• Founder President: The PCOS Society, India

• President : Indian Society for Assisted

Reproduction (ISAR)

• Past President FOGSI.

• Past Chairman ICOG.

• Founder Trustee “Women’s Empowerment Foundation”

• Director of Digital Education International Menopause Society

• Chair: Violence against Women Cell, FOGSI

• Honorary Fellow of the Royal College of Obst.& Gyn.

Prof.Duru Shah

The International Conference

“PCOS- Unraveling the Enigma”

18th June, 2017

Bengaluru

Should “Freeze all” be a strategy in all PCOS women

MD FRCOG FCPS FICS FICOG FICMCH DGO DFP

Dr. Duru Shah

Director : Mumbai, India

Freeze all Strategy• Ovarian Stimulation

• Ovum Pick up

• Fertilize eggs and create embryos

• DO NOT CARRY OUT EMBRYO TRANSFER

• Freeze all the embryos

• Transfer the thawed embryos in the next cycle

without ovulation induction.

Rationale of Freeze-all Strategy

• Prevention of OHSS

• Improving Pregnancy Rates by improving embryo

implantation.

- ↑ embryo quality

- ↑ endometrial receptivity

• OHSS is iatrogenic, management difficult.

• Lethal complication encountered during COS in IVF

• Occurs in approx. 1-14% of ART cycles

• Related to ↑ vascular permeability (VP)

• Hcg, either exogenous /endogenous is the most

probable triggering factor.

PCOS and OHSS

Ref: de Mouzon J et.al. Hum Reprod. 2012;27:954-66

Gomez R et. Al. Semin Reprod. Med. 2010; 28:448-57

OHSS Phathogenesis

• Abdominal Cavity

• Pleural Cavity

• Pericardial Cavity

Thromboembolism

Hemoconcentration

In intravasc. spaceAscites

Third space

Intravascular spaceProtein rich fluid

Capillary permeability

Ovarian Enlargement

Ovarian Stimulation

Multiple Organ Failure

OHSS Pathogenesis

↑ gonadotropin stimulation

Large no. of growing follicles+ +

↑ E2 ↑ VEGF

↑ VEGF-R

Levels peak 48 hrs.

after Hcg.

Hcg98% reversed by anti-

VEGF antibody

Intravascular space Extra vascular space

Haemoconcentration Abdominal Distension

↑ intraabd pressure

Shift of fluid

↑ Vascular Permeability (VP)

+ Angiogenesis

VEGF- VEGF

R Binding

• By use of GnRh a trigger – instead of Hcg early

OHSS can be prevented.

• By freezing all embryos, and not performing Embryo

Transfer, we can prevent a pregnancy, thus

preventing late OHSS.

• Occasional OHSS reported even after following the

adoption of “freeze all strategy”

Prevention of OHSS

Ref: Fatemi HM et. Al. Fertil Steril 2014; 101: 1008-11

Ling LP, Reprod Biomed online 2014 doi: 10.1016

• Improved Vitrification

techniques.

• Oocyte cryopreservation has

become a good option in those

at risk for OHSS eg. PCOS pts.

• Frozen oocytes survival rates

are excellent with comparable

pregnancy and safety rates as

fresh oocytes.

Cryopreservation

Ref: Fatemi HM et. Al. Fertil Steril 2014; 101: 1008-11

Ling LP, Reprod Biomed online 2014 doi: 10.1016

Contd..

• Hence Frozen Embryo Transfer

(FET) has become a safe and

effective procedure during IVF

treatment.

• Transfer of frozen thawed

embryos do not seem to have

an adverse effect on neonatal

outcomes

• Hence the “Freeze all” policy

has been created.

Cryopreservation- is it safe?

Ref: Ishihara O, et. al. Fertil Steril 2014; 101: 128-33

Bedoschi G, et.al. Fertil Steril 2013- 99:1496-502

Contd..

• COS is related to endometrial advancement as noted

during histological evaluation in a fresh IVF cycle.

• In the group with:

Endometrial advancement > 3 days → no pregnancy

→ all pts. had Prog. levels > 1.1 ng/ml on day of trigger

→ mean no. of retrieved oocytes = 15.8

• In the group with:

Endomet advancement < 3 days → p levels < 1.1 ng ml.

