Maternal and perinatal outcomes after fresh versus frozen embryo transfer—what is the risk-beneﬁt ratio? Siladitya Bhattacharya, M.D. Aberdeen Fertility Centre, Institute of Applied Health Sciences, University of Aberdeen, Aberdeen, United Kingdom
Fresh ET has been the conventional strategy in IVF, but there is a growing opinion suggesting that its maternal and perinatal outcomes can be enhanced by a policy of elective freezing of embryos, followed by transfer at a later date. Available studies suggest a number of improved maternal and perinatal outcomes after frozen ET, although there is also a suggestion of large for gestational age babies associated with this strategy. The observational nature of the available data limit our conﬁdence in the results of available studies. A genuinely unbiased estimate of the advantages of a policy of elective ET can only be conﬁrmed by a deﬁnitive randomized controlled trial with an adequate length of follow-up of the offspring. (Fertil SterilÒ 2016;106:241–3. Ó2016 by American Society for Reproductive Medicine.) Key Words: Frozen embryo transfer, perinatal, maternal, outcomes Discuss: You can discuss this article with its authors and with other ASRM members at https://www.fertstertdialog.com/posts/ 10586-maternal-and-perinatal-outcomes-after-fresh-versus-frozen-embryo-transfer-what-is-the-risk-beneﬁt-ratio
ince its inception, the conventional strategy in IVF has been to place one or more highquality fresh embryos in the uterus. The advent of cryopreservation technology allowed the possibility of freezing any remaining embryos for subsequent use (1). Further advances in cryobiology have improved outcomes (2), and although fresh ET still remains the default strategy, there is a growing view that elective frozen ET could yield better maternal and perinatal outcomes.
POTENTIAL BENEFITS OF FROZEN ET A policy of elective single ET provides a means of minimizing the risk of multiple pregnancies without compromising
cumulative live-birth rates (3). By ensuring that any surplus embryos are available for future use, it reduces pressure on patients and clinicians to transfer more than one embryo at a time (4, 5). This in turn safeguards an ensuing pregnancy from the added maternal and perinatal risks associated with twins or higher order multiples. A more direct beneﬁt of a policy of elective embryo freezing followed by delayed transfer is reduction of the risk of ovarian hyperstimulation syndrome (OHSS) (6). Exposure to the rising serum bhCG levels that accompany an early pregnancy can aggravate the risk of OHSS in women, particularly in those with a brisk response to gonadotropin stimulation. Avoiding exposure to bhCG by triggering ovulation by means of GnRH agonist (7) can be a
Received May 3, 2016; revised and accepted June 24, 2016. S.B. has nothing to disclose. Reprint requests: Siladitya Bhattacharya, M.D., Aberdeen Fertility Centre, Institute of Applied Health Sciences, University of Aberdeen, Aberdeen AB25 2ZL, United Kingdom (E-mail: [email protected]
abdn.ac.uk). Fertility and Sterility® Vol. 106, No. 2, August 2016 0015-0282/$36.00 Copyright ©2016 American Society for Reproductive Medicine, Published by Elsevier Inc. http://dx.doi.org/10.1016/j.fertnstert.2016.06.038 VOL. 106 NO. 2 / AUGUST 2016
safer option, but this has been shown to affect the endometrial receptivity and the chances of implantation. This is where elective freezing of embryos with a view to replacement in a future natural or hormonally mediated nonstimulation cycle can reduce the risk of OHSS without compromising pregnancy rates (6). A number of groups have studied maternal and perinatal outcomes in IVF pregnancies. In the absence of any suitable randomized trials with an adequate duration of follow-up, a systematic review of observational studies (8) suggests that singleton pregnancies resulting from frozen ET are associated with lower obstetric and perinatal morbidity. This meta-analysis (8) showed that the combined relative risks (95% conﬁdence intervals [CIs]) of antepartum hemorrhage, preterm birth, small for gestational age, low birth weight, and perinatal mortality were 0.67 (0.55, 0.81); 0.84 (0.78, 0.90); 0.45 (0.30, 0.66); 0.69 (0.62, 0.76); and 0.68 (0.48, 0.96), respectively. A subsequent study based on analysis of a large Nordic data set (9) has conﬁrmed many 241
VIEWS AND REVIEWS of these ﬁndings. Singletons conceived from the transfer of frozen embryos had reduced odds of low birth weight, preterm birth, and small for gestational age (adjusted odds ratio (ORs) [95% CI] ¼ 0.81 [0.71, 0.91]; 0.84 [0.76, 0.92]; 0.72 [0.62, 0.83], respectively).
