乌鸦传媒

Prenatal exposure to the newer anti-epileptic drugs levetiracetam (Keppra) or topiramate (Topamax) was not associated with reduced cognitive abilities in school-age children compared with those born to mothers with untreated epilepsy, researchers found.

However, kids exposed to increasing doses of valproate (Depacon) had significantly lower performance on cognitive ability testing than those exposed to higher doses of levetiracetam or topiramate, , of the Royal Manchester Children's Hospital in England, and colleagues .

Although the risks of in utero exposure to increasing doses of valproate have been demonstrated in other work, these data confirm that when the dose of valproate is kept as low as possible, risks to cognitive functioning in childhood may be reduced, Bromley told 乌鸦传媒.

"The treatment of epilepsy in the childbearing years or during pregnancy is challenging and requires consideration of both maternal and fetal health," Bromley said. "Our results indicate that the risk to fetal cognitive development may be lower for levetiracetam or topiramate exposure in comparison to valproate. However, we need more data to comprehensively understand any potential effects these medications may have on fetal development."

For the study, a total of 171 mother-infant pairs were retrospectively enrolled by treatment group from the United Kingdom Epilepsy and Pregnancy Register (UK-EPR). All infants had been a live birth between September 2004 and May 2007.

Forty-two mothers were taking levetiracetam monotherapy, 27 were on topiramate, 47 were taking valproate, and 55 were untreated during pregnancy. Assessor-blinded neuropsychological assessments were conducted on children between 5 and 9 years of age.

Although the groups were comparable demographically, women taking levetiracetam had the most seizures (43%). Women who took valproate during pregnancy were older and had the highest mean maternal IQ and level of folate supplementation, the researchers said.

They found that prenatal exposure to levetiracetam was not associated with full-scale IQ (FSIQ), verbal abilities, nonverbal abilities, or processing speed as the children grew up. Further, dose was not predictive of poorer outcomes, they reported.

The finding is consistent with their earlier work in and in , they noted.

Similarly, prenatal exposure to topiramate monotherapy was not associated with poorer cognitive outcomes across the same domains. However, children in this group demonstrated better performance on a single aspect of attention and executive functioning when compared to the control children, the researchers said.

Bromley and colleagues also found that in children exposed prenatally to half the median dose of valproate (half being 400 mg/d), there were no significant differences in FSIQ or in verbal or non-verbal reasoning compared with children exposed to half the median dose of levetiracetam (750 mg/d) or of topiramate (100 mg/d) or to controls.

As prenatal exposure to valproate increased, however, reductions in FSIQ, verbal, and non-verbal reasoning were consistently more pronounced than in the control group or in the topiramate and levetiracetam groups.

At 1,600 mg/d of valproate -- twice the median dose -- FSIQ scores dropped by 11 to 16 points, verbal reasoning by 17 to 21 points, and non-verbal reasoning by 6 to 14 points compared with the control group or to those exposed prenatally to twice the median dose of topiramate (400 mg/d) or levetiracetam (3,000 mg/d).

"The data here highlighted the substantial effect higher doses of valproate have on cognitive functioning in comparison to higher doses of topiramate and levetiracetam," the researchers said.

Similar to , the study did not find an association between cognitive functioning in the child and the type of maternal epilepsy or the number of seizures.

In the treatment of generalized epilepsy, the is making levetiracetam "an encouraging alternative to valproate," the researchers noted.

With topiramate, however, they acknowledged their findings are in conflict with a reporting an increased rate (4.2%) of major congenital malformation, specifically in nine patients exposed to topiramate in utero.

They pointed out that their study cohort was larger, with a narrower age range, underwent blinded assessment, included more potentially confounding factors and supports preclinical data showing a lack of association between topiramate exposure and impaired neuropsychological function.

Study limitations include a low rate of recruitment (171 out of 449 invited to participate), a higher rate of participation in the levetiracetam group (60% of this group was part of an earlier study), a lack of data on seizure exposure or anti-epileptic drug dose alterations towards the end of pregnancy, and the fact that comparisons across drugs were made at different dose levels.

It's also important to consider the age of the children at assessment, the researchers said. "In middle childhood," they noted, "cognitive development is still dynamic and as age-appropriate cognitive skills become more complex, differential results might be seen."

Bromley added that a better understanding of the use of anti-epileptic drugs in pregnancy and the child's subsequent neurodevelopment requires more research funding and focus. Investigation into the impact of prenatal exposure to certain anti-epileptic drugs "lags behind the work completed on the risk of congenital malformations," she said.

In the meantime, clinicians should discuss the risks and benefits of all treatments with their patients, Bromley said.

"They should also be clear with women about what we still have to learn with regard to some of these medications," she added.

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