Using Automated Databases to Assess Fetal Effects of Maternal Medication Use

1. Using Automated Databases to Assess Fetal Effects of Maternal Medication Use FDA/OWHPregnancy and Prescription Medication Use Symposium William Cooper, M.D., M.P.H. Vanderbilt University School of Medicine

2. Objectives • Discuss role of automated databases in conducting studies of maternal drug exposures and fetal effects • Review findings from OWH funded studies • Consider future directions

3. Lessons Learned from Thalidomide • Epidemiology played a critical role • Response to signal • Epidemiologic assessment • Placenta not protective • Need for regulation and monitoring of medications and effects on fetus

4. Population-Based Studies • Provide estimates of potential exposures • Test signals with adequate power • Provide directions for targeted study • Maternal differences • Fetal differences • Opportunities for informing policies • Identify medications with low risk • Identify medications with high risk

5. Role of Epidemiologic Studies Signal Detection Case-controlStudies CohortStudies Assess Risk

6. Administrative Data: Tennessee • Linked data system dating to 1974* • Critical elements validated • Used in over 300 research studies • Filled pharmacy claims • Validated as measure of drug exposure† • Avoids maternal recall bias *Ray et al Annals Epidem 1989 Cooper & Kuhlthau Amb Pediatr 2001 †Landry et al Gertontologist 1988; Leister Med Care 1981; Johnson J Am Ger Soc 1991

7. Evaluation: Administrative Data TENNCARE FILES BIRTH CERTIFICATE DEATH CERTIFICATE LINK FILE MEDICAL RECORDS CENSUSDATA ALL-PAYERSDATA *Ray et al Am J Epidem 1989; Cooper et al Paediatr Perinatal Epi 2008

8. Unique Considerations: Databases • Choosing the right question • Cohort identification • Exposure ascertainment • Outcome • Identification • Validation

9. Choosing the Right Question • Signal • Vigilant health care providers • FDA adverse event reports • Registries (HIV-infected women, Accutane) • Surveillance (CDC, Teratology Services) • Public Health Importance • Bioterrorism Antibiotics and Fetal Risks • FDA OWH • Biologic Plausibility

10. Choosing the Right Question • Feasibility • Timing of exposure (trimester) • Potential outcomes measurable • Sufficient use • Statistical power • Public health guidance needed for safety

11. Antidepressant Exposures Cooper, Willy et al, Am J Obstet Gynecol 2007;197

12. Cohort • Selection of pregnancies • Enrollment throughout pregnancy* • Complete information • Selection of appropriate comparison group • Non-users • Active comparators *Cooper et al, New Engl J Med 2006; 354;23-31

13. Exposures LMP* DOB • Date of prescription through days supply • Drugs with long half-lives (biologics) • Drugs in combination • Drugs with overlap 1st PRE 2nd 3rd *LMP validated 94% of time (Cooper et al Pharmepi Drug Safety 2008)

14. Antibiotics and Pregnancy* *Cooper et al, Paed Perinatal Epidemiol 2008; 23:18 †Mutually exclusive categories (i.e. Any cipro, Any azithro (no cipro), etc.

15. Outcomes • Major Congenital Malformations • CDC* definitions • Possible: vital records or claims in first year of life • Confirmed: review of medical records† • Blinded adjudication by two investigators • Malformation-specific confirmation rules • e.g. Transposition of the Great Vessels • Echo, cardiac cath, surgical note, or autopsy finding *Metropolitan Atlanta Congenital Defects Program † Cooper et al Pharmacoepidemiol Drug Safety 2008

16. Confirmed Defects [n=869 (2.9%)] *Cooper et al, Paed Perinatal Epidemiol 2008; 23:18

17. Positive Predictive Value *Cooper et al, Pharmacoepi Drug Safety 2008; 17:455

18. Antibiotics & Malformations Cooper et al, Paediatric and Perinatal Epidemiology 2009

19. Antibiotics: Implications • Antibiotics that might be needed in the event of bioterrorism attack should not result in a greater incidence of overall congenital malformations in infants whose mothers take these medications.

20. Studies of Pregnancy Exposures

21. Ongoing Work • Immunosuppressives (NIAMS, AHRQ) • HIV Medications (NICHD) • Medication Exposures in Pregnancy Research and Evaluation Program [MEPREP] (FDA)

22. Immunosuppressives in Pregnancy • Immunosuppressives • Biologics, methotrexate, others • Used to treat autoimmune conditions • Little or no information to guide pregnancy use • Outcomes • Malformations and perinatal outcomes • Participating sites • Vanderbilt (lead site) • Kaiser Permanente • Northern California • Southern California   

23. Distributed Data Network KPNC VU KPSC Common protocol Standardized datasets at local sites Lead site for each study generates code, sends to local sites Case Reviews at local sites sent to lead site for confirmation Limited use data files sent to lead site - combined for analysis

24. In Utero HIV Medications • Several treatments, all understudied • Collaboration with two other sites • Harvard School of Public Health • Brigham and Women’s Pharmacoepidemiology Unit • Outcomes • Malformations • NICU hospitalization • Death

25. Pregnancy Network (MEPREP) • Multiple sites • HMO Research Network (15 health plans) • Kaiser Permanente (2 health plans) • Vanderbilt (Tennessee Medicaid) • Standardized data files/distributed data • Increased sample size and distribution • Collaboration with FDA

26. What is Needed? • Active surveillance • Follow-up of signal with studies • No study design is perfect • Draw on strengths of various designs • Consortia to assess signal • Methods for conveying information • Information for policy makers • Information for health care providers • Information for women of child-bearing age

27. Collaborators Vanderbilt Wayne Ray Gerald Hickson Mike Stein Harvard Sonia Hernandez-Diaz Kaiser Permanente De-Kun Li Craig Cheetham FDA Mary Willy Judy Staffa Rita Ouellet-Hellstrom Pam Scott Kristin Phucas Biostatistics Patrick Arbogast Lisa Kaltenbach Hua Ding Trainees Michael Bowen Megan Cevasco Brooke Thompson Stephen Pont Astride Jules Research Staff Programmers Judy Dudley Kathi Hall Tony Morrow Research Nurses Pat Gideon Leanne Balmer Michelle DeRanieri Dee Wood Research Coordinators Shannon Stratton Lynne Caples Funders AHRQ HS 13084 NIAMS AR 07001 FDA 223-02-3003, 223-05-10100 NICHD HD 056940 Acknowledgments