Exposure to sodium valproate or a combination of antiepileptic drugs (AEDs) in utero is associated with worse attainment on national educational tests for 7-year-olds, according to a study published online March 26 in the Journal of Neurology, Neurosurgery & Psychiatry.
Arron S. Lacey, from Swansea University Medical School in the United Kingdom, and colleagues identified children born to mothers with epilepsy and linked these children to their national attainment Key Stage 1 (KS1) tests in mathematics, language, and science at age 7. The children were compared with matched children born to mothers without epilepsy.

Exposure to sodium valproate, combo of antiepileptic drugs tied to worse attainment on national tests

Data were included for 440 children born to mothers with epilepsy with available KS1 results. The researchers found that fewer children with mothers being prescribed sodium valproate during pregnancy achieved the national minimum standard in the core subject indictor (CSI), mathematics, language, and science versus the matched control group (−12.7, −12.1, −10.4, and −12.2%, respectively). Even fewer children with mothers being prescribed multiple AEDs during pregnancy achieved a national minimum standard in CSI, mathematics, language, and science compared with the control group (−20.7, −21.9, −19.3, and −19.4%, respectively).
“These results give further support to the cognitive and developmental effects of in utero exposure to sodium valproate as well as multiple AEDs, which should be balanced against the need for effective seizure control for women during pregnancy,” the authors write.

Source: Health Day News


Children exposed in the womb to the drug sodium valproate, used to treat epilepsy, or a combination of anti-epileptic drugs, had poorer academic scores in math, language and science in early elementary school, found a new study. There were many possible factors that could have contributed to the results that the researchers could not measure, but the findings match up with past studies finding negative effects in children exposed before birth to sodium valproate.

“Our findings support previous studies that provide consistent evidence that in utero exposure to sodium valproate and anti-epileptics in combination are linked to adverse neurodevelopmental outcomes,” wrote Arron Lacey, from the Wales Epilepsy Research Network at Swansea University Medical School in the United Kingdom, and his colleagues in the Journal of Neurology, Neurosurgery, and Psychiatry.


Background on Anti-Epileptic Drugs

Anti-epileptics, also called anticonvulsants, are a group of medications used to curb seizures in those with epilepsy. They are also prescribed to stabilize mood in those with bipolar disorder or similar mental health conditions.


Sodium valproate, the most effective drug at controlling seizures, is most commonly sold as Depakote, and other brand names include Convulex, Epilim and Stavzor. Sodium valproate has long been linked to a higher risk of neural tube defects, incomplete closure of the early-developing spinal cord that can potentially lead to conditions such as spina bifida. In addition, research has shown that up to 3 or 4 of every 10 children exposed to valproate will have a lower IQ and cognitive difficulties or a neurodevelopment disorder.


However, other factors could contribute to these children’s poorer academic success.

“It is also possible that the mothers with epilepsy not taking antiepileptics have less frequent seizures, thus reducing the risks to the unborn child associated with exposure to maternal seizures,” the researchers wrote.


The children of mothers with epilepsy who didn’t take anticonvulsants had similar academic scores as children not exposed to epilepsy or any anti-epileptic drugs. But that doesn’t mean skipping prescribed anti-epileptics is wise for expectant mothers with epilepsy.

“While this study highlights the risk of cognitive effects in the children of mothers prescribed sodium valproate or multiple anti-epileptics, it is important to acknowledge that some epilepsies are difficult to treat without these treatment regimes,” the authors noted. Uncontrolled seizures can threaten the life of the mother and her developing fetus. Regardless, doctors should tell women about the risks of these drugs and discuss possible alternatives before becoming pregnant, the authors wrote.


How This Study Was Done

In this study, the researchers used medical records to identify all children born between 1996-2001 in Wales to mothers with a diagnosis of epilepsy and what medications the mothers had been prescribed during pregnancy. The mothers were categorized as having taken only carbamazepine, only lamotrigine, only sodium valproate, a combination of multiple anti-epileptics or no anti-epileptics at all.

Then the authors compared the children’s scores on nationally administered academic assessment tests between 2003-2008, when the children were 7 years old. The tests assessed children’s learning in math, language and science. To compare scores, each child was matched to four other children whose mothers didn’t have epilepsy. They were matched based on their mother’s age, the family’s socioeconomic status, and the pregnancy week when the child was born (gestational age).

Among the 440 children included in the study, 26% were prenatally exposed to sodium valproate, and 9% were exposed to multiple anti-epileptics, approximately half of whom took valproate. The individual numbers of the groups remained small, however: 115 children exposed to sodium valproate and 39 exposed to multiple drugs. Twenty-four mothers (5%) took lamotrigine and 84 (19%) took carbamazepine. Then 178 children’s mothers (40%) did not take any anti-epileptics.


What the Study Found

Compared to the control group of 1,756 children whose mothers did not have epilepsy or take valproate, 12.7% fewer valproate-exposed children met the national minimum standard for all three subject areas. Overall, 12.1% fewer exposed children met the minimum math standard, 10.4% fewer met the language standard, and 12.2% fewer met the science standard, compared to unexposed children.

The proportion of children who met minimum standards dropped further if their mothers had been prescribed more than one anti-epileptic during pregnancy:
—20.7% fewer children exposed to multiple anti-epileptic drugs met standards for all three subject areas than children not exposed to valproate
—21.9% fewer multi-exposed children met the math standard
—19.3% fewer met the language standard
—19.4% fewer met the science standard

Children prenatally exposed to carbamazepine, lamotrigine or no epilepsy drugs did not have lower scores than the control group of children. However, the numbers of children in these groups was to small to calculate reliable risks. When the researchers excluded children from their analysis who had epilepsy or whose mothers smoked during pregnancy, the overall findings did not change.


What Else Could Affect These Results?

However, multiple other factors could play a role in the lower scores among children exposed to sodium valproate and multiple anticonvulsants. The mothers taking those medications had lower incomes, which is already more common among those with epilepsy. And the authors were not able to include any of the following in their analysis:
Mothers’ IQ
Mothers’ weight
Mothers’ use of alcohol or illegal drugs during pregnancy
Mothers’ consumption of folic acid (necessary to prevent poor neurodevelopment) during pregnancy
Parenting style or ability
Anti-epileptic dosage
Mothers’ epilepsy type
Mothers’ seizure frequency or epilepsy severity

“It is possible that mothers with poorly controlled seizures may have an effect on their child’s education in terms of parental support outside of school setting,” the authors suggested. “It is possible that the mothers prescribed sodium valproate as well as those prescribed multiple anti-epileptics have more severe epilepsy, and this may explain the difference in results.”

Past studies on exposure to carbamazepine and lamotrigine in the womb have mostly found no negative effects on children, but some studies have been contradictory, and it’s difficult to consider all the possible factors that can affect academic performance.

The study was funded by the Health and Social Care Research Wales. One of the study authors has received honoraria from Eisai, Sanofi and UCB, all pharmaceutical or scientific research companies. No other authors reported having industry connections.