Guidelines for the number of embryos to transfer following in vitro fertilization

JOINT SOGC–CFAS GUIDELINE
JOINT SOGC–CFAS GUIDELINE
Guidelines for the Number of Embryos to
Transfer Following In Vitro Fertilization
Abstract
This guideline was reviewed by the Reproductive Endocrinologyand Infertility Committee and the Maternal-Fetal Medicine Objective: To review the effect of the number of embryos transferred
Committee and approved by the Executive and Council of the on the outcome of in vitro fertilization (IVF), to provide guidelines Society of Obstetricians and Gynaecologists of Canada and the on the number of embryos to transfer in IVF-embryo transfer (ET) Board of the Canadian Fertility and Andrology Society.
in order to optimize healthy live births and minimize multiplepregnancies.
PRINCIPAL AUTHORS
Options: Rates of live birth, clinical pregnancy, and multiple
pregnancy or birth by number of embryos transferred are Ed Hughes, MB, ChB, MSc, FRCSC, Hamilton ON Outcomes: Clinical pregnancy, multiple pregnancy, and live birth
REPRODUCTIVE ENDOCRINOLOGY AND
INFERTILITY COMMITTEE
Evidence: The Cochrane Library and MEDLINE were searched for
English language articles from 1990 to April 2006. Search terms Anthony P. Cheung, MBBS, MPH, MBA, FRACOG, FRCSC, included embryo transfer (ET), assisted reproduction, in vitro fertilization (IVF), intracytoplasmic sperm injection (ICSI), multiple Paul Claman (Chair), MD, FRCSC, Ottawa ON pregnancy, and multiple gestation. Additional references wereidentified through hand searches of bibliographies of identified Gwendolyn J. Goodrow, MD, FRCSC, Cambridge ON Values: Available evidence was reviewed by the Reproductive
Endocrinology and Infertility Committee and the Maternal-Fetal Medicine Committee of the Society of Obstetricians andGynaecologists of Canada and the Board of the Canadian Fertility Louise Lapensée, MD, FRCSC, Outremont QC and Andrology Society, and was qualified using the Evaluation of Evidence Guidelines developed by the Canadian Task Force onthe Periodic Health Exam.
Sabrina Stewart, MD, FRCSC, Prince Albert SK Benefits, Harms, and Costs: This guideline is intended to minimize
the occurrence of multifetal gestation, particularly high-order Benjamin Chee-Man Wong, MD, FRCSC, Calgary AB multiples (HOM), while maintaining acceptable overall pregnancyand live birth rates following IVF-ET.
MATERNAL-FETAL MEDICINE COMMITTEE
Recommendations
The recommendations made in this guideline were derived mainly Marie-France Delisle, MD, FRCSC, Vancouver BC from studies of cleavage stage embryos—those cultured for two or Dan Farine (Chair), MD, FRCSC, Toronto ON 1. Individual IVF-ET programs should evaluate their own data to identify patient-specific, embryo-specific, and cycle-specificdeterminants of implantation and live birth in order to develop embryo transfer policies that minimize the occurrence of multifetal gestation while maintaining acceptable overall pregnancy and livebirth rates. (III-B) 2. In general, consideration should be given to the transfer of fewer blastocyst stage embryos than cleavage stage embryos, particularly in women with excellent prognoses and high-qualityblastocysts. (I-A) Summary Statement
Key Words: Embryo transfer, in vitro fertilization, intracytoplasmic
The following recommendations are generally intended for sperm injections, multiple pregnancy, multifetal gestation, assisted cleavage stage embryos transferred on day two or three. Because This guideline reflects emerging clinical and scientific advances as of the date issued and is subject to change. The information
should not be construed as dictating an exclusive course of treatment or procedure to be followed. Local institutions can dictate
amendments to these opinions. They should be well documented if modified at the local level. None of these contents may be
reproduced in any form without prior written permission of the SOGC.
SEPTEMBER JOGC SEPTEMBRE 2006 l
JOINT SOGC–CFAS GUIDELINE
Table 1. Criteria for quality of evidence assessment and classification of recommendations
Evidence obtained from at least one properly designed A. There is good evidence to support the recommendation that the condition be specifically considered in a periodic healthexamination.
II-1: Evidence from well-designed controlled trials without B. There is fair evidence to support the recommendation that the condition be specifically considered in a periodic health II-2: Evidence from well-designed cohort (prospective or retrospective) or case-control studies, preferably frommore than one centre or research group.
C. There is poor evidence regarding the inclusion or exclusion of the condition in a periodic health examination.
II-3: Evidence from comparisons between times or places with or without the intervention. Dramatic results from D. There is fair evidence to support the recommendation uncontrolled experiments (such as the results of treatment that the condition not be considered in a periodic health with penicillin in the 1940s) could also be included in this E. There is good evidence to support the recommendation that III: Opinions of respected authorities, based on clinical the condition be excluded from consideration in a periodic experience, descriptive studies, or reports of expert *The quality of evidence reported in these guidelines has been adapted from the Evaluation of Evidence criteria described in the Canadian Task Forceon the Periodic Health Exam.55†Recommendations included in these guidelines have been adapted from the Classification of Recommendations criteria described in the CanadianTask Force on the Periodic Health Exam.55 blastocyst stage embryos have higher implantation rates than pursued. (III-C) Whenever reasonable, consideration should be cleavage stage embryos, fewer blastocyst stage embryos may given to the transfer of a single embryo. (II-3B) 11. Couples should be adequately counselled regarding the Recommendations (continued)
obstetrical, perinatal, and neonatal risks of multifetal gestation tofacilitate informed decision making regarding the number of 3. In women under the age of 35 years, no more than two embryos embryos to transfer. (II-3B) Emphasis on healthy singleton live should be transferred in a fresh IVF-ET cycle. (II-2A) birth as the measure of success in IVF-ET may be beneficial in 4. In women under the age of 35 years with excellent prognoses, the promoting a reduction in the number of embryos transferred. (III-C) transfer of a single embryo should be considered. Women with 12. A strategy for public funding of IVF-ET must be developed for the excellent prognoses include those undergoing their first or second effective implementation of guidelines limiting the number of IVF-ET cycle or one immediately following a successful IVF-ET embryos transferred. In the context of this strategy, total health cycle, with at least two high-quality embryos available for transfer.
care costs would be lower as a result of reductions in the incidence of multifetal pregnancies and births. (III-C) 5. In women aged 35 to 37 years, no more than three embryos should 13. Efforts should be made to limit iatrogenic multiple pregnancies be transferred in a fresh IVF-ET cycle. In those with high-quality resulting from non–IVF-ET ovarian stimulation through the embryos and favourable prognoses, consideration should be given development of suitable guidelines for cycle cancellation and the to the transfer of one or two embryos in the first or second cycle.
removal of financial barriers to IVF-ET. (III-B) Validation: This guideline was reviewed by the Reproductive
6. In women aged 38 to 39 years, no more than three embryos should Endocrinology and Infertility Committee and the Maternal-Fetal be transferred in a fresh IVF-ET cycle. (III-B) In those with Medicine Committee and approved by the Executive and Council high-quality embryos and favourable prognoses, consideration of the Society of Obstetricians and Gynaecologists of Canada and should be given to the transfer of two embryos in the first or the Board of the Canadian Fertility and Andrology Society.
Sponsor: Society of Obstetricians and Gynaecologists of Canada.
7. In women over the age of 39 years, no more than four embryos The quality of evidence reported in this document has been should be transferred in a fresh IVF-ET cycle. (III-B) In those older described using the Evaluation of Evidence criteria outlined in the women with high-quality embryos in excess of the number to be Report of the Canadian Task Force on the Periodic Health Exam transferred, consideration should be given to the transfer of three embryos in the first IVF-ET cycle. (III-B) J Obstet Gynaecol Can 2006;28 (9)799–813 8. In exceptional cases when women with poor prognoses have had multiple failed fresh IVF-ET cycles, consideration may be given tothe transfer of more embryos than recommended above in INTRODUCTION
9. In donor–recipient cycles, the age of the oocyte/embryo donor InCanada,1645deliveriesresultedfromembryotransfer should be used when determining the number of embryos to following in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) in 2001.1 Of these, 31.5% were 10. In women with obstetrical or medical contraindication to multifetal multiple births. Data from the Canadian Fertility and gestation, fewer embryos should be transferred to minimize the Andrology Society (CFAS) show that the incidence of mul- chance of multifetal gestation. In such cases, pre-treatmentconsultation with a maternal-fetal medicine specialist should be tiple deliveries after IVF-embryo transfer (ET) had l SEPTEMBER JOGC SEPTEMBRE 2006
Guidelines for the Number of Embryos to Transfer Following In Vitro Fertilization Table 2. IVF-ET Births
Table 3. Canadian 2001 IVF-ET birth outcomes1
Perinatal mortality rate (per 1000 births); GA, Gestational age; preterm birth: < 37 weeks; very preterm birth: < 34 weeks;low birth weight: < 2500 g; extremely low birth weight: < 1000 g.
