Use of Topiramate in early pregnancy
for treating epilepsy is associated with nearly 8 times higher risk of oral
clefts in newborn reports the results of a large population based cohort study
published December 27, 2017 in journal Neurology.
The observed association was not very
strong for lower doses of topiramate used for treating migraines and bipolar
disorder.
A diagnosis of oral cleft includes
cleft lip and cleft palate.
Previous studies have demonstrated a
5-fold increased risk of oral cleft in women taking around 200 mg of topiramate
daily for epilepsy, but the association was unclear about consumption of lower
dose.
To assess the risk of oral dose, the
investigators analyzed a large cohort of 1,360,101 pregnant women with a
live-born infant enrolled in Medicaid from 3 months before conception through 1
month after delivery over a period of 10 years.
The prescription information was
obtained from nationwide Medicaid Analytic eXtract (MAX) which keeps a record
of all diagnoses and procedures and prescription filled outside hospitals.
The analyses of data identified 2425
women who were exposed to topiramate in early pregnancy as shown by atleast one
filled prescription of the drug in first trimester.
The neonatal outcome for this cohort
was compared to a reference group of 1,322,955
pregnant women who did not fill prescription for topiramate or other
anticonvulsant drugs.
The multivariate analysis included many
potential confounders like maternal age, race, topiramate indication (epilepsy,
migraine, bipolar disorder, pain condition), obesity, smoking, comorbidities,
concomitant medications, and overall health status.
Regression analysis showed that women with
topiramate consumption in early pregnancy are 3 times increased risk of giving
birth to a baby with oral cleft, as compared to women who have never taken the
drug for any indication.
Risk was also assessed for consumption
of another anticonvulsant medication, lamotrigine in first trimester. The risk
with lamotrigine was only slightly more as compared to non-exposed population and
the patients using topiramate were nearly 2.5 times at increased risk of oral clefts
as compared to lamotrigine.
Women with epilepsy were nearly 8
times increased risk of oral cleft as compared to non-exposed.
Lead author, Dr Hernandez-Diaz, MD,
professor of epidemiology, Harvard T.H. Chan School of Public Health, Boston,
Massachusetts said, "Our best estimate is that women with epilepsy using
200 mg or more of topiramate have around an 8-fold increased risk, and those
using lower doses had a twofold or lower risk. The results suggest that the
risk with lower doses, if it is there, is much less than for higher
doses."
The researchers carried out multiple
sensitivity analyses, with different doses of topiramate and window of exposure,
but the association between topiramate and oral clefts remained the same.
The study confirms the results of earlier
studies and stress upon the fact that “dose does matter.” The risk ratio for
oral clefts for > 100 mg of topiramate was nearly 5 times more than that of
< 100 mg.
In addition, topiramate does interfere
with oral contraceptives and may be responsible for many unplanned pregnancies
because of contraceptive failures. Hence, women who are on topiramate and do
not want to conceive should additionally use a barrier method of contraception.
The study limitations include poor
socioeconomic status of women (which itself is a risk for oral clefts), and not
controlling for folic acid use.
Women with anti-epileptic medication should
take folic acid which reduces the chances of oral clefts.
But sometimes it is prescribed
off-label to treat obesity and control weight gain. In 2012, the United
States Food and Drug Administration (FDA) approved topiramate in combination
with phentermine (Qsymia) to treat weigh gain issues.
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