Prof.Duru Shah Founder President The PCOS Society (India) President Elect of the Indian Society for Assisted Reproduction (ISAR) Honorary Fellow of the Royal College of Obs. & Gyn. First Indian to receive FIGO s Distinguished Merit Award for Services towards women s health. Director Gynaecworld.. The Center for Womens Health & Fertility Prof.and : Breach Candy Hosp. Cons. Obs. Jaslok Hospital & Gyn Global Hospital
Assisted Reproduction for PCOS-are the results different? Prof. MD FRCOG FCPS FICS FICOG FICMCH DGO DFP PCOS Understanding the Science and Practice 19 th June, 2016 Mumbai
Background PCOS patients comprise 75% of ovulatory infertility. Studies have suggested that PCOS women may have less favorable outcomes with ARTconflicting evidence PCOS patients have oocytes, but of impaired quality fertilization, cleavage, implantation rates and miscarriage rates. Re. Standmauer L. et.al.(2005) Treat Endocrinol 4:279-292 Heijnen EM et. al. (2006) Hum Reprod. Update 12: 13-21 Sahu K., et. al.(2008) Arch Gynecol Obstet 277: 239-244
Areas to be discussed Does PCOM affect the quality of eggs and embryos? Does obesity due to PCOS affect results in ART? Is the outcome of ART in PCOS women different from non-pcos women?. Is the Fertile window extended in women with PCOS? Is In Vitro Maturation (IVM) a better solution?
Does PCOM affect the quality of eggs and embryos? Prospective comparative study of 194 PCOS pts. with age matched controls treated concurrently. COH + ICSI All 194 women had exclusive male infertility 97 had PCOM and 97 were normal (control group) 1013 oocytes from PCOM patients compared with 774 oocytes from controls. Ref. Sigale et.al. Fertil Steril Jan 2015
Results Mean number of total + M II oocytes sig. in PCOM group. Rate of M II morphologically abnormal oocytes equivalent between both groups. Mean no. of embryos significantly in PCOM group. Percentage of top quality embryos on Day 3 similar between both the groups. Ref. Sigale et.al. Fertil Steril Jan 2015
Results Implantation and clinical pregnancy rates were significantly in PCOM group. Conclusions PCOM does not have a negative impact on the quality of oocytes and embryos or the outcome of IVF / ICSI. Ref. Sigale et.al. Fertil Steril Jan 2015
Does Obesity affect ART results in PCOS? Retrospective Cohort Study 101 cycles in 79 PCOS women < 40 yrs. Lean (51) - 18.7-24.9 kg/m 2 Overweight (19) - 25-29.9 kg/m 2 Obese (31) - > 30 kg/ m 2 Aim was to study the effect of BMI on ART outcomes in a PCOS population. Ref. Amelia P. Bailey et.al. Am J. Obstet Gynecol 2014: 211: 163
Conclusions:- PCOS has 2 distinct populations lean and obese Both have different IVF outcomes Obese PCOS have a 75% chance of pregnancy rate per ET, compared with lean PCOS The odds of live birth were 77% lower per ET in obese v/s lean PCOS There is a chance of OHSS in BMI in women with PCOS - 19.6 % in lean PCOS - 10.5 % overweight - 3.2 % obese Ref. Amelia P. Bailey et.al. Am J.Obstet Gynecol 2014:211:163
Outcome of ART in PCOS v/s Non PCOS women Prospective Study Group I - 140 women with PCOS with 122 Group II - 91 women with tubal factor infertility Re. Salem WH et.al. Androl Gynecol: Curr Res 2014,2:3
Outcome of ART in women with PCOS v/s Tubal Factor Ovarian stimulation characteristics PCOS (n=122) Re. Salem WH et.al. Androl Gynecol: Curr Res 2014,2:3 Tubal Factor (n=91) P-Value Agonist 0% 70.3% <0.001 Antagonist 100% 29.7% <0.001 Total duration of treatment (days) 9.5 ± 1.9 9.8 ± 2.1 NS Total dose of rfsh or Gonadotropin (IU) 1910 ± 681 2725 ± 1040 <0.001 Serum E 2 on day of HCG(ng/mL) 2370 ± 1180 2384 ± 1247 NS Serum P 4 on day of HCG(ng/mL 1.1 ± 0.6 0.81 ± 0.4 <0.01 # Follicles 14 on day of HCG 15.6 ± 8.0 11 ± 5.6 <0.001 # Follicles 16 on day of HCG 9.4 ± 6.0 7.3 ± 3.8 <0.01 Endometrial thickness (mm) on day of HCG 10.6 ± 2.0 11.5 ± 2.0 <0.01
