Authors: Javier del Río, Noemi Díaz and Belén Gómez
What is cryopreservation?
The first successful in vitro fertilization (IVF) treatment was in 1978. Since that, there have been a remarkable number of advances in assisted reproductive technologies (ART). Initially, all available embryos were transferred in IVF treatments owing to its low success rate. However, improvements on clinical and laboratory aspects led not only to increased pregnancy rates, but also to increased risk of multiple pregnancies. To prevent this, fewer embryos are transferred and leftover embryos are cryopreserved for potential future cycles use (1).
The first pregnancy resulting from transferring a thawed cryopreserved human embryo was reported in 1983 in Australia (2), and the first live birth following embryo cryopreservation was reported in 1984 in The Netherlands (3). Subsequently, the need for an effective cryopreservation program arose from rapid development and improvements of assisted reproductive technology protocols (1).
Cryopreservation is a method that requires cells and embryos to be exposed to non-physiological ultra-low temperatures (from -20°C to -196°C) (Fig.2). It aims to achieve “cryogenic suspension of life” through multiple steps, although this puts the elements at risk of damage or “cryoinjury” during temperature changes and phase transitions. These damages could be chilling injury or ice crystal formation, for instance, as a result of the water exchange between the intra- and extracellular compartments, consequence of dramatic changes in osmotic potential (osmotic shock). Therefore, vitrification requires the use of cryoprotectants to avoid the formation of ice crystals in the cells. Two types of cryoprotectants are necessary: permeating and non-permeating. Mixing both at different relative concentrations reduces intracellular ice formation by removing water from inside the cell. Additionally, it creates an osmotic gradient that helps restrict water movement across the cell membrane, thereby preventing osmotic shock (4).
There are two typical methods used for cryopreservation: slow freezing and rapid freezing to achieve vitrification.
Vitrification is a term used to describe the transformation of a solution into glass by a dramatic increase in viscosity. This method requires to minimize the time for the sample to be exposed to temperature ranges associated with chilling injury and ice crystal formation. As slow freezing, vitrification causes cell dehydration using cryoprotectants. However, unlike that, there is no attempt to maintain equilibrium on both sides of cell membrane (4).
The time frame required to reach ultralow temperatures by vitrification is very brief, almost instantaneous. But, the main concern is the need for using high concentrations of cryoprotectant solutions. These might lead to osmotic shock and it could be toxic to cells, affecting embryo survival. Nevertheless, it is possible to limit toxicity by mixing different cryoprotectants, thereby decreasing their relative concentration and the exposure time of embryos to the solution (5).
How efficient is the vitrification?
This technique seems to be more attractive than slow freezing because it does not require expensive equipment. It uses small amount of liquid nitrogen and it is a simpler technique to perform once the embryologist has gained enough experience in it (6).
A recent research performed by Viladimoiv et al. suggests advantages arising from the freezing and thawing process; the authors hypothesize a theory about “cryo-treatment of the embryo”. According to these authors, as a result of freezing or thawing of the embryos there is a decrease in reactive oxygen species levels, in the rate of mitochondrial DNA mutation and cells detoxification is carried out. Also, the authors describe another mechanism involved in restoring the mitochondrial activity (“jumping effect”) which is part of the physiological process of implantation. However, current available data cannot confirm the hypothesis yet (7).
Advantages and disadvantages of fresh and frozen cycles
Nowadays, fresh embryo transfers (ET) are the most common choice in IVF cycles (8). Nevertheless, in the last years, controlled ovarian stimulation has increased the uncertainty on the possible adverse effects of the ovarian hyperstimulation syndrome (OHSS), and also on possible deleterious effects on the endometrium and implications in obstetric and perinatal results (9).
In spite of this, recent developments in cryopreservation of oocytes and embryos have led to substantial improvement in IVF outcomes. This resulted in a significant increase in the number of cycles with frozen embryo transfer (FET), which subsequently led to the enhancement of live births rate (10).
