International research in preventing and treating infertility

Joseph B. Stanford, MD, MSPH, DFPMTracey Parnell, MD, Fam Med, UBC

Kristi Panchuk RN, MN, Fam Med, UBCMary Ellen Haggerty, MD, Edmonton, Alberta

22 January 2010

AcknowledgmentsKirsten Stoesser, MD

UU DFPM

Bernie LaSalleUU Center for Clinical Translational Science

Xiaoming Sheng, PhDUU Pediatrics

Phil Boyle, MBGalway Clinic, Ireland

International Institute of Restorative Reproductive Medicine

Funding

Funding for iNEST provided bySt. Augustine FoundationUniversity of Utah Health Studies FundUniversity of Utah Primary Care Research CenterAtlas Foundation

BackgroundSensitivity and specificity of the Creighton

Model chart for identifying female infertilityClinical observations and questionDesign

International practice-based research in treating infertility (iNEST)Design, progress, lessons, next steps

Questions for you

What would make these two studies more interesting and attractive to potential funders?

What would improve the science?What would facilitate the logistics?

Background

What does infertility have to do with primary care and public health?

What is natural procreative technology (NPT)?

Infertility and primary care

Common problem: 10-15% of couplesonly half of these seek treatment

Couples problem- both woman and manChronic conditionOther health implicationsLifestyle issuesPsychosocial dimensionsSound primary approaches needed

Infertility and public health

Cost, access of treatmentCultural acceptability of treatmentPreventionChild outcomes

Multiple gestation, low birth weight, birth defects, developmental delay

Risk factor for cancer and other conditions

Natural Procreative Technology (NPT)

A systematic cooperative approach to optimize reproductive function- primarily in women. Health education: Creighton NaProTracking

Biomarkers to guide evaluation and treatmentVaginal bleeding and cervical mucus discharge

Medical evaluation and managementSurgical correction, if indicatedGoal is to facilitate in vivo conception over 12

optimized cycles.Applied in Family Medicine and OBGYN practices

Sensitivity and specificity of the Creighton Model FertilityCare chart for identifying female infertility

Creighton Model chart review study

Basic premise: underlying physiologic abnormalities of infertility are reflected in the woman’s standardized observations and charting.Not systematically demonstrated

ExamplesResearch questionDesign

PCOS, prior failed ARTThis patient, who previously lost sextuplets from an ART procedure, shows herCrMS chart which is strikingly consistent with polycystic ovarian disease (From:Pope Paul VI Institute).

Hilgers TW: The Medical & Surgical Practice of NaProTechnology. Pope Paul VI Institute Press, Omaha, NE, 2004.Hilgers TW: The Medical & Surgical Practice of NaProTechnology. Pope Paul VI Institute Press, Omaha, NE, 2004.

34 yo, endometriosis, infertility

Recurrent miscarriage, variable PPP, abnormal bleeding, split peak

Objective

To determine the specificity and sensitivity of NaProTracking to discriminate between patients with known infertility and known fertility, through expert assessment based on standardized assessment algorithm.

Design- CrM chart review study

Toronto CrM centerNew patients charting who subsequently

successfully conceive and have a live birthNew patients charting who have a history of

infertilityMatched 1:1 by age and prior gravidity

Or just select those with no prior pregnancy

Design- CrM chart review study

Blind review of charts by NPT-trained physicians5 independent reviewers

Rate parameters: mucus score, abnormal bleeding, length of post-peak phase

Classify as likely fertile or infertile

CrM chart review study- analysis

Sensitivity and specificity: 2x2 tableInter-rater (and intra-rater?) reliability with

kappa statisticAssociation of specific chart characteristics with

fertility status: logistic regression

Questions

Other centers?Miscarriage patients as an additional

component?

