Fresh Vs Frozen Embryo Transfer What’s The Current Practice? : Dr Sharda Jain

1. 27th May 2023
International Speaker Program

2. 1. Fondly known as Teacher of Teachers
2. Director Lifecare Centre & Lifecare IVF
3. Founder & Secretary general of Delhi Gynaecologist forum , a body of over 2500 members .
4. Founder & Chairperson of North India Gynaecologist forum (NIGF) , body cover 10 sates .
5. NMC / MCI : Ethical committee member ,an apex body of 14 lacs modern Medicine doctors since 2018
6. Business World : Included her in Top 20 Most Influential women in Healthcare in INDIA (8/03/22)
7. DMC Expert since 2009 to till date
8. Passionate medical activist..has given leadership role in removing Female Feticide , Movement of Anemia, Save
Uterus Campaign, Save ovary Campaign and Every Mother Counts etc.
9. Given concept of JANANI SURAKSHA YOJNA & ASHA WORKER to GOI.
10. Spearheading movement of Doctors safety /Medico legal Awareness Unity of North India Gynaecologists
11.Decorated with many Lifetime achievement & Living Legend Award from many bodies including LHMC AA,
FOGSI ,DMA ,DGF , WOW India
Dr. Sharda Jain
M.D. (PGIMER), MNAMS,FICOG,FIMSA,DHM,
QM &AHO
PGDMLS (SYMBIOSIS)

3. Dr Sharda Jain
What’s The Current
Practice?

4. Infertility & IVF

5. As per the “age but no birth” definition,
the prevalence of primary infertility in India
was 3.9% (age–standardized to 25–49 years)
and 16.8% (age–standardized to 15–49
years).2
Of the couples
suffering from
infertility globally,
almost 25% are in
India alone.2
One in six
couples worldwide
experience some form of
infertility problem at least
once during their
reproductive lifetime1
Infertility
1. ART Fact Sheet. ESHRE. January 2022. Available at: https://www.eshre.eu/Europe/Factsheets-and-infographics. Accessed on 4th May 2023. 2. Katole A, et al. Indian J Community Med.
2019;44(4):337.

6. Infertility & IVF: The Indian Scenario
‘Call for Action: Expanding IVF treatment in India’ EY. July 2015 http://www.ey.com/Publication/vwLUAssets/EY-call-for-action-expanding-ivf-treatment-in-india/$FILE/EY-call-for-action-
expanding-ivf-treatment-in-india.pdf [Accessed 17 February 2017]
Vishal B, Monika D, Onkar S (2022) India In-vitro Fertilization (IVF) Services Market India In Vitro Fertilization Services Market Statistics, Forecast, 2030 (alliedmarketresearch.com)
Nearly
27.5 million couples
who are actively seeking
children suffer from infertility
Availability of over
1750 IVF
clinics and hospitals
India does an average of
250,000 cycles/year
India needs to perform
approximately
6,00,000 cycles
to meet the demand of
infertility related issues

7. babies have been born
worldwide using IVF1
reported each year worldwide
(ICMART 2022)1
> 10 million
3 million ART cycles
IVF: The most common ART procedure
1. ART Fact Sheet. ESHRE. January 2022. Available at: https://www.eshre.eu/Europe/Factsheets-and-infographics. Accessed on 4th May 2023.
Treatment cycles per region1
1,007,5981
306,1971
84,0641
1,000,0001
ART, assisted reproductive technology; IVF, in vitro fertilization

8. Embryo Transfer Strategies in IVF
Wong KM, et al. Cochrane Database Syst Rev. 2017;3(3):CD011184.
IVF: In vitro fertilization; OHSS: Ovarian hyperstimulation syndrome.
Embryo transfer in IVF can be performed using two strategies:
• Transfer of a single or more of fresh embryos
Conventional IVF strategy
• Transfer of frozen‐thawed embryos only and no fresh embryo
transfer
• Embryo transfers are disengaged from ovarian stimulation in
the ovarian stimulation cycle
• Lowers the risk of OHSS
'Freeze‐all' strategy
Conventional strategy
'Freeze‐all' strategy

