# Presentation: 334319

## Pregnancy Follow-up Studies

**Lessons from Glaxo Wellcome**
**Experience**

## Outline

**Historical case study**
**Lessons learned**
**Future possibilities**
**Key issues **

## Points to Consider in Deciding When to Establish a Pregnancy Follow-up Study

**Likelihood of 1st trimester exposure**
**Potentially large exposed population of sexually active women Ages 15-44**
**Animal data and relationship to**** ****effect on human fetus**
**Underlying medical condition**
**Medication’s mechanism of action**
**FDA pregnancy category rating**

## Case-study: AcyclovirBackground

**Antiviral medicine to treat herpes simplex virus infections  **
**Pregnancy registry established in 1984 due to:**
**Potential for unintentional 1st trimester exposure to new chemical entity**
**Historic precedent of less specific antiviral agents for toxic effects**

## Acyclovir Study - Origins

**Acyclovir Study established 1984**
**Part of broad epidemiologic safety program**
**Joint effort with CDC**
**Objective: Monitor for risks of birth defects following antenatal acyclovir exposure**
**Duration: Use registry approach until other, more efficient,  methods could address the question**

## Design Considerations (1)

**Exposures of potential interest**
_**Oral acyclovir**_
_**IV acyclovir**_
**Topical acyclovir**
_**Maternal exposures**_
**Paternal exposures**
**Trimester **_**1**_**, 2, 3**

**Outcomes of potential interest**
_**Overall major birth defects**_
_**Specific birth defects**_
**Minor events **
**Delayed development**
**Maternal complications**
**Spontaneous abortion**

## Design Considerations (2)

**Objective: Estimate risk of major birth defects**
**Cohort study neither ethical nor feasible because outcomes are too rare**
** ****Case-control not feasible **
**Exposures too rare**
**No *****a priori***** hypotheses **
**No existing data resources available and sufficient**

## Design Considerations (3)

**Exposure registration and followup study **
**Prospective enrollment required**
**Birth defect comparator needed (population rate)**
**Outcomes: birth defects consistent with CDC definitions**
**Other outcomes not within scope (e.g., maternal events, spontaneous abortion) because **
**different / more data needed**
**methods not appropriate**

## Inclusion Criteria

- Trimester 1

- Trimester 2

- Trimester 3

- Birth

- Ultrasound
- 16 weeks

- PROSPECTIVE
-  (included)
**Case reported **
***before***** outcome known**

- RETROSPECTIVE
- (excluded)
**Case reported **
***after***** outcome known**

## Method - Data Collection

**Initial data collected at enrollment **
**Exposure, timing, EDD, prenatal testing**
**Potential confounders specific to the study**
**Basic information from single reporter **
**Likely to be motivated**
**Likely to have exposure and outcome information**
**Will not require additional steps**

## Methods - Follow-Up

**Follow-Up:**
**Form sent to health professional at EDD**
**Monthly reminders until data obtained**
**Patient identifiers (not names) used and  deleted at completion**
**Thank you letter with encouragement to register other exposures, and to solicit longer term outcomes, if known**

## Targeted Follow-Upof Birth Defects

**Initiated by registry staff**
**Targeted to specific birth defect cases reported**
**Based on CDC teratology review**
**Could include questions from GW Drug Surveillance M.D. **

## Methods - Analysis

**Separate prospective/retrospective reports**
**Estimate birth defect risk (proportion) from prospective reports**
**Compare risk against “expected” risk**
**Evaluate specific birth defects**
**Analyze defects for evidence of patterns or uniqueness**
**Review of all data by Advisory Committee**

## Recruitment

**Challenge: Encourage enrollment without communicating an inappropriate message **
**Avoid implying drug should be used in pregnancy **
**Avoid suggesting a known risk exists**
**Options:**
**Use existing health information lines**
**Referrals from TIS, CDC, FDA**
**Medical newsletters, journals, MMWR**
**Scientific meetings, presentations**
**Package insert**

