thesis defense o abdalmageed

مبسم هللا الرحمن الرحي

“IVF Outcomes for Women with PCOS

after Fresh and Frozen Embryo

Transfer “

Osama S. AbdalmageedAssistant lecturer OB/GYN , Assiut University

Mentors

Prof. Dr. Sayed Abdelhamid Abdullah, MDProfessor of Obstetrics and Gynecology

Faculty of Medicine, Assiut University, Assiut, Egypt

Prof. Dr. Atef Mohamad Mostafa Darwish, MD, PHD

Professor of Obstetrics and Gynecology Faculty of Medicine, Assiut University, Assiut, Egypt

Prof. Dr. Alaa Eldin Mahmoud Ismail, MDProfessor of Obstetrics and Gynecology

Faculty of Medicine, Assiut University, Assiut, Egypt

Prof. Ashok AgarwalDirector and Professor, Center for Reproductive Medicine

Cleveland Clinic, Cleveland, Ohio, USA

IntroductionPCOS

Common 8-25%

40-70% infertile.

Rotterdam criteria,

2004.

Lines of infertility

ttt, ASRM,2007.

1st • OI using CC

2nd • LOD/ Gonadotropins

3rd • IVF

(Sirmans and Pate 2013)(Teede, Deeks et al. 2010)

IntroductionPCOS may be Challenging in IVF

OHSS

More oocytes are retrieved BUT

Poorer Fertilization rate.

Higher total fertilization failure.

No much improvement in PR.

Higher miscarriage rate.

Risk for pregnancy and neonatal complications.

?

(Balen, Tan et al. 1993)(Dor, Shulman et al. 1990)(Dale, Tanbo et al. 1991)(Boomsma, Eijkemans et al. 2006)

IntroductionDevelopment of In Vitro Fertilization

1978

• Conventional IVF

• Robert Edward & Patrick Steptoe

1988

• PZD (partial zona dissection)

• Cohen et al

1988

• SUZI (subzonal insemination)

• Ng et al

1992

• ICSI

• Michal Tucker

IntroductionICSI

It has been suggested that ICSI, which wasinitially developed to overcome male factorinfertility, can be applied in other non malefactor infertility such as complete fertilizationfailure or low fertilization rate.

BUT!! The use of ICSI as a method of fertilizationhas been abruptly increased without associatedjustified indications.

(Oehninger and Gosden 2002)(Mahutte and Arici 2003)(Boulet, Mehta et al. 2015)

IntroductionTrends of ICSI (2004-2013) in US

IntroductionTrends ICSI for fertilization in Europe, 2005

IntroductionIs ICSI advantageous for PCOS?!!

The wide use of ICSI in the couples withnormo-zoospermic semen parameters catchesdoubt on its possible advantages overconventional IVF regarding the outcomes inPCOS.

Limited number of studies and the resultsare still conflicting !!

(Walls, Junk et al. 2012)(Bahceci and Ulug 2005)

IntroductionSuperovulation and Fresh ET

Superovulation may carry and additionalrisk for an abnormal pregnancies.

Elevated peak E2 increase the risk ofpregnancy complications in women conceivedvia IVF.

(Hayashi, Nakai et al. 2012)(Thomopoulos, Tsioufis et al. 2013)(Haavaldsen, Tanbo et al. 2012)(Imudia, Goldman et al. 2014)(Imudia, Awonuga et al. 2012)

IntroductionFrozen-Thawed ET

Frozen-thawed ET may have better obstetricoutcomes when compared to fresh ET cycles.

It is suggested that elective cryopreservationof all embryos reduced the pregnancycomplications as opposed to fresh ET ofelevated E2 > 3450 pg/dl

(Maheshwari, Pandey et al. 2012)(Weinerman and Mainigi 2014)(Sazonova, Kallen et al. 2012)(Imudia, Awonuga et al. 2013)

IntroductionIs Frozen-thawed ET Better than Fresh ET in

PCOS?!!

PCOS women undergoing IVF cycles with freshET are expected to have superovulation andsupra-physiological levels of steroidhormones.

(Jabara and Coutifaris 2003)

IntroductionIR and PCOS

IR has a central role in the pathogenesis ofPCOS.

