President : Indian Society for Assisted Reproduction (ISAR) Past President FOGSI. Past Chairman ICOG. Founder Trustee Women s Empowerment Foundation

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1 Founder President: The PCOS Society, India Honorary Fellow of the Royal College of Obst.& Gyn. Prof.Duru Shah 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

2 Should Freeze all be a strategy in all PCOS women Dr. Duru Shah MD FRCOG FCPS FICS FICOG FICMCH DGO DFP The International Conference PCOS- Unraveling the Enigma 18 th June, 2017 Bengaluru Director : Mumbai, India

3 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.

4 Rationale of Freeze-all Strategy Prevention of OHSS Improving Pregnancy Rates by improving embryo implantation. - embryo quality - endometrial receptivity

5 PCOS and OHSS 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. Ref: de Mouzon J et.al. Hum Reprod. 2012;27: Gomez R et. Al. Semin Reprod. Med. 2010; 28:448-57

6 OHSS Phathogenesis Ovarian Stimulation Ovarian Enlargement Capillary permeability Protein rich fluid Intravascular space Ascites Abdominal Cavity Pleural Cavity Pericardial Cavity Third space Hemoconcentration In intravasc. space Thromboembolism Multiple Organ Failure

7 OHSS Pathogenesis gonadotropin stimulation Large no. of growing follicles + + E 2 VEGF VEGF-R Hcg Intravascular space VEGF- VEGF R Binding Vascular Permeability (VP) + Angiogenesis Levels peak 48 hrs. after Hcg. 98% reversed by anti- VEGF antibody Shift of fluid Extra vascular space Haemoconcentration Abdominal Distension intraabd pressure

8 Prevention of OHSS 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 Ref: Fatemi HM et. Al. Fertil Steril 2014; 101: Ling LP, Reprod Biomed online 2014 doi:

9 Improved Vitrification techniques. Cryopreservation 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. Ref: Fatemi HM et. Al. Fertil Steril 2014; 101: Ling LP, Reprod Biomed online 2014 doi: Contd..

10 Cryopreservation- is it safe? 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. Ref: Ishihara O, et. al. Fertil Steril 2014; 101: Bedoschi G, et.al. Fertil Steril : Contd..

11 Endometrial Receptivity- PCOS & COS COS is related to endometrial advancement as noted during histological evaluation in a fresh IVF cycle. Ref: Ubaldi et.al 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) Contd..

12 Contd.. Endometrial Receptivity Comparing the endometrial biopsies in the same oocyte donors on 7 th 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 Contd..

13 Endometrial Receptivity Correlation between Endometrial dating by Noyes criteria and endometrial gene expression demonstrated Above changes could be resp. for obstetric + perinatal complications.. Van Vaerenbergh 2009 All above suggested that COS might be detrimental to implantation by endometrial genes that are crucial for embryo implantation. Ref: Horcajedas JA Hum Reprod et. al Mar 11(3):

14 COS and Endometrial Receptivity levels of E 2 + 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 Ref: Bamhart KT et.al. Fertil Steril 2014;102:1-2 Huang R. et.at. Rertil Steril 2012; 98: Contd..

15 Contd.. COS and Endometrial Receptivity No consensus on threshold in a cycle which leads to endometrial receptivity. No effect of above seen on embryo quality Ref: Bamhart KT et.al. Fertil Steril 2014;102:1-2 Huang R. et.at. Rertil Steril 2012; 98:664-70

16 In PCOS Patients 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. Ref: Kolibianakis et.al. Fertil Steril 2002, Nov. Contd..

17 COS and Uterine Contractility level of hormones UC. UC in COS cycles v/s natural cycles. Increased Uterine contractions (UC) during ET adversely affect IVF outcome Ref: Moraloglu O et.al. Reprod Biomed Online 2010;21: Zhu I et. Al. Hum. Reprod.2012;2;27:2684-9

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19 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?

20 Fresh Embryo Transfer v/s Frozen Systematic Review and Meta analysis of 3 RCT s : 3 Trials with 633 cycles: Pts yrs Conclusions: IVF outcomes may be improved by performing FET v/s Fresh ET Embryo Transfer (FET) This could be due to a better embryo endometrium synchrony achieved with endometrium preparation cycles Ref: Roque M. et.al. Fertil Steril 2013 Jan. Contd..

21 Fresh Embryo Transfer v/s Frozen Embryo Transfer (FET) Ref: Roque M. et.al. Fertil Steril 2013 Jan.

22 IVF/ ICSI outcomes of fresh v/s frozen thawed embryos 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 Ref: Shapiro BS et.al. Fertil Steril 2014;102:3-9 Shapiro BS et.al. Fertil Steril 2011;96:344-8 Contd..

