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 ster Internacional Medicina Reproductiva, Hospital del Mar, and b Department of Obstetrics and Gynecology, Parc de Ma noma de Barcelona, Barcelona, Spain; c Origen Center for Reproductive Medicine, Belo Salut Mar, Universitat Auto d n Humana, Barcelona, Spain; e Iberoamerican Cochrane Center, Horizonte, Brazil; Centro de Infertilidad y Reproduccio Barcelona, Spain; f Institute of Biomedical Research (IIB Sant Pau), Barcelona, Spain; g CIBER Epidemiología y Salud blica, Barcelona, Spain; and h Universidade Federal de Minas Gerais, Belo Horizonte, Brazil Pu
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 Use your smartphone Society for Reproductive Medicine.) to scan this QR code Key Words: Fresh embryo transfer, frozen embryo transfer, endometrial receptivity, pregnancy and connect to the outcome Discuss: You can discuss this article with its authors and with other ASRM members at http:// fertstertforum.com/roquem-fresh-versus-frozen-embryo-transfer/
I
mplantation represents one of the important steps for the success of assisted reproduction techniques (ART) (1). Its effectiveness relies on three main parameters: embryo quality, endometrial receptivity (ER), and a well-balanced embryoendometrium interaction (2). The im-
plantation window is a self-limited period in which the endometrium has acquired the adequate morphologic and functional state for the blastocyst attachment. Therefore, ER is essential for conception in natural and infertility treatment cycles. However, it has
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 to disclose. S.G. has nothing to disclose. R.C. has nothing to disclose. M.A.C. has nothing to disclose. 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:
[email protected]). Fertility and Sterility® Vol. -, No. -, - 2012 0015-0282/$36.00 Copyright ©2012 American Society for Reproductive Medicine, Published by Elsevier Inc. http://dx.doi.org/10.1016/j.fertnstert.2012.09.003 VOL. - NO. - / - 2012
discussion forum for this article now.*
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been suggested that controlled ovarian hyperstimulation (COH) adversely affects ER during ART cycles (3–5). This interaction is mediated by the supraphysiologic levels of estradiol (E2) and progesterone (P) during the follicular phase, leading to morphologic and biochemical endometrial alterations and a more advanced endometrium than in natural cycles. Ultimately, these physiologic changes may affect the success rates of the treatments. These altered hormone levels could mediate an asynchrony between the endometrium and the transferred 1
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 cryopreservation 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 selected for FET and the ER can be improved in these cycles, one can expect to obtain higher implantation rates, thus improving overall ART success. The purpose of the present systematic review and metaanalysis 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 associated 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 Metaanalysis (PRISMA statement) to report the results of this systematic 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, clinicaltrials.gov, and the International Clinical Trials Registry Platform from the World Health Organization. We used relevant terms and related variants for the interventions and population 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
Eligibility Criteria and Data Extraction We included randomized controlled trials (RCTs) of couples undergoing in vitro fertilization (IVF), with or without intracytoplasmic 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.) assessed all of the abstracts retrieved from the search, and then they obtained the full manuscripts of citations that fit the inclusion 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 analyzed 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 randomized), and miscarriage rates (per woman randomized). Ongoing pregnancy was defined as pregnancy proceeding beyond the 10th gestational week. Clinical pregnancy was defined 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 sequence allocation, allocation concealment, blinding, and incomplete 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. Statistical 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 heterogeneity 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 metaanalysis, 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, VOL. - NO. - / - 2012
Fertility and Sterility® 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.
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.
Description of Included Studies
Internal Validity of Included Studies
Three RCTs assessing the outcome of fresh versus FET in women undergoing IVF (with or without ICSI) met the inclusion criteria, and all reported data on the outcomes analyzed in this review are based on those studies. Overall, the three included studies account for 633 ART cycles in women, with ages ranging from 27 to 33 years. One of the trials (13) included 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)
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
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.
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ORIGINAL ARTICLE: ASSISTED REPRODUCTION
TABLE 1 Characteristics of the clinical trial included in the review. Age, y (Fresh/FET)
Day of embryo transfer
Study ID
Patients (Fresh/FET)
Duration of trial
Aflatoonian et al. (24)
374 (187/187) High responders
28.1 3.5/27.3 4.4
February 2007– February 2009
Day 2
Shapiro et al. (13)
137 (67/70) Normal responders
32.9 3.7/33.0 3.8
October 2007– October 2010
Day 5 (blastocyst)
Shapiro et al. (25)
122 (62/60) High responders
31.4 3.7/30.6 3.7
July 2007–July 2010
Day 5 (blastocyst)
Outcome Ongoing pregnancy Implantation Clinical pregnancy Miscarriage rate Ongoing pregnancy Implantation Clinical pregnancy Early pregnancy loss Ongoing pregnancy Implantation Clinical pregnancy Early pregnancy loss
Roque. Elective frozen-thawed embryo transfer. Fertil Steril 2012.
263 events, showed that FET resulted in a statistically significant 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 observed 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 statistical 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 consisting 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 endometrial 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 available 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 impairment of the ER, whereas the embryo itself is responsible for only one-third of the failures (2). At the end of the follicular 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 (reference)
Explicit eligibility criteria
Aflatoonian et al. (24)
Yes
Shapiro et al. (13)
Yes
Shapiro et al. (25)
Unclear
Sequence generation
Allocation concealed
Patient blinding
Outcome assessor blinding
Yes Computer-generated sequence Yes Drawing of envelopes
Yes Sealed opaque envelopes Yes Sealed opaque unmarked envelopes
No Open trial
Yes
Unclear
No Open trial
Unclear
Unclear
Unclear
Unclear
Unclear
137 women randomized, 103 analyzed (75%). In the rest the transfer was canceled (in 15% for no viable embryos) Unclear
Patient follow-up
Roque. Elective frozen-thawed embryo transfer. Fertil Steril 2012.
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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 cyVOL. - NO. - / - 2012
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 embryoendometrium synchrony (13, 20, 25). Although the three studies included in the present metaanalysis 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 measure 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 involved the selection of the best embryos by improving the proportion of good embryos in the FET group, thereby overestimating 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 rationale for conducting further randomized clinical trials and multicenter studies to assess the consequences of COH on endometrial receptivity and ART outcomes as they relate to the FET.
14.
Acknowledgments: The authors thank Ara Cantillo and Susan García for their collaboration with literature searches, retrieving identified trials, and scientific advice.
19.
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