The unfavorable outcomes in PCOS womencan be related to

Higher BMI

Higher waist-to-hip ratio

IR

(Tsilchorozidou, Overton et al. 2004)(Fedorcsak, Storeng et al. 2000)(Dale, Tanbo et al. 1991)

IntroductionMetformin

Conflicting results in PCOS.

2015 worldwide web-based survey: noclear evidence to support the use ofmetformin to improve the IVF outcomes inPCOS women.

(Moll, van der Veen et al. 2007)(Stadtmauer, Toma et al. 2001)(Christianson, Wu et al. 2015)

IntroductionWhen to use Metformin in PCOS women?!!

Metformin in PCOS is recommended to berestricted to women with glucose intoleranceand/or insulin resistance.

However, metformin has commonly been usedas a co-treatment with COH in PCOS womenundergo IVF.

It is not clear which group will benefit frommetformin administration in IVF. (ASRM/ESHRE, 2008)

(Bouchard 2010)(Nestler 2002)

Thesis

Clinical Study (1)

Fresh versus Frozen-Thawed ET in Women

with PCOS Undergoing

Autologous IVF Cycles

Clinical Study (2)

IVF versus ICSI for Couples with

PCOS and Normozoosperm

ic Semen: An Analysis of 4679 Cycles from SART

Clinical Study (3)

Impact of Metformin on

IVF Outcomes in Overweight and Obese Women

with PCOS

Clinical Study (1)

Fresh versus Frozen-Thawed ET in Women with PCOS Undergoing

Autologous IVF Cycles

Clinical Study (1)Objectives

To compare CPR between fresh and frozen-thawed embryo transfer in women with PCOSundergoing autologous IVF cycles.

To compare implantation, miscarriage, andLBRs between the fresh and frozen-thawed ET.

To examine the various predictors that mayinfluence the favorable CPR in the fresh orfrozen-thawed cycles.

Clinical Study (1)Patients & Methods

Type of the study: Retrospective andprospective study during the period 2010through 2015.

Patients enrollment:

Inclusion criteria

Exclusion Criteria

Data collection tool:

Clinical Study (1)Results

Reviewing of 600 cycles autologous IVF, 133 cycles met the inclusion criteria. 67 of them were fresh cycles.

Demographic and basal cycle characteristics of the study population:


Cycle outcomes:

Relation between CPR with different studied parameters

Cycle outcome

Test of sig. pNo pregnancy

(n = 62)

IUP

(n = 71)

No. % No. %

Type of the Cycle

Frozen-Thawed ET x-donor 40 64.5 26 36.6 2=

10.303*0.001*

Fresh ET x-donor 22 35.5 45 63.4

AMH level (ng/ml) 7.74 ± 6.28 6.77 ± 4.76 Z= 0.885 0.376

D2 FSH level (mIU/ml) 6.16 ± 1.66 5.95 ± 1.67 Z=0.276 0.782

Peak estradiol level (pg/ml) 1602.76 ± 1631.02 2127.45 ± 1503.97 Z=2.323* 0.020*

Antral Follicles Count 29.0 ± 14.18 28.80 ± 14.22 Z=0.018 0.986

Embryo transferred 2.0 ± 0.72 2.23 ± 0.59 t= 1.976* 0.050*

Clinical Study (1)Discussion

Our study is the first study illustrated thecomparison between the fresh and the frozen-thawed ET in PCOS women.

We hypothesized that the supraphysiologicallevels of steroid hormones in the fresh ET mightadversely impact the IVF outcomes in PCOS.

Surprisingly, we found that the CPL,Implantation rate and LBR are much better inthe fresh cycles as compared to the frozen-thawed PCOS cycles.


In agreement with our study:Author Study Question Methods Main Results

Sunkara et al.(2011)

Association between number of eggs andLBR in IVF

Retrospective cohort study.400,135 IVF cycles (1991-2008, UK)

Strong association between the number of oocytes retrieved and LBR until about 15 oocytes and plateau from 15-20 then decline beyond 20

Baker et al.(2015)

Association between the number of retrieved oocytes with LBR and low birth weight.

Retrospective SART data analysis (2004-2010) analysis of 231,815 cycles

Increase number of retrieved oocytes higher LBR and lower lower birth weight.


