Prenatal exposure to anticonvulsants associated with increased risk of intellectual disability

Therapy Breakthroughs 23. dec 2020 2 min Clinical Professor Jakob Christensen Written by Morten Busch

About 1 in 100 people have epilepsy and thus risk disabling seizures and, in the worst case, death. Fortunately, anticonvulsants can reduce the number of seizures. New research shows, however, that pregnant women with epilepsy need to be careful, since valproate, a common anticonvulsant, is associated with both physical and intellectual disabilities among children whose mothers took it prenatally. The researchers think that prenatal exposure to valproate should be reduced. They hope other anticonvulsants can be found that reduce children’s risk.

Epileptic seizures are caused by sudden disturbances in nerve cells in the brain. Sometimes the seizures are ultra-short with total loss of consciousness. Others are minute-long convulsive seizures. Anticonvulsants enable about two thirds of people with epilepsy to become seizure-free. Unfortunately, anticonvulsants also have side effects. A very serious one affects children whose mothers have epilepsy.

“Our study shows that children whose mothers used the anticonvulsant valproate during pregnancy had a 4.5-fold higher risk of intellectual disability than children whose mothers did not take valproate during pregnancy. Treatment with valproate should therefore be minimized during pregnancy. The results indicate that other anticonvulsants may have similar side effects, so we are working on finding safe alternatives” explains Jakob Christensen, who is a consultant in the Department of Neurology at Aarhus University Hospital and Clinical Associate Professor in the Department of Clinical Medicine, Aarhus University.

Six times greater risk of delayed development

Valproate is used primarily to treat epilepsy but is also used to treat other conditions such as bipolar disorder and migraine. The researchers from Aarhus University and Aarhus University Hospital followed more than 900,000 children born from 1997 to 2016, of whom 580 were born to mothers who had redeemed prescriptions for valproate during pregnancy.

“Previous studies have focused on the physical disabilities associated with using valproate, such as congenital malformations of arms and legs. We linked the Danish National Prescription Registry with the Danish Psychiatric Central Registry and compared the children born to mothers who redeemed prescriptions for valproate during pregnancy with those born to mothers who did not take valproate during pregnancy and thereby determine whether children exposed to valproate prenatally had a greater risk of intellectual disability or delayed development,” explains Jakob Christensen.

Exposure to valproate during pregnancy increased the risk of intellectual disability by 4.5-fold and increased the risk of intellectual disability and delayed development combined by as much as 6-fold.

“Thankfully, intellectual disability is rare – even after prenatal exposure to valproate. However, intellectual disability is a serious condition, and we should therefore pay special attention to the children whose mothers took valproate during pregnancy, so that they can be offered the support they need if necessary,” says Jakob Christensen.

Major Nordic study underway

The mechanism of action of valproate has not been definitively clarified, but it reduces or prevents seizures by increasing the amount of gamma-aminobutyric acid (GABA) in the brain. Valproate has a calming effect because GABA blocks signal transmission in the neurons in the brain and the rest of the central nervous system.

“Valproate’s mechanism of action also seems to affect the development of the nerve pathways and thus the development of the fetal brain. Although the statistical material is not as large, our analysis of other anticonvulsants unfortunately also suggests that prenatal exposure may also be associated with a similar increased risk of intellectual disability,” explains Jakob Christensen.

The researchers are now conducting an even larger Nordic study to obtain sufficient data to conclude whether other anticonvulsants have the same effect or whether certain types are more suitable for pregnant women. In addition, the researchers hope to determine whether anticonvulsants are equally harmful during all stages of pregnancy.

“We know that the first 3 months of fetal development are very important for the risk of being born with congenital malformations, but the brain continues to develop especially in the last part of pregnancy. Since pregnant women with epilepsy need treatment to avoid having seizures, we hope that the new study can answer some of the key questions that can help pregnant women and their children optimally,” says Jakob Christensen.

Association of Prenatal Exposure to Valproate and Other Antiepileptic Drugs With Intellectual Disability and Delayed Childhood Milestones” has been published in JAMA Network Open. In 2017, the Novo Nordisk Foundation awarded a grant to Jakob Christensen for the project Traumatic Brain Injury and the Risk of Epilepsy.

In his research Jakob Christensen incorporates data which combines information from Danish social and health registers and biobanks. Biobanks have gat...

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