Improvements in techniques of cryopreservation have radically changed the way assisted reproductive technologies have been delivered, funded, and reported. In this report I will summarize the outcomes following cryopreservation of embryos as well as the implications for the treatments.
Traditionally embryos are created and transferred within same week (fresh embryo transfer). Only spare good quality ones were frozen for future use. These are used if fresh treatment did not work or for sibling pregnancies. With move toward transferring single embryo and better embryo survival after freezing thawing, increased proportion of embryo transfers are following frozen embryos. Hence, there is an increasing body of the literature to advice on outcomes and implications following thawed frozen embryos.
Complications of treatment
Cryopreservation of embryos has been used to reduce the risk of ovarian hyperstimulation syndrome (OHSS), which is rare but has serious consequences. Meta-analysis of 2 randomized trials have shown significant reduction in the incidence of early onset OHSS [0.24 (95% confidence interval—CI, 0.15–0.38)]1.
Meta-analysis of existing 4 randomized trials (1 has been excluded; 2 on hyper responders and 1 on normal responders) suggest that there is no difference in the clinical pregnancy rate among the 2 groups [odds ratio (OR), 0.82; 95% CI, 0.63–1.06] (Fig. 1)2,3.
The meta-analysis of 4 randomized trials show no difference in the cumulative live birth rate in fresh embryo transfers compared with frozen embryo transfer (OR, 1.09; 95% CI, 0.91–1.31)1. Two have reported on data from blastocyst stage transfer while other 2 on cleavage stage transfer.
As the implantation of frozen embryos may be better, there should be a reduction in risk of ectopic pregnancy. Observational data suggest that the risk is lowest with frozen blastocyst transfer4.
There is a significant reduction in the miscarriage rate in pregnancies subsequent to frozen embryo transfer when compared with fresh embryo transfer (OR, 0.67; 95% CI, 0.52–0.86) based on data from 4 randomized trials1. This is again explained by better implantation.
Data on obstetric outcomes is based on observational studies only.
Singleton pregnancies subsequent to frozen embryo transfer are associated with lower risk of preterm delivery when compared with those after fresh embryo transfer [relative risk (RR), 0.90; 95% CI, 0.84–0.97]5. It is not known whether these are spontaneous or induced deliveries.
There is increase in the risk of hypertensive disorders of pregnancy in singleton pregnancies subsequent to frozen embryo transfer when compared with fresh embryo transfer (RR, 1.29; 95% CI, 1.07–1.56)5. Five studies have reported on hypertensive disorders of pregnancies.
There is no difference in the risk of antepartum hemorrhage (RR, 0.82; 95% CI, 0.66–1.03)5 between the 2 groups.
Data on neonatal outcomes is based on observational studies only.
Singleton pregnancies subsequent to frozen embryo transfer are associated with lower risk of low–birth weight (RR, 0.72; 95% CI, 0.67–0.77)5 and small for gestational age babies (RR, 0.62; 95% CI, 0.58–0.65)5 in singleton pregnancies subsequent to frozen embryo transfer when compared with fresh embryo transfer.
There is significant increase in large for gestational age babies in singleton pregnancies subsequent to frozen embryo transfer when compared with fresh embryo transfer (RR, 1.54; 95% CI, 1.48–1.61)5.
There is no difference in the risk of congenital anomalies (RR, 1.01; 95% CI, 0.87–1.16)5 and perinatal mortality (RR, 0.92; 95% CI, 0.78–1.08)5 in singleton pregnancies as a result of frozen embryo transfer when compared with those after fresh embryo transfer. Both major and minor anomalies were reported.
So far there has been no concern raised in long-term follow-up studies on children conceived as a result of frozen embryo transfer. However, data are limited due to length of follow-up.
Freezing is associated with extra cost to the clinic as well as patients. None of the studies published so far have evaluated the cost-effectiveness of strategy of elective freezing of embryos compared with current default policy of fresh embryo transfer. There may be both long-term and short-term costs.
Electively freezing embryos in preference to fresh embryo transfer leads to delay in having a baby. Although this delay can be as little as 6 weeks; however, this may not be acceptable to patients. There are no patient preference studies available in the literature so far.
Most IVF centers charges separately for freezing and thawed frozen embryo transfer treatment. Public funding may or may not include frozen embryo transfer. In the United Kingdom, National Institute of Health and Care Excellence guidance recommends that an egg collection, followed by use of all embryos created (fresh and frozen) should be counted as 1 treatment; however, it is not followed by all clinics.
Traditionally pregnancy rates were reported for fresh embryo transfer as per started treatment or per embryo transfer episode. With increased use of frozen embryos, the reporting has been changed for some registries to cumulative live birth rates (eg, Human Embryology Fertilisation Authority in the United Kingdom and Society of Assisted Reproductive Technology in the United States of America).
To summarize there is a gradual increase in the use of cryopreserved embryos, sometimes in preference to fresh embryos. There is a significant reduction in OHSS risk in those who had frozen embryo transfer. There is lower risk of miscarriage and ectopic pregnancy but no reduction in the chances of live birth if frozen embryos are used in preference to fresh embryos.
Singleton pregnancies as a result of frozen embryo transfer are associated with reduced risk of low–birth weight babies, preterm delivery, small for gestational age but a higher risk of hypertensive disorders of pregnancy and large for gestational age babies.
Long-term outcomes on the babies born as a result of frozen embryo transfer are reassuring so far.
If frozen embryo transfers were to be used preferentially in routine practice, there will be implications for cost (to both health care and society), public funding and reporting of IVF treatments.
Conflict of interest statement
The author declares that there is no financial conflict of interest with regard to the content of this report.
1. Wong KM, van Wely M, Mol F, et al. Fresh versus frozen embryo transfers in assisted reproduction. Cochrane Database Syst Rev 2017;3:CD011184. Doi:10.1002/14651858.CD011184.pub2.
2. Roque M, Lattes K, Serra S, et al. Fresh embryo transfer versus frozen embryo transfer
in in vitro fertilization cycles: a systematic review and meta-analysis. Fertil Steril 2012;99:156–62.
3. Chen ZJ, Shi Y, Sun Y, et al. Fresh versus frozen embryos for infertility in the polycystic ovary syndrome. N Engl J Med 2016;375:523–33.
4. Li Z, Sullivan EA, Chapman M, et al. Risk of ectopic pregnancy lowest with transfer of single frozen blastocyst. Hum Reprod 2015;30:2048–54.
5. Maheshwari A, Pandey S, Amalraj Raja E, et al. Is frozen embryo transfer
better for mothers and babies? Can cumulative meta-analysis provide a definitive answer? Hum Reprod Update 2018;24:35–58.