What is the difference between fresh and frozen embryo transfers?

The key difference between a frozen and fresh embryo transfer cycle is whether the embryos were cryopreserved or not. There is also another difference: in a fresh embryo transfer, the embryo is transferred during the same cycle in which the ovaries were hyperstimulated; that is, the patient took medication intended to stimulate the ovaries to produce more than one mature egg in preparation for egg retrieval. For frozen embryo transfers, the embryo is transferred in a different cycle from ovarian stimulation.

There has been a significant increase in the number of frozen embryo transfer cycles being performed in the last decade for several reasons:ⁱⁱⁱ

• Better cryopreservation techniques
• Improvement in embryo culture media (the nutrient-rich fluid in the petri dish in which the embryos develop)
• Providers choosing the “freeze-all” strategy to avoid ovarian hyperstimulation syndrome
• More patients undergoing embryo banking for fertility preservation or family planning
• Advancements in preimplantation genetic testing (PGT)

Fresh embryo transfer

The transfer of fresh embryos usually occurs five days after egg retrieval and fertilization, with the day of retrieval and fertilization referred to as “Day 0.” In some cases, embryos may be transferred earlier, on Day 3. (Although less common, embryos can be transferred on other days of the cycle as well.) A Day 3 embryo, also called a cleavage-stage embryo, has approximately six to ten cells in total. A Day 5 embryo has approximately 150 to 200 cells and is also called a blastocyst.^iv Any viable embryos that are not transferred on these days can be cryopreserved (frozen).

Frozen embryo transfer

Frozen embryos must be thawed prior to being transferred. Overall, this process is now very safe. Advancements in cryopreservation and thaw techniques have increased the chance of embryos surviving the freezing and thawing process (called thaw survival rate).^v

The most important advancement in cryopreservation is a technique called vitrification. Vitrification involves freezing the embryos^vi using cryoprotecting agents to reduce the amount of water in the cell, which minimizes the formation of ice crystals that could damage the embryo. On average, 95 to 98 percent of frozen embryos survive the thaw after vitrification.^vii,viii The previously used technique of slow-freezing embryos had much lower embryo survival rates.

The frozen embryo is usually thawed and prepared (post-thaw culture) on the day of the transfer procedure, a few hours before a patient arrives for the transfer appointment.  Embryos that were frozen on Day 3 at the cleavage stage may undergo an additional culture to reach blastocyst development before being transferred. However, most clinics now prefer to freeze embryos at the blastocyst stage and thaw them on the day of embryo transfer, usually in the morning.^ix

Following the thaw, the clinic will evaluate whether the embryo survived the thaw and may re-grade the embryo. The embryologist will look at whether the embryo is still intact, referring to the percentage of cells that are still viable, and ensure there are no signs of injury to the zona pellucida. When less than 50 percent of the embryo’s cells survive, the embryo is usually deemed unviable and not suitable for transfer — in other words, it did not survive the thaw.^x

Assisted hatching

The freezing process tends to harden the outer shell of the embryo (called the zona pellucida), so a procedure called “assisted hatching” is usually applied to thawed embryos. Assisted hatching involves using a laser to create a hole in the zona pellucida to help the embryo hatch out of its shell and better implant in the uterus at the time of transfer.

In contrast, laser-assisted hatching is optional for fresh embryo transfers. According to the latest American Society for Reproductive Medicine (ASRM) guidelines (2022), it does not appear that laser-assisted hatching improves live birth rates in the general population of IVF patients. Furthermore, the published evidence has mixed results as to whether laser-assisted hatching improves live birth rates in patients with a poor prognosis and in frozen transfers.^xi

Embryologists also use assisted hatching when performing embryo biopsy for preimplantation genetic testing (PGT). Hatching allows the embryos to come out of the zona pellucida to allow for biopsy of the trophectoderm (the outer cells of the embryo destined to become the placenta) and not the inner cell mass (the cells destined to become the fetus).

How are fresh and frozen embryo transfers similar?

The pregnancy rates after thawed embryo transfer are similar to the rates after fresh embryo transfer, as discussed in detail below. Both fresh and frozen embryo transfers usually require the patient to take additional progesterone and often supplemental estrogen.^xii In addition, some clinics may perform a “mock embryo transfer” in advance of either fresh or frozen embryo transfer to help ensure the procedure will run smoothly.^xiii Mock embryo transfers involve using an empty catheter (with no embryo inside) to measure the path through the cervix and to the top of the uterus, to mimic what would occur during the actual transfer.

