)

28 (multiple$ adj2 embryo$).tw. (13)

29 (multiple$ adj2 blastocyst$).tw. (1)

30 (quadruple adj2 embryo$).tw. (0)

31 (quadruple adj2 blastocyst$).tw. (0)

32 or/6-31 (11591)

33 5 and 32 (255)

 

Appendix 5. CINAHL search

1 Embryo Transfer/ (96)
2 (Embryo$ adj5 Transfer$).tw. (90)
3 (blastocyst$ adj5 transfer$).tw. (9)
4 or/1-3 (154)
5 (single embryo$ or one embryo$).tw. (14)
6 (two embryo$ or double embryo$).tw. (7)
7 (three embryo$ or four embryo$).tw. (5)
8 (multiple embryo$ or (number adj5 embryo$)).tw. (28)
9 or/5-8 (44)
10 4 and 9 (30)
11 from 10 keep 1-30 (30)

 

Appendix 6. PsycINFO search

Database: PsycINFO <1806 to July 17 2013>

1 exp Infertility/ or exp Reproductive Technology/ (2388)

2 (Embryo$ adj5 Transfer$).tw. (121)

3 (blastocyst$ adj5 transfer$).tw. (3)

4 or/1-3 (2434)

5 (two adj2 embryo$).tw. (27)

6 (double adj2 embryo$).tw. (6)

7 DET.tw. (88)

8 (three adj2 embryo$).tw. (10)

9 (triple adj2 embryo$).tw. (0)

10 (two adj2 blastocyst$).tw. (0)

11 (three adj2 blastocyst$).tw. (0)

12 (one adj2 embryo$).tw. (22)

13 (single adj2 embryo$).tw. (13)

14 (four adj2 embryo$).tw. (7)

15 or/5-14 (165)

 

Appendix 7. CINAHL search strategy


# Query Results

S28S12 AND S2686

S27S12 AND S26124

S26S13 OR S14 or S15 or S16 OR S17 OR S18 OR S19 OR S20 OR S21 OR S22 OR S23 OR S24 OR S25Display

S25TX allocat* random*Display

S24(MH "Quantitative Studies")Display

S23(MH "Placebos")Display

S22TX placebo*Display

S21TX random* allocat*Display

S20(MH "Random Assignment")Display

S19TX randomi* control* trial*Display

S18TX ( (singl* n1 blind*) or (singl* n1 mask*) ) or TX ( (doubl* n1 blind*) or (doubl* n1 mask*) ) or TX ( (tripl* n1 blind*) or (tripl* n1 mask*) ) or TX ( (trebl* n1 blind*) or (trebl* n1 mask*) )Display

S17TX ( (trebl* n1 blind*) or (trebl* n1 mask*) )Display

S16TX ( (trebl* n1 blind*) or (trebl* n1 mask*) )Display

S15TX clinic* n1 trial*Display

S14PT Clinical trialDisplay

S13(MH "Clinical Trials+")Display

S12S3 AND S11306

S11S4 OR S5 OR S6 OR S7 OR S8 OR S9 OR S101,189,815

S10TX three165,919

S9TX triple3,133

S8TX two258,377

S7TX double670,325

S6TX multiple139,923

S5TX one264,468

S4TX single73,642

S3S1 OR S2530

S2"blastocyst transfer"23

S1(MM "Embryo Transfer") OR "embryo transfer"526



 

What's new

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms

Last assessed as up-to-date: 17 July 2013.


DateEventDescription

1 June 2014AmendedAnalyses of single embryo transfer versus double embryo transfer changed so that single embryo transfer is now regarded as the intervention and double embryo transfer as the control, in order to make the nature of the comparison more clinically appropriate. Text and summary of findings table edited accordingly. Errors in display of some of tables of analysis corrected in order to show OR consistently. Assessed as up to date and Search dates corrected.