Kolibianakis E. et.al. Fertil Steril 2002 Nov 78(5)

Endometrial Receptivity- PCOS & COS

Ref: Ubaldi et.al. 1997

Contd..

• Comparing the endometrial biopsies in the same

oocyte donors on 7th day of LH surge in both non stim

& stim cycles.

→ Over 200 genes related to implantation either over/

under expressed during COS v/s natural cycle.

• Gene expression differences were found between pts.

with P> 1.1 ng/ml on day of trigger v/s pts with normal

P levels.

…….. Labarte et.al. 2011

Contd..

Endometrial ReceptivityContd..

→ Correlation between Endometrial dating by Noyes’

criteria and endometrial gene expression

demonstrated

→ Above changes could be resp. for obstetric +

perinatal complications.

……. Van Vaerenbergh 2009

Ref: Horcajedas JA Hum Reprod et. al. 2005 Mar 11(3): 195-205

• All above suggested that COS might be detrimental to

implantation by endometrial genes that are crucial for

embryo implantation.

Endometrial Receptivity

• ↑↑ levels of E2 + P during COS

→ morphological, biochemical modifications →

↓ impaired endometrial receptivity

Embryo endometrial asynchrony

↓

reduced Implantation Rates in IVFcycles

• ↑↑ levels of Estradiol and subtle ↑ in progesterone in

follicular phase.

↓

negative impact on endometrium

COS and Endometrial Receptivity

Ref: Bamhart KT et.al. Fertil Steril 2014;102:1-2

Huang R. et.at. Rertil Steril 2012; 98:664-70

Contd..

• No consensus on threshold in a cycle which leads

to ↓ endometrial receptivity.

• No effect of above seen on embryo quality

COS and Endometrial Receptivity

Ref: Bamhart KT et.al. Fertil Steril 2014;102:1-2

Huang R. et.at. Rertil Steril 2012; 98:664-70

Contd..

↑↑ LH in PCOS pts.

↓

↑↑ Androgen prod from theca cells

↓

earlier app of Prog. Receptors in the endomet

↓

premature secretory changes in the endometrium

↓

endometrial advancement on day of OPU

↓

↓↓ pregnancy rates if adv is > 2.5 days.

In PCOS Patients

Contd..

Ref: Kolibianakis et.al. Fertil Steril 2002, Nov.

• ↑↑ level of hormones ↑ UC.

• UC↑↑ in COS cycles v/s natural cycles.

• Increased Uterine contractions (UC) during ET

adversely affect IVF outcome

COS and Uterine Contractility

Ref: Moraloglu O et.al. Reprod Biomed Online 2010;21:338-43

Zhu I et. Al. Hum. Reprod.2012;2;27:2684-9

Questions

• By freezing all embryos and transferring in the next

cycle.

- do we get equally good pregnancy rates?

- is it safe for the pregnancies?

- are there any complications?

- is it more expensive?

Systematic Review and Meta – analysis of 3 RCT’s :

• 3 Trials with 633 cycles:

• Pts. 27 – 33yrs

Conclusions:

• IVF outcomes may be improved by performing FET

v/s Fresh ET

• This could be due to a better embryo endometrium

synchrony achieved with endometrium preparation

cycles

Fresh Embryo Transfer v/s Frozen Embryo Transfer (FET)

Ref: Roque M. et.al. Fertil Steril 2013 Jan.

Contd..

Ref: Roque M. et.al. Fertil Steril 2013 Jan.

Fresh Embryo Transfer v/s Frozen Embryo Transfer (FET)

• Better IVF outcomes when performing

elective Frozen Embryo Transfer

(FET)

• All embryos frozen, hence they are

not the “second best” embryos

frozen as in a fresh transfer cycle.

• Better results in the ongoing

pregnancy rate when elective FET

performed v/s FET after failed fresh

cycle

IVF/ ICSI outcomes of fresh v/s frozen thawed embryos

Ref: Shapiro BS et.al. Fertil Steril 2014;102:3-9

Shapiro BS et.al. Fertil Steril 2011;96:344-8

Contd..

