International research in preventing and treating infertility Joseph B. Stanford, MD, MSPH, DFPM Tracey Parnell, MD, Fam Med, UBC Kristi Panchuk RN, MN, Fam Med, UBC Mary Ellen Haggerty, MD, Edmonton, Alberta 22 January 2010

Acknowledgments Kirsten Stoesser, MD  UU DFPM Bernie LaSalle  UU Center for Clinical Translational Science Xiaoming Sheng, PhD  UU Pediatrics Phil Boyle, MB  Galway Clinic, Ireland International Institute of Restorative Reproductive Medicine

Funding Funding for iNEST provided by  St. Augustine Foundation  University of Utah Health Studies Fund  University of Utah Primary Care Research Center  Atlas Foundation

Background Sensitivity and specificity of the Creighton Model chart for identifying female infertility  Clinical observations and question  Design 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 couples  only half of these seek treatment Couples problem- both woman and man Chronic condition Other health implications Lifestyle issues Psychosocial dimensions Sound primary approaches needed

Infertility and public health Cost, access of treatment Cultural acceptability of treatment Prevention Child 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 treatment Vaginal bleeding and cervical mucus discharge  Medical evaluation and management  Surgical correction, if indicated  Goal 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 Examples Research question Design

PCOS, prior failed ART

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 center New patients charting who subsequently successfully conceive and have a live birth New patients charting who have a history of infertility Matched 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 physicians  5 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 table Inter-rater (and intra-rater?) reliability with kappa statistic Association 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 Miscarriage iNEST

Cumulative pregnancy rates for different treatment strategies Stanford JB, et al. Fertil Steril 2009 Mar 26 epub

Comparing cohorts Netherlands ART N=1351 Mean female age=32.8 Duration infertility=3.6 yrs Prior ART=0% Prior pregnancy=47% Pregnancy rate at 1 year  Crude=42.4%  Lifetable=64.7% Ireland NPT N=1072 Mean female age=35.8 Duration infertility=5.6 yrs Prior ART=33% Prior pregnancy=47% Live birth rate at 2 years  Crude=25.5%  Lifetable=52.8% Lintsen et al. Hum Reprod 2007Stanford et al. JABFM 2008

Comparing cohorts Netherlands ART Twins 22% Birth < 2500 grams  Not reported Ireland NPT Twins 4.5% Birth < 2500 grams  4.5% Lintsen et al. Hum Reprod 2007Stanford et al. JABFM 2008

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

iNEST rationale Document outcomes for peer-review Improve 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 which constitute natural experiments from which we could learn important lessons. These care changes, however, usually come up too quickly to allow the usual approach to development and funding 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 these innovations. 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 cohort  Couples based NPT practice-based initiation Patient follow-up independent of practice Follow all couples regardless of treatment continuation or discontinuation Obtain 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 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 place  Boyle, Galway, Ireland  Tham, Toronto, Canada Practices very close  Parker, Ohio, USA  Kho and Rota, Perth, Australia  Stegman, 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 NPT Examine in terms of baseline characteristics and treatment choices

Interim progress 87 couples enrolled  27 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 tracking Add general health questions to the entrance and follow-up questionnaires Add diet assessment or tracking

Next steps Methods paper describing study design and web-based innovations Addition of practices Additional funding Keeping the cohort going!

Big picture Potentially high pay-off study FMB has played essential role in start up Potential 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.  Outcomes  Access  Cost iNEST can provide key quality improvement data to improve the practice and outcomes of NPT internationally.