 

History

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms

Protocol first published: Issue 1, 2002
Review first published: Issue 4, 2004


DateEventDescription

25 July 2013New citation required but conclusions have not changedNo change to conclusions

25 July 2013New search has been performedThe search was updated to July 2013

Comparisons of different numbers of blastocysts were added (previously only cleavage-stage embryo comparisons were included)

Seven extra completed studies were included (ASSETT 2003, Gardner 2004, Komori 2004, Thurin 2005, ECOSSE 2006, Mostajeran 2006, Manuel-Fernandez 2012)

The structure of the table of comparisons was reformatted

29 August 2011New search has been performedReview updated Aug 2011.

Objective- wording has been changed

Three unplished trials (ASSETT 2003; Thurin 2005; ECOSSE 2006) have been added to comparison 1

Comparison 2 has been changed to DET vs SET (2 or more cycles), the sub comparisons now include DET vs 2 fresh SET, DET vs SET plus 1FZET, DET plus FZET vs SET +FZET and has additional data from 2 unpublished trials. The original Comparison 3 from previous review has therefore been deleted and included in comparison 2. Comparison 5 from previous review has also been deleted and added to comparison 4 of the updated review. This updated review will have 3 comparisons.

8 May 2008AmendedConverted to new review format.

8 May 2008New search has been performedA new literature search was performed on 30/03/2008 by two reviewers independently (ZP, OO).

Five new trials were identified using the Cochrane search strategy for identifying new trials.Search redesigned and run March 2008 . Three new trials were added to the review.

One trial (Thurin 2004) included blastocyst transfers. Blastocyst transfers were excluded from the data analysed.

Two trials (Thurin2004 and van Montfoort 2006) compared one embryo transfer versus two embryo transfer. One trial (Thurin 2004) also compared one embryo transfer followed by a frozen-thawed single embryo transfer versus two embryo transfer.

Livebirth rates from Van Montfoort 2006 study was derived from another publication from the same study and appears as van Montfoort* 2006 in the review and references.

A single trial (Heijnen 2006) compared two embryo transfer versus three embryo transfer. The trial also determined the cumulative effect of multiple transfers of two and three embryos.

A trial included in the original review (Lukassen 2002) that compared single embryo transfer versus double embryo was updated and published in 2005. This review has also been updated with this trial.

Two trials (Komori 2004; Mostajeran 2006) that compared three embryo transfer versus two embryo transfer were identified with the new literature search but were excluded as the method of randomisation was unclear in both trials.

The review has been converted into the new Rev man 5 format.

The order of appearance of the comparisons have been changed.

Two additional tables (1, 2) has been added.

12 June 2007New citation required and conclusions have changedSubstantive amendment



 

Contributions of authors

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms

Zabeena Pandian: checked literature searches, data extraction, study selection, quality assessment, entered and checked data, data analysis, completed and checked risk of bias tables, wrote the first draft of the review.

Jane Marjoribanks: 2013 update of literature search, redrafted text and comparison tables, added new studies and summary of findings table, entered and checked data, completed and checked risk of bias tables.

Ozturk Ozkan: development of protocol, literature search in 2009.

Gamal Serour: revised the final draft of the 2009 review.

Siladitya Bhattacharya: study selection, quality assessment, responsible for final draft of the review.

 

Declarations of interest

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms

None

 

Sources of support

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms
 

Internal sources

  • Department of Obstetrics & Gynaecology, University of Aberdeen, UK.

 

External sources

  • No sources of support supplied

 

Differences between protocol and review

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms

The structure of the comparisons was reformatted to prioritise comparisons of repeat single embryo transfer. Live birth and cumulative live birth rates were amalgamated as a single primary outcome.

Studies of blastocyst transfer were added (previously only cleavage-stage transfers included).