23 Ref: Shapiro BS et.al. Fertil Steril 2014;102:3-9 Shapiro BS et.al. Fertil Steril 2011;96:344-8 IVF/ ICSI outcomes of fresh v/s frozen thawed embryos 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

24 Freeze all v/s Fresh ET in PCOS 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. Ref: Chen ZJ New England J Med 2016 Aug 11;375(6) Contd..

25 Freeze all v/s Fresh ET in PCOS Results: Fresh ET Frozen ET P Value Live Birth 42.0 % 49.3 % Preg. Loss 32.7% 22.0 % p < 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 Ref: Chen ZJ New England J Med 2016 Aug 11;375(6)

26 Fresh v/s Thaw ET Gynaecworld Experience Fresh Embryo Transfer Frozen Thaw Embryo Transfer p - value No. of cycles Pregnancy rate 42.20% 39.08% Abortion rate 3.26% 1.29% Biochemical Pregnancy rate 1.08% 3.89% Live Birth Rate 40.36% 37.05% Gynaecworld unpublished data 2017

27 Obstetric and Perinatal outcomes from fresh ET v/s FET 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. Ref: Shapiro BS et.al. Fertil Steril 2014;102:3-9 Shapiro BS et.al. Fertil Steril 2011;96:344-8 Contd..

28 Ref: Shapiro BS et.al. Fertil Steril 2014;102:3-9 Shapiro BS et.al. Fertil Steril 2011;96:344-8 Contd.. Ectopic pregnancy rates in IVF v/s natural conception (due to UC, levels of E 2 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

29 FET & Ectopic Pregnancy Retrospective study of 31,925 women undergoing IVF- ET over a period of 7 years in a teaching hospital in China Aim To compare the incidence of Ectopic pregnancy between Fresh Embryo transfer cycles (ET v/s Frozen thawed cycles) (FET) Ref: Bo Huang et.al Fertil Steril 102, Nov 2014

30 Results FET & Ectopic Pregnancy Fresh ET Frozen ET Embryo transfer Preg. Rate 42.7% 6431) Ectopic preg. Rate Incidence of EP/ Clinical preg. 45.4% (5564) 1.97% (297) 1.01% (124) 4.6% 2.22% (statistically significant) Ref: Huang B et. al. Fertil Steril Nov 2014, 102 (5):

31 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) Contd..

32 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) Contd..

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

34 Aim: Cost effectiveness of freeze all Policy To evaluate the cost effectiveness of freeze all cycles v/s Fresh Embryo Transfer cycles Study: Cost of 530. ICSI cycles Jan Dec 2013 with GnRh antagonist protocol and Day 3 ET Fresh Embryo Transfer Freeze all cycles Ref: Roque et.al. JBRA Assisted Reproduction 2015; 19(3): Contd..

35 Cost effectiveness of freeze all Policy FRESH (n=351) FREEZE-ALL (n=179) ICSI cycle 3, , rfsh 2, ± , ± GnRH antagonist ± ± Trigger NA LPS ± NA EP + LPS ± NA Hormone measurements- COS NA Hormone measurements-fet ± 8.39 NA US Scan FET ± NA US- obstetrics ± ± Embryo cryopreservation ± ± Miscarriage cost ± ± Total treatment cost per patient 7, ± , ± Ref: Roque M. et.al. JBRA Assisted Reproduction 2015; 19(3): P Contd.. Treatment cost per ongoing pregnancy 23, ± 2, , ± 1,

36 Cost effectiveness of freeze all Results:- Policy 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 Ref: Roque et.al. JBRA Assisted Reproduction 2015; 19(3): Contd..

37 Conclusions of Freeze-all Policy 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. Contd..

38 Contd.. Growing evidence that freeze all policy may decrease the risk of OHSS development and obstetric and perinatal morbidity and mortality.

39 Block your Dates The next PCOS Conference June 22 nd 24 th, 2018 Gurgaon

40 COS and Uterine Contractility level of hormones UC. UC in COS cycles v/s natural cycles. Increased Uterine contractions (UC) during ET adversely affect IVF outcome Ref: Moraloglu O et.al. Reprod Biomed Online 2010;21: Zhu I et. Al. Hum. Reprod.2012;2;27:2684-9

41 FET & Ectopic Pregnancy Retrospective study of 31,925 women undergoing IVF- ET over a period of 7 years in a teaching hospital in China Aim To compare the incidence of Ectopic pregnancy between Fresh Embryo transfer cycles (ET v/s Frozen thawed cycles) (FET) Ref: Bo Huang et.al Fertil Steril 102, Nov 2014

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

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