remained unchanged to 2003.2 The incidence of multiple hospitalization.15,17 Even after adjustment for prematurity, delivery after IVF-ET in Canada was closer to that of the twin neonates are more often admitted to NICU and United States (34.2%) than to the incidence in Europe require longer stays.19,21 They also suffer from increased (24.5%)3,4 (Table 2). The proportion of multifetal gestations rates of congenital malformations,11,19,22 some cognitive attributed to IVF-ET is higher than after spontaneous con- development difficulties,22–24 childhood hospitalization, ception. In the United States, IVF-ET contributed to 1.1% and surgeries.25,26 Unlike in spontaneous cohorts, the of all infants born in 2002 but accounted for 17.1% of all increased incidence of cerebral palsy has not been consis- multiple births and 43.8% of high-order (triplet or more) tently found with IVF-ET twin deliveries.27,28 Finally, deliveries.5 The incidence of twin and high-order multiple IVF-ET multiple births may be associated with increased (HOM) births after IVF-ET was 14-fold and 54-fold parental stress, marital discord, and financial hardship incomparison with singleton births.23,29–34 greater than after spontaneous conception, respectively.6 It is well established that multifetal gestations are associatedwith a significantly greater incidence of complications than Although there have been reductions in the incidence of singleton gestations; most of these complications are high-order multiples with IVF-ET, twin delivery rates have directly related to increased rates of prematurity.7–11 More remained unchanged.3,5 In Canada in 2001, almost one half than 50% of twins and 90% of triplets are born preterm of all children born after IVF-ET were from multifetal ges- (< 37 weeks’ gestation) and low birth weight (< 2500 g).12 tations, 86.6% of which were twins1 (Table 3). Although it is Compared with singletons, twins are born an average of recognized that twin gestations suffer increased rates of three weeks earlier and 1000 g lighter, and triplets are born adverse neonatal and maternal outcomes when compared more than six weeks earlier and weigh 1600 g less.12 The with singletons, there is still some debate among IVF-ET rates of very preterm and very low birth weight infants are practitioners regarding the need to limit iatrogenic twin disproportionately higher in multiples, and perinatal mor- pregnancy.7,35–40 Given that twins are by far the most com- tality increases with increasing plurality of birth1,5,13,14 mon multiple after IVF-ET, the bulk of excess morbidity and mortality attributable to IVF-ET conceptions occur in Twin gestations are associated with increased rates of twin gestations.11,41–43 Furthermore, there is recent evidence maternal morbidity, including hypertensive disorders,15,16 that IVF-ET births associated with vanishing fetuses are at Caesarean section,16–20 and postpartum hemorrhage,15 increased risk for perinatal and long-term neurological SEPTEMBER JOGC SEPTEMBRE 2006 l
JOINT SOGC–CFAS GUIDELINE
The excess occurrence of multifetal gestation following LIMITING THE NUMBER OF
IVF-ET has resulted directly from the replacement of mul- EMBRYOS TO TRANSFER IN IVF-ET
tiple embryos per transfer.1,3,5 According to an analysis of The existing literature on the number of embryos to trans- United States registry data from 1996 to 2002, there has fer in IVF-ET is difficult to translate into strict guidelines.
been a decrease in the transfer of three or more embryos There are few randomized controlled trials providing with a corresponding increase in double embryo transfer robust evidence. Conclusions are difficult to draw from (DET). Over the same period, the overall pregnancy rate observational studies given that comparison groups gener- has increased from 33.7 to 42.2%, owing to an improve- ally differ in prognosis and are often not contemporary.
ment in embryo implantation rates. Unfortunately, in most Furthermore, comparisons among studies are confounded age groups, the multiple gestation rates after DET in 2002 by heterogeneous methodology, insufficient reporting of were comparable with those following triple embryo trans- key prognostic variables, and differences in baseline perfor- fer (TET) in 1996. Consequently, while there has been a mance of individual IVF-ET programs. Finally, improve- decline in high-order multiples, the proportion of multiple ments in implantation rates over time often render all but pregnancies has actually increased from 46.5 to 49.9% because of a concurrent increase in twins.43 In the UnitedStates in 2003, three or more embryos were transferred in Nevertheless, several observational studies have identified 56.2% of fresh cycles.5 In Canada in 2001, at least three threshold values for the number of embryos transferred, embryos were transferred in 50.6% of fresh IVF-ET above which pregnancy and live birth rates do not increase, cycles.1 However, by 2004, only one or two embryos were although multiple pregnancy rates do.56–59 Furthermore, many programs have reported maintenance of pregnancyand birth rates with reductions in multiple and HOM rates Multifetal reduction can be used to decrease the occurrence when decreasing the number of embryos routinely of HOM delivery; however, reduction of twins to a single- transferred, particularly in young patients with favourable ton is generally not performed. The risk of pregnancy loss after reduction performed in experienced centres rangesfrom 4.5% to 15.4%.50 Moreover, morbidity may be higher Although the most effective strategy to reduce the inci- for twins resulting from multifetal reduction than for dence of IVF-ET multiples is to limit the number of non-reduced twins.51–53 Psychologically, elective reduction embryos transferred per attempt, indiscriminate application is often difficult for couples who have achieved pregnancy of such policies would unnecessarily reduce the chance of after a long duration of infertility. For some, the process can pregnancy for many couples. Instead, decisions limiting the be highly stressful, and long-term guilt may follow.54 For number of embryos transferred should be made according others, reduction may not be an option for ethical or reli- to the relevant probabilities of pregnancy and multifetal gious reasons. Furthermore, the need for travel to centres gestation.65,66 Several studies have characterized determi- with expertise in reduction can result in additional burdens nants of pregnancy and embryo implantation poten- for the couple. Ideally, primary prevention of HOM preg- tial,59,67–71 and others have generated prediction models to nancy is preferable, and the need for multifetal reduction However, it is difficult and not always appropriate to gener- This guideline reviews available data on pregnancy, live alize the results of individual studies to IVF-ET programs birth, and multiple pregnancy and birth rates following with heterogeneous patient populations and embryo fresh embryo transfer after conventional IVF/ICSI. Rec- implantation rates. Furthermore, there is currently no con- ommendations regarding the number of embryos to trans- sensus regarding acceptable rates of twin and HOM fer are presented with the principal aim of reducing the gestations after IVF-ET. The determination of acceptable occurrence of multifetal gestation while maintaining accept- Canadian rates should be a priority for researchers and prac- able clinical pregnancy and live birth rates. These recom- titioners in reproductive medicine, as well as other stake- mendations are not specifically applicable to frozen-thawed holders. In the absence of such consensus targets, and with embryo transfer cycles, or to embryos derived from previ- recognition of the varying performance of individual ously cryopreserved or in vitro-matured oocytes.
IVF-ET programs, the following recommendations havebeen made based upon the existing, worldwide published The quality of evidence reported in this guideline has been literature. Given the rapidity of advances in IVF-ET,43 it described using the Evaluation of Evidence criteria outlined must be acknowledged that these recommendations will in the Report of the Canadian Task Force on the Periodic require regular revision to accurately reflect ongoing l SEPTEMBER JOGC SEPTEMBRE 2006
Guidelines for the Number of Embryos to Transfer Following In Vitro Fertilization Recommendation
In women with lower quality embryos but otherwise similar 1. Individual IVF-ET programs should evaluate their own prognoses, TET has resulted in higher pregnancy rates than data to identify patient-specific, embryo-specific, and DET; however, rates were not as high as with DET of good cycle-specific determinants of implantation and live embryos.86,87,89 Although TET in women with lower quality birth, in order to develop embryo transfer policies that embryos resulted in multiple rates similar to DET in minimize the occurrence of multifetal gestation while women with good embryos, HOM rates were still higher maintaining acceptable overall pregnancy and live birth after TET.86,89 Compared with DET in good prognosis patients, TET in patients with poorer prognoses resulted insimilar or lower pregnancy rates, with increased multiple Cleavage Stage Versus Blastocyst Stage Embryos
The recommendations made in this guideline were derived Based upon 44 236 cycles performed in the United King- mainly from studies of cleavage stage embryos—those cul- dom from 1991 to 1995, when the legislated maximum tured for two or three days. Although a recent meta-analysis number of embryos transferred was three, Templeton and did not demonstrate a difference in live birth and multiple Morris generated estimates for live birth and multiple birth pregnancy rates between the transfer of cleavage stage rates standardized for nulliparious women with tubal infer- embryos and blastocyst embryos cultured for five or six tility and one to three prior IVF attempts. In women aged days,75 several studies have shown higher implantation rates 30 years with greater than four fertilized eggs, DET resulted following blastocyst culture, particularly for high-quality in the same live birth rate as TET (21.3% vs. 21.1%) with a blastocysts.68,76–81 A recently published randomized con- significantly lower multiple birth rate (28.6% vs. 39.4%, trolled trial of elective single embryo transfer in young P < 0.001). Similar findings were reported in women with women with good prognosis demonstrated a significant improvement in live birth rate following blastocyst com-pared with cleavage stage transfer.82 Consequently, consid- Schieve et al.92 reported a retrospective analysis of eration should be given to the transfer of fewer blastocyst 35 554 fresh, non-donor embryo transfers performed in stage embryos than of comparable quality cleavage stage the United States in 1996. Unlike in the United Kingdom, there was no legislated maximum number of embryos per- Recommendation
mitted for transfer. In women aged 30 to 34 years, therewere significant increases in both live birth rates (35.1% vs.