Guidelines on the number of embryos to transfer are the same for both fresh and frozen transfers: the ASRM recommends transferring one embryo (known as elective single embryo transfer) in most cases to minimize twin pregnancies.^xiv

The transfer procedure itself is identical for fresh and frozen embryo transfers. In both cases, the patient is lying on their back with legs raised (knees bent and calves supported by padded leg supports). A speculum is inserted into the vagina, and a soft transfer catheter that contains the embryo(s) is passed through the cervix and into the upper portion of the uterus. The embryo(s) are gently injected from the catheter into the uterus under ultrasound guidance. The ultrasound may be on the abdomen, requiring a full bladder, or in the vagina, requiring an empty bladder. There is usually no anesthesia given and the patient goes home the same day.^xv Patients can often watch the transfer process on an ultrasound monitor or TV screen. Embryo transfer is usually not uncomfortable and, in most cases, does not require any pain relief.^xvi

Why choose fresh embryo transfer?

There are various reasons that a patient may prefer a fresh embryo transfer including costs, travel time to the clinic, fear of losing the embryo due to cryopreservation, embryo quality, and more. (Reasons related to success rates are discussed in a later section.)

Cost and logistics

For some patients, cost is one reason to choose fresh transfer. Fresh embryo transfers usually cost less because the fresh transfer is included in a clinic’s IVF treatment package, whereas a frozen embryo transfer comes with additional fees. Clinics may charge extra for the embryo cryopreservation, annual embryo storage fees (to keep the embryos frozen), thawing, the laser-assisted hatching procedure, and the frozen transfer itself. Because the transfer is done in a later cycle, patients may also have to pay for additional endometrial priming medications and cycle monitoring.^xvii

Cost and time factors can be especially relevant for individuals travelling out of town or overseas to receive IVF treatment. Choosing a fresh transfer within days of the egg retrieval would reduce the number of trips to the fertility clinic.

Cryopreservation concerns

A patient may choose a fresh embryo transfer if they have only one (or a small number) of viable, good-quality embryos after going through the egg retrieval and IVF process. A fresh embryo transfer would minimize the potential for the loss of any embryos through cryopreservation and thawing.^xviii

The cryopreservation process mainly involves cooling the cells of the embryo down to sub-zero temperatures to stop all biological activity and save the embryo for a future transfer. Despite advancements in the cryopreservation technique, concerns remain regarding the impact of the freeze-thaw cycle on embryo quality and the potential to lose embryos during the process. Currently, there are several protocols that exist for the freezing and thawing process involving different cryoprotectants (chemical agents that protect cells against the formation of ice crystals and cell death due to freezing). This lack of standardization can lead to inconsistency between frozen embryo transfer survival rates across clinics.^xix It is important for patients to discuss anticipated embryo thaw survival rates with their doctor.

Low-grade embryos

Clinicians and embryologists often will not freeze low-quality embryos, such as grade CC blastocysts, due to reduced chance of thaw survival and/or implantation.^xx As such, some patients may choose to transfer them fresh instead of discarding them, especially given that low-grade embryos can still be euploid (genetically normal) and lead to healthy live births.

One study showed that although the live birth rate of “C” grade embryos was lower than that of “A” or “B” grades, transfers of CC embryos still resulted in an overall live birth rate of 13.3 percent.^xxi Although this was one third of the live birth rate of AA embryos, it highlights that many CC graded embryos lead to live birth.^xxii Another study had similar results, with live birth rates of 17 percent from CC grade embryos.^xxiii The researchers suggest that CC blastocysts should be transferred and not discarded, especially for infertile females.^xxiv These findings may encourage females with low-grade blastocysts to transfer them in a fresh transfer as opposed to discarding them or risking losing them in the freeze-thaw process.

Maternal age

Females may also decide on a fresh embryo transfer because of advanced maternal age. As more females are choosing to delay childbearing, there is a time constraint involved with delaying an embryo transfer to a subsequent cycle after egg retrieval and fertilization. Patients may not want to increase their age at delivery any further. In addition, embryos from females over 40 years old may be more fragile (because they were created from older eggs), and some patients may be worried about losing embryos during the freeze-thaw process.

One study by Chen et al compared pregnancy outcomes in 720 females of advanced maternal age (375 receiving a first fresh embryo transfer vs. 345 receiving a first frozen embryo transfer).^xxv The clinical pregnancy rate was significantly lower in the frozen embryo transfer group (26.4 percent for frozen vs. 33.6 percent for fresh), though there was no difference in live birth rate between fresh and frozen transfers.^xxvi

Why choose frozen embryo transfer?