In agreement with our study:Author Study Question Methods Main Results

Rehman et al.(2012)

Effect of E2 levels on Pregnancy outcomes in obese women

Quasi-experimental study.323 women grouped accordingto BMI

Obese women had lower estradiolwomen with decreased CPR.

Chen CH et al.(2003)

Relationship between peak serum estradiol levels and treatment outcome in in vitro fertilization cycles

Retrospective 697 IVF-ET cycles 1999 to 2001

high peak E2 was associated with improved pregnancy rates after ET on day 5 but not on day 3.


Against!Author Study Question Methods Main Results

Simon et al.(1998)

Increasing uterine receptivity by decreasing E2 levels during preimplantation periods in high responders during FSH step down protocol

-prospective controlled study.-91 IVF cycles (high responders)-not randomized.-Stepdown protocol.

With the use of step-down protocol in the prospective high responders, endometrial receptivity can be improved when E2 decreased in the preimplantation period.


Against!!Author Study Question Methods Main Results

Shapiro et al.(2011)

Evidence of impaired endometrial receptivity after ovarian stimulation for IVF

-prospective randomized controlled trial -122 patients with AFC>15-main outcome was CPR

CPR was 80% in the cryopreservation group and 65% in the fresh group.

Clinical Study (1)Conclusion

Our study suggests that CPR and LBR isbetter in the fresh ET cycles in comparison tofrozen-thawed ET in PCOS women.

Clinical Study (2)

IVF versus ICSI for Couples with PCOS and Normozoospermic Semen:

An Analysis of 4679 Cycles from SART


The main objective of this study was todetermine whether patients with PCOS havebetter pregnancy outcomes following ICSIversus IVF.


Retrospective cohort study

319584 autologous IVF cycles were reported in SART in the period between January 1st 2011 until December 31 2012

cleavage stage

n=1634

IVF=822

ICSI=812

blastocyst stage

n=3045

IVF=1395

ICSI=1650

Exclusion criteria:

1-Any abnormal semen parameters.

2-Women age 40 years and more

2-women who had one or more causes of infertility (other than PCOS)

3-Donor and frozen-thawed ET cycles

4-cycles with split fertilization of the oocytes (both IVF and ICSI)


Outcome measures:

Statistical analysis:


Cleavage (day 2-3, age <40, only PCOS), n = 1634

ICSI IVF P value

n 812 822 NA

Age (at the start of the cycle) years 32.6 32.50 0.63

Basal FSH (mIU/ml) 6.7 6.3 0.01

BMI 28.60 27.40 0.002


Blastocyst (day 5-6, age <40, only PCOS), n = 3045

ICSI IVF P value

n 1650 1395 NA

Age (at the start of the cycle) years 32.10 31.80 0.07

Basal FSH (mIU/ml) 6.40 6.20 0.02

BMI 26.90 26.10 0.005

# of days of stimulation 11.96 11.96 0.96T


Cycle outcomes table:

Cleavage , n = 1634 Blastocyst , n = 3045

ICSI IVF P value ICSI IVF P value

n 812 822 NA 1650 1395 NA

#Oocytes retrieved 11.47 13.05 <0.001 17.96 18.63 2.97E-02

#2PN 5.89 6.89 <0.001 11.17 11.92 <0.001

Fertilization rate 54.60 55.60 0.52 64.00 66.00 0.005


Cycle outcomes (the cleavage stage ET):

Cleavage (day 2-3, age <40, only PCOS), n = 1634

ICSI IVF P value

n 822 812 NA

Clinical pregnancy rate (%) 46.9 50.0 0.34

Live birth rate (%) 38.7 39.9 0.3

Implantation rate (%) 69 63 0.7


Cycle outcomes (the blastocyst stage ET):

Blastocyst stage (day 2-3, age <40, only PCOS), n =****

ICSI IVF P value

n 1395 1650 NA

Clinical pregnancy rate (%) 61 67.5 0.01

Live birth rate (%) 51.2 58.7 0.01

Implantation rate (%) 76 83 <0.001


Against!


With!!!