2. In general, consideration should be given to the transfer 19.4%, P < 0.01) and multiple birth rates (39.8% vs. 19.7%, of fewer blastocyst stage embryos than cleavage stage P < 0.01) after TET compared with DET, and the transfer embryos, particularly in women with excellent prognoses of four or more embryos resulted in increased multiple births, particularly high order (6.7%), without substantial WOMEN UNDER THE AGE OF 35 YEARS
improvement in live birth rates. Similar findings were notedin women aged 20 to 29 years.92 Reflecting significant A small (n = 56) randomized controlled trial published improvement in embryo implantation rates, analysis of more than 10 years ago compared DET with transfer of 2002 United States registry data found that in unmatched four embryos (QET) in good prognosis patients under the women aged under 35 years, DET gave similar live birth age of 35 years. DET resulted in lower live birth (28.6% vs.
rates to TET (46.3% vs. 43.7%) with lower multiple (36.1% 53.6%) and multiple pregnancy rates (10.7% vs. 21.4%).
vs. 42.3%) and HOM (0.8% vs. 7.2%) rates.5 HOM pregnancies did not result from DET, and four offive multiples after QET were triplet.83 A more recent SUMMARY STATEMENT
randomized controlled trial comparing DET with TET in212 women found the live delivery rate was similar for DET The following recommendations are generally intended for and TET (30.1% vs. 24.5%), and multiple (15.0% vs.
cleavage stage embryos transferred on day two or three.
41.4%, P < 0.05) and HOM pregnancies (0% vs. 6.9%) were Because blastocyst stage embryos have higher implantation substantially decreased for DET compared with TET.84 rates than cleavage stage embryos, fewer blastocyst stageembryos may need to be transferred. (II) Several observational studies have reported comparablepregnancy rates, with an accompanying maintenance or Recommendation
reduction in multiples, for DET compared with TET inyoung women with good prognoses. Although a significant 3. In women under the age of 35 years, no more than two incidence of HOM was reported after TET in all studies embryos should be transferred in a fresh IVF-ET cycle.
(3.9–18.0%), none resulted from DET in these series.85–89 SEPTEMBER JOGC SEPTEMBRE 2006 l
JOINT SOGC–CFAS GUIDELINE
Table 4. eSET versus DET: randomized controlled trials
n: number; eSET: elective single embryo transfer; DET: double embryo transfer.
* Ongoing pregnancy rate per transfer: Gerris 1999 (> 12 weeks), Gardner 2004 (> 6.5 weeks), and van Montfoort (> 7 weeks).
† Live birth rate per transfer: Martikainen 2001, Thurin 2004, and Lukassen 2005.
§ First fresh eSET cycle only||Not significant ELECTIVE SINGLE EMBRYO TRANSFER
more heterogeneous prognosis. Although the participants To date, six randomized controlled trials have compared were also young (mean age 32.5), only 42% had at least one pregnancy, live birth, and multiple rates following DET good quality embryo available for transfer. The ongoing with those following elective single embryo transfer pregnancy rate was twice as high after DET than after eSET (eSET)93–98 (Table 4). When at least two embryos were (40.2% vs. 21.4%, P < 0.05).98 Moreover, the ongoing preg- available for transfer in fresh IVF-ET cycles, DET resulted nancy rate in the eSET group was the lowest of all random- in a higher pregnancy or live birth rate than eSET. Although ized controlled eSET trials (Table 4).
some studies failed to demonstrate a statistically significant Several observational studies have also reported the efficacy difference,93,95,96 a systematic review of four of these trials of eSET in minimizing twin gestations (Table 6). Unlike the confirmed that DET resulted in significantly higher clinical randomized trials, the majority of these studies found simi- pregnancy rates (odds ratio [OR] 2.16; 95% confidence lar clinical pregnancy rates after eSET and DET, likely interval [CI], 1.65–2.82) and live birth rates (OR 1.94; 95% reflecting the heterogeneity in embryo quality and patient CI 1.46–2.55) per woman than eSET.99 Multiple pregnancy prognosis in the DET groups.91,102–112 Analysis of the 2002 rates were also significantly increased with DET (OR 23.55; US registry data supports the application of eSET in 95% CI, 8.00–69.29).99 Elective eSET was effective in pre- good-prognosis patients. In women aged under 35 years venting HOM and reducing the incidence of twins to that of with excess embryos “set aside for future use,” eSET monozygotic twinning associated with IVF-ET.100,101 There resulted in a 47.4% live birth rate per transfer with no multi- was a 1.6% rate of twins in the eSET groups, and 2.2% of ples. DET was associated with a higher live birth rate multiples in the DET groups were triplets (Table 4).
(51.8%) but high twin (38.8%) and HOM birth rates Participation in four of the six eSET randomized controlled trials was restricted to patients with optimal prognosis(Table 5). In the five trials that provided demographic data, Cumulative rates including contributions of
participants on average were aged under 34 years and cryopreserved embryos
undergoing their first or second IVF-ET attempt. The In the largest eSET randomized controlled trial published mean number of oocytes retrieved was greater than nine, by Thurin et al., women in the eSET group who did not with a high number of embryos available for transfer.93,95–98 achieve a live birth after the fresh embryo transfer were sub- In the Martikainen et al. trial, older age was not a specific sequently eligible for the transfer of a single frozen-thawed exclusion criteria for 70% of participants, however the embryo.97 The per protocol analysis demonstrated an insig- mean age of participants was 31 years.96 The van Montfoort nificantly lower cumulative live birth rate with the eSET et al. trial was specifically conducted in a population with a strategy than in the fresh DET group (38.8% vs. 43.4%), l SEPTEMBER JOGC SEPTEMBRE 2006
Guidelines for the Number of Embryos to Transfer Following In Vitro Fertilization Table 5. Eligibility criteria for eSET trials
³ 2 available; 4 or 5 cells on day 2 and ³ 7 cells on day 3,no multinucleation and < 20% fragmentation ³ 4 available; even-sized blastomeres and < 20% ³ 2 available; < 20% fragmentation and 4-6 cells on day 2 or 6-10 cells on day 3 or expanded blastocysts on day 5/6 eSET: elective single embryo transfer; FSH: follicle stimulating hormone; E2: estradiol; hCG: human chorionic gonadotropin while maintaining a significant reduction in multiple rates Recommendation
(0.8% vs. 33.1%, P < 0.001).97 A few cohort studies havealso demonstrated the benefit of cryo-augmentation. With 4. In women under the age of 35 years with excellent the inclusion of pregnancies from frozen-thawed embryos, prognoses, the transfer of a single embryo should be pregnancy rates per woman following eSET were similar to considered. Women with excellent prognoses include those after fresh DET, with minimal increases in multiple those undergoing their first or second IVF-ET cycle or pregnancies resulting from the transfer of more than one one immediately following a successful IVF-ET cycle, with at least two high-quality embryos available for trans- It is noteworthy that 17% of women eligible for frozen-thawed embryo transfer in the Thurin et al. trial97did not receive a transfer because cryopreserved embryos WOMEN AGED 35 TO 39 YEARS
did not survive the thaw. It is likely that at least a portion of Schieve et al. published an analysis of 1996 IVF-ET registry these women would have achieved a pregnancy if they had data from the United States.92 Among women aged 35 to 39 received a fresh DET.114 This suggests that assessment of a years, live birth rates increased with the transfer of increas- clinic’s embryo cryopreservation program is important ing numbers of embryos, peaking at four. Transfer of four embryos (QET) resulted in a higher live birth rate than TET(33.3% vs. 23.0%, P < 0.01). Multiple birth rates (37.5% vs.
Estimated Impact of eSET
29.4%, P < 0.01) and HOM birth rates (5.4% vs. 2.2%, It was estimated that application of eSET in 25% to 30% of P < 0.01) were also higher after QET than after TET.
all IVF-ET cycles in Europe would result in a reduction of Although DET decreased the occurrence of multiple births multiple births from 25–50% to 12–15%.35 However, the (11.6%) and eliminated HOM births, the decrease in the live 2002 European registry data suggest eSET has yet to have significant impact.3 A few programs with young patientpopulations have reported a significant uptake of eSET In 1222 unmatched transfer cycles, Svendsen et al. in 1996 (41–65%). These European programs have demonstrated found non-significant increases in ongoing and multiple that multiple pregnancy rates can be minimized (7–11%) pregnancy rates with up to four embryos transferred.121 while maintaining acceptable clinical pregnancy rates Clinical pregnancy and multiple pregnancy rates with QET (29–42%).101,117–120 Finland remains the only nation to dem- were 23.4% and 24.2% respectively. A similar proportion of onstrate a reduction in multiple birth in IVF-ET.117 It has HOM pregnancies occurred following TET (3.2%) and been estimated that about 30% of IVF-ET cycles per- QET (3.9%), and none followed DET.121 Hu et al. in 1998 formed in the United States are in young, good-prognosis reported a similar analysis of 224 unmatched transfers of up patients who would be eligible for eSET.114 to five embryos.122 With poor quality embryos, pregnancy SEPTEMBER JOGC SEPTEMBRE 2006 l
JOINT SOGC–CFAS GUIDELINE
Table 6. Elective single versus double embryo transfers: observational studies
eSET: elective single embryo transfer; DET: double embryo transfer.
