Birth Defects Associated With Exposure to Lamotrigine in Pregnancy (EUROCAT)

Overview

In 2007 a case control study was completed within the EUROCAT European network of congenital anomaly registers to test the hypothesis that first trimester lamotrigine monotherapy exposure is associated with an increased risk of isolated oral clefts. This study found no statistically significant increased risk of oral clefts compared with other defects following lamotrigine exposure in the uterus. The EUROCAT Antiepileptic Drug (AED) Database, established for the original case control study in 2007, will now be expanded to include an additional five to six years worth of data. These data will provide greater power to investigate the risk of isolated oral clefts, specific cleft types and potential associations with additional specific malformation types (e.g. neural tube defects). Data on cases of isolated oral clefts registered between 1993 and 2012 will be extracted from EUROCAT member registers meeting set inclusion criteria (ensuring completeness of outcome and exposure data). The primary comparison group will include all non oral cleft, non chromosomal malformations as the registers do not collect data on non malformed infants. This study will also be powered to include a second control group of chromosomal malformations, very unlikely to be associated with medication exposure. Data on exposure to anti-epileptic drugs (AEDs) during the first trimester of pregnancy will be extracted along with other key covariates including age of mother, history of epilepsy and gestational age of the infant. Primary analyses, using logistic regression, will compare the lamotrigine monotherapy versus no AED use across case and control groups and a secondary analysis will compare lamotrigine monotherapy versus other AED monotherapy (with and without valproate). Data will also be monitored for patterns of lamotrigine exposure across additional specific malformation groups of interest.

Full Title of Study: “Monitoring of Specific Birth Defects Associated With Exposure to Lamotrigine in Pregnancy Through the EUROCAT Network”

Study Type

• Study Type: Observational
• Study Design
  • Time Perspective: Retrospective
• Study Primary Completion Date: December 2013

Interventions

• Drug: Lamotrigine monotherapy
  • Exposure to lamotrigine monotherapy in the first trimester of pregnancy (time period from first day of menstrual period to 12th week of gestation).
• Drug: No anti-epileptic drug exposure
  • No exposure to anti-epileptic drugs in the first trimester of pregnancy (time period from first day of menstrual period to 12th week of gestation).
• Drug: Non lamotrigine anti-epileptic drug monotherapy
  • Exposure to non lamotrigine monotherapy (with or without valproate) during the first trimester of pregnancy (time period from the first day of the menstrual period to the 12th week of gestation)

Arms, Groups and Cohorts

• Infants/foetuses w/malformations registered in EUROCAT network
  • Pregnancies resulting in foetus/infant with malformation registered through participating registers within the EUROCAT network

Clinical Trial Outcome Measures

Primary Measures

• Non chromosomal, non monogenic, isolated oral clefts
  • Time Frame: Retrospective case control study. All isolated oral cleft malformations registered on congenital malformation registers participating in the EUROCAT anti-epileptic drug database will be extracted irrespective of timing of diagnosis pre- or post natally.

Secondary Measures

• Non oral cleft, non chromosomal malformations
  • Time Frame: Retrospective case control study. All non oral cleft, non chromsomal malformations recorded on congenital malformation registers participating in EUROCAT anti-epileptic drug database extracted irrespective of diagnosis timing pre or post-natal.
• All chromosomal malformations
  • Time Frame: This is a retrospective case control study. All chromosomal malformations recorded on congenital malformation registers participating in the EUROCAT anti-epileptic drug database will be extracted irrespective of timing of diagnosis pre- or post natally.

Participating in This Clinical Trial

Inclusion Criteria

• Individual population-based registers within EUROCAT are eligible to participate if: – Anti-epileptic drug exposure is recorded for at least 3 per 1000 malformed infants/fetuses (figures below this threshold indicate potential under reporting of medication exposure). – Specific drug names or complete 7 digit Anatomical Therapeutic Chemical (ATC) classification codes are available for at least 80% of AED exposed infants/fetuses. Exclusion Criteria:

• As above

Gender Eligibility: All

Minimum Age: N/A

Maximum Age: N/A

Are Healthy Volunteers Accepted: No

Investigator Details

• Lead Sponsor
  • GlaxoSmithKline
• Provider of Information About this Clinical Study
  • Sponsor
• Overall Official(s)
  • GSK Clinical Trials, Study Director, GlaxoSmithKline