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Fresh embryo transfer vs. frozen embryo

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systematic review and meta-analysis

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ORIGINAL ARTICLE: ASSISTED REPRODUCTION

Fresh embryo transfer versus frozen

embryo transfer in in vitro
fertilization cycles: a systematic
review and meta-analysis
, B.Psych.,e,f,g
Matheus Roque, M.D.,a,c Karinna Lattes, M.D.,a,d Sandra Serra, M.Sc.,a,d Ivan Sola
 n Carreras, Ph.D.,b and Miguel Angel Checa, Ph.D.b,d
Selmo Geber, Ph.D.,c,h Ramo
a
Ma ster Internacional Medicina Reproductiva, Hospital del Mar, and b Department of Obstetrics and Gynecology, Parc de
Salut Mar, Universitat Auto  noma de Barcelona, Barcelona, Spain; c Origen Center for Reproductive Medicine, Belo
d
Horizonte, Brazil; Centro de Infertilidad y Reproduccio  n Humana, Barcelona, Spain; e Iberoamerican Cochrane Center,
Barcelona, Spain; f Institute of Biomedical Research (IIB Sant Pau), Barcelona, Spain; g CIBER Epidemiología y Salud
Pu blica, Barcelona, Spain; and h Universidade Federal de Minas Gerais, Belo Horizonte, Brazil

Objective: To examine the available evidence to assess if cryopreservation of all embryos and subsequent frozen embryo transfer (FET)
results in better outcomes compared with fresh transfer.
Design: Systematic review and meta-analysis.
Setting: Centers for reproductive care.
Patient(s): Infertility patient(s).
Intervention(s): An exhaustive electronic literature search in MEDLINE, EMBASE, and the Cochrane Library was performed through
December 2011. We included randomized clinical trials comparing outcomes of IVF cycles between fresh and frozen embryo transfers.
Main Outcome Measure(s): The outcomes of interest were ongoing pregnancy rate, clinical pregnancy rate, and miscarriage.
Result(s): We included three trials accounting for 633 cycles in women aged 27–33 years. Data analysis showed that FET resulted in
significantly higher ongoing pregnancy rates and clinical pregnancy rates.
Conclusion(s): Our results suggest that there is evidence that IVF outcomes may be improved by performing FET compared with fresh
embryo transfer. This could be explained by a better embryo-endometrium synchrony achieved
with endometrium preparation cycles. (Fertil SterilÒ 2012;-:-–-. Ó2012 by American
Society for Reproductive Medicine.) Use your smartphone
Key Words: Fresh embryo transfer, frozen embryo transfer, endometrial receptivity, pregnancy to scan this QR code
outcome and connect to the
discussion forum for
this article now.*
Discuss: You can discuss this article with its authors and with other ASRM members at http://
fertstertforum.com/roquem-fresh-versus-frozen-embryo-transfer/ * Download a free QR code scanner by searching for “QR
scanner” in your smartphone’s app store or app marketplace.

I
mplantation represents one of the plantation window is a self-limited been suggested that controlled
important steps for the success period in which the endometrium has ovarian hyperstimulation (COH) ad-
of assisted reproduction tech- acquired the adequate morphologic versely affects ER during ART cycles
niques (ART) (1). Its effectiveness and functional state for the blastocyst (3–5). This interaction is mediated
relies on three main parameters: em- attachment. by the supraphysiologic levels of
bryo quality, endometrial receptivity Therefore, ER is essential for con- estradiol (E2) and progesterone (P)
(ER), and a well-balanced embryo- ception in natural and infertility during the follicular phase, leading
endometrium interaction (2). The im- treatment cycles. However, it has to morphologic and biochemical
endometrial alterations and a more
Received May 30, 2012; revised August 31, 2012; accepted September 5, 2012.
M.R. has nothing to disclose. K.L. has nothing to disclose. S.S. has nothing to disclose. I.S. has nothing
advanced endometrium than in
to disclose. S.G. has nothing to disclose. R.C. has nothing to disclose. M.A.C. has nothing to natural cycles. Ultimately, these
disclose. physiologic changes may affect the
Reprint requests: Miguel Angel Checa, Ph.D., Department of Obstetrics and Gynecology, Parc de Salut
Mar, PasseigMarítim 25–29, E-08003 Barcelona, Spain (E-mail: macheca@parcdesalutmar.cat). success rates of the treatments.
These altered hormone levels could
Fertility and Sterility® Vol. -, No. -, - 2012 0015-0282/$36.00
Copyright ©2012 American Society for Reproductive Medicine, Published by Elsevier Inc.
mediate an asynchrony between the
http://dx.doi.org/10.1016/j.fertnstert.2012.09.003 endometrium and the transferred

