Embryo Transfers
Written By: Katherine Moran, MD, MBA
What is a Fresh Embryo Transfer?
When embryos are transferred into the uterus shortly after oocyte retrieval, typically on day 3 following fertilization (cleavage-stage transfer) or day 5 (blastocyst transfer). [1]
Remaining oocytes or embryos from retrieval can be frozen for future use
One benefit of this technique is a shorter time to conception compared to frozen embryo transfer
What is a Frozen Embryo Transfer (FET)?
When embryos are transferred after being frozen/cryopreserved, not in the same IVF cycle when the oocytes were retrieved. This can be done months to years later.
Embryos can be stored indefinitely after being frozen.
The uterus is prepared with medication (programmed) or by using your natural menstrual cycle to time embryo transfer
Frozen embryo transfers have shown to result in a higher rate of cumulative live births compared to fresh embryo transfer when greater than 10 oocytes are retrieved (71.3% versus 57.8%, p<0.001). This may be due to a more normal physiologic state of the uterus during time of implantation with frozen embryo transfers because estrogen levels are lower. [2,3,4,5]
Indications for FET
Ovarian Hyperstimulation Syndrome (OHSS)
OHSS is a syndrome caused by abnormal hormonal signaling following IVF due to multiple follicles being recruited/eggs retrieved. OHSS is associated with electrolyte abnormalities and fluid collection in the abdomen in addition to the lungs. [2,3,4,5,6]
Fresh transfers have a higher risk of severe OHSS due to persistent stimulation of the ovaries by the hCG hormone if pregnancy develops. [4]
Elevated Progesterone
Progesterone levels that rise early in an IVF cycle led to changes in the endometrial lining (luteinization). These changes shift the window of implantation and are associated with decreased pregnancy rates.
Frozen transfers may be beneficial to women with serum progesterone levels >2 ng/ml during an IVF cycle. [7]
Preimplantation genetic Testing (PGT)
PGT is genetic testing of an embryo prior to embryo transfer.
Candidates for preimplantation genetic testing include:
Couples with pieces of chromosomes in the wrong location (translocation) that can increase the chance for chromosomal abnormalities in the embryo (PGT for structural rearrangements, PGT-SR). [8]
Couples who carry genes for significant medical conditions (i.e. cystic fibrosis, sex-linked disorders, autosomal dominant disease (PGT for monogenic disorders (PGT-M)). [8]
Patients wishing to transfer an embryo with a normal number of chromosomes (PGT for aneuploidy, PGT-A). This has been shown to increase pregnancy rates in women over the age of 35 and may be beneficial for couples with recurrent pregnancy loss. [8]
Programmed versus Natural FET
Programmed/Medicated FET [9]
Refers to the use of exogenous/supplementary estrogen and progesterone to mimic a menstrual cycle
Estrogen is needed to build the endometrial lining while progesterone is needed to prepare for implantation. [10]
Estrogen can be administered orally, vaginally or via a patch and progesterone is given as either an intramuscular (IM) shot or vaginally
This method allows for more control over timing for embryo transfer and is often used for women who do not ovulate on their own.
Natural Cycle FET [9]
Using one’s own natural menstrual cycle to prepare the endometrium without the use of exogenous hormones
Ideal transfer will be timed based on your natural ovulation using laboratory tests and/or ultrasounds
This method offers less control over timing compared to programmed FETs but has other benefits (see below)
For this method it is imperative to avoid unprotected intercourse to prevent risk of sperm fertilizing an egg produced during natural ovulation, which can form an embryo that can implant and lead to a twin or triplet pregnancy
Benefits of Natural versus Programmed FET
Natural FETs are associated with a lower risk of postpartum hemorrhage compared to programmed FETs, although the overall risk is low (0.7% versus 0.2%, p<0.0001). [11,12]
Natural FETs are associated with lower rates of high blood pressure in pregnancy and pre-eclampsia compared to programmed FETs (8.6 versus 3.8%, p<0.0001). [11,12]
Programmed FETs are associated with higher birth weights and macrosomia compared to natural FETs. [12]
Luteal Phase Support
Luteal phase support refers to hormonal support with progesterone for implantation
Luteal support for Fresh Embryo Transfers [13]
Luteal support for Programmed FET
In a 2012 retrospective cohort study, pregnancy and live birth rates were higher with IM progesterone versus vaginal progesterone (Crinone) for day 3 FET. [18]
In a 2014 retrospective study, pregnancy and live birth rates were similar for IM and vaginal progesterone for day 5 FET. [19]
A 2021 randomized control trial compared daily IM progesterone versus IM injections every 3 days with vaginal progesterone twice daily versus vaginal progesterone alone twice daily. They found higher live birth rates and lower miscarriage rates for both IM progesterone groups compared to vaginal progesterone. [20]
Luteal support for natural FET
Vaginal progesterone has been determined to be sufficient for natural FET cycles. [21]
In summary there have been many studies comparing vaginal versus IM progesterone in addition to combinations of the two methods of delivery. Vaginal progesterone is sufficient for luteal support following fresh embryo transfer. IM injections may be associated with more discomfort during administration however this method typically has been shown to be superior to vaginal progesterone when used for frozen embryo transfer either daily or every third day with vaginal progesterone daily.