What are the advantages of a frozen cycle?
Ovarian hyperstimulation syndrome
The first strong argument for FET strategy is the prevention of OHSS, that results from an increase in vascular permeability (11,8). OHSS is a medical condition affecting the ovaries of some women who take fertility medication to stimulate oocyte growth. OHSS arguably remains a major cause of morbidity in IVF treatment (10).
During a fresh cycle, a woman has to undergo hormonal treatment to regulate her menstrual period, to stimulate the development of multiple oocytes (superovulation), and to encourage their maturation (11, 12). However, in a frozen cycle (FC) the patient does not have to go through ovarian stimulation or egg retrieval depending on their circumstances (13). Many people find that FETs are less stressful than fresh cycles because they do not have to worry about oocytes production or whether there will be viable embryos, since those procedures have already been done (9).
Deleterious effects on the embryo
The optimization of vitrification protocols has reduced the deleterious effects that this process may produce in embryos. Also, it have been observed similar survival and embryo development in FCs compared to fresh cycles (10). Moreover, best quality embryos, morphologywise, can be stored and transferred in a future cycle in better conditions. These data have allowed for an increment of success rates and the confidence of sanitary personnel and patients over FCs (5).
The implantation process, one of the crucial steps in the success of ART, requires a reciprocal interaction between the embryo and the endometrium during a small period of time called window of implantation. This interaction involves the embryo, along with its inherent molecular program of cell growth and differentiation, as well as differentiation of endometrial cells into an adequate uterine receptivity (11). Some patients may find easier to turn to FCs, since dealing with the whole process of medication during a normal cycle for ovarian stimulation may result psychologically and emotionally overwhelming. In this regard, FC may also provide a better outcome (3).
The importance of an adequate endometrial environment in ART is highlighted in those patients who resort to oocyte donation, where there must be a synchronization between donor and recipient in fresh cycles. Those cases that require an improvement in endometrial receptivity to stimulate implantation of these donor oocytes seem to obtain better results in frozen cycles or in the next fresh cycle (8).
Multiplet pregnancies are one of the major safety concerns of IVF due to the increased risk of neonatal and maternal complications. To achieve good results, to would be ideal to select the optimal single embryo to be transferred. Elective single embryo transfer (eSET) is the most effective way to reduce those risky pregnancies (14).
How can cryopreservation damage embryos?
Upon analyzing some ART studies and results, embryos are able to adapt and develop in a large range of culture media, showing different gene expression models in different environments. Cryopreservation causes stress in embryos and it is known as “hormesis”(5) (Fig.3).
However, if the conditions are too unfavorable or toxic, mitochondrial activity is suppressed below the threshold necessary for the development of the embryo, so that implantation in the endometrium will be affected (5).
Results of embryo transfer in fresh cycles vs. frozen cycles
The main current objective of IVF professionals is to improve pregnancy rates in both fresh and frozen-thawed cycles. It is clear that embryo and endometrial receptivity are important factors to promote pregnancy rate. Recently, many researches showed FET can enhance the embryo utilization rate and improve the success rate in contrast to other research lines (15).
In Roque et al. systematic meta‐analysis for 633 cycles in women aged 27-33 years old showed that FET resulted in a statistically significant increase in the ongoing pregnancy rate and clinical pregnancy compared with the fresh transfer group (8). Interestingly, the fresh group showed a higher miscarriage rate, but no statistical difference was found when compared with the frozen group. According to these data, it seems that the results of IVF-ICSI cycles can be improved by performing the FET especially in patients with normal or high follicular response. This advantage could be explained thanks to a more physiological preparation of endometrium. Several studies have also shown good results with cryopreservation of all embryos and subsequent FET in those patients most susceptible to develop OHSS (8, 16-19).