* Indicates the major publication for the study

References

References to studies included in this review

  1. Top of page
  2. AbstractRésumé scientifique
  3. Summary of findings
  4. Background
  5. Objectives
  6. Methods
  7. Results
  8. Discussion
  9. Authors' conclusions
  10. Acknowledgements
  11. Data and analyses
  12. Appendices
  13. What's new
  14. History
  15. Contributions of authors
  16. Declarations of interest
  17. Sources of support
  18. Differences between protocol and review
  19. Characteristics of studies
  20. References to studies included in this review
  21. References to studies excluded from this review
  22. References to studies awaiting assessment
  23. References to ongoing studies
  24. Additional references
ASSETT 2003 {unpublished data only}
  • Norman RJ, Wang JX, Davies MJ. Australian Study of Single Embryo Transfer (ASSET) clinical protocol. A multi-centre double blind randomised controlled trial to compare the outcomes of pregnancy following the transfer of either a single embryo (SET) or two embryos (DET) in an optimal group of patients undergoing in-vitro fertilization (IVF) with or without intra-cytoplasmic sperm injection (ICSI). www.controlled-trials.com/isrctn/pf/86466058 2006.
ECOSSE 2006 {unpublished data only}
  • Bhattacharya S. Efficacy and Cost Effectiveness of Selective Single Embryo transfer. www.controlled-trials.com/isrctn/pf/86466058. 2006.
Fernandez-Sanchez 2012 {published data only}
  • Fernandez-Sanchez. Elective single embryo transfer (e-SET) vs. double embryo transfer (eDET): live birth outcome and patient acceptance in a prospective randomized open trial. Fertility and Sterility In press.
  • Fernandez-Sanchez. Single vs Double Embryo Transfer (SET). http://www.clinicaltrials.gov/ct2/show/NCT00814398?term=embryo+AND+transfer&rank=15 2011.
Gardner 2004 {published data only}
Gerris 1999 {published data only}
  • Gerris J, De Neubourg D, Mangelschots K, Van Royen E, Vande Meerssche M, Valkenburg M. Prevention of twin pregnancy after in-vitro fertilization or intracytoplasmic sperm injection based on strict embryo criteria: a prospective randomized clinical trial. Human Reproduction 1999;14(10):2581-7.
Heijnen 2006 {published data only}
  • Heijnen EMEW, Klinkert ER, Schmoutziguer APE, Eijkemans MJC, te Velde ER, Broekmans FJM. Prevention of multiple pregnancies after IVF in women 38 and older: a randomized study. Reproductive BioMedicine Online; www.rbmonline.com/Article/2339 on web 5 July 2006;13(3):386-93.
Komori 2004 {published data only}
  • Komori S, Kasumi H, Horiuchi I, Hamada Y, Suzuki C, Shigeta M, et al. Prevention of multiple pregnancies by restricting the number of transferred embryos: randomized control study. Archives of Gynecology and Obstetrics 2004 Sep;270(2):91-3.
Lukassen 2005 {published data only}
  • Lukassen HGM, Braat DDM, Wetzels AMM, Zeilhuis GA, Adang EMM, Scheenjes E, Kremer JAM. Two cycles with single embryo transfer versus one cycle with double embryo transfer: a randomized controlled trial. Human Reproduction 2005;20(3):702-8.
Martikainen 2001 {published data only}
  • Martikainen H, Tiitinen A, Tomas C, Tapanainen J, Orava M, Tuomivaara L et al. Finnish ET study group. One versus two embryo transfer after IVF and ICSI: a randomized study. Human Reproduction 2001;16(9):1900-3.
Mostajeran 2006 {published data only}
  • Mostajeran F, Haftbaradaran E. Pregnancy and multiple births rate after transferring 2 or 3 embryos. Journal of Research in Medical Sciences 2006;11(2):113-5.
Thurin 2004 {published data only}
  • Thurin A, Hausken J, Hillensjo T, Jablonowska B, Pinborg A, Strandell A, Bergh C. Elective single-embryo transfer versus double-embryo transfer in in vitro fertilization. The New England Journal of Medicine 2004;351:2392-402.
  • Thurin-Kjellberg A, Olivius C, Bergh C. Cumulative live-birth rates in a trial ofsingle embryo or double embryo transfer. The New England Journal of Medicine 2009;361:18-9.
Thurin 2005 {unpublished data only}
  • Thurin. Elective single embryo transfer. Dissertation 2005.
van Montfoort 2006 {published data only}
  • Fiddelers AAA, van Montfoort A, Dirksen CD, et al. Single versus double embryo transfer: cost-effectiveness analysis alongside a randomized clinical trial. Human Reproduction 2006;21(8):2090-7.
  • Fiddlers AAA, van Montfoort APA, Dirksen CD, et al. Single versus double embryo transfer: cost-effectiveness analysis alongside a randomized controlled trial. Human Reproduction 2006;21(8):2090-7.
  • van Montfoort APA, Fiddelers AAA, Janssen JM, Derhaag JG, Dirksen CD, Dunselman GAJ, et al. In unselected patients, elective single embryo transfer prevents all multiples, but results in significantly lower pregnancy rates compared with double embryo transfer: a randomized controlled trial. Human Reproduction 2006;21(2):338-3.
Vauthier-Brouzes 1994 {published data only}
  • Vauthier-Brouzes D, Lefebvre G, Sylvie L, Gonzales J, Darbois Y. How many embryos should be transferred in in vitro fertilization? A prospective randomized study. Fertility and Sterility 1994;62(2):339-42.