Sources:
(1) Zhang J, Du M, Li Z et al. Fresh versus frozen embryo transfer for full-term singleton birth: a retrospective cohort study. J Ovarian Res 11, 59 (2018). https://doi.org/10.1186/s13048-018-0432-x
(2) Boynukalin FK, Turgut NE, Gultomruk M, Ecemis S, Yarkiner Z, Findikli N, et al. (2020) Impact of elective frozen vs. fresh embryo transfer strategies on cumulative live birth: Do deleterious effects still exist in normal & hyper responders? PLoS ONE 15(6): e0234481. https://doi.org/ 10.1371/journal.pone.0234481
(3) Wei D, Liu JY, Sun Y, et al. Frozen versus fresh single blastocyst transfer in ovulatory women: a multicentre, randomised controlled trial. Lancet. 2019;393(10178):1310-1318. doi:10.1016/S0140-6736(18)32843-5
(4) Shi Y, Sun Y, Hao C, et al. Transfer of Fresh versus Frozen Embryos in Ovulatory Women [published correction appears in N Engl J Med. 2021 Nov 4;385(19):1824]. N Engl J Med. 2018;378(2):126-136. doi:10.1056/NEJMoa1705334
(5) Zhang B, Wei D, Legro RS, et al. Obstetric complications after frozen versus fresh embryo transfer in women with polycystic ovary syndrome: results from a randomized trial. Fertil Steril. 2018;109(2):324-329. doi:10.1016/j.fertnstert.2017.10.020
(6) Kumar P, Sait SF, Sharma A, Kumar M. Ovarian hyperstimulation syndrome. J Hum Reprod Sci. 2011;4(2):70-75. doi:10.4103/0974-1208.86080
(7) Hill MJ, Royster GD 4th, Taneja M, et al. Does elevated progesterone on day of oocyte maturation play a role in the racial disparities in IVF outcomes? Reprod Biomed Online. 2017;34(2):154-161. doi:10.1016/j.rbmo.2016.11.002
(8) Gleicher N, Orvieto R. Is the hypothesis of preimplantation genetic screening (PGS) still supportable? A review. J Ovarian Res. 2017;10(1):21. Published 2017 Mar 27. doi:10.1186/s13048-017-0318-3
(9) Kang HJ. Programmed versus natural frozen embryo transfer: which is the best nest?. Fertil Steril. 2018;110(4):636-637. doi:10.1016/j.fertnstert.2018.06.020
(10) Yanushpolsky EH. Luteal phase support in in vitro fertilization. Semin Reprod Med. 2015;33(2):118-127. doi:10.1055/s-0035-1545363
(11)Wang Z, Liu H, Song H, et al. Increased Risk of Pre-eclampsia After Frozen-Thawed Embryo Transfer in Programming Cycles. Front Med (Lausanne). 2020;7:104. Published 2020 Apr 8. doi:10.3389/fmed.2020.00104
(12) Ginström Ernstad E, Wennerholm UB, Khatibi A, Petzold M, Bergh C. Neonatal and maternal outcome after frozen embryo transfer: Increased risks in programmed cycles. Am J Obstet Gynecol. 2019;221(2):126.e1-126.e18. doi:10.1016/j.ajog.2019.03.010
(13) Haahr T, Roque M, Esteves SC, Humaidan P. GnRH Agonist Trigger and LH Activity Luteal Phase Support versus hCG Trigger and Conventional Luteal Phase Support in Fresh Embryo Transfer IVF/ICSI Cycles-A Systematic PRISMA Review and Meta-analysis. Front Endocrinol (Lausanne). 2017;8:116. Published 2017 Jun 7. doi:10.3389/fendo.2017.00116
(14) Engmann L, Benadiva C, Humaidan P. GnRH agonist trigger for the induction of oocyte maturation in GnRH antagonist IVF cycles: a SWOT analysis. Reprod Biomed Online. 2016;32(3):274-285. doi:10.1016/j.rbmo.2015.12.007
(15) Stormlund S, Løssl K, Zedeler A, et al. Comparison of a 'freeze-all' strategy including GnRH agonist trigger versus a 'fresh transfer' strategy including hCG trigger in assisted reproductive technology (ART): a study protocol for a randomised controlled trial. BMJ Open. 2017;7(7):e016106. Published 2017 Jul 31. doi:10.1136/bmjopen-2017-016106
(16) Griesinger G, Diedrich K, Devroey P, Kolibianakis EM. GnRH agonist for triggering final oocyte maturation in the GnRH antagonist ovarian hyperstimulation protocol: a systematic review and meta-analysis. Hum Reprod Update. 2006;12(2):159-168. doi:10.1093/humupd/dmi045
(17.) Youssef MA, Van der Veen F, Al-Inany HG, et al. Gonadotropin-releasing hormone agonist versus HCG for oocyte triggering in antagonist-assisted reproductive technology. Cochrane Database Syst Rev. 2014;(10):CD008046. Published 2014 Oct 31. doi:10.1002/14651858.CD008046.pub4
(18) Kaser DJ, Ginsburg ES, Missmer SA, Correia KF, Racowsky C. Intramuscular progesterone versus 8% Crinone vaginal gel for luteal phase support for day 3 cryopreserved embryo transfer. Fertil Steril. 2012;98(6):1464-1469. doi:10.1016/j.fertnstert.2012.08.007
(19) Shapiro DB, Pappadakis JA, Ellsworth NM, Hait HI, Nagy ZP. Progesterone replacement with vaginal gel versus i.m. injection: cycle and pregnancy outcomes in IVF patients receiving vitrified blastocysts. Hum Reprod. 2014;29(8):1706-1711. doi:10.1093/humrep/deu121
(20) Devine K, Richter KS, Jahandideh S, Widra EA, McKeeby JL. Intramuscular progesterone optimizes live birth from programmed frozen embryo transfer: a randomized clinical trial. Fertil Steril. 2021;116(3):633-643. doi:10.1016/j.fertnstert.2021.04.013
(21) Schwartz E, Bernard L, Ohl J, et al. Luteal phase progesterone supplementation following induced natural cycle frozen embryo transfer: A retrospective cohort study. J Gynecol Obstet Hum Reprod. 2019;48(2):95-98. doi:10.1016/j.jogoh.2018.10.011