In contrast, Shavit et al. found lower rates of clinical pregnancy and live births in the vitrified-warmed blastocyst group. The difference in implantation and pregnancy rates could be attributed to a higher proportion of good-quality embryos in the fresh blastocysts transfer group. They suggest that in fresh cycles highest quality blastocyst is selected for transfer and the rest are usually vitrified. Thus, vitrified-warmed blastocysts may have slightly poorer grade after warming and prior to transfer (20).
In addition, it is necessary to take into account those cycles with frozen oocytes. Braga et al. found that warmed oocytes transferred in endometrial prepared cycles yield better clinical outcomes than fresh ETs. Indeed, they found that fertilization rate, embryo quality, and developmental competence was decreased in embryos derived from vitrified oocytes (12). Conversely, previous studies have suggested that the results of oocyte vitrification followed by ICSI are not inferior with regard to fertilization, embryo developmental competence, pregnancy rates, and live birth (21, 22, 23).
An interesting point found in Braga et al. research is that even with lower embryo developmental quality, warmed oocytes transferred in endometrial prepared cycles resulted in higher pregnancy and implantation rates compared with transfer in fresh cycles. This finding strongly suggests that controlled ovarian stimulation impacts endometrial receptivity, which may be a possible cause of implantation failure after ovarian stimulation (12). Indeed, some studies have suggested that pregnancy rate is inversely related to serum progesterone levels on the day of hCG administration (24-27). It has been demonstrated that elevated progesterone levels on hCG trigger day negatively influence the pregnancy, regardless of the oocyte quality. Raised concentrations of progesterone in the late follicular phase are likely to influence the secretory changes of the endometrium, leading to an asynchrony between embryo and endometrial dialogue, which may result in reduced implantation rate (12).
Another issue to consider is the obstetric and perinatal outcomes of frozen-thawed cycles. Maheshwari et al. quantified in a meta-analysis the obstetric and perinatal risks for singleton pregnancies after FET and compared it with those after fresh embryo transfer (28). They indicated better perinatal outcomes in singleton pregnancies after the transfer of frozen‐thawed embryos when compared to fresh IVF embryos. This could be explained by antepartum hemorrhage, very preterm birth (delivery at <32 weeks), preterm delivery (delivery at <37 weeks), small for gestational age, low birth weight (birth weight <2500 g), and perinatal mortality significantly lower in women who received frozen embryos than those transferred with fresh embryos (29, 28).
It is important to note that most studies comparing perinatal outcome of singleton births conceived after fresh and cryopreserved ETs included both single and multiple ETs. Therefore, part of the adverse perinatal outcome may be attributed to the vanishing twin phenomenon, which occurs in up to 10% of multiple ETs resulting in a singleton live birth (20).
What can we conclude?
Elective embryo cryopreservation followed by single FET has attracted increasing attention and has been regarded as a potential innovation of IVF treatment. Choosing the well-selected embryo could further increase the chance of live birth of a eSET, which is of high clinical significance. However, there are great gaps in the literature about the risk/benefit ratio of this strategy, which includes multiple steps of treatment (30).
The good outcomes in FC might be associated with having a well‐balanced embryo‐endometrium interaction in FC, and also with lacking controlled ovarian hyperstimulation, which may adversely affect endometrial receptivity during fresh IVF cycles. In addition, when hormone replacement cycles were applied in FETs, estrogen and progesterone were given in physiological doses to mimic natural cycles, while supraphysiological doses of gonadotropins were given in fresh cycles (31).
On the other hand, other authors find fresh cycles as the best choice, especially in patients who resort to oocyte donation. In fact, it seems that there is a higher proportion of good-quality embryos in fresh blastocysts compared to vitrified-warmed blastocysts, which may have slightly poorer grade after warming and prior to transfer. (8, 20).
In conclusion, each case must be individualized in relation to clinical characteristics of the patients and to oocyte, seminal and embryo quality. By doing so, results will be optimized in each cycle and the chances of achieving a live birth will be highly improved.