References to studies excluded from this review

  1. Top of page
  2. AbstractRésumé scientifique
  3. Summary of findings
  4. Background
  5. Objectives
  6. Methods
  7. Results
  8. Discussion
  9. Authors' conclusions
  10. Acknowledgements
  11. Data and analyses
  12. Appendices
  13. What's new
  14. History
  15. Contributions of authors
  16. Declarations of interest
  17. Sources of support
  18. Differences between protocol and review
  19. Characteristics of studies
  20. References to studies included in this review
  21. References to studies excluded from this review
  22. References to studies awaiting assessment
  23. References to ongoing studies
  24. Additional references
Bowman 2004 {published data only}
  • Bowman M. Reducing the multiple pregnancy rate in ART. Journal of the Medical Association of Thailand 2004;Suppl 3:S132-5.
Elgindy 2011 {published data only}
  • Elgindy EA, Abou-Setta AM, Mostafa MI. Blastocyst-stage versus cleavage-stage embryo transfer in women with high oestradiol concentrations: randomized controlled trial. Reproductive Biomedicine Online 2011;23(6):789-98. [PUBMED: 22050864]
Forman 2012 {published data only}
  • Forman EJ, Hong KH, Ferry KM, Tao X, Treff NR, Scott RT. Blastocyst euploid selective transfer (BEST): An RCT of comprehensive chromosome screening single embryo transfer (CCS-SET) vs double embryo transfer (DET)-equivalent pregnancy rates, eliminates twins. 68th Annual Meeting of the American Society for Reproductive Medicine, San Diego, CA United States. 2012; Vol. 98 (3 Suppl 1):S49.
Frattarelli 2003 {published data only}
  • Frattarelli JL, Leondires MP, McKeeby JL, Miller BT, Segars JH. Blastocyst transfer decreases multiple pregnancy rates in in vitro fertilization cycles: a randomized controlled trial. Fertility and Sterility 2003;79(1):228-30.
Gardner 1998 {published data only}
  • Gardner D K, Schoolcraft W B, Wagley L, Schlenker T, Stevens J, Hesla J. A prospective randomized trial of blastocyst culture and transfer in in-vitro fertilization. Human Reproduction 1998;13(12):3434-40.
Guerif 2011 {published data only}
  • Guerif F, Frapsauce C, Chavez C, Cadoret V, Royere D. Treating women under 36 years old without top-quality embryos on day 2: A prospective study comparing double embryo transfer with single blastocyst transfer. Human Reproduction 2011;26(4):775-81.
Heijnen 2007 {published data only}
  • Heijnen EM, Eijkemans MJ, De Klerk C, Polinder S, Beckers NG, Klinkert ER, et al. A mild treatment strategy for in-vitro fertilisation: a randomised non-inferiority trial. Lancet 2007;369(9563):743-9.
Levitas 2004 {published data only}
  • Levitas E, Lunenfeld E, Hackmon-Ram R, Sonin Y, Har-Vardi I, Potashnik G. A prospective, randomized study comparing blastocyst versus 48-72 h embryo transfer in women failed to conceive three or more in-vitro fertilization treatment cycles. Abstracts from the 57th Annual Meeting of ASRM. 2001.
  • Levitas E, Lunenfeld E, Har-Vardi I, Albotiano S, Sonin Y, Hackmon-Ram R, et al. Blastocyst-stage embryo transfer in patients who failed to conceive in three or more day 2-3 embryo transfer cycles: a prospective, randomized study. Fertility and Sterility 2004;81(3):567-71.
  • Levitas E, Lunenfeld E, Shoham-Vardi I, Hackmon-Ram R, Albotiano S, Sonin Y, et al. Blastocyst stage versus 48-72h embryo transfer in women who failed to conceive on three or more IVF treatment cycles: a prospective, randomized study. ESHRE Conference. Bologna, 2000:O-021.
Livingstone 2001 {published and unpublished data}
  • Bowman M. Reducing the multiple pregnancy rate in ART. Journal of the Medical Association of Thailand 2004;Suppl 3:S132-5.
  • Livingstone M, Bowman M. Single blastocyst transfer: a prospective randomised trial. Abstracts of the 17th World Congress on Fertility and Sterility 2001:218.
  • Livingstone MS. Single blastocyst transfer: a prospective randomized trial. Master of Medicine Treatise, Faculty of Medicine, University of Sydney 2003.
Motta 1998 A & B {published data only}
  • Motta LA, Alegretti JR, Pico M, Sousa JW, Baracat EC, Serafini P. Blastocyst vs. cleaving embryo transfer: a prospective randomized trial. Fertility and Sterility 1998;70 Suppl 1:17.
Moustafa 2008 {published data only}
  • Moustafa MK, Sheded SA, Mousta MAEL. Elective single embryo transfer versus double embryo transfer in assisted reproduction. Reproductive BioMedicine Online 2008:Article 3173.
Pantos 2004 {published data only}
  • Pantos K, Makrakis E, Stavrou D, Karantzis P, Vaxevanoglou T, Tzigounis V. Comparison of embryo transfer on day 2, day 3, and day 6: a prospective randomized study. Fertility and Sterility 2004;81(2):454-5.
Staessen 1993 {published data only}
  • Staessen C, Janssenswillen C, Van Den Abbeel E, Devroey P, Van Steirteghem AC. Avoidance of triplet pregnancies by elective transfer of two good quality embryos. Human Reproduction 1993;8(10):1650-3.
van Montfoort 2005 {published data only}
  • van Montfoort APA, Dumoulin JCM, Land JA, Coonen E, Derhaag JG, Evers JLH. Elective single embryo transfer (eSET) policy in the first three IVF/ICSI treatment cycles. Human Reproduction 2005;20(2):433-6.