## Sources of Calls and Referrals

**Registry**

** ****CDC**

**Health Care**
**Providers**

**Patients**

**Clinical Trials**

**Operating**
** ****Companies **

**International**
**Sources **

**Genetic**
**Counselors**

**Company**
** ****Sales Force**

**Teratogen **
**Information**
**Services**

**Other **
**Manufacturers**

## Advisory Committee

**Reviewed data**
**Assisted in disseminating information**
**Members represented**
**Centers for Disease Control and Prevention**
**Academic medical practitioners/epidemiologists**
**Glaxo Wellcome medical department**
**Could be expanded to include other disciplines, groups**
**Expertise in STDs, Obstetrics, Teratology, Pediatrics,  Epidemiology**

## Acyclovir Registry -- Prospective Reports June 1984 - April 1999

## Results:  Birth Defects

**First -Trimester Exposure: 19/596**
** ****3.2% (95% CI: 2.0%, 5.0%)**
**Any Trimester Exposure: 28/1082**
** ****2.6% (95% CI: 1.8%, 3.8%)**
**Does not differ from general population**

## Conclusions

**No pattern among prospectively or retrospectively reported birth defects**
**Potential limitations should be recognized (underreporting, differential reporting, losses to follow-up) **
**Despite these limitations, these results are useful in the course of**** ****counseling women following inadvertent prenatal exposure**

## Information useful to patients and physicians
Useful to GW in evaluation of safety
Information included in product label
Changed label from Category C to B
Study data informed the CDC STD Treatment Guidelines

**Useful to GW in evaluation of safety**
**Information included in product label**
**Changed label from Category C to B**
**Study data informed the CDC STD Treatment Guidelines**

**Value of the Study**

## Pregnancy Follow-up Studies

**Acyclovir  --  June 1984 (now closed)**
**Antiretrovirals****a**** -- 1 Jan 1989**
**Lamotrigine -- 1 Sept 1992**
**Valacyclovir --  Jan 1995 (now closed)**
**Sumatriptan --  1 Jan 1996**
**NA AED Pregnancy Registry****a**** -- Nov 1996**
**Bupropion -- 1 Sept 1997**
**Naratriptan --  1 Oct 1997**
**a**** *****Multi-company sponsored studies***

## Lessons 

**Design must be targeted to the questions**
**Simplicity is essential in data gathering**
**Voluntary recruitment of sufficient numbers of relevant exposures is difficult**
**Follow-up is a challenge**
**Ideal must be balanced by practicality**

## Probability 

**Ideal study **
**design**

**Probability **
**of ****obtaining**
**useful **
**data**

**MEDICATION SAFETY STUDIES**

## TAILOR DESIGN TO THE QUESTION

**Broad surveillance for increased risks of major **
**birth defects ?**

**Basic Approach**

**Monitoring for specific birth defect?**

**Case-control study**

**Monitoring for subtle or delayed event?**

**Targeted follow up study**

**Yes**

**NO**

**Basic Approach**

**Yes**

**TAILOR DESIGN TO THE QUESTION**

## SELECT THE METHOD APPROPRIATE TO THE OUTCOMES OF INTEREST

**Basic registry designed to evaluate risk of major birth defects**
**Other outcomes can be better studied with different methods**
**spontaneous abortion**
**maternal outcomes**
**infant outcomes requiring long-term follow-up**
**infant outcomes requiring medical examination for confirmation**

## Selecting the Right Approach

***High***

***Low***

**Sample**** ****Size**

**Complexity**

**Nature of Information **

**Frequency of major**
**birth defects**

**Delayed effects**

**Cross-drug**
**comparison**

**Frequency**
**of all birth defects**
** ****in first year**

## Impact of Methods on Case Capture and Follow-up

- Consent required

- Number of Referral steps

- Complexity of  data collection

- Duration of follow-up

**100%**

**? 50 %**

## Other Approaches

**Large linked databases offer promise **
**Identification of all exposures within a population**
**Not dependent on voluntary reporting  **
**Follow-up information collected for other purposes**
**Sample size may be achievable if multiple populations can be used**
**Case-Control studies remain useful**

## Issues 

**New consent/IRB considerations must balance individuals’ interests with impediments to  conducting voluntary registries. Regulations should facilitate, not hinder, public health monitoring functions**
**Adverse event reporting should follow study guidelines, not spontaneous guidelines **
**Value and use of information need to be better understood (confirm safety & identify new signals)  **