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Year : 2020  |  Volume : 3  |  Issue : 1  |  Page : 7-12

Elective frozen embryo transfer – What is the evidence?

Dr. Patil's Fertility and Endoscopy Clinic, Bengaluru, Karnataka, India

Date of Submission25-Dec-2020
Date of Acceptance26-Dec-2020
Date of Web Publication30-Jan-2021

Correspondence Address:
Dr. Madhuri Patil
Dr. Patil's Fertility and Endoscopy Clinic, Bengaluru, Karnataka
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/tofj.tofj_8_20

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Fresh embryo transfer (ET) has been the norm in Assisted reproductive technology (ART) treatment. However, there has been a concern about decreased implantation and pregnancy rates due to altered endometrial receptivity, resulting from the supra-physiological hormonal levels associated with controlled ovarian stimulation (COS). Improvement in embryo survival rates with vitrification has led to an increase in the use of elective freezing of all good quality embryos and transfer in subsequent cycles, i.e., elective frozen ET (eFET). The use of gonadotropin-releasing hormone (GnRH) agonist trigger and segmental in vitro fertilization (IVF) to prevent ovarian hyperstimulation syndrome in hyper responders, has further enhanced the use of e FET. Significantly higher pregnancy rates after frozen-thawed ET in some reports have encouraged wider use of elective freeze-all cycles in ART. Recent studies have shown that in patients with regular menstrual cycles, a freeze-all strategy with GnRH agonist triggering did not result in higher on-going pregnancy rates and live birth rates (LBRs) as compared to fresh transfers with the use of human chorionic gonadotropin for the trigger. There have been no studies comparing fresh verses eFET in poor responders. Significant benefit of e FET has been documented only in hyperresponders. Despite the potential advantages, it seems that e FET is not designed for all IVF patients and a careful patient selection is advocated to derive true benefit from this strategy.

Keywords: Cryopreservation, cumulative pregnancy rate, elective frozen-thawed embryo transfer, freeze-all, fresh transfer, in vitro fertilization/intra-cytoplasmic sperm injection/live birth/ovarian hyperstimulation syndrome, live birth rate, obstetric outcomes, perinatal outcomes, preimplantation genetic testing for aneuploidy

How to cite this article:
Patil M. Elective frozen embryo transfer – What is the evidence?. Onco Fertil J 2020;3:7-12

How to cite this URL:
Patil M. Elective frozen embryo transfer – What is the evidence?. Onco Fertil J [serial online] 2020 [cited 2021 May 10];3:7-12. Available from: https://www.tofjonline.org/text.asp?2020/3/1/7/308409

  Introduction Top

The first live birth after in vitro fertilization (IVF) was reported in 1978 after a fresh embryo transfer (ET),[1] whereas the first live birth after frozen ET (FET) was reported in 1984.[2] Improvement in embryo survival and implantation potential using the vitrification technique for embryo freezing, encouraged the use of FETs in assisted reproduction technology (ART). Embryo cryopreservation is a valuable tool that aids in enhancing ART results by increasing the cumulative conception rate and decreasing the multiple pregnancy rate, through the use of single ET.

In recent years, the use of elective freezing of all embryos with a subsequent FET has become very popular, due to the improved pregnancy rates and safety profile reported. Elective FET (eFET) is advocated in patients with an increased risk of ovarian hyperstimulation syndrome (OHSS), progesterone elevation (PE) on the day of ovulation trigger, fertility preservation for cancer patients or women wanting to postpone pregnancy. Elective FET is also used in personalized Et, which is based on endometrial receptivity array profile in women with recurrent implantation failure (RIF) and when preimplantation genetic testing for aneuploidy (PGT-A) is used as an embryo selection technique.

  Search Methods Top

An electronic literature search was performed in PubMed/Medline and EMBASE to identify all relevant RCTs published from 2010 to 2020 using search terms-Freeze-all, elective frozen-thawed ET, fresh transfer, cryopreservation, live birth rate (LBR), cumulative pregnancy rate,/IVF/intra-cytoplasmic sperm injection (ICSI)/live birth/OHSS, obstetric outcomes, perinatal outcomes, PGT-A. A total of 74 articles were retrieved. Appropriate cross-references were then manually searched.