References to ongoing studies

  1. Top of page
  2. AbstractRésumé scientifique
  3. Summary of findings
  4. Background
  5. Objectives
  6. Methods
  7. Results
  8. Discussion
  9. Authors' conclusions
  10. Acknowledgements
  11. Data and analyses
  12. Appendices
  13. What's new
  14. History
  15. Contributions of authors
  16. Declarations of interest
  17. Sources of support
  18. Differences between protocol and review
  19. Characteristics of studies
  20. References to studies included in this review
  21. References to studies excluded from this review
  22. References to studies awaiting assessment
  23. References to ongoing studies
  24. Additional references
Abuzeid 2012 {unpublished data only}
  • Abuzeid M. Comparing the results of one blastocyst transfer versus two in good prognosis patients going through in vitro fertilisation (IVF) with intra cytoplasmic sperm injections (ICSI) and embryo transfer (ET): a prospective, randomized study. http://www.controlled-trials.com/ISRCTN69937179 2012.
Scott 2013 {unpublished data only}
  • Scott RT. Single Embryo Transfer of a Euploid Embryo Versus Double Embryo Transfer [ClinicalTrials.gov identifier: NCT01408433]. http://www.clinicaltrials.gov/ct2/show/NCT01408433?term=embryo+transfer&rank=1.

Additional references

  1. Top of page
  2. AbstractRésumé scientifique
  3. Summary of findings
  4. Background
  5. Objectives
  6. Methods
  7. Results
  8. Discussion
  9. Authors' conclusions
  10. Acknowledgements
  11. Data and analyses
  12. Appendices
  13. What's new
  14. History
  15. Contributions of authors
  16. Declarations of interest
  17. Sources of support
  18. Differences between protocol and review
  19. Characteristics of studies
  20. References to studies included in this review
  21. References to studies excluded from this review
  22. References to studies awaiting assessment
  23. References to ongoing studies
  24. Additional references
ASRM 2012
Berkowits 1996
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Chambers 2007
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De Mouzon 2010
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ESHRE 2000
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ESHRE 2012
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FIVNAT 1995
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Garel 1992
Garel 1997
Gelbaya 2010
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Glujovsky 2012
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Ledger 2006
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Ludwig 2000
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Marek 1999
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Martin 1998
McKinney 1996
McLernon 2010
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Papanikolaou 2006
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Preutthipan 1996
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Roberts 2011
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Sebire 2000
Thurin 2006
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Tiitinen 2001
van Heesch 2010
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Vilska 1999
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Wadhawan 2009
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Wennerholm 2000
Westergaard 2000
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Yaron 1997
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