Outcome Measurement for Assisted Reproductive Technology DAVID L. KEEFE, M.D. Tufts New England Medical Center, Boston, Massachusetts Laboratory for Reproductive.

Outcome Measurement for Assisted Reproductive Technology

DAVID L. KEEFE, M.D.Tufts New England Medical Center, Boston, MassachusettsLaboratory for Reproductive Medicine, Marine Biological Laboratory, Woods Hole, MABrown University, and Women & Infants Hospital, Providence, RI

Overview of Presentation• Introduction to ART procedures

• Study population– How factor in study populations for ART studies– How should IVF/ICSI/Donor Egg be factored in?

• Study Design– Efficacy measures: Primary and secondary endpoints– How should success be defined?– Safety endpoint measures

• A look into the future of ART outcome measurement

Assisted Reproductive Technologies

• In Vitro Fertilization/Embryo Transfer (IVF-ET), w/ or w/o ICSI

• Gamete Intrafallopian Tranfer (GIFT)

• Zygote Intrafallopian Transfer (ZIFT)

• Tubal Embryo Transfer (TET)

• Controlled Ovarian Hyperstimulation (COH) w/ Intrauterine Inseminations

IVF Steps• Ovarian down-regulation w/ OCP, GnRH

agonist or antagonist

• Controlled ovarian hyperstimulation with gonadotropins; U/S, E2 monitoring

• Trigger maturation with hCG

• Retrieval

• Fertilization by IVF or ICSI

• Culture embryos

• Transfer embryos w/ or w/o hatching

• Luteal support

IVF- Clinical ProcessesIVF- Clinical Processes

IVF- Laboratory ProcessesIVF- Laboratory Processes

Eggs retrieved

Eggs stripped and cleaned

Assess sperm quality and count

Wash sample

Sperm collection

Egg equilibration

Fertilization- IVF or ICSI

Assess fertilization

Incubate

Wash/removeexcess sperm

Assess &Transfer Embryos

Controlled Ovarian Hyperstimulation Regimens for Assisted Reproductive Technology

GnRH AntagonistGnRH AntagonistProtocolsProtocols

GnRH GnRH AgonistAgonistProtocolsProtocols

225 IU per day225 IU per day(150 IU Europe)(150 IU Europe) Individualized Dosing of FSH/HMGIndividualized Dosing of FSH/HMG

250 250 g per day antagonistg per day antagonist

Individualized Dosing of FSH/HMGIndividualized Dosing of FSH/HMG

GnRHa 1.0 mg per day GnRHa 1.0 mg per day up to 21 daysup to 21 days 0.5 mg per day of GnRHa0.5 mg per day of GnRHa

225 IU per day225 IU per day(150 IU Europe)(150 IU Europe)

Day 6Day 6of FSH/HMGof FSH/HMG

DayDay

of of hCGhCG

Day 1 Day 1 of FSH/HMGof FSH/HMG

Day 6Day 6of FSH/HMGof FSH/HMG

DayDayof hCGof hCG

7 – 8 days7 – 8 daysafter estimated ovulationafter estimated ovulation

Down regulationDown regulation

Day 2 or 3Day 2 or 3of mensesof menses

Day 1 Day 1 FSH/HMGFSH/HMG

OCP





Differences in Study Populations be Factored Into ART Studies

• IVF/ICSI/Donor Egg patients differ in underlying disease

• Differ in rate of egg dysfunction IVF>ICSI>Egg donor

• Egg dysfunction (a.k.a. ovarian reserve, age, etc.) best predictor of outcome (can determine log-order differences in pregnancy rates among groups of patients)

• Studies should control for study population differences through inclusion/exclusion criteria, case-control or stratification





Outcome Measures for ART

• Deliveries/initiated cycles- the gold standard

• Surrogate clinical outcomes– Ongoing viable pregnancy (+FH)– Clinical pregnancy rate (+FH)– Biochemical pregnancy rate

• Surrogate biologic outcomes– Number of follicles– Peak E2– Number eggs aspirated– Fertilization rate– Embryo cleavage and morphology rates

Outcome Measures for ART-Deliveries/Initiated Cycles

• The gold standard

• Large power needed

• Expensive

• Difficult-to-measure, but important patient differences have greater impact than drug therapy on this outcome

Outcome Measures for ART-Surrogate Clinical Outcomes

• Close to gold standard• Less power needed• Clinically important outcome• May miss clinically-important differences,

e.g. miscarriage rates• Contaminated by clinic practices, e.g.

cancellation policies

Outcome Measures for ART-Surrogate Biologic Outcomes

• Far from gold standard• Much less power needed• May not reflect clinically important outcome,

e.g. young women with low response to COH still have excellent outcomes; subtle differences in drug potency on egg yield and E2 can be managed by altering dosing

How Should Success be Defined?

