This document outlines a proposed transdisciplinary study to assess in vitro maturation (IVM) of oocytes as an alternative infertility treatment compared to conventional in vitro fertilization (IVF). The study would have three pillars: 1) comparing the biology of IVM and IVF through animal studies; 2) evaluating the clinical efficacy, safety, costs and psychological impacts of IVM versus IVF through human studies; and 3) studying pregnancy complications and birth outcomes from IVM, IVF and spontaneous pregnancies using population health data. The goal is to provide a comprehensive evaluation of IVM across biological, clinical, economic and population levels to determine its potential as a treatment option for infertile couples.

1. In vitro maturation of oocytes as a promising treatment option for infertile couples: a transdisciplinary study Beum Soo An, Junling Chen Xi-Kuan Chen, Jack Huang Se-Hyung Park, Qiuying Yang

2. Background In-vitro maturation (IVM) Immature eggs are retrieved from ovary and mature in laboratory. Once eggs are matured, in vitro fertilization (IVF) is then performed.

3. Background In vitro maturation (IVM) of oocytes vs. conventional in vitro fertilization (IVF) Proposed advantages of IVM: Simplify treatment and reduces cost Avoids potential side effects-weight gain, bloating, breast tenderness, nausea, mood swings, and OHSS Fear of potential risk of malignancy associated with repeated cycles of ovarian stimulation.

4. Overall Objective To assess biological, clinical, psychological and economical impact of in vitro maturation (IVM) of eggs

5. 3 Pillars IVM Pillar 1: Biology Pillar 2: Clinical, psychological, economical Pillar 3: Population

6. Pillar I: Biological assessment of IVM

7. Biological approach for IVM group Objectives To compare life cycles and occurrences of disease from IVF and IVM treated offspring To compare gene profile in maternal placenta of IVM and IVF derived embryos

8. Hypotheses IVM or IVF offspring have no difference in life cycles and occurrences of diseases. Maternal placentas from IVM or IVF embryos do not have different gene profile.

9. Research design Using animal models (mouse or rat), we will compare life cycles and occurrences of diseases after IVF or IVM We will analyze gene profile in the maternal placenta using microarray after IVF or IVM embryo injection, and confirm this by real time PCR and western blot in the different gestational stages

10. Pillar II: Clinical, psychological, economical impact of IVM

11. Objectives To evaluate: Efficacy of IVM-pregnancy and live birth rates. Safety of IVM-complication rates Cost of health service Psychological impact on infertile couples

12. Hypotheses IVM treatment will result in comparable clinical efficacy as standard IVF (i.e. pregnancy and live birth). IVM decreases the risk of maternal complications and does not increase the risk of fetal, neonatal and long term complications. IVM is more cost effective than IVF IVM reduces psychological stress of infertile couples

13. Research Design Multicenter prospective randomized control trial comparing IVM to IVF Cohort study-follow up babies from IVM vs. IVF and spontaneous pregnancy -1 year Health economic analysis Psychological assessment using validated structured questionnaire Focus group discussion-clinicians, nurses, clients

14. Outcomes Efficacy of IVM vs. IVF: Fertilization Implantation Pregnancy Live birth Safety of IVM vs. IVF: Maternal complications (i.e. OHSS, miscarriage) Fetal complications (i.e. congenital anomalies) Newborn (Gestational age, birth weight, APGAR) Follow up of IVM vs. IVF vs. spontaneous pregnancy babies as a cohort Cost-effectiveness of IVM vs. IVF Impact of IVM and IVF treatment on psychological well being of infertile couples.

15. Pillar III: IVF and pregnancy complication and birth outcomes: a population based study

16. Objective To assess the effects of IVF and IVM on pregnancy complications and perinatal outcomes

17. Methods-subjects A population-based retrospective cohort 2004-2008 Niday Perinatal Database, Ontario 120 000 births in Ontario every year 900-1000 births with assistant reproduction technology

18. Methods-exposure and control Exposure: IVF and IVM Control: spontaneous pregnancy Frequency matched by: Year of birth Postal code of residence Plurality Parity Maternal age

19. Outcome Pregnancy complications: Gestational hypertension Preeclampsia Eclampsia Gestational diabetes Obstetric complications Placenta previa Placenta abruption

20. Methods-outcomes Birth outcomes: Birth defects Apgar score Gestational age: Preterm birth Birth weight: LBW, SGA Mortality Fetal death ( ≥20 gestational weeks) Early neonatal death Late neonatal death

21. Methods-confounders Aboriginal status First language of mother Maternal age Parity Initiation time of prenatal care Maternal smoking Reproductive history Induction during labor C-section

22. Timetable and Budget Timetable Preparation and coordination (6 months) Implementation (4 years) Report writing (6 months) Budget

23. Research Team Biologists Clinicians Psychologists Ethicists Epidemiologists Lawyers

24. Interaction and integration IVM Pillar 1: Biology Pillar 2: Clinical, psychological, economical Pillar 3: Population Health Policy makers

25. STIRRHS Mentors Dr. Raymond Lambert Dr. Marcel Melancon Dr. Roger Pierson Dr. Peter Leung (UBC) Dr. Seang Lin Tan (McGill) Dr. Mark Walker (U Ottawa) Dr. Shi Wu Wen (U Ottawa) Acknowledgement