9. Fresh Vs Frozen Embryo Transfer

10. Impaired Endometrial Receptivity in
Fresh ET Cycles After Ovarian Stimulation
Shapiro BS, et al. Fertil Steril. 2011;96(2):344–348.
Impaired endometrial receptivity in fresh ET cycles after ovarian stimulation apparently
accounted for most implantation failures in the fresh group.
Clinical pregnancy rates
84.0% in FET and
54.7% in the fresh group
Implantation rates Ongoing pregnancy rates
70.8% in FET and
38.9% in the fresh group
78.0% in FET and
50.9% in the fresh group
ET: Embryo transfer; FET: Frozen embryo transfer.

11. Reduced risk of OHSS
Need for Frozen Embryo Transfer
- The Biologically Plausible Hypothesis
Transfer in
subsequent
Unstimulated cycle
Controlled Ovarian
Stimulation
Supraphysiologic
Hormone Levels may
cause impaired
endometrial receptivity
Circumvents
the effects of COS on
endometrial
receptivity
Increased
risk of OHSS
Transfer frozen
thawed embryo
1. Roque M, et al. Hum Reprod Update. 2019;25(1):2–14. 2. Wong KM, et al. Cochrane Database Syst Rev. 2017;3(3):CD011184
FET: Frozen embryo transfer; COS: Controlled ovarian stimulation; ET: Embryo transfer.

12. FET Has Emerged as an Alternative to Fresh ET
to Improve IVF Outcomes
1. Griesinger G, et al. Fertil Steril 2011;95:2029–2033. 2. Devroey P, et al. Hum Reprod. 2011;26(10):2593–2597. 3. Shapiro BS, et al. Fertil
Steril. 2008;89(1):20–26. 4. Basile N, et al. J Assist Reprod Genet. 2016;33(12):1543–1550.
FET: Frozen embryo transfer; OHSS: Ovarian hyperstimulation syndrome; IVF: In vitro fertilization.
What has led to the possible shift to FET?4
FET not only decreases the
risk of OHSS, but also
improves the reproductive
outcomes of IVF treatment.1–3
Evolution of cryopreservation techniques: toward
vitrification
Improvements in stimulation protocols: toward
antagonist protocols and OHSS-free clinics
Inevitable increase in genetic screening: toward the
transfer of a healthy embryo
Data on perinatal and obstetric outcomes: toward safer
mothers and offspring

13. FET for All Normal Responders?
1. Roque M, et al. Fertil Steril. 2015;103(5):1190–1193.
2. Roque M, et al. J Assist Reprod Genet. 2017;34(2):179–185.
FETs are associated with an increased
implantation rate, CPR, and ongoing
pregnancy rate.
Roque M et al. 2015 study1
Differences in implantation rate and ongoing
pregnancy rate were being driven by the higher
responders with 10–15 oocytes retrieved.
Roque M et al. 2017 study2
Implantation rates Ongoing pregnancy rates
Fresh cycle FET Fresh cycle FET
Group 1
(4–9 retrieved oocytes)
17.9% 20.5% 31% 33%
Group 2
(10–15 oocytes)
22.1% 30.1% 34% 47%
CPR: Clinical pregnancy rate, FET: Frozen embryo transfer.

14. Freeze–all with FET is Beneficial in
High Responders
Acharya KS, et al. Fertil Steril. 2018;110(5):880–887.
Freeze–all with FET cycles have
higher pregnancy rates than
fresh transfers in high responders
(with 15 or more oocytes
retrieved).
High
responders
Intermediate
responders
Low
responders
FET cycles vs. fresh ET cycles
 CPR: 61.5 % vs. 57.4%
 LBR: 52.0 % vs. 48.9%
 CPR: 44.2% vs. 49.6%
 LBR: 35.3% vs. 41.2 %
 CPR: 15.9% vs. 33.2%
 LBR: 11.5% vs. 25.9%
Higher after
fresh cycle
Higher after
fresh cycle
Higher after
FET cycle
CPR: Clinical pregnancy rate; ET: Embryo transfer; FET: Frozen embryo transfer; LBR: Live birth rate.