† all comparisons statistically significant rates increased after QET. With fair quality embryos, preg- compared with DET resulted in higher clinical pregnancy nancy rates did not increase after TET. With good quality rates (37.7% vs. 20.0%, P < 0.05) and higher live birth rates embryos, transfer of five embryos (5ET) resulted in the (30.6% vs. 20.0%, P < 0.05). Twin birth rates were similar highest pregnancy rate, but the HOM rate was significant at (3.8% vs. 0%) and there were no HOM in either group.86 40%. In this subgroup, HOM appeared with the transfer of Matson et al. in 1999 reported similar clinical pregnancy three or more embryos. When only fair quality embryos rates in 355 cycles after DET (24%) and TET (20%), with- were transferred, HOM pregnancies were first noted with out significant difference in multiple gestations.88 QET, and when poor quality embryos were transferred, Based on data from the 1996 United Kingdom registry, HOM pregnancies were first noted with 5ET.122 Templeton and Morris estimated that a woman aged In a review of 138 unmatched transfers in women aged 35 years with more than four fertilized eggs had the same 35 to 39 years, Giannini et al. in 2004 found TET resulted in probability of live birth after DET as after TET (17.0% vs.
a higher clinical pregnancy rate (42.0% vs. 34.2%) than 16.9%); however, the risk of multiple birth was significantly DET, but a similar multiple pregnancy rate (16.7% vs.
reduced (25.6% vs. 32.6%, P < 0.001) after DET.59 United 15.4%).123 In 814 fresh and frozen transfers in women aged States registry data from 2002 demonstrated that in women 37 years and over, Elsner et al. in 1997 reported increasing aged 35 to 37 years, live birth rates (39.7% vs. 37.7%) multi- live birth rates with the transfer of greater numbers of ple birth rates (36.6% vs. 29.2%) and HOM birth rates embryos up to three.57 TET resulted in significantly higher (4.4% vs. 0.8%) were higher after TET than after DET.5 live birth rates than DET (34.5% vs. 16.0%, P < 0.05).
When limited to cycles with surplus embryos remaining However, multiple pregnancy (29.1% vs. 8.0%, P < 0.05) after transfer, there was no benefit in live birth rate with and HOM (1.3% vs. 0%) rates were also higher after TET.57 TET over DET, and HOM rates remained higher after Similarly, Salha et al. in 2000 published outcomes of women TET.5 However, in unselected women aged 38 to 40 years, aged over 35 years undergoing their first cycle with at least live birth rates improved after TET compared with DET six embryos available for transfer.86 In 95 women with three (28.9% vs. 23.3%), with a corresponding increase in multi- good quality embryos remaining after transfer, TET ple (24.3% vs. 18.8%) and HOM births (2.6% vs. 0%). In l SEPTEMBER JOGC SEPTEMBRE 2006
Guidelines for the Number of Embryos to Transfer Following In Vitro Fertilization those with excess embryos following transfer, the birth rate the transfer of more embryos. In women receiving five or more embryos, live birth, multiple birth, and HOM birth Although some eSET studies have included a few older rates were 21.8%, 22.1%, and 2.5%, respectively. The corre- women (typically under 38 years),101,103,110–112,119 the applica- sponding rates resulting from transfer of four embryos tion of eSET in older women has not been extensively were 16.6%, 15.0%, and 0.9%, respectively.5 When reported. In 862 women aged 35 to 39 years with at least restricted to women with excess embryos remaining after four good quality embryos available for transfer, a 2003 transfer, live birth rates were similar after transfer of two study found that the clinical pregnancy rate after eSET was (27.9%) and five or more embryos (29.1%), but the transfer not significantly different from the rate after DET (26.7% of five or more embryos compared with DET resulted in vs. 30.5%).105 Other observational studies have also considerably higher rates of multiple birth (28.0% vs.
reported similar pregnancy rates after eSET in small num- Recommendation
Recommendations
7. In women over the age of 39 years, no more than four 5. In women aged 35 to 37 years, no more than three embryos should be transferred in a fresh IVF-ET cycle.
embryos should be transferred in a fresh IVF-ET cycle.
(III-B) In those older women with high-quality embryos In those with high-quality embryos and favourable prog- in excess of the number to be transferred, consideration noses, consideration should be given to the transfer of should be given to the transfer of three embryos in the one or two embryos in the first or second cycle. (II-2A) 6. In women aged 38 to 39 years, no more than three POOR PROGNOSIS
embryos should be transferred in a fresh IVF-ET cycle.
(III-B) In those with high-quality embryos and favour- In 1995, Azem et al. reported a significant improvement in able prognoses, consideration should be given to the pregnancy rates following the transfer of six or more transfer of two embryos in the first or second cycle.
embryos compared with five embryos in women with at least four prior failed IVF-ET attempts.126 Aside from thissingle study, there is no published evidence demonstrating WOMEN AGED OVER 39 YEARS
improvements in pregnancy or live birth rates after thetransfer of more embryos in subsequent IVF-ET cycles Compared with younger women, women over 39 years than the number transferred in previous failed cycles. Nev- have lower pregnancy, delivery, and multiple rates for any ertheless, the transfer of greater numbers of embryos in given number of embryos transferred.5 An unmatched ret- women with multiple fresh IVF-ET failures is not uncom- rospective review published in 1997 of 525 ICSI cycles in mon. This practice has also been extended to women pre- women over 39 years found that the transfer of four or dicted to have a poor probability of conception on the basis more embryos resulted in significant improvement in the of other prognosticators such as embryo quality, also with clinical pregnancy rate (20.4% vs. 10.0%, P < 0.005), and little supportive evidence regarding efficacy.122 Although higher twin rates (17.2% vs. 11.1%) than the transfer of one the preceding recommendations are not intended to be to three embryos.125 In an unmatched comparison of punitive for women with poorer prognoses for conception, 320 embryo transfers, Svendsen et al. in 1996 found that caution and sound clinical judgement must be exercised TET in these older women resulted in a higher ongoing when exceeding their prescribed maximums.
pregnancy rate than DET (14.4% vs. 3.2%), and HOM didnot occur in this series.121 Recommendation
When the maximum number of embryos transferred was 8. In exceptional cases when women with poor prognoses restricted to three, Templeton and Morris estimated that have had multiple failed fresh IVF-ET attempts, consid- women aged 40 years with more than four fertilized eggs eration may be given to the transfer of more embryos had the same probability of live birth (13.5% vs. 13.3%) and than recommended above in subsequent fresh IVF-ET multiple birth (22.8% vs. 26.5%) after DET and TET, respectively. With only three or four fertilized eggs, TETimproved the live birth rate without increasing multiples in DONOR–RECIPIENT CYCLES
Licciardi et al. reported a retrospective analysis of outcomes In women aged 41 to 42 years using fresh embryos, the of 449 donor–recipient cycles.127 With embryos derived most recent unadjusted registry data from the United States from young donors (aged 21 to 30 years), DET versus TET showed increasing live birth and multiple birth rates with resulted in similar clinical pregnancy (57.5% vs. 55.8%) and SEPTEMBER JOGC SEPTEMBRE 2006 l
JOINT SOGC–CFAS GUIDELINE
multiple pregnancy (40.5% vs. 51.0%) rates. However, fertility treatment.95,128–132 Some data suggest that counsel- DET versus TET resulted in significantly lower HOM rates ling regarding the risks of twins may be inadequate.133 Con- (0% vs. 13.7%, P < 0.01).127 In another unmatched retro- sultation with a specialist in maternal-fetal medicine may be spective study, eSET of good quality embryos resulted in helpful in providing a more accurate understanding of the similar live birth rates to those achieved after DET of risks associated with multifetal gestations, particularly with unknown quality embryos (32.6% vs. 32.1%), with a signifi- higher order multiples. Murray et al. found that even when cant reduction in twins (0% vs. 36.0%, P < 0.01).106 More informed about these risks, although two thirds of couples recently, a small retrospective study reported a clinical would prefer singletons, less than 10% would be deterred pregnancy rate of 88% without any multiple gestations by the prospect of twins.132 Emphasis on healthy singleton live birth rather than simply achieving pregnancy as a mea-sure of success would be beneficial in promoting reductions Recommendation
in the numbers of embryos transferred.
