Oocyte Donation; Factors Influencing The Outcome Mustafa BAHÇECİ,M.D Ulun ULUĞ, M.D. German Hospital and Bahceci Women Health Care Center Istanbul, Turkey

First pregnancy with donated oocyte (Lutjen et al, 1984) Oocyte donation was performed in almost 10% of all ART cycles carried out in US (CDC report, 1999)

SART stats, 2005 Oocyte donated ET contributes 12.1 % of all ART cycles (over 13.000 cycles)

Cumulative Pregnancy rates following Oocyte donated Embryo transfers (Remohi et al, Fertil Steril 1997)

Oocyte factor: Endometrial factor Why oocyte donation programs are more successful in terms of achieving pregnancy; despite to advanced recipient age ? Oocyte factor: Younger oocytes Capable for conception based on previous reproductive history Endometrial factor The recipient's endometrial receptivity is dissociated from folliculogenesis since it is artificially prepared to be more uniform and similar to that of a natural menstrual cycle

Indications for oocyte donation program Premature ovarian failure Poor responder Menopause (surgical, radiotherapy, chemotherapy) Advanced maternal age Recurrent implantation failure Poor oocyte quality Genetic Combined

Factors that can be detrimental for the outcome Donor Age and ovarian reserve COH for donor Number of oocytes retrieved Serum E2 levels of both donor and recipient Recipient Age Endometrial Thickness Indication for oocyte donation Embryo transfer timing and status Luteal phase support ….. Pregnancy follow up

Prenatal complications and dilemmas Gestational diabetes (?) Chronic Hypertension Preeclampsia Preterm delivery Third trimester hemorrhage Aortic dissection (Turner syndrome) How to screen for aneuploides ?

Donor Selection Normal physical and gynecological examination Uneventful medical history No family history of hereditary or chromosomal diseases Tested for STD Normal ovarian reserve (BAF by USG) Preferably uneventful (+) conception history ?

In a study of 257 ET oocyte donation cycles, neither the age of donors, nor the ovarian reserve or ovarian response variables were significantly related to implantation and pregnancy (Mirkin et al, JARG, 2003)

Retrospective analysis of 109 cycles Donor Age and Outcome Yoon et al, ASRM, 2005 Retrospective analysis of 109 cycles Pregnancy (+) Pregnancy (-) p Mean donor age 30.2 ±3.6 32.1 ± 4.3 0.01 Donor age <30 >34 p Pregnancy rate (%) 50.0 18.2 0.01

Long GnRH-agonist (mostly preferred) Multiple dose GnRH-antagonist COH for Donors Long GnRH-agonist (mostly preferred) Multiple dose GnRH-antagonist Although late onset OHSS is not considered, early onset OHSS could be associated

Multiple Antagonist protocol Time saving Less injections Less OHSS Similar outcome compared to long agonist Prapas et al, Hum Reprod, 2005

Alternative preparation of donors; a patient friendly approach In vitro maturation of oocytes collected from unstimulated ovaries for oocyte donation Holzer et al, Fertil Steril 8.7 mature oocytes per patient 18.2% implantation rate 50% clinical pregnancy rate

Number of Oocytes Retrieved and pregnancy (Letterie et al, JARG 2005) <5 6-10 11-15 16-20 21-25 >25 PR (%)* 67 50 44 56 49 61 Cryopreservation (%) 51 55 42 60 * Not significant (ANOVA)

Estradiol Levels in donor and outcome (Pena et al, Hum Reprod, 2002) Retrospective analysis of 330 consecutive fresh oocyte donation cycles E2 pg/ml 1499 < 1500-2999 >3000 Clinical pregnancy rate per ET (%) 38.0 41.2 47.7 Ongoing/delivered rate per ET (%) 33.8 34.6 44.0 All not-significant (ANOVA)

Estradiol (pg/ml) Level in Recipient and Outcome (Remohi et al, Hum Reprod 1997) E2 pg/ml <100 100-199 200-299 300-399 >400 PR (%) 46.2 50.8 55.3 39 47.2 IR (%) 12.2 19 21 14.7 16.7 All not-significant (ANOVA)

Endometrial Thickness and Pregnancy (Remohi et al, Hum Rep 1997) <7mm 7-9.9mm 10-11.9mm >12mm PR (%)* 46.7 45.3 42.5 54.8 IR (%) 13.4 14 15.4 26.1 *All not significant(ANOVA)

Endometrial Thickness and Implantation (2) Remohi et al There was a weak but significant correlation between endometrial thickness

Endometrial Thickness and Pregnancy Noyes et al, Fertil Steril, 2001

Recipient Age and Pregnancy (Soares et al, JCEM 2005) Age (yrs) <40 40-44 45-49 >49 PR (%)a 48.8 51 45.5 35.4 IR (%) 20.7 17.2 13.2b a Not significant b p=0.01 ANOVA