For patients who undergo a fresh embryo transfer and have extra embryos left over, cryopreservation allows them to store the remaining embryos for transfer at a later date (as frozen embryo transfers) if the first transfer was unsuccessful or when they are planning another pregnancy.^xxvii

Alternatively, when all off the embryos created in an IVF cycle are cryopreserved to be transferred in a later cycle, it is called a “freeze all” strategy.^xxiii There are various reasons why a provider or patient may choose the freeze-all approach. If a patient’s progesterone level rises or her estrogen levels are too high, frozen transfer is preferred. Providers may also choose to freeze all embryos to minimize the risk of ovarian hyperstimulation syndrome (OHSS), to improve endometrial receptivity, or when planning preimplantation genetic testing (PGT). There are also elective reasons such as banking embryos for family planning. (Reasons related to success rates are discussed in a later section.)

Reduced risk of ovarian hyperstimulation syndrome

One advantage of transferring a frozen embryo later is reducing the risk of an overreaction to the fertility drugs, known as ovarian hyperstimulation syndrome (OHSS), which can occur after a fresh embryo transfer.^xxix OHSS is a condition in which patients experience fluid collecting in the abdomen and lungs, electrolyte abnormalities, and an increased risk for blood clots. The risk of OHSS is significantly reduced with a freeze-all approach.

Endometrial receptivity

Another advantage of frozen embryo transfers is that the uterine environment may be more normal without the effects of the ovarian-stimulation medication (i.e., follicle-stimulating hormone and luteinizing hormone) taken before egg retrieval. The medication usually leads to high estrogen levels, which can impact the endometrium (the lining of the uterus in which the embryo implants). Studies have shown that controlled ovarian stimulation may potentially have a negative effect on endometrial growth and receptivity,^xxx depending on hormone levels, egg counts, and patient history.

Females that typically have a thin endometrium around the time of transfer may benefit from frozen embryo transfer. Adequate growth and development of the uterine lining is mainly affected by estrogen, and endometrial thickness has been associated with implantation rate. Since IVF medications impact estrogen levels, they have the potential to interfere with endometrial maturation and receptivity, and hence implantation rate.^xxxi

Some studies have suggested that hormone replacement therapy in a frozen embryo transfer cycle may allow for better endometrial receptivity in patients with a thinner endometrium. For example, a study by Guo et al (2020) demonstrated that females with a thin endometrium had significantly higher live birth (31 percent vs. 18 percent), clinical pregnancy (40 percent vs. 26.4 percent), and biochemical pregnancy (46.2 percent vs. 32.9 percent) rates after receiving a frozen embryo transfer compared to the group that received a fresh embryo transfer.^xxxii

When embryos need to be pushed to Day 6 or Day 7 to reach the blastocyst stage, these embryos will be frozen instead of transferred fresh, since evidence shows that Day 6 fresh blastocyst transfers have lower success rates compared to Day 5 fresh transfers.^xxxiii This lowered success rate is believed to be a result of the endometrial receptivity being out of sync with embryo development (since the embryos took one extra day to reach the blast stage, meaning one day past the optimal day for transfer). Freezing the embryos would allow patients to transfer them back to the uterus in a later cycle on a better day for the endometrium to receive them.^xxxiv

Preimplantation genetic testing (PGT)

A frozen transfer is necessary when patients choose to do preimplantation genetic testing (PGT), because patients need to wait for the results to come back before they can proceed with a transfer. Results are not usually available for two to four weeks, necessitating a frozen embryo transfer.

Embryo banking

Other patients may choose to undergo several cycles of egg retrieval and store all of the embryos created until they are ready to get pregnant, or until they feel they have enough embryos “banked” to complete their family. Banking allows for more embryos to be created when the patient is younger, with better egg quality, compared to waiting until after a first baby (or after a series of failed transfers) to do a second egg retrieval.^xxxv,xxxvi In this case, the frozen embryo transfer may happen years after embryo creation.

This process of embryo banking obviously necessitates frozen embryo transfers and is generally more common in patients starting their fertility journey at a later age and/or with diminished ovarian reserve (DOR). This same approach applies to patients banking embryos due to upcoming medical treatments, such as cancer-related surgery, chemotherapy, or gender-affirming therapy.