  The Rationale of Freeze-All Cycles Top

Implantation is a complex process during which the blastocyst becomes intimately connected with the maternal endometrium/decidua. Successful implantation requires a competent embryo at the blastocyst stage, a receptive endometrium, and synchronized dialogue between maternal and embryonic tissues. It is at this stage that an independently developing preimplantation blastocyst becomes dependent on the maternal environment for its continual development. Over the past 40 years of ART treatment and research, major progress has been made in improving stimulation protocols, fertilization procedures, optimizing embryo culture conditions, and preventing premature luteinization, however only a marginal improvement has been achieved in the implantation and pregnancy rates.

Disturbance in embryo–maternal dialog is one of the major reasons (60%) for pregnancy termination at the end of the peri-implantation period. This may be related to the high estradiol levels during controlled ovarian stimulation (COS), that result in the advancement of endometrial maturity.[3] Several studies have reported a negative effect of COS on endometrial receptivity due to an increase in steroid levels[4],[5],[6] and no pregnancies were achieved when the endometrial advancement was over 3 days, especially when progesterone levels were ≥1.1 ng/mL on the day of ovulation trigger.[3] This is related to the negative impact of high late follicular progesterone levels on endometrial receptivity and implantation.[6],[7],[8],[9],[10],[11] Moreover, an increase in uterine contractility encountered in stimulated cycles may contribute to implantation failure or may increase the risk of an ectopic pregnancy.[12],[13]

Horcajadas et al. found that there were over 200 genes related to implantation that were over or under-expressed during COS, when compared to a natural cycle.[5] These changes in the gene expression may be associated with the supra-physiologic hormonal levels observed during COS. The gene expressions were different in patients depending on the progesterone (P4) level on the day of trigger (P4 less or more than 1.1 ng/ml).[6] Those patients who did not achieve pregnancy had endometrial advancement of >3 days with an abnormal histological profile assessed by Noyes' criteria and the gene expression profile.[14] A FET performed in a natural cycle or hormone replacement cycle (HRT) replaces embryos in a more physiological environment, thereby improving implantation potential. This rationale has made many clinics shift to a “freeze for all” policy to achieve a better IVF outcome. However, the evidence supporting a freeze-all strategy in all patients is patchy and controversial. Moreover, there is some evidence for lower risk of low-birth-weight,[15],[16],[17] preterm birth[15],[18],[19],[20],[21] small for gestational age babies[15],[17],[22] after FET when compared to fresh ET.

  Effectiveness of Freeze-All Cycles Top

Most trials and a major meta-analysis conducted have found outcome benefit with an increase in the on-going pregnancy rate only in high responders.[23] Results of FET may vary based on embryo quality, morphology at freezing and post-thaw, cryopreservation procedure which could potentially impair preimplantation development resulting in reduced cell numbers at the blastocyst stage and reduced survival rates after cryopreservation.[24] One also needs to take into consideration the patient dynamics such as age and ovarian reserve and expected ovarian response.

No difference in the LBR between eFET in preference to fresh ET at blastocyst stage with the exclusion of PGT-A cycles has been reported.[25] There was also no significant difference in the cumulative LBR observed between the eFET and fresh ET groups in the overall IVF/ICSI population.[25] The grade and quality of evidence for the above observation were low, due to inter-study heterogeneity.[25] After subgroup analyses superiority of eFET in respect to LBR was seen only in hyper-responders, in whom intramuscular (IM) progesterone was used for luteal phase support (LPS) in FET cycles and in those couples who had undergone PGT-A.[25] This superiority was not evident in normo-responders and even in hyper-responders in whom oral or vaginal progesterone was used for LPS in FET cycles.[25] The reason for the difference in the LBR observed favoring eFET only with IM progesterone administration for LPS could probably be due to insufficient circulating serum progesterone levels achieved with vaginal or oral progesterone only.[26] However, there was one trial which found benefit in normally ovulating subjects.[27] The Chinese trial recently published in 2019 concluded that deferred frozen single blastocyst transfer in normally ovulating women resulted in significantly higher rates of singleton live birth than fresh transfers (50.4% vs. 39.9%).[27] Existing studies for freeze all strategy have not compared a freeze-all strategy using gonadotropin-releasing hormone (GnRH) agonist trigger with a fresh transfer strategy using human chorionic gonadotropin (hCG) trigger.

