Mais les résultats doivent être attendus longtemps et il n'y a généralement pas de temps amoxicilline prix L'autre cas, c'est que l'achat d'un ou d'un autre antibiotique dans une pharmacie classique nécessite des dépenses matérielles considérables et pas toutes les personnes ne peuvent acheter des produits pharmaceutiques aussi coûteux.
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-
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SEPTEMBER JOGC SEPTEMBRE 2006 l
Electromedicine CES in the Treatment of Depression, Part 2 This second article, of a two-part series on the efficacy of Cranial Electrotherapy Stimulation (CES) in treating depression, reviews the results of meta-analysis conducted on CES studies. By Daniel L. Kirsch, PhD, DAAPM, FAIS and Marshall F. Gilula, MDCranial electrotherapy stimulation them with three, 30 minute CES sessions i
Nitroglycerine for Ischemic Chest Pain Protocol Preamble Ischemic chest pain is caused by decreased blood flow through the coronary arteries. Nitroglycerine dilates the coronary arteries and may increase myocardial blood flow, relieving ischemic chest pain. Requirements 1. Fully licensed Technician-Paramedic. 2. Certification in nitroglycerine for ischemic chest pain pro