Personal and logistical reasons

Patients may choose a frozen embryo transfer because of personal reasons, such as the desire to schedule a transfer on a date that is more convenient for them instead of three or five days after their egg retrieval.^xxxvii Some individuals may find the process of controlled ovarian stimulation physically and emotionally challenging and want a break before transferring an embryo. As such, they choose to freeze their embryo(s) and wait until a later cycle after they have had time to rest, both physically and mentally.

Success rates of fresh vs. frozen embryo transfers

Patients often ask the question “Should I do a fresh or frozen embryo transfer?” because they want to optimize their chance of success. Several studies have attempted to compare reproductive and IVF outcomes between fresh and frozen embryo transfers. The results between studies are not always consistent, but the overall trend across published research shows that the clinical pregnancy and live birth rates are similar for fresh and frozen embryo transfers for patients with normal response in an IVF cycle. As such, each patient should discuss their specific case with their physician. The results from various studies and meta-analyses are described below.

U.S. IVF clinics report outcome data to the Centers for Disease Control (CDC), which compiles an Annual National ART Summary Report.^xxxiii Historical trends favored fresh transfers. However, as cryopreservation techniques have improved, FETs have become more successful compared to transfers performed after previous slow-freezing methods. Comparing recent data on fresh versus frozen transfer using a patient’s own eggs would be misleading since FETs include transfers after preimplantation genetic testing (PGT), which would skew the results in favor of FET. However, a good comparison is examining donor egg fresh embryo transfers versus donor egg frozen embryo transfers. For example, from the 2015 annual report, the percentage of transfers resulting in live births was 55.6 percent for fresh transfers using donor eggs, versus 42.3 percent for frozen transfers using donor eggs.^xxxiv Data on fresh versus frozen transfer results with donor eggs was not reported in the annual summaries from 2016 onwards. In contrast, other studies show no differences in outcomes between fresh versus frozen transfers, as discussed below.

A recent randomized controlled trial of over 600 females compared individuals randomly assigned to undergo a fresh transfer to individuals randomly assigned to receive a frozen transfer.^xl The study included females ages 18 to 42 with at least three good-quality Day 3 embryos who were undergoing their first, second, or third IVF/ICSI cycle. (People using donor sperm or donor eggs, individuals doing PGT, and patients planning for freeze-all cycles were not included in the study.) The live birth rate was higher in fresh transfers (34.3 percent) compared to frozen embryo transfers (28.3 percent), but this difference was not statistically significant.^xli The data also showed that the freeze-all approach was less cost effective.

Similarly, a Cochrane meta-analysis using data from eight randomized control trials, which included a total of 4,712 females undergoing cleavage-stage and/or blastocyst transfer, reported no significant difference in cumulative birth rate between the freeze-all strategy (58 percent) and fresh embryo transfer (57 to 63 percent).^xlii The authors report there is little evidence to support that one strategy is better than the other in terms of live birth rate and ongoing pregnancy rate.^xliii

A randomized controlled trial published by Shi et al (2021) assessed 2,157 females who underwent their first IVF cycle with either fresh or frozen embryos (up to two cleavage-stage embryos were transferred per patient).^xliv They reported no significant differences in the live birth, implantation, clinical pregnancy, overall pregnancy loss, and ongoing pregnancy rates between the two groups. As expected, females undergoing frozen transfer had a lower rate of ovarian hyperstimulation syndrome.^xlv

When looking at annual summary statistics across European clinics, similar clinical pregnancy rates are reported for both fresh and frozen transfers. The European Society of Human Reproduction and Embryology (ESHRE) collects assisted reproductive technology data generated by national registries, clinics, and professional societies. The 2018 report included 1,422 clinics across 39 countries and more than 1 million treatment cycles.^xlvi In the past (from 1997 to 2016), delivery rates were higher for fresh embryo transfers. However, in 2017 and 2018 delivery rates per transfer were similar between fresh and frozen embryo transfers using patients’ own eggs. (They were both approximately 25 percent.)^xlvii

Situations in which frozen embryo transfer success rates are higher

Under certain conditions, studies have shown higher pregnancy rates with frozen embryo transfer. One of these situations is when a patient’s progesterone levels elevate during IVF cycles, which may shift the time when the endometrium is ready for an embryo to implant. This shift may decrease pregnancy rates with fresh transfer. Two studies compared IVF outcomes of Day 3 fresh versus frozen embryo transfer cycles in which patients’ progesterone levels were elevated (>1.5 ng/mL) on the day of their trigger shot (an injection taken approximately 36 hours before egg retrieval). Both studies observed significantly better IVF outcomes in the group using the freeze-all strategy compared with the group completing fresh embryo transfers.^xliii,llix

The effect of elevated progesterone on Day 5 fresh embryo transfers, which are now much more common than Day 3, has also been assessed. Some studies examining Day 5 fresh embryo transfers in females with elevated progesterone found no statistically significant difference between the fresh and freeze-all groups, whereas others found better outcomes for the freeze-all approach when serum progesterone was elevated.^{l,li,lii,liii} As such, doctors may suggest frozen transfers when a patient’s progesterone levels are prematurely elevated in a cycle.