When comparing eFET with fresh ET, time to pregnancy (TTP) also needs to be taken into account when evaluating efficacy.[28] An RCT by Vuong et al., assessed the TTP in a post hoc analysis of clinical outcomes after 12 months and found that there was an increase in the median TTP in patients undergoing eFET as compared to fresh ET (absolute difference, 1.4 months; 95% confidence interval: 0.95–1.84; P < 0.001).[29] However, a recent multicentric randomized controlled trial (RCT) which compared a freeze-all strategy with GnRH agonist trigger and a fresh transfer strategy with hCG trigger did not show a higher ongoing pregnancy and LBR in normally menstruating women. A longer TTP was also reported in the freeze-all group.[30] Therefore, fresh ET strategy should be used in women with regular menstrual cycles and freeze all strategies should be reserved for women exhibiting a hyper-response. Two more trials published earlier also did not report any advantage of freeze-all over fresh ET in ovulatory patients. The benefit of freeze all was seen only in women with PCOS[29],[31] and high responders.[25]

The Cochrane review and meta-analysis published in 2017 found limited gain with freeze all strategy in high responders, otherwise freeze-all was associated with lower LBRs than fresh ETs.[32] There are a few observational studies but no RCTs comparing fresh ET and eFET in poor ovarian responders. These observational studies have contradictory evidence, with most studies showing no benefit on on-going pregnancy rates and LBR,[33],[34],[35] while one study did show increased implantation and pregnancy rates with eFET in poor responders.[36]

Elective FET is also more effective than fresh ET in patients undergoing PGT-A with trophectoderm biopsy on day 5 after oocyte retrieval.[37] The poor outcome of fresh ET cycle may be related to embryo–endometrial asynchrony as the trophectoderm biopsy is performed on day 5 and ET is done on day 6.[38],[39]

No difference was seen in the incidence of ectopic pregnancy, preterm birth, and congenital anomalies, between patients undergoing fresh ET and eFET.[25] Stormlund et al. reported an increased risk of preterm birth with fresh single blastocyst transfer.[30] However, there were no differences seen in any other complication of the pregnancy in the obstetric, and perinatal outcome analysis.[30] The secondary outcome analyzed in this study was the incidence of OHSS. None of the patients except one had moderate or severe OHSS in the fresh ET group.[30] A multicentric RCT in women with polycystic ovary syndrome observed a trend toward higher neonatal death after FET compared with fresh embryo replacement.[31]

Apart from the clinical outcome there could be damage to the embryo due to low temperature, cryoprotectant used and freezing process per se which are depicted in [Table 1].
Table 1: Effects of embryo cryopreservation

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The results after transfer of cryopreserved embryos can be affected by biological consequences post-thaw of embryo cryopreservation, which include cell loss, arrested/compromised development, altered function/metabolism in the blastomeres and absent further cleavage and blastocyst formation.[40] In a cleavage cell embryo after cryopreservation, there could be decrease in implantation rate with decreased survival of the blastomeres and absence of resumption of mitosis.[40] ET after post-thaw extended culture from for cleavage sage embryos to blastocyst does not eliminate effects of cryo-damage though it reduces the transfer of the damaged and nonviable embryo.[41] Moreover, immediate post-thaw survival is not the only criteria for implantation as in a study by Yamanaka et al. it was observed that 36% of embryos degenerated, 18% got arrested and only 46% resumed development.[42]

The positive predictors of implantation after thawing of blastocyst include re-expansion, hatching, and the absence of extensive cytoplasmic granulation and large necrotic areas. The negative predictors of implantation post-thaw include cytoplasmic granulation, halo-like structure in the periphery of the cells, extensive exclusion of fragments, and presence of large necrotic foci, which are more than half of the inner cell mass.[43] We also need to take into consideration the loss of gametes due to the freezing method used, problem during storage which may result from low liquid nitrogen levels or scarcity of supply, equipment failure, problem with labeling or breach of packaging which may result in contamination.