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ORIGINAL ARTICLE: ASSISTED REPRODUCTION
embryos, leading to an endometrial environment that
could be responsible for implantation failure (6–10).
In ART, the highest pregnancy rates are obtained in fresh
oocyte donation cycles. In these cycles, the endometrium is
artificially primed and the embryos are therefore transferred
to an environment that had not suffered the effects of the
supraphysiologic hormonal levels that occur during COH
(8). Although the oocytes are of the same quality, some studies
of shared oocyte cycles found significantly higher pregnancy
rates in recipients compared with oocyte donors, and this may
be related to a superior quality of ER (7, 8). Similarly, in frozen
embryo transfers (FET), endometrial priming may be achieved
with the use of E2 and P, and the endometrial development
can be controlled more precisely than in cycles of COH with
gonadotropins (9, 10). To date, with the advances of the
embryo cryopreservation techniques, the quality of the
frozen embryos and their potential of implantation are
similar to the observed with fresh embryos (11, 12).
Although in most of the studies comparing fresh and FET,
the best-quality embryos are chosen for the fresh transfer,
and the results are similar between the two types of treatments
(13). Some studies have shown good results with the cryopres-
ervation of all embryos and subsequent FET in patients with
an increased risk ovarian hyperstimulation syndrome
(OHSS) (14–16). Therefore, if the best-quality embryos are se-
lected for FET and the ER can be improved in these cycles, one
can expect to obtain higher implantation rates, thus improv-
ing overall ART success.
The purpose of the present systematic review and meta-
analysis was to examine the literature and identify results
of randomized clinical trials to assess if the cryopreservation
of all embryos of good quality, and subsequent FET, is asso-
ciated with improvements in the ART outcomes compared
with fresh embryo transfer.
MATERIALS AND METHODS
Given that this was a meta-analysis and did not involve any
intervention in humans, the present study did not require the
approval of an International Review Board. We used the
Preferred Outcome Items for Systematic Reviews and Meta-
analysis (PRISMA statement) to report the results of this sys-
tematic review (17).
Search Strategy
An exhaustive electronic search was performed with the
MEDLINE AND EMBASE databases, as well as the Cochrane
Central Register of Controlled Trials, from their inceptions
through December 2011. We also searched the main ongoing
clinical trial registries, including controlled-trials.com, clini-
caltrials.gov, and the International Clinical Trials Registry
Platform from the World Health Organization. We used rele-
vant terms and related variants for the interventions and pop-
ulation study: in vitro fertilization with or without
intracytoplasmic sperm injection (ICSI) and fresh or frozen
embryo transfer. We restricted the search to articles published
in English. The search strategy was modified to fit with the
syntaxes required in each database. We also searched among
the references of the relevant articles.
2 VOL. - NO. - / - 2012
Eligibility Criteria and Data Extraction
We included randomized controlled trials (RCTs) of couples
undergoing in vitro fertilization (IVF), with or without intra-
cytoplasmic sperm injection (ICSI), that compared the ART
outcomes of fresh versus elective frozen embryo transfer. In
a first screening, two independent authors (K.L.A., S.S.T.) as-
sessed all of the abstracts retrieved from the search, and then
they obtained the full manuscripts of citations that fit the in-
clusion criteria. They evaluated the studies, eligibility, quality,
and extracted data, and any discrepancies were resolved by
mutual agreement and, if needed, by reaching a consensus
with a third author (M.A.C.). Inter-rater agreement was ana-
lyzed with the use of weighted kappa for the inclusion criteria.
Outcome Measures
The outcomes of interest for this systematic review included
the following variables: ongoing pregnancy rate (per woman
randomized), clinical pregnancy rate (per woman random-
ized), and miscarriage rates (per woman randomized). Ongo-
ing pregnancy was defined as pregnancy proceeding
beyond the 10th gestational week. Clinical pregnancy was de-
fined as the observation of intrauterine fetal heart motion by
7 weeks' gestation. Miscarriage included any pregnancies that
did not become ongoing pregnancies.
Risk of Bias Assessment
We assessed the risk of bias from included studies following
the guidance suggested by the Cochrane Collaboration (18).
We made explicit judgment regarding the generation of se-
quence allocation, allocation concealment, blinding, and in-
complete outcome data for each trial included in the review.
A judgment of ‘‘yes’’ for all domains indicates a low risk for
bias, whereas a judgment of ‘‘no’’ for one or more domains
indicates a high risk of bias. An ‘‘unclear’’ judgment in any
domain indicates an unclear risk of bias.
Analysis
For each study, the treatment effect was measured with risk
ratios (RRs) for dichotomous outcomes, presented with their
corresponding 95% confidence intervals (CIs). We extracted
event data following the intention-to-treat principle. Statisti-
cal significance was set at a P value of < .05. When possible,
we pooled outcome data from each study with the use of
a Mantel-Haenszel model, applying the fixed-effects model.
We quantified statistical heterogeneity with the use of the I2
statistic to describe variation across trials that is due to het-
erogeneity and not to sampling error (19). We used the Review
Manager 5 software for conducting the meta-analysis.
RESULTS
Our electronic search retrieved 64 articles. After the screening
of titles and abstracts, we determined that 46 of them were not
RCTs, 56 of them did not include the objectives of our meta-
analysis, and 52 of them did not inform on the outcomes of
interest, leaving seven articles considered to be eligible by
one or both reviewers. Among these, in a second selection,