9. In donor–recipient cycles, the age of the oocyte/embryo Recommendation
donor should be used when determining the number ofembryos to transfer. (II-2B) 11. Couples should be adequately counselled regarding the obstetrical, perinatal, and neonatal risks of multifetal ges- MEDICAL SINGLE EMBRYO TRANSFER
tation to facilitate informed decision making regardingthe number of embryos to transfer. (II-3B) Emphasis on In circumstances that make the avoidance of multifetal ges- healthy singleton live birth as the measure of success in tation more important than usual, it may be prudent to limit IVF-ET may be beneficial in promoting a reduction in the number of embryos transferred, regardless of a possible the number of embryos transferred. (III-C) reduction in the chance of achieving pregnancy. Obstetricalindications or medical conditions that may be exacerbated ECONOMIC CONSIDERATIONS
by multifetal gestation include severe maternal disease(e.g., diabetes mellitus, cardiovascular disease), morbid obe- Many patients and physicians are reluctant to reduce the sity, uterine malformation, history of cervical incompetence number of embryos transferred for fear of a reduction in or hysterotomy, previous preterm delivery, indication for the probability of pregnancy.66,93–95,97,134 This is particularly relevant when patients assume the costs of IVF-ET treat- hyperstimulation syndrome.101 In a retrospective analysis, ments and may not be able to afford multiple attempts. In Vilska et al.102 reported outcomes following eSET in this context, respect for patient autonomy should be 74 women with contraindications to multifetal gestation.
Compared with an unselected cohort receiving DET, the Studies in the United States have demonstrated reductions women receiving eSET had similar clinical pregnancy rates in the number of embryos transferred per attempt with sub- (29.7% vs. 29.4%) with a significant reduction in twins (0% sequent decreases in multiple and HOM rates in jurisdic- vs. 23.9%).102 A similar pregnancy rate (30.6%) has been tions providing insurance coverage for IVF.136,137 Surveys reported in a series of 72 women aged over 37 years receiv- have also suggested that the uptake of eSET would increase ing eSET for medical or obstetrical indications.117 with greater reimbursement of subsequent treatmentattempts.129,132 In Belgium, limits on the number of Recommendation
embryos transferred per attempt, including eSET in good 10. In women with obstetrical or medical contraindication prognosis patients, have been legislated; however, these to multifetal gestation, fewer embryos should be trans- policies are appropriately tied to state reimbursement of ferred to minimize the chance of multifetal gestation. In such cases, pre-treatment consultation with a maternal- Direct maternal and early neonatal costs are significantly fetal medicine specialist should be pursued. (III-C) elevated by plurality of birth.140,141 Although eSET results in Whenever reasonable, consideration should be given to a lower birth rate than DET, 93–97 analyses including the costs of IVF treatment have shown the cost per baby bornto be comparable after eSET and DET.95,108,141,142 When ATTITUDES TOWARDS MULTIFETAL GESTATION
considering the long-term costs associated with higher mor- Despite the significant body of evidence, many patients are bidity in children born from multifetal gestations, public unaware that twin pregnancies are associated with increased funding of IVF-ET may prove to be a cost-effective strat- risks of adverse maternal and neonatal outcomes.32,35,128,129 egy through improved participation in eSET and other For many patients suffering from long-term infertility, mul- strategies to reduce the incidence of iatrogenic multiple tiple birth is an acceptable and even desired outcome of l SEPTEMBER JOGC SEPTEMBRE 2006
Guidelines for the Number of Embryos to Transfer Following In Vitro Fertilization Recommendation
of successful implantation can be determined. Decisions onthe number of embryos to transfer should be based upon 12. A strategy for public funding of IVF-ET must be devel- prognosis determined by variables including the woman’s oped for the effective implementation of guidelines lim- age, prior outcomes, and the number and quality of iting the number of embryos transferred. In the context embryos available for transfer, and should be made to mini- of this strategy, total health care costs would be lower as mize the risk of multifetal gestation while maintaining a a result of reductions in the incidence of multifetal preg- high probability of healthy live birth.
REFERENCES
NON–IVF-ET INFERTILITY TREATMENTS AND
MULTIFETAL GESTATION
1. Gunby J, Daya S. Assisted reproductive technologies (ART) in Canada: 2001 results from the Canadian ART Register. Fertil Steril 2005;84:590–9.
A significant proportion of multiple pregnancies and births 2. Canadian Fertility and Andrology Society. CFAS press release: Human are derived from non–IVF-ET fertility treatments, particu- assisted reproduction live birth rates for Canada. November 17, 2005.
http://www.cfas.ca/english/news/Nov17–2005.asp Last updated larly superovulation. In 2000, 21% of twin and 40% of November 17, 2005. Cited April 7, 2006.
HOM births in the United States were attributed to ovarian 3. Assisted reproductive technology in Europe, 2002. Results generated from stimulation without IVF-ET.6 Similar statistics have been European registers by ESHRE. Hum Reprod 2006;21(7):1680–97.
reported from other jurisdictions.3,143 Although the efficacy 4. U.S. Department of Health and Human Services. Centers for Disease Control and Prevention. 2003 Assisted Reproductive Technology Success of superovulation is significantly less than that of Rates. Updated March 23, 2006. http://www.cdc.gov/ART/ART2003/ IVF-ET,144 superovulation is also much less expensive, and it therefore remains a frequently employed treatment 5. Wright VC, Schieve LA, Reynolds MA, Jeng G. Assisted reproductive modality. Although control over the occurrence of technology surveillance—United States, 2002. MMWR Surveill Summ2005;54:1–24.
multifetal, and especially HOM, gestations can be exercised 6. Reynolds MA, Schieve LA, Martin JA, Jeng G, Macaluso M. Trends in through limits on the number of embryos transferred in multiple births conceived using assisted reproductive technology, United IVF-ET, control over multiples from superovulation is not States, 1997–2000. Pediatrics 2003;111:1159–62.
7. Multiple gestation pregnancy. The ESHRE Capri Workshop Group. Hum In order to maximize any reduction in multifetal gestation 8. Multiple pregnancy associated with infertility therapy. Fertil Steril 2004;82 resulting from infertility therapy, the contribution of non-IVF-ET fertility treatments should also be addressed.
9. Adamson D, Baker V. Multiple births from assisted reproductive technologies: a challenge that must be met. Fertil Steril 2004;81:517–22.
One strategy is the formulation of appropriate guidelines 10. Devine PC, Malone FD. Maternal complications associated with multiple for the cancellation of superovulation cycles.146 Another is pregnancy. Clin Obstet Gynecol 2004;47:227–36.
to reduce the use of superovulation in favour of IVF-ET.147 11. Pinborg A. IVF/ICSI twin pregnancies: risks and prevention. Hum Reprod Removing the financial barriers to IVF-ET through public funding could reduce the incidence of iatrogenic multifetal 12. Alexander GR, Kogan M, Martin J, Papiernik E. What are the fetal growth gestation while increasing the overall efficacy infertility patterns of singletons, twins, and triplets in the United States? Clin Obstet 13. Blondel B, Kogan MD, Alexander GR, Dattani N, Kramer MS, Macfarlane Recommendation
A, et al. The impact of the increasing number of multiple births on the rates 13. Efforts should be made to limit iatrogenic multiple of preterm birth and low birthweight: an international study. Am J PublicHealth 2002;92:1323–30.
14. Alexander GR, Slay WM, Salihu H, Kirby RS. Fetal and neonatal mortality stimulation, through the development of suitable guide- risks of multiple births. Obstet Gynecol Clin North Am 2005;32:1–16, vii.
lines for cycle cancellation and the removal of financial 15. Pinborg A, Loft A, Schmidt L, Langhoff-Roos J, Nyboe Andersen A.
Maternal risks and perinatal outcome in a Danish national cohort of 1005twin pregnancies: the role of in vitro fertilization. Acta Obstet Gynecol 16. Koivurova S, Hartikainen AL, Karinen L, Gissler M, Hemminki E, The desired outcome of infertility treatment is the birth of a Martikainen H, et al. The course of pregnancy and delivery and the use of healthy child. As multifetal gestations are associated with maternal healthcare services after standard IVF in Northern Finland higher rates of morbidity and mortality, their disproportion- 1990–1995. Hum Reprod 2002;17:2897–903.
ately high occurrence after IVF-ET should be minimized.
17. Klemetti R, Gissler M, Hemminki E. Comparison of perinatal health of The transfer of fewer embryos per attempt should be children born from IVF in Finland in the early and late 1990s. Hum Reprod2002;17:2192–8.
employed as primary prevention. However, indiscriminate 18. Dhont M, De Sutter P, Ruyssinck G, Martens G, Bekaert A. Perinatal application of limitations upon the number of embryos outcome of pregnancies after assisted reproduction: a case-control study.
transferred would be inappropriate until accurate predictors Am J Obstet Gynecol 1999;181:688–95.
