BALTIMORE – In utero exposure to valproate appears to increase the risk of significant adverse effects on fetal brain development that persist into childhood.
In two separate studies, children whose mothers took valproate during pregnancy had a higher risk for lower IQ and other cognitive deficiencies, as well as autism and other disorders along the autistic spectrum. "All women with epilepsy of childbearing potential should be informed of the risks. I feel that valproate should not be a first choice antiepileptic drug in women of childbearing potential," Dr. Kimford J. Meador, director of the Emory Epilepsy Center and professor of neurology at Emory University, Atlanta, said in an interview.
The cognition data come from the NEAD (Neurodevelopmental Effects of Antiepileptic Drugs) study, a prospective observational study that enrolled pregnant women who were using any of several antiepileptic-drug monotherapies from October 1999 through February 2004 in 25 epilepsy centers in the United States and the United Kingdom. Dr. Meador and his colleagues previously published interim NEAD data showing impaired cognitive function in 309 offspring at 3 years of age (N. Engl. J. Med. 2009;360:1597-1605).
In June 2011, the Food and Drug Administration issued a safety alert about the increased risk of impaired cognitive development in children exposed to valproate products in utero.
The investigators have now followed the children in the NEAD study up to 6 years of age. The primary study outcome is IQ at age 6 years as measured by the Differential Ability Scales (DAS), and a second analysis measures verbal and nonverbal cluster scores from the DAS.
In a multivariate analysis of the intent-to-treat sample of 310 children, IQ was lower among children exposed in utero to valproate, compared with children of mothers who took other antiepileptic drugs (AEDs) during pregnancy. Adjusted mean IQs were 105 for carbamazepine, 108 for lamotrigine, and 106 for phenytoin, compared with 99 in the children of mothers who took valproate. The difference between valproate and each of the other three medication groups was significant (P = .002, compared with all three groups combined).
Overall, maternal IQ was also strongly associated with their children’s IQ at 6 years (P less than .001), and both lower maternal age and lower gestational age were associated with lower IQ in the child. (P = .04 and .03, respectively). However, maternal IQ was not associated with child IQ among the offspring of mothers who took valproate, whereas it was strongly associated with child IQ for the other three AEDs, Dr. Meador reported.
The verbal cluster score was less than the nonverbal cluster score across all AEDs combined (P less than .0001) and for carbamazepine (P less than .028), lamotrigine (P less than .003), and valproate (P less than .005) individually, he said.
The autism findings were from a population-based cohort study of 655,691 children born between 1996 and 2006 to 428,431 mothers who were identified from the Danish Civil Registration System, a nationwide registry in Denmark. Information on AED prescriptions filled 30 days prior to and during pregnancy was obtained from the Danish National Prescription Registry, and children diagnosed with autism spectrum disorder and childhood autism were identified from the Danish Psychiatric Register, said Dr. Jakob Christensen of the department of neurology at Aarhus (Denmark) University Hospital.
The relative risk of autism spectrum disorder following valproate exposure during pregnancy was more than doubled (2.6), compared with children who were not exposed to antiepileptic medication during pregnancy. The relative risk of childhood autism was even higher, at 4.8. The relative risk of autism spectrum disorder was 2.6 following valproate monotherapy exposure and 2.5 following polytherapy that included valproate. The relative risk of childhood autism was 4.1 following valproate monotherapy and 6.8 following polytherapy that included valproate, Dr. Christensen reported at the meeting.
According to Dr. Meador, "There is a subgroup of women with primary generalized epilepsy who may only respond to valproate. I recommend trying the other AEDs first even in women with primary generalized epilepsy. If the woman is ultimately only controlled by valproate and decides to consider pregnancy, then the dose should be kept as low as possible."
The NEAD study was funded by the National Institute of Neurological Disorders and Stroke. Dr. Meador has worked as a consultant for the Epilepsy Study Consortium that receives money from NeuroPace, Upsher-Smith Laboratories, and Vivus Pharmaceuticals, but these funds are paid to Emory University and not to him directly. Fees for his consultant work for GlaxoSmithKline, Johnson & Johnson (Ortho McNeil), Medtronics, and UCB Pharma have gone to a charity of the company’s choice. In 2010, he received travel support from Sanofi-Aventis, a manufacturer of valproate. The Danish study was funded by the Danish Epilepsy Society. Dr. Christensen disclosed that he has received honoraria from UCB Pharma and Eisai.