Another situation in which frozen embryo transfer is preferred over fresh transfer is when a patient has a high number of eggs retrieved, which may mean the patient has high estrogen levels. These high hormone levels are thought to be harmful to the growth of the uterine lining. In a study of patients with polycystic ovarian syndrome (PCOS) completing Day 3 embryo transfers, researchers found that frozen embryo transfers were associated with a higher rate of live birth than fresh transfer cycles.^liv A 2020 study found that patients under age 37 with more than 11 eggs retrieved had higher cumulative live birth rates using a freeze-all strategy compared to individuals who used fresh blastocyst transfer.^lv They did not observe the benefit of a freeze-all strategy in patients who retrieved less than 11 eggs.^lvi

A recent study also promoted FET over fresh transfer. A 2019 randomized controlled trial by Wei et al involving 1,650 females with regular menstrual cycles undergoing their first IVF cycle reported higher rates of singleton live births associated with a frozen single blastocyst transfer compared to a fresh single blastocyst transfer.^lvii

How long can frozen embryos be stored before transfer?

Patients often ask how long vitrified (frozen) embryos can be stored. Whether or not a long time in storage worsens pregnancy rates or outcomes is unclear, and the evidence is inconsistent.^{liii,lix,lx,lxi} There is some evidence to suggest that storing frozen embryos for more than six years could decrease thaw survival rates and clinical pregnancy rates.^lxii On the other hand, other studies have not found a negative impact of storage length on outcomes,^{lxiii,lxiv,lxv} but more research is needed to clarify.

Pregnancy and birth complications after fresh vs. frozen embryo transfers

Another factor patients often consider is whether there is any difference in obstetric outcomes (pregnancy-related complications) or perinatal outcomes (such as preterm birth, stillbirth, or newborn death) between fresh and frozen transfers. The research on these issues has conflicting results.

A systematic review and meta-analysis evaluating six clinical studies reported an increased risk of pregnancy complications after frozen embryo transfer compared to fresh transfer. These complications included pregnancy-induced hypertension, pre-eclampsia, and placenta accreta.^lxvi Further, a 2020 Cochrane meta-analysis found that among 4,172 females undergoing IVF transfers, the freeze-all strategy may have increased the risk of pregnancy hypertension and large‐for‐gestational‐age babies, although the authors cautioned that more research is required for confirmation.^lxvii

In contrast, one recent study by Herman et al compared females who had done a fresh transfer with one embryo and a frozen transfer with another embryo at a different time. The study did not find evidence for differences in obstetric and perinatal outcomes (including birthweight, small-for-gestational-age babies, and preterm birth) between a single fresh versus frozen embryo transfer in the same female.^lxiii They compared 107 fresh transfer pregnancies matched to 107 frozen transfer pregnancies with live singleton deliveries after at least 24 weeks of gestation and concluded that siblings delivered after fresh and frozen embryo transfers had similar prognosis and development.^lxix

In addition, the randomized controlled trial by Wei et al (described above) also reported that the risks of OHSS, pregnancy loss, other obstetric complications, and neonatal morbidity (newborn death) were similar between the two groups, except for a higher risk of pre-eclampsia in the frozen blastocyst transfer group.^lxx

In contrast, a study using SART data from 2004 to 2006 found that fresh transfers were associated with low birth weight compared to frozen transfers.^lxxi This data is older and based on Day 3 transfers, including many patients who transferred multiple embryos at a time, and thus should be interpreted with caution.

Overall, given the potential for pregnancy complications after FET, some researchers suggest the freeze-all strategy should only be used by certain patients with a clear reason to benefit from this approach.^lxxii On the other hand, some doctors may offer the freeze-all strategy to all patients.

Conclusion

There are many factors to consider when deciding between a fresh or frozen embryo transfer, though many individuals may have the opportunity to use both types of transfer at different points in their IVF journey. Each patient should consult with their physician to determine the most appropriate transfer protocols. Given that evidence-based success rates are similar between fresh and frozen transfers, the right approach for one individual may be different for the next.