# Presentation: 944009

## Outcome Measurement for Assisted Reproductive Technology

**Outcome Measurement for Assisted Reproductive Technology**

**DAVID L. KEEFE, M.D.**
*Tufts New England Medical Center, Boston, Massachusetts*
*Laboratory for Reproductive Medicine, Marine Biological Laboratory, Woods Hole, MA*
*Brown 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 Processes

**Assess sperm quality and count**

**Wash sample**

**Sperm collection**

**Egg equilibration**

** ****Assessment of fertilization**

**Incubate**

**Wash/remove**
**excess sperm**

- Assess &
- Transfer

## IVF- 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/remove**
**excess sperm**

**Assess &**
**Transfer Embryos **

## Controlled Ovarian Hyperstimulation Regimens for Assisted Reproductive Technology 

**GnRH Antagonist**
**Protocols**

**GnRH ****Agonist**
**Protocols**** **

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

**Individualized Dosing of FSH/HMG**

**250 ********g per day antagonist**

**Individualized Dosing of FSH/HMG**

**GnRHa 1.0 mg per day **
**up to 21 days**

**0.5 mg per day of GnRHa**

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

**Day 6**
**of  FSH/HMG**

**Day**
**of ****hCG**

**Day 1 ****of FSH/HMG**

**Day 6**
**of  FSH/HMG**

**Day**
**of hCG**

**7 – 8 days**
**after estimated ovulation**

**Down regulation**

**Day 2 or 3**
**of menses**

**Day 1 ****FSH/HMG**

**OCP**

## 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

## 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

## 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

## 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.)

**Antagonist**

**Agonist**

- vs.

*** 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)?

## 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***

## 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! 

***Development 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 PGD
- 				0 normal	1 normal	>1 normal
- #patients			27	26		55
- #embryos			114	118		322
- #transfers			8	14		48
- Births/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

- 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 

- Spindle Function Imaged by Polscope

## Eggs With Normal Spindles Develop Better

**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