IVF ICSI

n (total oocytes) 72 78

IVM oocytes (%) 79% 71%

Fertilization rate (%) 59% 68%

Blastocyst (%) 61% 55%

Cumulative implantation rate (%)

42.86% 42.86%


Contrary to previous studies, ICSI does not offer an

advantage over conventional IVF in terms of number

of oocytes fertilized, CPR, or LBR in PCOS women

undergoing IVF.

Clinical Study (3)

Impact of Metformin on in vitro fertilization (IVF) Outcomes in

Overweight and Obese Women with Polycystic Ovary Syndrome (PCOS)


The aim of this study was to determine ifmetformin therapy improves in vitrofertilization (IVF) outcomes in overweight andobese polycystic ovarian syndrome (PCOS)subjects.


Type of the study: Prospective non randomized and retrospective controlled study.

Study population:

Inclusion and exclusion criteria:

Recruitment:

Outcome measures:


(+) Metformin (-) Metformin p value

Number of the cycles (n) 51 51 N/A

Age (Mean± SD) 31.1 ± 3.7 32.89 ± 3.7 0.61

BMI (Mean± SD) 33.80 ± 4.4 32.90 ± 6.7 0.11

Duration of infertility (Mean± SD) 2.50 ± 1.1 2.79 ± 1.4 0.38

Patient’sbaseline characters


IVF cycle characters:

(+) Metformin (-) Metformin p-value

Number of the cycles 51 51 N/A

Basal estradiol* (Day 2) 25.16±17.8 23.59±8.4 0.57

Number of Antral Follicle Count (AFC)* (Day 2-5) 34.35 ± 13.77 30.43 ± 16.89 0.21

Basal FSH* (Day 2) 6.59 ± 1.95 6.05 ± 2.06 0.18

Basal LH* (Day 2) 7.44 ± 2.11 7.63 ± 2.74 0.85

TSH* 1.51 ± 0.81 1.79 ± 0.78 0.21

Triggering estradiol* 2098.33±

859.30

2997.89±

1540.69

0.005

Total gonadotropin doses* 1708.1±

533.42

1856.69±

761.63

0.23


The reproductive outcomes:(+) Metformin (-) Metformin p value

Number of the cycles 51 51 N/A

Retrieved oocytes* 9.06 ± 4.23 16.86 ± 8.30 < 0.01

# 2pn* 5.65 ± 2.66 9 ± 4.55 < 0.01

Fertilization rate (%) (288/462)62.33 (459/860)53.37 0.10

Clinical Pregnancy rate (%) (17/51) 33 (14/51) 27.5 0.52

Implantation rate (Sacs per total ET) % (24/153) 15.67 (18/153) 11.76 0.32

Miscarriage rate(%) (4/17) 23.52 (5/14) 35.71 0.46

Multiple pregnancy rate (%) (7/51) 13.37 (2/51) 3.9 0.08

Live birth rate (%) (13/51) 25.49 (9/51) 17.65 0.34


In agreement with our study:

Author Study Question Methods Main Results

Palomba et al.(2011)

Does metformin affect the ovarian response to gonadotropins for in vitro fertilization treatment in patients with polycystic ovary syndrome and reduced ovarian reserve?

Prospective, parallel, randomized, double-blind, placebo-controlled clinical trial

Enrollment was stopped after 88 participants had been randomized and analyzed due to an unacceptable increased risk of poor ovarian response in the metformin arm.

Costello et al. (2006)&Palomba et al.(2013)

metformin co-administration during gonadotrophin ovulation induction or IVF in women with polycystic ovary syndrome

A systematic review and meta-analysis of randomized controlled trials

co-administration of metformin to gonadotrophin OI does not significantly improve ovulation or pregnancy rates or live birth rates but reduces the risk of OHSS


The prospective hyperresponders overweight and

obese PCOS subjects will not benefit from short-

term Metformin administration regarding the IVF

outcomes.

International publications and presentations

(1)


(2)


(3)


(4)


(2)

Acknowledgement

To my dear supervisors for their great help, guidance in the study design and organization of the work.

To the members of Health sciences research department, Duke University , United States for analyzing the data and statistical work.

To the patients for their consent to participate in the study

To my colleagues and to the nursing staff for their kind assistance during the whole period of the study.

To my family whose love and support enabled me to keep the focus and drive towards carrying out this work.

thesis defense o abdalmageed

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