SEPTEMBER JOGC SEPTEMBRE 2006 l
JOINT SOGC–CFAS GUIDELINE
19. Pinborg A, Loft A, Nyboe Andersen A. Neonatal outcome in a Danish when evaluating success in assisted reproduction; both twin births and national cohort of 8602 children born after in vitro fertilization or singleton births should be counted as successes. Hum Reprod intracytoplasmic sperm injection: the role of twin pregnancy. Acta Obstet 39. Min JK, Breheny SA, MacLachlan V, Healy DL. What is the most relevant 20. Westergaard HB, Johansen AM, Erb K, Andersen AN. Danish National standard of success in assisted reproduction? The singleton, term gestation, In-Vitro Fertilization Registry 1994 and 1995: a controlled study of births, live birth rate per cycle initiated: the BESST endpoint for assisted malformations and cytogenetic findings. Hum Reprod 1999;14:1896–902.
reproduction. Hum Reprod 2004;19:3–7.
21. Dhont M, De Neubourg F, Van der Elst J, De Sutter P. Perinatal outcome 40. Olivennes F. Avoiding multiple pregnancies in ART. Double trouble: yes a of pregnancies after assisted reproduction: a case-control study. J Assist twin pregnancy is an adverse outcome. Hum Reprod 2000;15:1663–5.
41. Bergh T, Ericson A, Hillensjo T, Nygren KG, Wennerholm UB. Deliveries 22. Bonduelle M, Liebaers I, Deketelaere V, Derde MP, Camus M, Devroey P, and children born after in-vitro fertilisation in Sweden 1982–95: et al. Neonatal data on a cohort of 2889 infants born after ICSI a retrospective cohort study. Lancet 1999;354:1579–85.
(1991–1999) and of 2995 infants born after IVF (1983–1999). Hum Reprod 42. Kinzler WL, Ananth CV, Vintzileos AM. Medical and economic effects of twin gestations. J Soc Gynecol Investig 2000;7:321–7.
23. Pinborg A, Loft A, Schmidt L, Andersen AN. Morbidity in a Danish 43. Reynolds MA, Schieve LA. Trends in embryo transfer practices and multiple national cohort of 472 IVF/ICSI twins, 1132 non-IVF/ICSI twins and 634 gestation for IVF procedures in the USA, 1996–2002. Hum Reprod IVF/ICSI singletons: health-related and social implications for the children and their families. Hum Reprod 2003;18:1234–43.
44. Dickey RP, Taylor SN, Lu PY, Sartor BM, Storment JM, Rye PH, et al.
24. Mikkola K, Ritari N, Tommiska V, Salokorpi T, Lehtonen L, Tammela O, Spontaneous reduction of multiple pregnancy: incidence and effect on et al. Neurodevelopmental outcome at 5 years of age of a national cohort of outcome. Am J Obstet Gynecol 2002;186:77–83.
extremely low birth weight infants who were born in 1996–1997. Pediatrics2005;116:1391–400.
45. Friedman BE, Rosen MP, Shen S, Dobson AT, Shaline LK, Cedars MI. The effect of a vanishing twin on perinatal outcomes. Fertil Steril 2005;84:S1–S2.
25. Ericson A, Nygren KG, Olausson PO, Kallen B. Hospital care utilization of infants born after IVF. Hum Reprod 2002;17:929–32.
46. Hvidtjorn D, Grove J, Schendel D, Vaeth M, Ernst E, Nielsen L et al.
‘Vanishing embryo syndrome’ in IVF/ICSI. Hum Reprod 2005;20:2550–1.
26. Pinborg A, Loft A, Rasmussen S, Nyboe Andersen A. Hospital care utilization of IVF/ICSI twins followed until 2–7 years of age: a controlled 47. Pinborg A, Lidegaard O, la Cour FN, Nyboe Andersen A. Consequences of Danish national cohort study. Hum Reprod 2004;19:2529–36.
vanishing twins in IVF/ICSI pregnancies. Hum Reprod 2005;20:2821–9.
27. Stromberg B, Dahlquist G, Ericson A, Finnstrom O, Koster M, Stjernqvist 48. Schieve LA, Meikle SF, Ferre C, Peterson HB, Jeng G, Wilcox LS. Low and K. Neurological sequelae in children born after in-vitro fertilisation: very low birth weight in infants conceived with use of assisted reproductive a population-based study. Lancet 2002;359:461–5.
technology. N Engl J Med 2002;346:731–7.
28. Pinborg A, Loft A, Schmidt L, Greisen G, Rasmussen S, Nyboe Andersen 49. Wang YA, Sullivan EA, Black D, Dean J, Bryant J, Chapman M. Preterm A. Neurological sequelae in twins born after assisted conception: controlled birth and low birth weight after assisted reproductive technology-related national cohort study. BMJ 2004;329:311.
pregnancy in Australia between 1996 and 2000. Fertil Steril 2005;83:1650–8.
50. Evans MI, Berkowitz RL, Wapner RJ, Carpenter RJ, Goldberg JD, Ayoub 29. Bryan E. The impact of multiple preterm births on the family. BJOG MA, et al. Improvement in outcomes of multifetal pregnancy reduction with increased experience. Am J Obstet Gynecol 2001;184:97–103.
30. Ellison MA, Hall JE. Social stigma and compounded losses: quality-of-life 51. Angel JL, Kalter CS, Morales WJ, Rasmussen C, Caron L. Aggressive issues for multiple-birth families. Fertil Steril 2003;80:405–14.
perinatal care for high-order multiple gestations: Does good perinatal 31. Ellison MA, Hotamisligil S, Lee H, Rich-Edwards JW, Pang SC, Hall JE.
outcome justify aggressive assisted reproductive techniques? Am J Obstet Psychosocial risks associated with multiple births resulting from assisted reproduction. Fertil Steril 2005;83:1422–8.
52. Antsaklis AJ, Drakakis P, Vlazakis GP, Michalas S. Reduction of multifetal 32. McWhinnie A. Euphoria or despair? Coping with multiple births from ART: pregnancies to twins does not increase obstetric or perinatal risks. Hum what patients don’t tell the clinics. Hum Fertil (Camb) 2000;3:20–5.
33. Glazebrook C, Sheard C, Cox S, Oates M, Ndukwe G. Parenting stress in 53. Leondires MP, Ernst SD, Miller BT, Scott RT Jr. Triplets: outcomes of first-time mothers of twins and triplets conceived after in vitro fertilization.
expectant management versus multifetal reduction for 127 pregnancies.
Am J Obstet Gynecol 2000;183:454–9.
34. Olivennes F, Golombok S, Ramogida C, Rust J. Behavioral and cognitive 54. Bergh C, Moller A, Nilsson L, Wikland M. Obstetric outcome and development as well as family functioning of twins conceived by assisted psychological follow-up of pregnancies after embryo reduction. Hum reproduction: findings from a large population study. Fertil Steril 55. Woolf SH, Battista RN, Angerson GM, Logan AG, Eel W. Canadian Task 35. Prevention of twin pregnancies after IVF/ICSI by single embryo transfer.
Force on the Periodic Health Exam. Ottawa: Canada Communication ESHRE Campus Course Report. Hum Reprod 2001;16:790–800.
36. Adashi EY, Barri PN, Berkowitz R, Braude P, Bryan E, Carr J, et al.
56. Schnorr JA, Doviak MJ, Muasher SJ, Jones HW Jr. Impact of a Infertility therapy-associated multiple pregnancies (births): an ongoing cryopreservation program on the multiple pregnancy rate associated with epidemic. Reprod Biomed Online 2003;7:515–42.
assisted reproductive technologies. Fertil Steril 2001;75:147–51.
37. Buckett W, Tan SL. What is the most relevant standard of success in 57. Elsner CW, Tucker MJ, Sweitzer CL, Brockman WD, Morton PC, Wright assisted reproduction? The importance of informed choice. Hum Reprod G, et al. Multiple pregnancy rate and embryo number transferred during in vitro fertilization. Am J Obstet Gynecol 1997;177:350–5.
38. Dickey RP, Sartor BM, Pyrzak R. What is the most relevant standard of 58. Ozturk O, Templeton A. In-vitro fertilisation and risk of multiple success in assisted reproduction?: no single outcome measure is satisfactory l SEPTEMBER JOGC SEPTEMBRE 2006
Guidelines for the Number of Embryos to Transfer Following In Vitro Fertilization 59. Templeton A, Morris JK. Reducing the risk of multiple births by transfer of 78. Milki AA, Hinckley MD, Fisch JD, Dasig D, Behr B. Comparison of two embryos after in vitro fertilization. N Engl J Med 1998;339:573–7.
blastocyst transfer with day 3 embryo transfer in similar patient populations.
Fertil Steril 2000;73:126–9.
60. Grochowski D, Wolczynski S, Kulikowski M, Kuczynski W, Szamatowicz M. Prevention of high-order multiple gestations in an in vitro fertilization 79. Van der Auwera I, Debrock S, Spiessens C, Afschrift H, Bakelants E, program. Gynecol Endocrinol 1997;11:327–30.
Meuleman C et al. A prospective randomized study: day 2 versus day5 embryo transfer. Hum Reprod 2002;17:1507–12.
61. Fujii S, Fukui A, Yamaguchi E, Sakamoto T, Sato S, Saito Y. Reducing multiple pregnancies by restricting the number of embryos transferred to 80. Wilson M, Hartke K, Kiehl M, Rodgers J, Brabec C, Lyles R. Integration of two at the first embryo transfer attempt. Hum Reprod 1998;13:3550–4.
blastocyst transfer for all patients. Fertil Steril 2002;77:693–6.