Outcome of ART in women with PCOS v/s Tubal Factor Embryology Data PCOS (n=122) Tubal Factor (n=91) P-Value # Mature oocytes 15.0 + 6.8 10.0 + 5.5 <0.001 # 2 PN 11.5 + 5.7 8.0 + 4.8 <0.001 Fertilization rate 76.0% 79.6% <0.05 #Frozen zygote 2.2 + 4.0 0.8 + 2.5 <0.01 # Day 3 embryos 9.8 + 3.3 7.4 + 3.5 <0.001 # Day 5 blastocysts 4.8 + 3.0 3.0 + 3.0 <0.001 # Day 6 blastocysts 1.7 + 2.2 1.6 + 2.0 NS # Day 5 Frozen blastocyst 2.2 + 2.5 0.9 + 1.3 NS # Day 6 frozen blastocysts 1.0 + 1.4 0.8 + 1.3 NS # Total frozen blastocysts 2.4 + 2.6 1.0 + 1.7 NS Re. Salem WH et.al. Androl Gynecol: Curr Res 2014,2:3
Outcome of ART in women with PCOS v/s Tubal Factor Embryology Data PCOS (n=122) Tubal Factor (n=91) P-Value # Embryos transferred (Day 3) 1.4 + 1.5 1.6 + 1.4 NS Morula transferred (Day 5) 0.6 + 1.1 0.3 + 0.7 NS Blastocysts transferred (Day 5) 1.9 + 0.5 1.4 +0.9 <0.001 Excellent blastocysts 1.8 +0.4 1.6 + 0.5 <0.05 Good blastocysts 1.3 + 0.5 1.3 + 0.5 NS Early blastocysts 1.4 + 0.5 1.2 + 0.4 NS # total transferred Day 5 (morula and blastocyst) 2.2 + 0.5 2.3 + 0.7 NS % of Day 3 transfer 22.1% 41.8% <0.01 Re. Salem WH et.al. Androl Gynecol: Curr Res 2014,2:3
Outcome of ART in women with PCOS v/s Tubal Factor Pregnancy outcome PCOS (n=122) Tubal Factor (n=91) P-Value Implantation rate 40.9% 34.6% NS Clinical pregnancy(%) 76(62.3%) 49(53.8%) NS Delivered (%) 69(56.6%) 45(49.5%) NS Biochemical pregnancy (%) 9(10.6%) 2(3.9%) NS Miscarriage(%) 7(9.2%) 4(8.1%) NS Multiple pregnancy (%) 34(44.7%) 23(46.9%) NS Re. Salem WH et.al. Androl Gynecol: Curr Res 2014,2:3
Embryology Data Gynaecworld Data PCOS (n=189) Non-PCOS (n=133) P-Value Total number of follicles 3906 1624 <0.0001 Mean number of follicles 21 12 Total number of oocytes 2894 1375 <0.001 Mean number of oocytes 15 10 NS Total number of mature oocytes 2027 1157 <0.0001 Mean number of mature oocytes 10.5 11 8.5-9 Recovery rate of mature oocytes(%) 70.04% 84.14% Total number of immature oocytes 739 161 <0.001 Mean number of immature oocytes 4 1 1.5 Fertilization rates 74.00% (1500/2027) Cleavage rates 70.93% (1064/1500) Re. Gynaecworld unpublished data 2015-2016 80.03% (923/1157) 76.02% (704/926) <0.001 0.52(NS)
Pregnancy outcome Gynaecworld Data PCOS Non-PCOS P-Value OHSS 12.69% 8.27% (11/133) < 0.02 Significant Pregnancy rate 38.09% (72/189) Live birth rate 73.61% (53/72) Abortion rate 5.55% (4/72) Biochemical preg. Rate 8.33% (6/72) Ectopic preg.rate 2.77% (2/72) Re. Gynaecworld unpublished data 2015-2016 40.6% (54/133) 72.22% (39/54) 7.40% (4/54) 5.55% (3/54) 3.70% (2/54) < 0.65 NS < 0.86 NS < 0.67 NS < 0.651 NS < 0.72 NS
ART in PCOS- Multicentric Indian Trial Study: Prospective Observational study on PCOS carried out in 7 centers in India between Aug 2008- July 2010. 192 women undergoing IVF / ICSI included 77 - PCOS 115 Non PCOS All patients had Long protocols and Rec. FSH Ref. Pratap Kumar et.al. J Hum Reprod Sci. 2013 Jan- Mar.6(1) 49-53
ART in PCOS- Multicentric Indian Trial Results: PCOS Group Non PCOS Group Follicles 27.2 ± 8.8 13.6 ± 5.3 Oocytes 15.9 ± 6.3 10.9 ± 6.2 Recovery rate of oocytes 64% 80.3% Mature oocytes 61.1% 74.5% Total no. of top quality embryos Pregnancy Rates comp. to Non PCOS groups Comparable in both groups. Ref. Pratap Kumar et.al. J Hum Reprod Sci. 2013 Jan- Mar.6(1) 49-53
Is the Fertile window extended in women with PCOS? Known Facts PCOS women have density of small Antral follicles. Ovarian cortical biopsies show a 6 times density of primordial and primary follicles in women with PCOS v/s women with regular periods. Surrogate markers of ovarian reserve such as AMH and AFC are also increased in PCOS. Ref. Webber LJ. et.al. Lancet 2003; 362: 1017-21
This could suggest that either PCOS women are born with an increased no. of germ cells at birth or there is a rate of loss of germ cells. Does this mean that women with PCOS have a higher chance to be pregnant v/s non PCOS women as they age? How should we counsel our patients? Ref. Webber LJ. et.al. Lancet 2003; 362: 1017-21