  Safety of Freeze-All Cycles Top

It was Devroey and Bourgain in Brussels who first promoted the idea of freeze all strategy to eliminate the risk of OHSS in IVF.[44] They concluded that the use of an GnRH agonist trigger in an antagonist cycle eliminates the risk of OHSS.[45] However, fresh ET in agonist triggered cycles are still at risk of late-onset OHSS and compromised PRs.[45] An elective FET in such cases improves IVF outcome with decreased incidence of iatrogenic and potentially lethal OHSS.[44],[45] OHSS rate in a freeze all cycle was between 1% and 3% as compared to 7% in a conventional fresh ET cycle.[32]

One needs to understand that the improved PR's and reduced miscarriages in eFET may come at the cost of increased pregnancy complications.[32] A new cohort study suggests a three-times higher risk of preeclampsia from FET cycles programmed with hormone replacement therapy (HRT) as compared to natural cycles.[46] A possible explanation for this increased risk of preeclampsia relates to endometrial priming with estrogens performed during hormone replacement FET cycles. There is also some evidence for a higher incidence of large for gestational age babies,[21],[22],[30] and higher risk of placenta accreta[15],[47] associated with FET cycles. An association with low pregnancy-associated plasma protein-A levels in eFET cycles has also been reported.[48] The increased risk of hypertensive disorders and macrosomia after eFET in HRT cycles has been related to the absence of a corpus luteum, which plays an important part in maternal cardiovascular adaptation during pregnancy.[49],[50]

Cryopreservation can also result in epigenetic disturbances, imprinting disorders, and altered methylation of genes involved in growth and metabolism that might affect the developmental programming of fetal and placental tissue.[51] It can also affect the integrity of genome.[52] This is caused by increase in reactive oxygen species, use of cryoprotectants, low temperature, incorporation of calcium and zinc molecules in the DNA-protamine complex and intracellular crystallization.[52]

  Safety of Cryopreservation Technique Top

Miles et al. found that children born after IVF using frozen embryos are taller and with higher insulin growth factors 1 and 2 (IGF1 and IGF2) levels.[53] Even though vitrification seems to be the promising trend for successful clinical outcomes, there are still some concerns that need to be addressed. Long-term storage effects and long-term validation data on children born are needed as high concentrations of cryoprotectants have to be used for vitrification. Majority of the articles published on the clinical efficiency of vitrification for human cells utilized open carriers. Hence, liquid nitrogen still remains to be potential source of contamination since the technique is based on direct contact between the vitrification solution containing cryoprotectant agents and liquid nitrogen.[54] Therefore, from the clinical point of view closed system should be used to avoid contamination, especially based on the new regulations.[55] Only one study has verified the clinical efficacy of a noncommercial, aseptic closed vitrification system called microSecure for human embryos.[56] It is a low-cost, non-commercial, aseptic, closed system that offers technical simplicity and is reliable with excellent embryo survival and sustained viability.[56] More RCTs are required to show similar efficiency of closed systems and open carriers for cryopreservation. Probably, in future storage of cells in the vapor phase of nitrogen instead of liquid nitrogen can be an option. The other option to prevent contamination is to sterilize the liquid nitrogen.[57]

  Cost-Effectiveness Top

There are not many studies evaluating the cost-effectiveness of the freeze-all policy. However, freeze-all strategy results in increased cost due to freezing, maintenance of frozen embryos, FET cycle and increased time to pregnancy. Probably freeze-all when compared to fresh ET was more cost-effective in women at a higher risk of OHSS.

  Conclusion Top

The emerging trend of freeze-all is being widely used over the last couple of years as it is considered safe especially in women with increased risk of OHSS and for better embryo endometrial synchrony. Excellent postthaw survival of the embryos has made the freeze all policy a reality. Freeze-all policy has also lead to improved IVF outcome in selected group of patients. However, currently, there is no clinical data that supports the indiscriminate use of freeze-all policy in all patients to increase the implantation rate and LBR. Freeze all strategy may be beneficial in patients at risk of OHSS, in hyper-responders, and in those undergoing PGT-A at the blastocyst stage. The time taken to achieve a pregnancy is also increased with elective FET. The other potential disadvantages of freeze all include degeneration or loss of embryos during the freezing and thawing processes, the added financial costs, increase in the workload of the embryology laboratory, the emotional costs of deferring transfer, increased risks of having a large for gestational age baby and maternal hypertensive disorders. Therefore, the elective FET policy should be individualized depending on the patient profile. There is also not much data available on the long-term effects of freezing on the babies born after elective FET compared to fresh ET. This mandates more studies on eFET to report on follow-up data on the outcome of neonates and children. Thus a fresh ET should be a policy adopted in lieu of elective FET if no apparent treatment advantage or immediate risk of OHSS is present. Rationale to freeze all embryos is compelling but not proven, therefore time, and hopefully, high-quality research with large RCTs, need to establish if we are ready to eliminate the transfer of ''fresh'' embryos in IVF.

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Conflicts of interest

There are no conflicts of interest.

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