Recipient Age and Outcome (2) (Soares et al) Age Groups (yrs) <45 ≥45 p Implantation Rate (%) 20.7 16.8 0.02 Pregnancy Rate (%) 49.8 44.4 0.04 Miscarriage Rate (%) 23.3 0.03

Recipient Age and Outcome (3) (Toner et al, Fertil Steril, 2002) Analysis of SART stats between ’96-’98 17339 cycles 1. Older recipient age was associated with statistically reduced implantation, clinical pregnancy and delivery rates. 2. This effect appeared among recipients in their late 40s, and become more pronounced at age ≥50 years

Does Ovarian function of Recipient have any impact on the outcome ? The use of GnRH-a in women receiving oocyte donation does not affect implantation rates (Remohi et al, 1994) No differences were found according to whether ovarian function was present or absent in the recipient (Moomjy et al, 2000)

Multivariate Analysis Soares et al, JCEM 2005 (over 3000 ET cycles) Dependent variables Independent Variables PR IR Miscarriage Age 0.79 0.58 0.24 Endometrial Thickness 0.65 0.96 Days of Estradiol therapy* 0.01 0.02 0.38 Serum Estradiol 0.80 0.53 0.12 Good quality Embryos 0.008 0.2 * 7 weeks or more

Number of Embryos Transferred and Pregnancy (Mirkin et al, JARG 2003) * PR, non significant * p<0.05

Clinical pregnancy rate (%) Almost 40% of all conceptions from oocyte donation were twin or high order pregnancies (ASRM/SART, Fertil Steril, 2004) Single Embryo transfer in Recipients (Soderstrom-Antilla et al, Hum Reprod, 2003) Retrospective analysis of 127 oocyte donation cycles No. of ETs Age of recipient woman Clinical pregnancy rate (%) Delivery rate (%) eSET 49 33.4 ± 5.3 40.8 32.6 DET 78 35.5 ± 4.4 41.0 32.1

a variety of reproductive disorders and recurrent miscarriages Indications for Oocyte donation and Pregnancy Garcia-Velasco et al, Fertil Steril 2003 (shared oocytes study) Pregnancy (+)* (n=365) Pregnancy (-) POF (%) 44.5 44.3 Genetic (%) 1.5 1.9 RIF (%) 29.1 27.2 Poor responder (%) 17.6 19.7 RPR (%) 2.2 2.5 Others (%) 5.1 4.4 p: not significant Oocyte donation provides similar success rates when applied to women with a variety of reproductive disorders and recurrent miscarriages Budak et al, Fertil Steril (in press)

Male Factor and Pregnancy (Garcia-Velasco et al) Normozoospermic (%) 35.1 38.6 NS Asthenospermic (%) 32.9 26 Oligozoospermic (%) 1.4 3.3 Teratozoospermic (%) 0.5 0.6 OAT (%) 6.8 4.4 Azoospermia Non ejaculated (%) (epid/test) 32 33 Totally 12 patients

Intra and Interdonor Variabilities (Mirkin et al, JARG 2003) There was no impact of additional stimulations on the donors’ ovarian responses CPR was not significantly different when comparing results of consecutive cycles Donors who achieved a pregnancy were more consistent in demonstrating success in subsequent cycles

Cleavage state vs blastocyst ET Budak et al, Fertil Steril 2007 (over 7000 ET cycles) IR (%) PR (%) Ongoing PR (%) Day 2-3 34.8 50.5 45.9 Day 5-6 49.9 63.4 58.7 *Statistical comparisons were not performed

Effect of day of transfer on implantation and pregnancy outcome in oocyte donors (Schoolcraft and Gardner, Fertil Steril, 2000) Day 3 Day 5 No. of patients 116 113 Age 39.9 ± 0.43 41.3 ± 0.41 NS Implantation rate (fetal sac) (%) 47.1 65.8 <0.01 Clinical pregnancy rate per retrieval (%) 75.0 87.6 <0.05 Multiples (%) 40.5 44,2

Does Recipient’s body habitus have adverse impact on outcome ? Body mass index and uterine receptivity in the oocyte donation model (Wattankumtornkul et al, Fertil Steril 2003) Patients were segregated to 4 groups according to BMI (<19, 20-24, 25-30, >30) Pregnancy rates did not differ between groups The area under the curve, 0.51 (95% CI 0.41–0.62) suggests no relationship between BMI and implantation

Conclusion Prognostic factors can differ in oocyte donation programs than homologues IVF programs

IVF Oocyte Donation Age important not as much Infertility etiology not COH protocol Oocyte number Estradiol levels Duration of treatment to some extent Embryo quality Ovarian Response