• Superiority to comparator (placebo;active control)

• Equivalence to active comparator• Non-inferiority to active comparator• Success should be defined not only

according to pregnancy rate or its surrogate, but also according to convenience and discomfort level

Success Should be Defined Based on Equivalence or Non-Inferiority to

Comparator

• Superiority to comparator (placebo;active control)- not necessary for new drug to prove useful for patient care

• Equivalence or Non-inferior drugs would:– Spur competition in market– Allow multiple options affecting

convenience/comfort, which differ according to patient preference, e.g. vaginal vs. IM route for progesterone therapy

Example- Antagonist improves convenience w/o improving pregnancy outcome (also, vag. prog, s.q. gts.)

AntagonistAgonist

vs.

* Based on median duration of use. North American Ganirelix study.* Based on median duration of use. North American Ganirelix study.

Safety Endpoints

• Ovarian hyperstimulation syndrome

• Miscarriage rate

• Multiple pregnancy rate

• Ectopic pregnancy rate

Safety Endpoints- Ovarian Hyperstimulation syndrome

• Life-threatening

• Risk sets upper limit on COH

• Risk may be modified by lowering peak estradiol e.g. aromatase inhibors, LH

Safety Endpoints-Miscarriage Rate

• Common (15-70%)

• Affected by patient-specific factors (e.g. age, ovarian reserve)

• May be influenced by all stages of ART, e.g. stimulation regimens, luteal phase support, culture media, etc.

Multiple Gestations and ART• Common (15-50%)• Major obstetric, pediatric and public health concern

(prematurity, C.P., C/S rate, preeclampsia, gestational diabetes)

• Affected by patient-specific factors (e.g. age, ovarian reserve)• Affected by (elusive ) clinician practices, e.g. number of

viable embryos transferred• Monozygotic twinning also should be considered, since is

related to COH, increased in ART and causes significant morbidity (twin-twin tx)

• Should imprinting abnormalities (Beckwith-Wiedemann, Angelmann Sydromes, PIH) be considered an ART risk (DeBaun et al, AJHG, 2001)?





The Future of IVF Outcome Measurement

• Multicenter network to facilitate RCT’s

• Greater racial and ethnic diversity in clinical studies to ensure generalizability of data, as mandates increase access of working and middle class Americans to ART

• Improve biological surrogate outcomes

The Future of IVF Outcome Measurement-Improving Biological Surrogate Outcomes

• Aneuploidy ubiquitous and related to ART failure, through increased embryo apoptosis, implantation failure and miscarriage

• Thus, may provide a meaningful biologic surrogate outcome

• Safety problems with IVF stem from attempts to overcome egg aneuploidy through COH, e.g. OHSS and multiple gestations

• May be increased by COH (e.g. by short-cutting normal selection process, altering follicular environment)

• New technologies to dx aneuploidy e.g. CGH, SKY• May be able to dx predisposition to aneuploidy

Aneuploid Embryos Can Develop Normally Until Day 5 of Life!

Day 1

Day 5

Day 4Day 3

Day 2Development of Embryo with Trisomy 21, determined by PGD on day 3, with develoment to normal-appearing blastocyst

Preimplantation Genetic Diagnosis (PGD) Can Improve Implantation Rate

Identification of chromosomes X,Y,13,18,21,15,16,22

Implantation Rate

PGD 24.2%

Controls 12.4% (p<0.001)

Gianaroli et al F+S, 1999

Preimplantation Genetic Diagnosis (PGD) Predicts IVF Outcome

• Age >37• > 2 failed cycles of IVF• 216 couples• 3 groups, depending on # normal embryos available

after PGD0 normal 1 normal >1 normal

#patients 27 26 55#embryos 114 118 322#transfers 8 14 48Births/patient 4% 15% 31%

Ferraretti, et al World Congress IVF, 2002

Preimplantation Genetic Diagnosis (PGD) in Patients with Repeated Miscarriages

76% of embryos from patients with Recurrent Pregnancy Loss have aneuploidy

Pellicer, et al F+S 71:1033, 1999

Gt.s’ Play Key Role in Meiosis

Metaphase II (MII)

Metaphase I (MI)

FSH then LH(Gonal F, Repronex, Follistim, Bravelle, then hCG)

Immature Oocytes w/I

Follicles

Eggs From Older Women Have Abnormal Spindles

Age (years) % Abnormal Spindles

20-35 17

40-45 79

Battaglia et al, Hum Reprod. 1996;11:2217.

Spindle Function Imaged by Polscope

Eggs With Normal Spindles Develop Better

Telomere Shortening Explains Effects of Age on Aneuploidy:

• Late exit from the Production Line (Henderson and Edwards, 1968)

• The effects of low levels of MtDNA deletions (Keefe, 1995)

• Spindle abnormalities (Battaglia,1997)• Reactive oxygen species (Tarin, 1998)• Increased embryo arrest• Increased embryo death

Outcome Measurement for Assisted Reproductive Technology DAVID L. KEEFE, M.D. Tufts New England Medical Center, Boston, Massachusetts Laboratory for Reproductive.

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