62. Devreker F, Emiliani S, Revelard P, Van den Bergh M, Govaerts I, Englert 81. Wilson M, Hartke K, Kiehl M, Rodgers J, Brabec C, Lyles R. Transfer of Y. Comparison of two elective transfer policies of two embryos to reduce blastocysts and morulae on day 5. Fertil Steril 2004;82:327–33.
multiple pregnancies without impairing pregnancy rates. Hum Reprod 82. Papanikolaou EG, Camus M, Kolibianakis EM, Van LL, Van SA, Devroey P. In vitro fertilization with single blastocyst-stage versus single 63. Dean NL, Phillips SJ, Buckett WM, Biljan MM, Tan SL. Impact of reducing cleavage-stage embryos. N Engl J Med 2006;354:1139–46.
the number of embryos transferred from three to two in women under the 83. Vauthier-Brouzes D, Lefebvre G, Lesourd S, Gonzales J, Darbois Y. How age of 35 who produced three or more high-quality embryos. Fertil Steril many embryos should be transferred in in vitro fertilization? A prospective randomized study. Fertil Steril 1994;62:339–42.
64. Nijs M, Geerts L, van Roosendaal E, Segal-Bertin G, Vanderzwalmen P, 84. Komori S, Kasumi H, Horiuchi I, Hamada Y, Suzuki C, Shigeta M, et al.
Schoysman R. Prevention of multiple pregnancies in an in vitro fertilization Prevention of multiple pregnancies by restricting the number of transferred program. Fertil Steril 1993;59:1245–50.
embryos: randomized control study. Arch Gynecol Obstet 2004;270:91–3.
65. Coetsier T, Dhont M. Avoiding multiple pregnancies in in-vitro fertilization: 85. Staessen C, Janssenswillen C, Van den AE, Devroey P, Van Steirteghem who’s afraid of single embryo transfer? Hum Reprod 1998;13:2663–4.
AC. Avoidance of triplet pregnancies by elective transfer of two good 66. Bhattacharya S, Templeton A. What is the most relevant standard of success quality embryos. Hum Reprod 1993;8:1650–3.
in assisted reproduction? Redefining success in the context of elective single 86. Salha O, Dada T, Levett S, Allgar V, Sharma V. The influence of embryo transfer: evidence, intuition and financial reality. Hum Reprod supernumerary embryos on the clinical outcome of IVF cycles. J Assist 67. Engmann L, Maconochie N, Tan SL, Bekir J. Trends in the incidence of 87. Ludwig M, Schopper B, Katalinic A, Sturm R, Al-Hasani S, Diedrich K.
births and multiple births and the factors that determine the probability of Experience with the elective transfer of two embryos under the conditions multiple birth after IVF treatment. Hum Reprod 2001;16:2598–605.
of the German embryo protection law: results of a retrospective data 68. Gardner DK, Lane M, Stevens J, Schlenker T, Schoolcraft WB. Blastocyst analysis of 2573 transfer cycles. Hum Reprod 2000;15:319–24.
score affects implantation and pregnancy outcome: towards a single 88. Matson PL, Browne J, Deakin R, Bellinge B. The transfer of two embryos blastocyst transfer. Fertil Steril 2000;73:1155–8.
instead of three to reduce the risk of multiple pregnancy: a retrospective 69. Ludwig M, Schopper B, Al-Hasani S, Diedrich K. Clinical use of a analysis. J Assist Reprod Genet 1999;16:1–5.
pronuclear stage score following intracytoplasmic sperm injection: impact 89. Tasdemir M, Tasdemir I, Kodama H, Fukuda J, Tanaka T. Two instead of on pregnancy rates under the conditions of the German embryo protection three embryo transfer in in-vitro fertilization. Hum Reprod 1995;10:2155–8.
90. Staessen C, Nagy ZP, Liu J, Janssenswillen C, Camus M, Devroey P, et al.
70. Saldeen P, Sundstrom P. Nuclear status of four-cell preembryos predicts One year’s experience with elective transfer of two good quality embryos in implantation potential in in vitro fertilization treatment cycles. Fertil Steril the human in-vitro fertilization and intracytoplasmic sperm injection programmes. Hum Reprod 1995;10:3305–12.
71. Van Royen E, Mangelschots K, De Neubourg D, Valkenburg M, Van de 91. Gerris J, De Neubourg D, Mangelschots K, Van Royen E, Vercruyssen M, Meerssche M, Ryckaert G, et al. Characterization of a top quality embryo, a Barudy-Vasquez J, et al. Elective single day 3 embryo transfer halves the step towards single-embryo transfer. Hum Reprod 1999;14:2345–9.
twinning rate without decrease in the ongoing pregnancy rate of an 72. Hunault CC, Eijkemans MJ, Pieters MH, te Velde ER, Habbema JD, Fauser IVF/ICSI programme. Hum Reprod 2002;17:2626–31.
BC, et al. A prediction model for selecting patients undergoing in vitro 92. Schieve LA, Peterson HB, Meikle SF, Jeng G, Danel I, Burnett NM, et al.
fertilization for elective single embryo transfer. Fertil Steril 2002;77:725–32.
Live-birth rates and multiple-birth risk using in vitro fertilization. JAMA 73. Peterson CM, Reading JC, Hatasaka HH, Parker JK, Udoff LC, Adashi EY, et al. Use of outcomes-based data in reducing high-order multiple 93. Gardner DK, Surrey E, Minjarez D, Leitz A, Stevens J, Schoolcraft WB.
pregnancies: the role of age, diagnosis, and embryo score. Fertil Steril Single blastocyst transfer: a prospective randomized trial. Fertil Steril 74. Strandell A, Bergh C, Lundin K. Selection of patients suitable for 94. Gerris J, De Neubourg D, Mangelschots K, Van Royen E, Van de one-embryo transfer may reduce the rate of multiple births by half without Meerssche M, Valkenburg M. Prevention of twin pregnancy after in-vitro impairment of overall birth rates. Hum Reprod 2000;15:2520–5.
fertilization or intracytoplasmic sperm injection based on strict embryo 75. Blake D, Proctor M, Johnson N, Olive D, Blake D. Cleavage stage versus criteria: a prospective randomized clinical trial. Hum Reprod blastocyst stage embryo transfer in assisted conception. Cochrane Database 95. Lukassen HG, Braat DD, Wetzels AM, Zielhuis GA, Adang EM, Scheenjes 76. Gardner DK, Schoolcraft WB, Wagley L, Schlenker T, Stevens J, Hesla J.
E et al. Two cycles with single embryo transfer versus one cycle with double A prospective randomized trial of blastocyst culture and transfer in in-vitro embryo transfer: a randomized controlled trial. Hum Reprod fertilization. Hum Reprod 1998;13:3434–40.
77. Karaki RZ, Samarraie SS, Younis NA, Lahloub TM, Ibrahim MH.
96. Martikainen H, Tiitinen A, Tomas C, Tapanainen J, Orava M, Tuomivaara Blastocyst culture and transfer: a step toward improved in vitro fertilization L, et al. One versus two embryo transfer after IVF and ICSI: a randomized outcome. Fertil Steril 2002;77:114–8.
SEPTEMBER JOGC SEPTEMBRE 2006 l
JOINT SOGC–CFAS GUIDELINE
97. Thurin A, Hausken J, Hillensjo T, Jablonowska B, Pinborg A, Strandell A, 116. Gerris J, De Neubourg D, De Sutter P, Van Royen E, Mangelschots K, et al. Elective single-embryo transfer versus double-embryo transfer in in Vercruyssen M. Cryopreservation as a tool to reduce multiple birth. Reprod vitro fertilization. N Engl J Med 2004;351:2392–402.
98. van Montfoort AP, Fiddelers AA, Janssen JM, Derhaag JG, Dirksen CD, 117. Hyden-Granskog C, Tiitinen A. Single embryo transfer in clinical practice.
Dunselman GA, et al. In unselected patients, elective single embryo transfer prevents all multiples, but results in significantly lower pregnancy rates 118. Debrock S, Spiessens C, Meuleman C, Segal L, De Loecker P, Meeuwis L, compared with double embryo transfer: a randomized controlled trial. Hum et al. New Belgian legislation regarding the limitation of transferable embryos in in vitro fertilization cycles does not significantly influence the 99. Pandian Z, Templeton A, Serour G, Bhattacharya S. Number of embryos pregnancy rate but reduces the multiple pregnancy rate in a threefold way in for transfer after IVF and ICSI: a Cochrane review. Hum Reprod the Leuven University Fertility Center. Fertil Steril 2005;83:1572–4.
119. De Neubourg D, Mangelschots K, Van Royen E, Vercruyssen M, Ryckaert 100. Alikani M, Cekleniak NA, Walters E, Cohen J. Monozygotic twinning fol- G, Valkenburg M, et al. Impact of patients’ choice for single embryo trans- lowing assisted conception: an analysis of 81 consecutive cases. Hum fer of a top quality embryo versus double embryo transfer in the first IVF/ICSI cycle. Hum Reprod 2002;17:2621–5.