four articles were excluded because they were not RCTs (20–
23). The two authors had good agreement on the selection of
trials for inclusion (weighted kappa 0.78, 95% CI 0.64–0.93).
The complete selection process is depicted in Figure 1.
Description of Included Studies
Three RCTs assessing the outcome of fresh versus FET in
women undergoing IVF (with or without ICSI) met the inclu-
sion criteria, and all reported data on the outcomes analyzed
in this review are based on those studies. Overall, the three in-
cluded studies account for 633 ART cycles in women, with
ages ranging from 27 to 33 years. One of the trials (13) in-
cluded normal responders submitted to ovarian stimulation
with recombinant FSH and GnRH antagonist for pituitary
suppression. The other two studies included high responders
(24, 25). In one of them (24), the ovarian stimulation was
performed with GnRH agonist for pituitary suppression and
recombinant FSH, and in the other study (25) with
recombinant FSH and GnRH antagonist for pituitary
suppression. The endometrial priming in the FET group was
performed with either oral E2 and intramuscular P (24)
FIGURE 1
Preferred Outcome Items for Systematic Reviews and Meta-analysis flow diagram detailing selection of studies for inclusion. RCT ¼ randomized
controlled study.
Roque. Elective frozen-thawed embryo transfer. Fertil Steril 2012.
VOL. - NO. - / - 2012
Fertility and Sterility®
along with leuprolide acetate for pituitary down-regulation,
or oral E2 and E2 patches as needed, and intramuscular
P (13, 25). The characteristics of the studies included in the
review are presented in Table 1.
Internal Validity of Included Studies
The internal validity of the included trials was not threatened
due to major sources of bias, although the second Shapiro
et al. study (25) was published as correspondence and it was
not possible to assess the complete data. The other included
trials had properly randomized their participants and had
concealed the randomization allocations by means of sealed
opaque envelopes. The included studies showed sufficient
details to determine whether the outcome assessors were
blinded (Table 2).
Outcomes
All of the trials included in the review contributed to the
pooled analyses for the considered outcomes. The analysis
of the data available from the three included trials, including
3
ORIGINAL ARTICLE: ASSISTED REPRODUCTION

TABLE 1

Characteristics of the clinical trial included in the review.