RISKS OF A ROUTINE ‘‘FREEZE-ALL’’ POLICY A fundamental concern of clinicians and couples is that adoption of a policy of elective embryo freezing on grounds of safety could have an impact on the success of IVF. National registry data from both sides of the Atlantic have shown a steady rise in live-birth rates from frozen ET cycles to a point where these are comparable to those after fresh transfer (10, 11). Any comparisons need to acknowledge the usual limitations associated with observational cycle–based data with signiﬁcant risks of bias and confounding. Using the ET episode as the denominator can be misleading and lead to spurious results in some cases. For example, frozen ET cycles seem to be particularly successful in older women who undergo several episodes of ovarian stimulation before attempting an ET of thawed pooled embryos. There are few robust data on clinical effectiveness or safety from large randomized trials of frozen versus fresh ET. Although an initial meta-analysis of data from three small trials (12) has reported higher pregnancy rates after frozen ET (OR ¼ 1.32; 95% CI, 1.10–1.59), the methodological quality of these trials is suboptimal and their generalizability is limited. One of them (13) has since been retracted from the literature. The population included in the remaining trials represents women with normal or excessively brisk response to ovarian stimulation whose outcomes cannot be extrapolated to a wider population of women, including those with relatively few eggs and embryos. Women with a relatively poor prognosis have been excluded from the randomized trials published so far. As the decision to freeze is driven by the presence of adequate numbers of good-quality embryos, there is a systematic bias against these women in observational data on frozen ET cycles. Although most perinatal outcomes appear to be improved after frozen ET, there are some that remain a source of concern. For example, the Nordic study (9) has reported increased odds of large for gestational age (adjusted OR [95% CI] ¼ 1.45 [1.27, 1.64]) and macrosomic (adjusted OR [95% CI] ¼ 1.58 [1.39, 1.80]) offspring after frozen ET. These risks persisted after adjusting for birth order in a sibling cohort, suggesting that it is likely that they may be caused by embryo freezing and thawing (13). The Nordic data also suggest that offspring conceived through frozen ET are at higher risk of perinatal mortality (9). There are other reasons why an elective frozen ET strategy may appear to be a risky option. The concept of elective embryo freezing is counterintuitive for many clinicians and patients, who are aware that not all frozen embryos survive the freeze-thaw process. In addition, future achievement of a positive health status (in this case pregnancy) is often valued less than at the present time (14). Finally, the technical skill of the embryology laboratory is a key factor in shaping future pol242
icy, and IVF centers with suboptimal freezing outcomes may, rightly, question the need to change their practice.
INTERPRETATION OF THE AVAILABLE DATA There are serious limitations associated with aggregation of nonrandomized data, and therefore the results of the meta-analysis (8) should be treated with caution. First, there is heterogeneity in terms of the research methods used as well as the deﬁnition and ascertainment of key outcomes. As most studies have reported outcomes per fresh or frozen cycle (rather than per woman), there is a risk of clustering of women within cycles that can amplify the imprecision of any results. It is also difﬁcult to rule out a degree of bias in terms of the populations who undergo either fresh or frozen ET. Women in the latter category are, to a great extent, a self-selecting group who tend to be younger, respond better to ovarian stimulation, produce more embryos of quality, and have a better prognosis. There are also major differences among the included studies in the techniques used for cryopreservation (slow freezing or vitriﬁcation), thawing, the stage at which embryos were frozen (cleavage stage or blastocyst), and the choice of natural versus hormonally modulated cycles for frozen ET. The last factor is unlikely to be particularly inﬂuential, as a Cochrane review has failed to reveal any difference in success rates between the two strategies (15). Finally, it is not possible, in this type of meta-analysis, to adjust for confounding factors such as age, smoking, parity, and preexisting health conditions—all of which have an inﬂuential role in determining perinatal outcomes. Wennerholm et al. did adjust for a number of confounders but was unable to do so for maternal smoking and body mass index (9). Interpretation of the above data should also take into account the biological plausibility of the results. Replacement of embryos in a superovulated IVF cycle runs the risk of exposing them to a hostile uterine uterine environment associated with high levels of estrogen and P (16), which can be avoided by transfer in a subsequent natural or hormonally manipulated cycle. A more natural endometrial environment may be more conducive to placentation—thus resulting in lower risk of antepartum hemorrhage (17). A systematic review has shown that elevated P levels during the initial ovarian stimulation phase of IVF is associated with lower pregnancy rates, which can be avoided by elective freezing of the embryos and delayed transfer transfers (18). Although it is very unlikely that freezing and thawing improves embryo quality, these additional procedures could lead to better pregnancy outcomes by ﬁltering out those with poor growth potential.
CONCLUSION Elective freezing of all embryos currently offers beneﬁts that outweigh disadvantages in some women undergoing IVF at risk of OHSS. Our conﬁdence in the results of existing studies suggesting improved maternal and perinatal outcomes after frozen ET is limited by the observational nature of the available data. A genuinely unbiased estimate of the advantages of VOL. 106 NO. 2 / AUGUST 2016
Fertility and Sterility® a policy of elective ET can only be conﬁrmed by a deﬁnitive randomized controlled trial with an adequate length of follow-up of the offspring.
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