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Authors: Shuyana Deba, Javier Del Río, Isabel Sánchez and Sara Sanz
Fertilization is a sequence of coordinated events that results in the metabolic activation of the ootid (nearly mature oocyte) and triggers cleavage of the zygote (2).
Nowadays, in assisted reproduction laboratories cleavage can be evaluated in vitro and in real time. Once in vitro fertilization (IVF) has been accomplished, early development of the embryo can be recorded by using time-lapse systems (TLP) (3). This approach makes it possible to evaluate morphology, including dynamic parameters, based on the uninterrupted culture of the embryo, which also allows for a better embryo selection, thus rising pregnancy rates (4). Even so, there are still clinics all over the world that select embryos for transfer using light microscopy, which means the use of a conventional incubation method (5).
CRITERIA FOLLOWED FOR EMBRYO CLASSIFICATION
It is known that an international consensus is needed in the way embryos are assessed and described. The following standardized criteria is from Alpha Scientists in Reproductive Medicine and ESHRE Special Interest Group of Embryology, 2011 and includes ‘minimum standards’ for oocyte and embryo morphology scoring (6): the current expected observation for embryo development is 4 cells on day 2 and 8 cells on day 3 after fertilization (day 0). Moreover, embryos with <10% fragmentation, stage-specific cell size and not multinucleated are considered of good quality (6).
According to this consensus, scoring for day 4 (morula stage) regards as good embryos those that enter into a fourth round of cleavage, which implies evidences of compaction that virtually involve the whole volume of the embryo (6). Finally, on day 5 blastocysts are to be observed expanded with: a prominent inner cell mass (ICM) consisting of many cells, compacted and tightly adhered together; and a trophectoderm (TE), forming a cohesive epithelium (6).
Nevertheless, these parameters do not restrict laboratories to annotate further observations in order to select the best embryo for transfer (6).
BEST DAY TO PERFORM EMBRYO TRANSFER
One of the most important aspects that influence the success of ART is embryo transfer from the culture medium to the uterus (7). This has been a controversial subject that still generates quite some doubts. Morphological evaluation of embryos is sometimes a subjective process, and it provides limited information on the possible genetic abnormalities that embryos may have (8). Currently, there exists a great controversy on the optimal moment to carry out embryo transfer.
IN WHICH CASE DOES THIS TRANSFER USUALLY TAKE PLACE?
Day 2 transfer is usually indicated in cases of poorly responding patients. Indeed, it is also indicated when the sperm, oocyte and/or embryos are also of low quality and/or number (9, 10, 11).
WHAT DO EXPERTS SAY?
Several retrospective studies have compared embryo transfer on day 2, day 3 and day 5 after oocyte recovery, all of which presented conflicting results. A study performed by Mahdavi et al. among poor responder patients revealed no clinical differences between day-2 and -3 embryo transfer (10). However, this study found that pregnancy rates per oocyte retrieval and embryo transfer were significantly higher in the day-2 embryo transfer group compared to day 3 group. It is worth mentioning that other investigators did not find significant differences in pregnancy outcomes when they compared embryo transfer on day 2 and day 3 (11, 12).
Additional results from other studies have revealed higher clinical and ongoing pregnancy rates after embryo transfer on day 2 than on day 3 in poor responders. This suggests that the occurrence of miscarriage can be reduced by restricting embryo culture to only 2 days, which could also provide an alternative for managing poorly responding patients (11). That is the reason why embryo transfer on day 2 is still performed in many IVF centres; there is an actual risk of compromising the viability of embryos by prolonged in vitro culture in sub-optimal conditions, with an increased risk of obtaining no blastocysts to replace on day 5 (9, 13, 14).
Even though there seems to be a large number of benefits for these patients, certain disadvantages that may potentially occur must also be taken into account, as it can be seen below (Table 1).