15. FET vs. Fresh ET in High Responders
There was no clear evidence of a
difference in cumulative live birth rate
between FET and fresh ET (OR: 1.09, 95%
CI: 0.91–1.31).
Higher implantation rates and ongoing
pregnancy rates (52% vs. 45.3%) in
FET cycles compared with fresh.
Cochrane review and meta–analysis1 Large matched cohort study2
Majority of patients in both studies were reported to be
‘high responders.’1,2
ET: Embryo transfer; FET: Frozen embryo transfer.
1. Wong KM, et al. Cochrane Database Syst Rev. 2017;3(3):CD011184. 2. Wang A, et al. Fertil Steril. 2017;108(2):254–261.e4.

16. FET vs. Fresh ET in Specific IVF Populations
1. Chen ZJ, et al. N Engl J Med. 2016;375(6):523–533. 2. Vuong LN, et al. N Engl J Med 2018;378:137–147.
Women
with PCOS
FET resulted in a higher
frequency of live birth
after the first transfer
than did fresh transfer
(49.3% vs. 42.0%).1
Women without
PCOS
Rates of live birth were
almost similar:
33.8% and in the
frozen–embryo group
and 31.5% in the fresh-
embryo group.2
ET: Embryo transfer; FET: Frozen embryo transfer; IVF: In vitro fertilization; PCOS: Polycystic ovary syndrome; PGT–A: Preimplantation genetic testing for aneuploidy; PR: Pregnancy rate.
Fresh
Vs
Frozen

17. FET vs. Fresh ET in Specific IVF Populations
Ovulatory
women
Live-birth rate did not differ
significantly between the
frozen–embryo group and the
fresh–embryo group (48.7%
and 50.2%).1
Patients
undergoing PGT–A
Ongoing PR (80% vs. 61%) and
live birth rates (77% vs. 59%)
were significantly higher in
the frozen group compared
with the fresh group 2
1. Shi Y, et al. N Engl J Med. 2018;378(2):126–136. 2. Coates A, et al. Fertil Steril 2017;107:723–730.
ET: Embryo transfer; FET: Frozen embryo transfer; IVF: In vitro fertilization; PGT–A: Preimplantation genetic testing for aneuploidy; PR: Pregnancy rate.
Fresh
Vs
Frozen

18. Beneficiaries of the Freeze–All Policy
1. Basile N, et al. J Assist Reprod Genet. 2016;33(12):1543–1550. 2. Roque M, et al. Hum Reprod Update. 2019;25(1):2–14.
Patients at risk of
OHSS1
Patients with an
altered endocrine
and CV profile1
Patients with
inadequate
uterine cavity for
embryo transfer1
Patients who
are hyper–
responders2
Patients
undergoing PGT–A
at the blastocyst
stage2
Some probable indications for freeze–all embryo cycles are:1,2
CV: Cardiovascular; OHSS: Ovarian hyperstimulation syndrome; PGT–A: Preimplantation genetic testing for aneuploidy.