Is the Fertile window extended in women with PCOS? Most of the patients get pregnant with oral ovulation inducing agents, but some require ART due to co-existing causes of infertility or to prevent multiple pregnancy due to COH Ref. Hudeova M et.al. Hum. Reprod. 2009: 24:1176-83 Koivunen R. et.al. Hum. Reprod. 2008: 23:2134-9
Is the fertile window extended in women with PCOS? Retrospective Cohort study 42, 286 IVF cycles in women with PCOS and tubal factor infertility. Utilizing the SART Registry Out come Pregnancy and live birth rates. Ref. Kalra SK, Dokra A,. et.al. Fertility & Sterility vol. 100, July 2013: 0015-0282
Is the fertile window extended in women with PCOS? PCOS Tubal Factor P-Value Total IVF cycles 16,416 27.870 NS No. of oocytes retrieved 16.4 12.8 No. of cryopreserved embryos, mean ± SD 6 ± 5.1 5.1 ± 4.3 <.001 Subjects with cryopreserved embryos,% 42.4 33.8 <.001 Implantation rate,% 27.5 21.3 <.001 Clinical preg. rate/ cycle start,% 42.5 35.8 <.001 Miscarriage rate, % 16.6 17.4 <.001 Live-birth rate/ cycle start,% 34.8 29.1 <.001 Pregnancy plurality, % Singleton Twin 65.3 32.2 66.3 31.1 Higher order multiple preg.( triplet) 2.5 2.6 Re. Kalra SK, Dokra A, et.al Fertility & Sterility vol.100 2013: 0015-0282
Is the fertile window extended in women with PCOS? Conclusions In spite of an increased number of oocytes obtained in PCOS patients in all age groups, women above 40 years had the same clinical preg. rates and live birth rates as non PCOS women and there was no reproductive advantage. Ref. Kalra SK, Dokra A,. et.al. Fertility & Sterility vol. 100, July 2013: 0015-0282
Is the fertile window extended in women with PCOS? Conclusions These findings suggest that the reproductive window may not be extended in PCOS. Hence women with PCOS should also be treated in a timely manner in spite of high ovarian reserve indicators. Ref. Kalra SK, Dokra A,. et.al. Fertility & Sterility vol. 100, July 2013: 0015-0282
Invitro Maturation (IVM) In PCOS patients, COH may lead to:- Large cohort of foll. of uneven sizes and quality. Retrieval of Immature oocytes risk of OHSS To avoid above, earlier retrieval of immature oocytes followed by IVM + IVF / ICSI is suggested. But does IVM give comparable outcomes? Ref. Cochrane Database Syst. Rev. Oct. 2013
Aim: To compare the outcomes assosc. with IVM foll. by IVF/ ICSI v/s Conventional IVF / ICSI All RCT s reviewed for assessing eligibility and quality of trials. No RCT s were suitable for inclusion in the Review, 3 ongoing trials currently but. Conclusions:- Invitro Maturation (IVM) Promising data on IVM techniques have been published, yet no evidence from RCTS available in order to base any practice recommendations. Ref. Cochrane Database Syst. Rev. Oct. 2013
Are the children born after IVM Study normal? Obst. and Perinatal Data collected from all deliveries after IVM treatment Growth and development of IVM children were assessed at 6,12,24 months. 43 women del. 40 singleton infants 3 sets of Twins Ref. Soderstrom et. Al. Hum Reprod. June 2006
Obstetric & Perinatal Outcome after IVM Obst. Complications- 15 pregnancies (35%) Mean B.Wt. of singletons = 3550 ± 441 gms. Twins = 2622 ± 194 gms. Preterm Birth No perinatal deaths: at 12 months- 8 children (19%) minor devel. problems. 1 child optical glioma at 24 months- Neuro psychological development normal range Ref. Soderstrom et. Al. Hum Reprod. June 2006
Conclusions PCOM does not have a negative impact on the quality of oocytes and embryos or the outcome of IVF / ICSI Obesity with PCOS chance of pregnancy, live birth, OHSS. Pregnancy outcome is comparable in PCOS and non PCOS women. PCOS women above 40 do not have reprod. advantage over non PCOS women No evidence from RCTs to confirm if In vitro Maturation gives birth result.