PATIENTS IN WHICH TRANSFER D+3 SHOULD BE PERFORMED
There exists no criterion to select patients who should be transferred on D+3. Traditionally, embryo transfer has been performed on cleavage stage, so the chosen day was D+3 of embryo development (7). Generally speaking, embryo transfer was carried out on this day in all patients, until a culture medium was developed that allowed to keep embryos in the laboratory for 5-6 days, and with the exception of the cases previously mentioned (11).
SCIENTIFIC LITERATURE TO SUPPORT D+3 AS THE BEST DAY FOR EMBRYO TRANSFER
Many studies show contradictory results on whether it is better to transfer on D+2 or D+3. However, there are no significant differences as for implantation, clinical pregnancy or live birth rates when comparing transfer on these days. A study by Modares et al. (15) with patients under 40 years old showed a slight improvement in these results when transferring on D+3, although differences were not significant. The authors also showed embryo quality to be worse when the transfer was performed on D+3 than on D+2. Thus, implantation rate has been observed to be higher in D+3, because extending embryo culture for one day allows to discard those embryos that stop their development from D+2 to D+3 (16, 17).
Furthermore, it is necessary to consider that there are other external factors that affect embryo development and, consequently, the selection of the best day to transfer. Quinn et al. (18) determined that one of these factors is culture media. Thus, in sub-optimal lab conditions, it would be interesting to transfer on D+2 rather than D+3, in order to spend the shorter time possible in the media.
Regarding D+5 transfer, some studies have shown higher implantation rates in embryos transferred on the blastocyst stage compared to those transferred on D+3 (cleavage stage). However, it is necessary to consider that only 25% of embryos reach the blastocyst stage (15); this implies that the number of embryos transferred and vitrified in a cycle is lower than for D+2 and D+3. As a consequence, when considering cumulative pregnancy rates no significant differences are found between transferring on cleavage stage and blastocyst (7).
Again, benefits for the patients must be considered along with potential disadvantages (Table 2).
It has been observed that transfer on blastocyst stage helps to improve pregnancy rates and reduce the risk of a multiple pregnancy. Why? One reason might be that there is no method to determine whether embryos that initially seem to be of good quality are likely to develop up to blastocyst (19).
WHO ARE THE IDEAL PATIENTS?
1. Those with a large number of embryos (20).
2. Those whose day-3 embryos are of good quality (20).
3. Those in which day-1 embryos exhibit pro-nuclei and present a grading profile (20).
4. Young women with good ovarian response (21).
5. Those whose embryos display an early cleavage (22).
POTENTIAL BENEFITS OF BLASTOCYST-STAGE TRANSFER vs. CLEAVAGE-STAGE TRANSFER
First of all, the new culture media allow us to perform longer incubations in the laboratory, after which the best embryos can be selected with higher accuracy and with lower risk of aneuploidies (23). Moreover, there will exist a better synchronization between the embryo and the mother. Additionally, uterine contractility decreases during the luteal phase (24, 25). The size of these blastocysts is bigger, so some studies have found fewer cases of ectopic pregnancies in comparison to transfers on day 3 (26).
A parallel comparison of benefits vs. disadvantages for this procedure can be seen in below (Table 3).
IS IT BETTER TO TRANSFER ON DAY 5 OR ON DAY 6?
The optimal time for embryo transfer depends on a variety of factors, such as the embryo growth speed. However some studies have revealed both implantation and pregnancy rates to be more successful when embryos are transferred on day 5 compared to day 6. This is due to the fact that viability of embryos expanded on day 5 is higher than for those expanded on day 6 (30).
In conclusion, it seems difficult to define the most appropriate day for embryo transfer to be applied for each patient. Therefore, every single case must be individually analyzed. In addition, several factors should be taken into account when deciding on the day for embryo transfer, such as maternal age, sperm and oocyte quality or physiological response of the woman and/or the available embryos. By doing so, a good decision can always be made in order to improve implantation and pregnancy rates.
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