International NaProTechnology Evaluation and Surveillance of

Treatment for Infertility and MiscarriageiNEST

Cumulative pregnancy rates for different treatment strategies

Stanford JB, et al. Fertil Steril 2009 Mar 26 epub

Comparing cohorts

Netherlands ARTN=1351Mean female age=32.8Duration infertility=3.6 yrsPrior ART=0%Prior pregnancy=47%Pregnancy rate at 1 year

Crude=42.4%Lifetable=64.7%

Ireland NPTN=1072Mean female age=35.8Duration infertility=5.6 yrsPrior ART=33%Prior pregnancy=47%Live birth rate at 2 years

Crude=25.5%Lifetable=52.8%

Lintsen et al. Hum Reprod 2007 Stanford et al. JABFM 2008

Comparing cohorts

Netherlands ARTTwins 22%Birth < 2500 grams

Not reported

Ireland NPTTwins 4.5%Birth < 2500 grams

4.5%

Lintsen et al. Hum Reprod 2007 Stanford et al. JABFM 2008

32yo, longstanding amenorrhoea, then dry cycles, eventually ovulatory cycles

iNEST rationale

Document outcomes for peer-reviewImprove outcomes

Outcomes = live birth, health pregnancies, healthy babies, healthy children

iNEST Objectives

Improve NaPro treatment outcomes by systematically tracking the relationships between patient characteristics, diagnosis, and treatments.

Enhance efficiency and improve quality in the clinical practice of NaPro.

Provide guidance for future targeted randomized trials for the future.

Synergy between research and practice

Learning from each other

Care delivery is undergoing constant changes, many of whichconstitute natural experiments from which we could learnimportant lessons. These care changes, however, usually comeup too quickly to allow the usual approach to development andfunding of a research proposal that could evaluate their effects, and there are rarely research-practice connections that could coordinate the design and implementation of studies of theseinnovations.

Solberg LI et al. Ann Fam Med 2009;7:164-9

Learning from each other

[We should] convert the paradigm from “translate research into practice” to “optimize health and health care through research and quality improvement.”

[We should] develop and facilitate more partnerships among clinicians, researchers, and care delivery leaders for engaged scholarship in both research and quality improvement.

Solberg LI et al. Ann Fam Med 2009;7:164-9

iNEST Design

Prospective cohortCouples based

NPT practice-based initiationPatient follow-up independent of practiceFollow all couples regardless of treatment

continuation or discontinuationObtain treatment data from NPT physician

iNEST Design

Synergize study procedures with practice procedures

Provide added value for both practices and patients

iNEST Sites

Jean Golden-Tevald, Morningstar Family Health Care, New Jersey, began enrolling patients Feb. 2006

Joseph Stanford, University of Utah, began enrolling patients July 2007

Paul Carpentier, In His Image Family Medicine, began enrolling February 2009

Ira Winter and Anne Carus, Life FertilityCare Center, Leamington Spa, UK, April 2009

More iNEST practices

Practices with research ethics approval already in placeBoyle, Galway, IrelandTham, Toronto, Canada

Practices very closeParker, Ohio, USAKho and Rota, Perth, AustraliaStegman, Pennsylvania, USA

Participating patients

Written informed consent is obtained for 3-year follow-up with option for more.

Initial clinical questionnaire facilitates the clinical evaluation.

Future: if they enroll in the study, they can track their own cycles of evaluation and treatment online.

Main Outcome

Live birth up to 3 years after beginning NPTExamine in terms of baseline characteristics

and treatment choices

Interim progress

87 couples enrolled27 conceived (31%)

Online tracking and entrance questionnaire developed

Online system

Tracking log of eligible patients and those enrolled in study

Patients can complete initial evaluation questionnaire online:Data released to study only when consent received

Some flexibility for implementation based on individual practice needs

Future: track cycles of treatment, and hormonal support of pregnancy

Proposed modifications to iNEST

Only one detailed follow-up questionnaire at one year after entry

Add cycle review trackingAdd general health questions to the entrance

and follow-up questionnairesAdd diet assessment or tracking

Next stepsMethods paper describing study design

and web-based innovationsAddition of practicesAdditional fundingKeeping the cohort going!

Big picture

Potentially high pay-off studyFMB has played essential role in start upPotential for longitudinal cohort

Child outcomes

Data, experience, and infrastructure for randomized trial

Big picture

NPT has a potentially important role in infertility in relation to public health and primary care.OutcomesAccessCost

iNEST can provide key quality improvement data to improve the practice and outcomes of NPT internationally.