19. Freeze-All Policy

20. Developments that promoted Frozen
Embryo Transfer
Evolution of
cryopreservation
techniques: Toward
vitrification
Improvements in
stimulation protocols:
Toward antagonist
protocols and OHSS-
free clinics
Inevitable increase
in genetic
screening:
Toward the transfer
of a healthy embryo
Data on perinatal
and obstetric
outcomes:
Toward safer mothers
and offspring
FET: Frozen embryo transfer; OHSS: Ovarian hyperstimulation syndrome.
1. Noble, M, Child, T. Obstet Gynecol. 2020; 22(1):57- 68. doi:10.1111/tog.12630 2.Basile N, et al. J Assist Reprod Genet. 2016;33(12):1543–50.
Frozen embryos now account for more than one third of all IVF cycles

21. Common Protocols for Transfer of
Frozen-Thawed Embryos
03
• Ovulation occurs
naturally.
• Ovulation is triggered by
injection of hCG rather than
by the spontaneous LH surge.
• Luteal phase support with
progesterone.
• Ovulation is induced with
either clomiphene citrate,
letrozole, or gonadotropins,
resulting in one or more CLs.
• Ovary is suppressed;
lack of ovulation and
CL.
• Exogenous estradiol
and progesterone lead
to development of the
endometrium.
Natural
cycle
Modified
natural
cycle
Stimulated
cycle
Artificial
cycle
CL: Corpus luteum; E2: Estradiol; hCG: Human chorionic gonadotropin; LH: Luteinizing hormone; P: Progestogen.
In clinical practice, the artificial/programmed cycle is popular because it involves less
monitoring and embryo transfer can be scheduled on a day convenient for the patient
and the practice.
Singh B, et al. Frozen-thawed embryo transfer: The potential importance of the corpus luteum in preventing obstetrical complications. Fertil Steril.
2020;113(2):252–7.

22. Frozen Embryo Transfer Cycles: Inevitable
Dependence on Exogenous Progestogen
1. Mesen TB, et al. Obstet Gynecol Clin North Am. 2015;42(1):135–151. 2. Rashidi BH, et al. Asian Pac J Reprod. 2016; 5(6):490–494.
CL: Corpus luteum; hCG: Human chorionic gonadotropin; LH: Luteinizing hormone.
Endometrial changes necessary for implantation and
early pregnancy are totally dependent on exogenous
progesterone supplementation.2
Frozen
embryo transfer
cycles1,2
No ovulation
causes an
absence of
endogenous
CL1,2
No
endogenous
source of
progesterone1,2

23. Role of Progesterone in the Luteal Phase
Fatemi HM, et al. Hum Reprod Update. 2007;13(6):581–590.
IVF: In vitro fertilization.
Progesterone induces a secretory transformation of the endometrium
in the luteal phase and improves endometrial receptivity.
Decreased endometrial receptivity is considered largely
responsible for the low implantation rates in IVF.
Progesterone also promotes local vasodilatation and uterine musculature
quiescence by inducing nitric oxide synthesis in the decidua.
Inadequate uterine contractility may lead to ectopic
pregnancies and miscarriages.
Improves endometrial receptivity
Promotes local vasodilatation

24. Choosing The Right Progesterone for LPS
Griesinger G, et al. Hum Reprod. 2018;33(12):2212–2221.
AEs: Adverse events; IVF: In vitro fertilisation; LPS: Luteal phase support.
Oral micronized
progesterone
Oral
Dydrogesterone
Low bioavailability and AEs
such as drowsiness,
dizziness and headaches.
Injection-site pain and
abscesses
Intramuscular
progesterone
But it is associated with
administration-related side
effects such as vaginal
irritation
Potent oral progestin with
improved bioavailability
Micronized vaginal
progesterone :
Preferred over oral and
intramuscular progesterone

25. Comparing Oral Dydrogesterone With IM and Vaginal
Progesterone Supplements for LPS in Artificial FET Cycles
Rashidi BH, et al. Asian Pac J Reprod. 2016;5(6):490–4.
FET: Frozen embryo transfer; IM: Intramuscular; LPS: Luteal phase support.
A total of 180 patients were
divided into three groups:
Group A: 50 mg IM progesterone ampules
twice daily
Group B: Oral dydrogesterone 20 mg twice
daily
Group C: 400 mg vaginal progesterone
suppository twice daily
Comparison of the clinical efficacy of oral dydrogesterone with vaginal
and IM progesterone for LPS in FET artificial cycles
Treatment protocol was
continued until 12 weeks
of pregnancy.