Day of embryo
Study ID Patients (Fresh/FET) Age, y (Fresh/FET) Duration of trial transfer Outcome
Aflatoonian et al. (24) 374 (187/187) 28.1  3.5/27.3  4.4 February 2007– Day 2 Ongoing pregnancy
High responders February 2009 Implantation
Clinical pregnancy
Miscarriage rate
Shapiro et al. (13) 137 (67/70) 32.9  3.7/33.0  3.8 October 2007– Day 5 (blastocyst) Ongoing pregnancy
Normal responders October 2010 Implantation
Clinical pregnancy
Early pregnancy loss
Shapiro et al. (25) 122 (62/60) 31.4  3.7/30.6  3.7 July 2007–July 2010 Day 5 (blastocyst) Ongoing pregnancy
High responders Implantation
Clinical pregnancy
Early pregnancy loss
Roque. Elective frozen-thawed embryo transfer. Fertil Steril 2012.

263 events, showed that FET resulted in a statistically signif-
icant increase in the ongoing pregnancy rate compared with
the rate observed with fresh transfer (RR 1.32, 95% CI 1.10–
1.59; I2 ¼ 0; Fig. 2A). This pattern of results was also ob-
served for the rates of clinical pregnancies, which was
higher in the women allocated in the FET group (280 events;
RR 1.31, 95% CI 1.10–1.56; I2 ¼ 0; Fig. 2B). Finally, the
fresh group showed a higher miscarriage rate compared
with the FET group, but this difference did not reach statis-
tical significance (33 events; RR 0.83, 95% CI 0.43–1.60; I2
¼ 0; Fig. 2C).
DISCUSSION
This systematic review showed that the use of FET, compared
with fresh embryo transfer, significantly improved clinical
and ongoing pregnancy rates, in patients submitted to ART.
To our knowledge, this is the first comprehensive review con-
sisting of a pooled analysis that has addressed the question
of whether the cryopreservation of all viable embryos and
subsequent FET is associated with improved ART outcomes
compared with fresh embryo transfer. The results of this
meta-analysis suggest that, in normal- and high-responder
patients, it may be advantageous to cryopreserve all viable
embryos and use them in a subsequent FET. Importantly,
the data were extracted to allow for an intention-to-treat
analysis.
The results favoring FET instead of fresh embryo
transfer may be related to the adverse effects of COH on en-
dometrial receptivity, as well as the improved results that
can be achieved with current cryopreservation methods
(13, 24, 25).
The quality of the available evidence that supports these
results is moderate (26), and the main limitation of the avail-
able evidence is that most of the estimates of the outcomes of
interest are based on few events and a type 1 error cannot be
ruled out.
Embryo implantation is one of the important steps for
reproductive success, and implantation failure remains an
unsolved problem in ART. In two-thirds of the implantation
failures, the primary responsible source of failure is the im-
pairment of the ER, whereas the embryo itself is responsible
for only one-third of the failures (2). At the end of the follic-
ular phase in COH, the subtle increases in serum P levels (i.e.,
premature luteinization) show a positive correlation with FSH
levels, and this increase is associated with an advanced
endometrial ultrastructural morphology and echogenicity
(9, 27–33). In fresh cycles with COH, the elevated P may
lead to advanced endometrial maturation, without affecting
the quality of the embryo, and this may cause decreased

TABLE 2

Quality assessment of included trials.

