Prenatal Valproate Exposure Linked to Lower School Performance

Pauline Anderson

March 28, 2018

Prenatal exposure to sodium valproate, or to multiple antiepileptic drugs (AEDs), is strongly linked to lower school performance in young children, new research confirms.

The new study supports previous research showing an association between prenatal exposure to valproate or combination AEDs and later adverse neurodevelopmental outcomes.

However, unlike previous research, this new study looked at "real life" educational tests, study author William Owen Pickrell, PhD, Wales Epilepsy Research Network, Swansea University, United Kingdom, told Medscape Medical News.

"We used compulsory tests that every child in Wales took during the study time period, so sort of real-world kind of tests, as opposed to the IQ tests that people used in the past," said Pickrell.

"At the end of the day, this is what matters most."

The study was published online March 26 in the Journal of Neurology Neurosurgery and Psychiatry .

Longitudinal Data

Researchers used routinely collected health information from the Secure Anonymous Information Linkage (SAIL) databank. SAIL contains primary care records for 80% of Welsh general practitioners (GPs), corresponding to 77% of the Welsh population (about 2.3 million).

Patients were deemed to have epilepsy if the GP record contained an epilepsy diagnosis code and a record of repeat AED prescriptions.

Researchers also obtained data on educational levels of children in Wales, where every child is tested at five time points, beginning at age 7 years with Key Stage 1 (KS1).

The study included 440 children with KS1 results available between 2003 and 2008 who had mothers with epilepsy. It also included a control group matched for maternal age, gestational age, and socioeconomic deprivation.

Researchers examined scores for mathematics, language, science, and "core subject indicator" (CSI), which looks at all three subjects together.

They divided mothers with epilepsy into groups according to prescribed AEDs. These included monotherapy with carbamazepine, lamotrigine or sodium valproate, multiple AEDs, and no AED prescription. About 54% In the polytherapy group were prescribed valproate.

The investigators found that compared with controls, children born to mothers prescribed valproate during pregnancy had a lower percentage of passes in KS1 tests across all indicators except language.

The differences were as follows: −12.7% (P = .035) for CSI, −12.1% (P = .011) for math, and −12.2% (P ≤ .004) for science. In the language category, the difference was −10.4% (P = .188).

Will Kids Catch Up?

Pickrell noted that the study period was before much of the evidence surrounding negative outcomes of valproate use during pregnancy had been uncovered.

"There are now more guidelines for clinicians to make sure they give the correct information to women who are pregnant."

The study also found that compared with controls, children born to mothers with epilepsy who were prescribed multiple AEDs during pregnancy had a lower level of achievement across all indicators other than language. The differences here were −20.7% (P = .042) for CIS, −21.9% (P ≤ .007) for math, −19.4% (P = .010) for science, and −19.3% (P = .269) for language.

While the differences in language scores weren't statistically significant, "the trend is more or less the same" as for the other educational categories, noted Pickrell.

It's possible that the epilepsy itself leads to poorer school performance. Pickrell pointed out that it's generally women with more severe epilepsy who are receiving polytherapy during pregnancy.

"This might be due to a more severe underlying brain pathology, which is partly genetic and may be passed on to the child."

In the polytherapy group, researchers analyzed school scores for moms taking and not taking sodium valproate. They found no significant difference between these two groups across any educational attainment indicator.

Scores did not differ for children exposed to carbamazepine or lamotrigine or for whose mothers did not take AEDs during pregnancy.

"This study, with the necessary provisos, adds more evidence that taking drugs whilst pregnant not only increases the risk of congenital malformations but may also affect the child's performance in school," said Pickrell.

Among such "provisos" were the lack of information on the mother's performance on educational tests or on parental social and behavior issues that can affect educational outcome.

Valproate has been linked to the following in offspring: birth defects, such as spina bifida; heart and kidney problems; and autism.

The study reinforces the message that clinicians should discuss the pros and cons of AEDs with their patients with epilepsy who are of child-bearing age, said Pickrell.

But he stressed that not taking these drugs during pregnancy can also pose severe risks for the child.

The researchers have obtained data for subsequent KS tests and will aim to see if the score differences "disappear" when the children are older, said Pickrell.

"Holes in the Data"

The study results are useful and add to the existing literature, Kimford J. Meador, MD, professor of neurology and neurological sciences at Stanford University School of Medicine, Palo Alto, California, told Medscape Medical News. Meador has studied the effects of AEDs on offspring of women with epilepsy.

Among the strengths of the study were its large size, relatively long follow-up for school performance measures, and use of a cohort matched on several factors, said Meador.

But the study had weaknesses, he added. These included small numbers for polytherapy combinations and lack of information on maternal IQ, AED dosages, alcohol use during pregnancy, and maternal folate use.

"So there are some holes in the data in that regard."

In an accompanying editorial, Robert FM Chin, Muir Maxwell Epilepsy Center, University of Edinburgh, and Department of Pediatric Neurosciences, Royal Hospital for Sick Children, Edinburgh, United Kingdom, praised the study for its "innovative" and "relatively cost effective and efficient" approach of linking routinely collected health and national education data.

With such an approach, Chin writes, the results are likely to be "truly representative of the general population" and have "vast potential to be applicable" to other conditions.

He added that prospective parents may find the study's "functional" outcome data "readily tangible." This information, he concluded, "should be included in information given to women with epilepsy prior to pregnancy."

Pickrell , Meador, and Chin have disclosed no relevant financial relationships.

J Neurol Neurosurg Psychiatry. Published online March 27, 2018. Full text, Editorial

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