101. Gerris JM. Single embryo transfer and IVF/ICSI outcome: a balanced 120. Saldeen P, Sundstrom P. Would legislation imposing single embryo transfer appraisal. Hum Reprod Update 2005;11:105–21.
be a feasible way to reduce the rate of multiple pregnancies after IVF treat-ment? Hum Reprod 2005;20:4–8.
102. Vilska S, Tiitinen A, Hyden-Granskog C, Hovatta O. Elective transfer of one embryo results in an acceptable pregnancy rate and eliminates the risk 121. Svendsen TO, Jones D, Butler L, Muasher SJ. The incidence of multiple of multiple birth. Hum Reprod 1999;14:2392–5.
gestations after in vitro fertilization is dependent on the number of embryostransferred and maternal age. Fertil Steril 1996;65:561–5.
103. Catt J, Wood T, Henman M, Jansen R. Single embryo transfer in IVF to prevent multiple pregnancies. Twin Res 2003;6:536–9.
122. Hu Y, Maxson WS, Hoffman DI, Ory SJ, Eager S, Dupre J, et al. Maximiz- ing pregnancy rates and limiting higher-order multiple conceptions by deter- 104. De Sutter P, Van der Elst J, Coetsier T, Dhont M. Single embryo transfer mining the optimal number of embryos to transfer based on quality. Fertil and multiple pregnancy rate reduction in IVF/ICSI: a 5-year appraisal.
Reprod Biomed Online 2003;6:464–9.
123. Giannini P, Piscitelli C, Giallonardo A, Sbracia M, Morgia F, Torti M, et al.
105. Kovacs G, MacLachlan V, Rombauts L, Healy D, Howlett D. Replacement Number of embryos transferred and implantation. Ann N Y Acad Sci of one selected embryo is just as successful as two embryo transfer, without the risk of twin pregnancy. Aust N Z J Obstet Gynaecol 2003;43:369–71.
124. Milki AA, Hinckley MD, Westphal LM, Behr B. Elective single blastocyst 106. Soderstrom-Anttila V, Vilska S, Makinen S, Foudila T, Suikkari AM. Elec- transfer. Fertil Steril 2004;81:1697–8.
tive single embryo transfer yields good delivery rates in oocyte donation.
Hum Reprod 2003;18:1858–63.
125. Adonakis G, Camus M, Joris H, Vandervorst M, Van Steirteghem A, Devroey P. The role of the number of replaced embryos on 107. Tiitinen A, Unkila-Kallio L, Halttunen M, Hyden-Granskog C. Impact of intracytoplasmic sperm injection outcome in women over the age of 40.
elective single embryo transfer on the twin pregnancy rate. Hum Reprod 126. Azem F, Yaron Y, Amit A, Yovel I, Barak Y, Peyser MR, et al. Transfer of 108. Gerris J, De Sutter P, De Neubourg D, Van Royen E, Van der Elst J, six or more embryos improves success rates in patients with repeated in Mangelschots K, et al. A real-life prospective health economic study of elec- vitro fertilization failures. Fertil Steril 1995;63:1043–6.
tive single embryo transfer versus two-embryo transfer in first IVF/ICSIcycles. Hum Reprod 2004;19:917–23.
127. Licciardi F, Berkeley AS, Krey L, Grifo J, Noyes N. A two- versus three-embryo transfer: the oocyte donation model. Fertil Steril 109. Martikainen H, Orava M, Lakkakorpi J, Tuomivaara L. Day 2 elective single embryo transfer in clinical practice: better outcome in ICSI cycles. HumReprod 2004;19:1364–6.
128. Ryan GL, Zhang SH, Dokras A, Syrop CH, Van Voorhis BJ. The desire of infertile patients for multiple births. Fertil Steril 2004;81:500–4.
110. van Montfoort AP, Dumoulin JC, Land JA, Coonen E, Derhaag JG, Evers JL. Elective single embryo transfer (eSET) policy in the first three 129. Pinborg A, Loft A, Schmidt L, Nyboe Andersen A. Attitudes of IVF/ICSI treatment cycles. Hum Reprod 2005;20:433–6.
IVF/ICSI-twin mothers towards twins and single embryo transfer. HumReprod 2003;18:621–7.
111. Criniti A, Thyer A, Chow G, Lin P, Klein N, Soules M. Elective single blastocyst transfer reduces twin rates without compromising pregnancy 130. Goldfarb J, Kinzer DJ, Boyle M, Kurit D. Attitudes of in vitro fertilization rates. Fertil Steril 2005;84:1613–9.
and intrauterine insemination couples toward multiple gestation pregnancyand multifetal pregnancy reduction. Fertil Steril 1996;65:815–20.
112. Henman M, Catt JW, Wood T, Bowman MC, de Boer KA, Jansen RPS.
Elective transfer of single fresh blastocysts and later transfer of cryostored 131. Grobman WA, Milad MP, Stout J, Klock SC. Patient perceptions of multi- blastocysts reduces the twin pregnancy rate and can improve the in vitro ple gestations: an assessment of knowledge and risk aversion. Am J Obstet fertilization live birth rate in younger women. Fertil Steril 2005;84:1620–7.
113. Tiitinen A, Halttunen M, Harkki P, Vuoristo P, Hyden-Granskog C. Elec- 132. Murray S, Shetty A, Rattray A, Taylor V, Bhattacharya S. A randomized tive single embryo transfer: the value of cryopreservation. Hum Reprod comparison of alternative methods of information provision on the accept- ability of elective single embryo transfer. Hum Reprod 2004;19:911–6.
114. Davis OK. Elective single-embryo transfer—has its time arrived? N Engl J 133. Porter M, Bhattacharya S. Investigation of staff and patients’ opinions of a proposed trial of elective single embryo transfer. Hum Reprod2005;20:2523–30.
115. Tiitinen A, Hyden-Granskog C, Gissler M. What is the most relevant stan- dard of success in assisted reproduction? The value of cryopreservation on 134. Blennborn M, Nilsson S, Hillervik C, Hellberg D. The couple’s deci- cumulative pregnancy rates per single oocyte retrieval should not be forgot- sion-making in IVF: one or two embryos at transfer? Hum Reprod l SEPTEMBER JOGC SEPTEMBRE 2006
Guidelines for the Number of Embryos to Transfer Following In Vitro Fertilization 135. Chervenak FA, McCullough LB, Rosenwaks Z. Ethical dimensions of the 142. De Sutter P, Gerris J, Dhont M. A health-economic decision-analytic model number of embryos to be transferred in in vitro fertilization. J Assist comparing double with single embryo transfer in IVF/ICSI. Hum Reprod 136. Jain T, Harlow BL, Hornstein MD. Insurance coverage and outcomes of in 143. Bolton P, Yamashita Y, Farquhar CM. Role of fertility treatments in multi- vitro fertilization. N Engl J Med 2002;347:661–6.
ple pregnancy at National Women’s Hospital from 1996 to 2001. Aust N Z 137. Reynolds MA, Schieve LA, Jeng G, Peterson HB. Does insurance coverage decrease the risk for multiple births associated with assisted reproductivetechnology? Fertil Steril 2003;80:16–23.
144. Dmowski WP, Pry M, Ding J, Rana N. Cycle-specific and cumulative fecundity in patients with endometriosis who are undergoing controlled 138. Gordts S, Campo R, Puttemans P, Brosens I, Valkenburg M, Norre J, et al.
ovarian hyperstimulation-intrauterine insemination or in vitro fertiliza- Belgian legislation and the effect of elective single embryo transfer on IVF tion-embryo transfer. Fertil Steril 2002;78:750–6.
outcome. Reprod Biomed Online 2005;10:436–41.
139. Ombelet W, De Sutter P, Van der Elst J, Martens G. Multiple gestation and 145. Dickey RP. It has really been 15 years of inaction on high-order multiple infertility treatment: registration, reflection and reaction—the Belgian pro- pregnancies due to ovulation induction. Fertil Steril 2003;79:28–9.
ject. Hum Reprod Update 2005;11:3–14.
146. Dickey RP, Taylor SN, Lu PY, Sartor BM, Rye PH, Pyrzak R. Risk factors 140. Callahan TL, Hall JE, Ettner SL, Christiansen CL, Greene MF, Crowley WF for high-order multiple pregnancy and multiple birth after controlled ovar- Jr. The economic impact of multiple-gestation pregnancies and the contri- ian hyperstimulation: results of 4,062 intrauterine insemination cycles. Fertil bution of assisted-reproduction techniques to their incidence. N Engl J Med 141. Kjellberg AT, Carlsson P, Bergh C. Randomized single versus double 147. Gleicher N, Oleske DM, Tur-Kaspa I, Vidali A, Karande V. Reducing the embryo transfer: obstetric and paediatric outcome and a cost-effectiveness risk of high-order multiple pregnancy after ovarian stimulation with gon- analysis. Hum Reprod 2006;21:210–6.
adotropins. N Engl J Med 2000;343:2–7.
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