Medical Biology of Women's Health
A Pharmacogenomics study of the teratogenicity anti-epileptic drugs based on the prospective Australian Register for Anti-epileptic Drugs in Pregnancy
Supervisors: Professor Frank Vajda (vajda@netspace.net.au), Epilepsy and Neuropharmacology Group; The Department of Medicine; Professor Terence O’Brien, Epilepsy and Neuropharmacology Group (obrientj@unimelb.edu.au); The Royal Melbourne Hospital; Associate Professor Les Sheffield (les.sheffield@ghsv.org.au), The Murdoch Childrens Research Institute.
It is long been recognised that women with epilepsy who become pregnant while taking an anti-epileptic drug (AED) have an increased risk of having a foetus or infant with a birth defect (BD). Despite the increased risk associated with taking AED in pregnancy, most women with epilepsy who become pregnant, or plan to do so in the near future, cannot simply cease the drugs because of the risk to the health and safety of the mother and child of uncontrolled seizures. The development of methods that would allow the prediction that a specific drug would be associated with a higher risk of a birth defect in a particular woman would be of great potential benefit. There is evidence from family and twin studies that genetic factors may play a role in determining predisposing an individual to having a child with an AED associated birth defect. The Australian Register of Anti-epileptic Drugs in Pregnancy has been established in an attempt to obtain more accurate information about the risks of specific AEDs. This is a prospective, voluntary, telephone interview based study that enrols pregnant women with epilepsy, prior to the outcome of the pregnancy being known, and follows the outcomes of their pregnancies. The study has been running since July 1999, and to date has enrolled more than 1400 pregnant women.
This study will attempt to identify genetic markers that predict the risk of valproate-induced birth defects. Participants will be identified through the Australian Registry of Anti-epileptic drugs in pregnancy. Women with epilepsy who were taking an AED in the first trimester, and their partners, will be offered enrollment. Two types of genetic tests will be performed:
- A case-control genetic association studies comparing genetic information from mothers and infants taking a specific AED during the first trimester with those who were taking the same drug but did not have a child with a birth defect.
- A transmission disequilibrium test (TDT), design will be also be employed. This test looks for significant disequilibrium in the transmission of the allele of interest in the patient with a characteristic of interest. It therefore eliminates any potential sources of bias between the affected patients and non-affected controls, which may occur in case-control association studies. Blood for genetic analysis would be taken from the mother, father and infant.