• Lack of higher quality RCT’s

regarding freeze all Policy and

- its relationship to IVF outcomes

- the best development stage of

embryo cryopreservation

- the best endometrial priming to

perform the FET

IVF/ ICSI outcomes of fresh v/s frozen thawed embryos

Ref: Shapiro BS et.al. Fertil Steril 2014;102:3-9

Shapiro BS et.al. Fertil Steril 2011;96:344-8

Aim:

• To evaluate the pregnancy rates in PCOS women in

fresh v/s frozen ET.

Methods:

• 1508 infertile PCOS women randomly assigned to

fresh ET or frozen ET in their first cycle of IVF. Day 3,

2 fresh / frozen embryos transferred.

Freeze all v/s Fresh ET in PCOS

Ref: Chen ZJ New England J Med 2016 Aug 11;375(6) 523-33

Contd..

Results:

Freeze all v/s Fresh ET in PCOS

Ref: Chen ZJ New England J Med 2016 Aug 11;375(6) 523-33

Fresh ET Frozen ET P Value

Live Birth 42.0 % 49.3 % 0.004

Preg. Loss 32.7% 22.0 % p < 0.001

OHSS 7.1% 1.3% p<0.001

Preeclampsia 1.4% 4.4% p<0.009

Neonatal deaths NIL 5 P = 0.06

Other pregnancy

and neonatal

complications

No differences

Fresh v/s Thaw ET – Gynaecworld Experience

Fresh Embryo

Transfer

Frozen – Thaw

Embryo Transfer

p - value

No. of cycles 218 197

Pregnancy rate 42.20% 39.08% 0.518

Abortion rate 3.26% 1.29% 0.403

Biochemical

Pregnancy rate

1.08% 3.89% 0.231

Live Birth Rate 40.36% 37.05% 0.489

Gynaecworld unpublished data 2017

• Risks of obst. and perinatal

complications ↑ in singleton

preg. after ART v/s natural

conception

• Some observational studies →

better outcome in FET v/s Fresh

ET cycles.

Obstetric and Perinatal outcomes from fresh ET v/s FET

Contd..Ref: Shapiro BS et.al. Fertil Steril 2014;102:3-9

Shapiro BS et.al. Fertil Steril 2011;96:344-8

• Ectopic pregnancy rates ↑ in IVF v/s natural conception

(due to ↑ UC, ↑ levels of E2 during COS)

• Altered placentation due to ↑ hormone levels in COS ↑

risk of :

- Pre-ecclampsia

- LBW

- SGA

- Prematurity

- APH

- Perinatal death

• No diff in congenital malformation rates.

• ↑ risk of macrosomia in singletons born after FET

Contd..

Ref: Shapiro BS et.al. Fertil Steril 2014;102:3-9

Shapiro BS et.al. Fertil Steril 2011;96:344-8

• Retrospective study of 31,925 women undergoing

IVF- ET over a period of 7 years in a teaching hospital

in China – 2006 – 2013

Aim

• To compare the incidence of Ectopic pregnancy

between Fresh Embryo transfer cycles (ET v/s

Frozen thawed cycles) (FET)

FET & Ectopic Pregnancy

Ref: Bo Huang et.al Fertil Steril 102, Nov 2014

• Results

FET & Ectopic Pregnancy

Fresh ET Frozen ET

Embryo transfer 15042 12255

Preg. Rate 42.7%

6431)

45.4%

(5564)

Ectopic preg.

Rate

1.97% (297) 1.01% (124)

Incidence of EP/

Clinical preg.

4.6% 2.22%

(statistically

significant)

Ref: Huang B et. al. Fertil Steril Nov 2014, 102 (5): 1345-9

To Compare the outcomes of ET’s using cryopreserved embryos cryopreserved

oocytes, fresh embryos

Ref: Braga DP et.al. Fertil Steril 2016, Sept 106(3) 615-22 Contd..

To Compare the outcomes of ET’s using cryopreserved embryos cryopreserved

oocytes, fresh embryos

Ref: Braga DP et.al. Fertil Steril 2016, Sept 106(3) 615-22 Contd..

Ref: Braga DP et.al. Fertil Steril 2016, Sept 106(3) 615-22

Results:

• ↓↓ embryo quality and ↓↓ rates of blastocyst formation

from frozen oocytes.