Study Explicit Sequence Allocation Patient Outcome
(reference) eligibility criteria generation concealed blinding assessor blinding Patient follow-up
Aflatoonian et al. (24) Yes Yes Yes No Yes Unclear
Computer-generated Sealed opaque Open trial
sequence envelopes
Shapiro et al. (13) Yes Yes Yes No Unclear 137 women randomized,
Drawing of envelopes Sealed opaque Open trial 103 analyzed (75%).
unmarked In the rest the transfer
envelopes was canceled (in 15%
for no viable embryos)
Shapiro et al. (25) Unclear Unclear Unclear Unclear Unclear Unclear
Roque. Elective frozen-thawed embryo transfer. Fertil Steril 2012.

4 VOL. - NO. - / - 2012


FIGURE 2
Meta-analysis results.
Roque. Elective frozen-thawed embryo transfer. Fertil Steril 2012.
implantation rates owing to asynchrony between embryo and
the endometrium in fresh cycles (3, 34).
Uterine receptivity is better achieved during natural cycles
or with hormone replacement therapy with exogenous E2 and
P, compared with stimulated cycles (7, 35, 36). There is
evidence showing that high E2 levels (>2,500 pg/mL) may
impair the endometrium maturation and implantation (37,
38). Several studies have described an advanced endometrium
in the early luteal phase of women submitted to COH, and
that if this advancement exceeded 3 days, no pregnancy was
observed (3–5, 30, 39, 40). The gene expression profile of
human endometrium may be over- or underexpressed in
patients undergoing COH, and the expression of E2 and P
receptors is altered in stimulated cycles, indicating an
advance in the endometrium maturation compared with
natural cycles (38, 41–44).
The cryopreservation of embryos has become a routine
procedure in ART when embryo transfer is either impossible
or inconvenient. When the FET is performed, the endometrial
preparation may be achieved in a natural or an artificial way.
It is suggested that during the endometrial priming for FET,
the endometrium is more receptive than in fresh embryo cy-
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Fertility and Sterility®
cles (45–49). There are different ways to perform the
endometrial preparation, but there is a lack of evidence to
recommend any one particular protocol for endometrial
priming regarding ART outcomes after FET (50). The recent
use of vitrification technique has shown a higher embryo
survival rate, compared with slow freezing, resulting in
significantly higher implantation and pregnancy rates per
transfer (45, 51–57). Therefore, the use of elective
cryopreservation of viable embryos could be an alternative
to avoid the deleterious effects of the COH in embryo-
endometrium synchrony (13, 20, 25).
Although the three studies included in the present meta-
analysis did not evaluate live birth rates, earlier conclusions
on treatment effects based solely on the clinical and ongoing
pregnancy rates as the main outcomes are generally accepted
(23), and these variables are comparable to live birth as a mea-
sure of efficacy (13, 58). In all of the studies, the endometrial
receptivity could be inferred only, not directly assessed. It is
possible that the frozen-thaw process may have indirectly in-
volved the selection of the best embryos by improving the
proportion of good embryos in the FET group, thereby over-
estimating the effects attributed to the better endometrial
5
ORIGINAL ARTICLE: ASSISTED REPRODUCTION
quality in FET (13). Because all the trials in this meta-analysis
included potentially normal- and high-responder patients,
these results should not be extrapolated to all types of patients
submitted to ART.
In summary, the results of this meta-analysis suggest that
there is evidence of moderate quality that the implantation,
clinical, and ongoing pregnancy rates of ART cycles may be
improved by performing FET compared with fresh embryo
transfer. These results may be explained by improved
embryo-endometrium synchrony achieved with endometrium
preparation cycles instead of COH cycles. The data provide a ra-
tionale for conducting further randomized clinical trials and
multicenter studies to assess the consequences of COH on endo-
metrial receptivity and ART outcomes as they relate to the FET.
Acknowledgments: The authors thank Ara Cantillo and
Susan García for their collaboration with literature searches,
retrieving identified trials, and scientific advice.
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