The children of
women who used the epilepsy drug valproate while pregnant are at greater risk
for having low IQ. That's the finding of research presented at the American Academy
of Neurology's 59th Annual Meeting, in Boston. In an
ongoing study, now in its seventh year, of the effects of four common antiepileptic
drugs (AEDs) — carbamazepine, lamotrigine, phenytoin and valproate —
researchers have determined that children of women with mild epilepsy who had
taken valproate during pregnancy have a lower average IQ. These children are also
more likely to have an IQ in the mental retardation range (less than 70 points)
than the offspring of mothers taking the three other drugs. "Children
exposed to valproate [in utero] seem to display an IQ reduction of between nine
and 11 points. This is clinically significant and even financially significant,
if you look at what happens to children that lose this much cognitive function,
over a lifetime of earnings or medical costs," says lead investigator Dr Kimford
J Meador, professor of neurology at University of Florida. SIGNIFICANT
DIFFERENCE
Dr Meador's study is a multicentre prospective, parallel-group
observational study following 187 AED-affected children, currently two-years-old,
from birth to six years. Within the four AED groups, 48 women took carbamazepine,
68 took lamotrigine, 42 took phenytoin and 29 took valproate. When
adjusted for maternal IQ and dosage, two-year-old children whose mothers had taken
valproate during pregnancy had an average Bayley Mental Developmental Index IQ
of 84, compared to 93 for those whose mothers used either carbamazepine or phenytoin,
and 96 for those who took lamotrigine. Similarly, 24% of the children affected
by valproate showed an IQ in the mental retardation range, compared to 12% for
either carbamazepine or phenytoin, and 9% for lamotrigine. "Although
valproate remains an important treatment option in women who aren't able to use
other epilepsy drugs," says Dr Meador, "valproate should not be used as the drug
of first choice for women of child-bearing potential, and when used, its dosage
should be limited if possible." This study is not the
first to describe the negative effects on fetal development of AEDs in general.
Animal studies conducted two decades ago showed that the class of drugs negatively
affected the cognitive abilities of developing fetuses, and more recent studies
have looked at how, like fetal alcohol syndrome, AEDs appear to trigger apoptosis
of neural cells in the developing brain. Also, a few smaller recent studies have
suggested the higher risk of negative teratogenic effects of valproate in particular.
However, Dr Meador's study is the most definitive to date. SURPRISING
SWITCH
Interestingly, neither valproate, the drug with the worst teratogenic
effects, nor lamotrigine, the one with the least serious effects, were originally
included in the study. The former replaced phenobarbital due to its discontinuation
from widespread use at tertiary epilepsy treatment centres, while the latter was
included because it was a new, promising drug. "Initially,
there was no a priori hypothesis that valproate would have the worst effects.
But, within a few months, AED pregnancy registry data from several countries began
coming out, most of them showing that valproate carried an increased risk of fetal
malformation and cognition problems," says Dr Meador. "When we compared the IQs
of the mothers and children, we noticed that there was a correlation for all the
AED groups except valproate. Somehow, valproate has interfered with that normal
relationship and destroyed it." Nevertheless, he cautioned
against giving epileptic women a bleak prognosis. "The majority of women with
epilepsy have normal babies, even those taking AEDs. I still see women whose doctors
tell them 'You shouldn't get pregnant'," he says, noting that, until a few decades
ago, several states in the US prohibited epileptic women from having children.
"These women certainly have more trouble getting pregnant and have more risks,
but the majority of their children will be normal. We're just trying to figure
out how to allow an even greater number to be born healthy." Equally
importantly, Dr Meador advises doctors with epileptic female patients to address
this issue long before pregnancy. "From an anatomical standpoint, by the time
a woman realizes she's pregnant and goes to see her doctor, the [fetus's] organs
are formed. And trying to change a patient's epilepsy drug regimen — lowering
the dosage, switching from valproate or from poly- to monotherapy — in the
middle of pregnancy is difficult, at best," he says.
|