• Highest pregnancy and implantation rates observed in

thaw cycles, foll. by banked donor egg group, and

fresh cycles had the lowest rates.

• The freeze all method resulted in exceptional

outcomes.

Contd..

Aim:

• To evaluate the cost effectiveness of freeze all cycles

v/s Fresh Embryo Transfer cycles

Study:

• Cost of 530. ICSI cycles Jan 2012- Dec 2013 with

GnRh antagonist protocol and Day 3 ET

- 351 Fresh Embryo Transfer

- 179 Freeze all cycles

Cost effectiveness of freeze all Policy

Ref: Roque et.al. JBRA Assisted Reproduction 2015; 19(3): 125-130

Contd..

Cost effectiveness of freeze all Policy

Ref: Roque M. et.al. JBRA Assisted Reproduction 2015; 19(3): 125-130

Contd..

FRESH

(n=351)

FREEZE-ALL

(n=179)

P

ICSI cycle 3,618.50 3,361850 -

rFSH 2,293.65 ± 692.38 2,123.72 ± 644.47 0.006

GnRH antagonist 480.24 ± 73.58 479.15 ± 75.53 0.874

Trigger 111.63 111.63 NA

LPS 268.98 ± 192.31 - NA

EP + LPS - 377.30 ± 211.29 NA

Hormone measurements- COS 111.28 111.28 NA

Hormone measurements-FET - 30.61 ± 8.39 NA

US Scan – FET - 72.72 ± 19.93 NA

US- obstetrics 84.57 ± 106.26 104.29 ± 109.02 0.046

Embryo cryopreservation 416.32 ± 381.59 2521.45 ± 357.43 0.002

Miscarriage cost 38.59 ± 161.54 47.49 ± 178.79 0.550

Total treatment cost per patient 7,423.79 ± 755.59 7,598.48 ± 686.47 0.010

Treatment cost per ongoing pregnancy 23,059.72 ± 2,347.02 19,156.73 ± 1,732.99 0.001

Results:-

• Scenario 1: (fresh ET + FET)

All cost assosc. with COS, OPU, ET, medical costs,

IVF lab, freezing of extra embryos + costs of thaw cycle.

• Scenario 2 (Freeze all cycles)

All above + costs of Thaw transfers

Conclusions:

• Freeze all is a cost effective strategy compared to fresh

embryo transfer + Thaw ET

Cost effectiveness of freeze all Policy

Ref: Roque et.al. JBRA Assisted Reproduction 2015; 19(3): 125-130

Contd..

• For better pregnancy rates by transfering good quality

embryos into a more receptive endometrium

• For better endometrial receptivity in cycles where

GnRh-a has been used by a trigger instead of Hcg. to

avoid OHSS

• For fertility preservation, either for medical or social

reasons.

• To reduce the risk of OHSS due to use of Hcg. and

pregnancy in a hyperstim cycle to avoid the effect of

premature “P” elevation.

• Whilst awaiting the results of PGD or PGS.

Conclusions of “Freeze-all Policy”

Contd..

• Growing evidence that freeze all policy may decrease

the risk of OHSS development and obstetric and

perinatal morbidity and mortality.

Contd..

The next PCOS Conference

June 22nd – 24th, 2018

Gurgaon

Block your Dates

• ↑↑ level of hormones ↑ UC.

• UC↑↑ in COS cycles v/s natural cycles.

• Increased Uterine contractions (UC) during ET

adversely affect IVF outcome

COS and Uterine Contractility

Ref: Moraloglu O et.al. Reprod Biomed Online 2010;21:338-43

Zhu I et. Al. Hum. Reprod.2012;2;27:2684-9

• Retrospective study of 31,925 women undergoing

IVF- ET over a period of 7 years in a teaching hospital

in China – 2006 – 2013

Aim

• To compare the incidence of Ectopic pregnancy

between Fresh Embryo transfer cycles (ET v/s

Frozen thawed cycles) (FET)

FET & Ectopic Pregnancy

Ref: Bo Huang et.al Fertil Steril 102, Nov 2014

Ref: Huang B et. al. Fertil Steril Nov 2014, 102 (5): 1345-9

Ref: Huang B et. al. Fertil Steril Nov 2014, 102 (5): 1345-9