26. Oral Dydrogesterone Has Comparable Efficacy as IM or
Vaginal Supplements in Artificial FET Cycles
Rashidi BH, et al. Asian Pac J Reprod. 2016;5(6):490–4.
FET: Frozen embryo transfer; IM: Intramuscular.
Comparable pregnancy and
live birth rates in all the three
groups (p=0.466, 0.487 and
0.367 respectively).
.
Miscarriage rates were not
significantly different among
the groups (p=0.487).
All the resulting pregnancies for
each group were intrauterine.

27. Meta-Analysis Comparing Oral Dydrogesterone With
Vaginal Progesterone Capsules
Barbosa MWP, et al. JBRA Assist Reprod. 2018;22(2):148–156.
AE: Adverse event;; LPS: Luteal phase support; MVP: Micronized vaginal progesterone.
The systematic review and meta-analysis compared the efficacy and safety of
oral dydrogesterone vs. MVP for LPS.
Methodology of the review and meta-analysis
Included studies:
Nine studies were
included in the analysis
(n=1957 for individual
participant data analysis;
safety sample: n=2059).
Interventions:
• Oral dydrogesterone
(20 mg to 40 mg)
• MVP capsules (600 mg
to 800 mg)
• Gel (90 mg)
Primary outcomes:
Ongoing pregnancy
rates
Secondary outcomes:
Live birth rate, incidence
of AE

28. Micronized Progesterone Plus Dydrogesterone Vs.
Micronized Progesterone for Luteal Phase Support In
Frozen–thawed Cycle: MIDRONE Trial
Vuong LN, et al. Hum Reprod. 2021;36(7):1821–1831.
The study highlights the role of oral Dydrogesterone in addition to vaginal progesterone as luteal phase
support in FET cycles to reduce the miscarriage rate and improve the live birth rate.

29. Freeze-all: a SWOT analysis
• Increased maternal safety-
OHSS free clinic
• Improved pregnancy rates
• Lower ectopic pregnancy
rates
• Better obstetrical and
perinatal outcomes
• Evidence of 3 RCTs only
• OHSS not completely
avoided even after GnRH
agonist trigger
• More oocytes
• Scheduling possibilities
• Stimulation starting at
any day of the cycle
• Patient friendliness
• Change in current IVF practice
• Optimization of
cryopreservation techniques
• Cost increment
• Outcome: Large for
Gestational Age
Adapted from: Blockeel. C et al. A fresh look at the freeze-all protocol: a SWOT analysis Hum Reprod, Volume 31, Issue 3, March 2016,
Pages 491–497, https://doi.org/10.1093/humrep/dev339

30. Conclusion
• In ART, choice of fresh or frozen embryo transfer is important and governs the
posology of luteal phase support
• Outcomes for Frozen–thawed Embryo Transfer (FET) are similar
to fresh embryo transfer.
• It has enhanced cycle scheduling and improved organization of the IVF unit.
• Taken together, these developments may lead to a new era in modern ART.
• Nevertheless, confirmation of the clinical benefits of a freeze-all strategy through
well-designed clinical trials is mandatory prior to shifting our current ART practice.
1. Noble, M, Child, T. The role of frozen–thawed embryo replacement cycles in assisted conception. Obstet Gynecol. 2020; 22(1):57- 68. doi:10.1111/tog.12630. 2. Blockeel C,
Drakopoulos P, Santos-Ribeiro S, Polyzos NP, Tournaye H. A fresh look at the freeze-all protocol: a SWOT analysis. Hum Reprod. 2016;31(3):491-497. doi:10.1093/humrep/dev339.

31. THANK YOU

32. Table of Content
 Infertility & IVF
 Fresh vs Frozen Embryo Tranfer
 Freeze-all policy
 Conclusion