Interview conducted by April Cashin-Garbutt, BA Hons (Cantab)
Please can you give a brief introduction to valproate?
Valproate (sodium salt of valproic acid) is an anticonvulsant used in the treatment of epilepsy, migraine and bipolar disorder as well as some other off label psychiatric indications. Less than half of the prescriptions in the USA for valproate are written for epilepsy. Valproate is particularly effective in the treatment of primary generalized seizures (e.g., Juvenile Myoclonic Epilepsy).
How many people take valproate during pregnancy?
The exact numbers are not clear but its use in women of childbearing age is common. In 2007, it was the second most commonly prescribed antiepileptic medication to women of childbearing age in the general population. Note that many of these prescriptions were not for epilepsy. A recent study found that in women of childbearing age treated with mood stabilizers, 20% receive valproate.
Are there any alternatives to valproate that women can take during pregnancy?
Yes, there are alternatives for each indication for which valproate is used. There is a small subset of women who may only respond to valproate.
Please can you give a brief introduction to the IQ of children?
IQ is short for Intelligence Quotient. It is a score derived from several standardized tests, and was originally devised to predict school performance. IQ gives an estimate of general intelligence, but does not measure all cognitive functions and can be influenced by social and educational factors.
How is IQ measured in children?
There are several standardized measures of IQ. The tests and how they are scored vary across age of the child.
Does a child’s IQ predict their IQ as an adult?
Yes, the correlation of IQ at ages 5, 6 and 7 years old to ages 17 and 18 years old is high (r=.86).
What was previously known about the effect of maternal valproate use during pregnancy on children’s IQ?
Prior to the beginning of our study in 1999, virtually nothing was known. During our study, reports from two retrospective studies and a small prospective study suggested that fetal valproate exposure is detrimental to cognitive abilities, but these were limited by their retrospective nature or small sample size.
What prompted your research into this topic?
Animal studies in the 1980’s demonstrated that antiepileptic drugs at dosages less than those, which are required to produce congenital malformations could produce cognitive deficits. These findings raised the question as to whether this could occur in humans.
What did your research involve?
Early in pregnancy, we enrolled women with epilepsy, who were taking an antiepileptic drug. A large array of potentially confounding factors were assessed prospectively and collected during the course of the study.
We followed the women through pregnancy and followed their children to age 6 years performing cognitive testing at ages 2, 3, 4.5 and 6 years.
Age 6 IQ was our primary outcome because it is standardized and predictive of school performance and adult IQ. We also assessed a range of cognitive functions at age 6.
What did your research find?
The NEAD Study is the largest prospective study examining the cognitive effects of fetal antiepileptic drug exposure. We previously published our findings at ages 3 and 4.5 years old in which the IQ of children exposed in utero to valproate was lower than the IQ of children exposed to 3 other commonly used antiepileptic drugs.
Our present publication in Lancet Neurology confirms this finding at age 6 years demonstrating reduced IQ by 7-10 points in the valproate group.
The age 6 assessments were also the first to include measurement of a large array of cognitive functions. We found that fetal valproate exposure is associated with dose-dependent impairments (i.e., worse performance if exposed to a higher dose of valproate) on a wide range of cognitive domains (i.e., verbal, non-verbal, memory, executive).
In addition, we found that valproate exposure was associated with lower verbal than non-verbal abilities and with reduced right-handedness, suggesting that it might alter the normal development of cerebral lateralization.
How do you think these results can be explained?
Fetal alcohol exposure can cause neuronal apoptosis (i.e., death of nerve cells in the brain) and impair the function of the surviving nerve cells. Some antiepileptic drugs can also produce this adverse effect on the immature brain.
Notably, valproate can induce the apoptosis and does so at a relatively lower blood level (in regards to therapeutic levels) than other antiepileptic drugs tested in this model. This may explain why fetal valproate exposure in humans is associated adverse cognitive outcomes in the children more than other commonly used antiepileptic drugs.
What impact do you think this work will have?
Fetal valproate exposure poses special risks for both malformations and cognitive impairments. Women requiring an antiepileptic drug and their clinicians should be aware of these findings in choosing their treatment.
We think that if women are given adequate informed consent, the use of valproate will be reduced in women of child bearing potential and that the occurrence of adverse outcomes will be reduced.
Do you have any plans for further research into this topic?
Yes, we have just begun a new study funded by the NIH to address many remaining unanswered questions. The new study is entitled Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD). It will examine the effects of new drugs and drug combinations on both child and maternal outcomes.
Where can readers find more information?
They can find our paper here: http://www.thelancet.com/journals/laneur/article/PIIS1474-4422%2812%2970323-X/abstract
Would you like to make any further comments?
Our study also found that children had higher IQ (mean 6 points) whose mothers took periconceptional folate (i.e., they were taking folate at the time of conception before diagnosis).
Several other recent studies have also reported a positive effect on cognition of children of women without epilepsy. Further research is needed to confirm this finding.
About Professor Kimford Meador
Dr. Meador is Professor of Neurology and Pediatrics, and Director of Epilepsy and Director of Clinical Neuroscience Research at Emory University, Atlanta, Georgia. He is a behavioral neurologist and epileptologist.
Dr. Meador has authored over 300 peer-reviewed publications. His research interests include: pharmacology and physiology of cognition, and epilepsy with focus on behavioral and cognitive co-morbidities and the impact of therapies. He is a recipient of the Clinical Research Award from the American Epilepsy Society.