E-DRUG: Teratogenicity of antiepileptic drugs
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[This BMJ editorial is a useful update on a problem area of practice when epileptics want to become pregnant. Copied as fair use. Thanks to Andy for spotting. WB][Several of these also used for bipolar disorders now. KM]
http://bmj.bmjjournals.com/cgi/content/full/333/7569/615
BMJ 2006;333:615-616 (23 September), doi:10.1136/bmj.38961.437639.BE
Editorial
Teratogenicity of antiepileptic drugs
Women should consider stopping, minimising, or switching drugs before
pregnancy
Prescribing for women with epilepsy is complicated by the potential
teratogenicity of antiepileptic drugs. Current guidelines recommend that
the most effective drug should be chosen before conception and
prescribed at its lowest effective dose, ideally as monotherapy.1 2 But
which antiepileptic drug is safest in pregnancy?
Early research on the safety of antiepileptic drugs in pregnancy was
unreliable. Several countries set up pregnancy registries in the late
1990s, and data from these registries are now appearing.
To date the UK Epilepsy and Pregnancy Registry has recruited more than
3500 women, of whom 72% were given antiepileptic monotherapy. The
overall rate of major congenital malformation in women given
antiepileptic drugs during pregnancy was 4.2%, compared with 3.5% in
women with epilepsy who were not given such drugs.3 By three months of
age, infants exposed to sodium valproate monotherapy during gestation
had the highest frequency of major congenital malformation (6.2%),
confirming similar findings from an Australian register.4 Lamotrigine
monotherapy was associated with a 3.2% frequency of malformation, but in
a multivariate analysis this frequency was not significantly different
from that seen with valproate monotherapy. The risk with lamotrigine at
doses above 200 mg a day was similar to that of valproate doses of 1000
mg/day. Carbamazepine was associated with the lowest frequency of major
congenital malformation (2.2% for monotherapy). Polytherapy with
antiepileptic drugs was associated with a significantly higher frequency
of major malformation than monotherapy (6% v 3.7%).
The North American Pregnancy Registry found that valproate monotherapy
was associated with a 10.7% frequency of major congenital malformation.
This represents an increased relative risk of 7.3 compared with a
control group from one US teaching hospital's malformation surveillance
programme.5 The US registry had previously reported an increased risk of
malformation in babies exposed to phenobarbital6-an important finding as
this antiepileptic drug is still widely used in many countries.
These registries provide observational data only, and include many
variables (such as type of epilepsy, seizure frequency, and drug
compliance) that may influence results. Furthermore, major congenital
malformations are defined differently by each registry, so results are
not directly comparable.
The potential for antiepileptic drugs to cause developmental delay in
childhood is even more difficult to measure than major congenital
malformation. Adab and colleagues found that valproate monotherapy in
pregnancy was associated with decreased verbal IQ when compared with
carbamazepine or phenytoin monotherapy, and that this was dose
related.w1 They also reported that 30% of children exposed to valproate
needed special educational support in school, compared with 3-6% of
those exposed to monotherapy with other antiepileptic drugs.w2 Similar
results were reported in a Finnish study.w3 A further study has,
however, shown adverse neurodevelopmental effects in children exposed to
a variety of antiepileptic drugs during gestation, not only valproate.w4
The neurodevelopment effects of antiepileptic drugs (NEAD) study is
currently investigating behavioural outcomes in children exposed to
antiepileptic drugs in pregnancy (www.neuro.mcg.edu/np/NEAD.htm).
Overall, evidence shows that valproate is associated with a higher
frequency of major congenital malformation than other antiepileptic
drugs and seems more likely to cause neurodevelopmental delay.
Carbamazepine is associated with the lowest incidence of major
congenital malformation, while lamotrigine is probably not as safe as
previously thought. No reliable data are available on the safety of most
of the newer antiepileptic drugs in pregnancy.
What does all of this mean for doctors and their patients? Ideally,
women with epilepsy should plan pregnancy in advance and discuss this
with their doctor and epilepsy nurse. All women should take folic acid 5
mg a day before conception and for at least the first trimester of
pregnancy.
Doctors should consider whether individual patients need antiepileptic
drugs at all during pregnancy. Women with focal seizures alone, women
who have been seizure-free for at least two years, or women who have
infrequent generalised seizures may prefer to stop their antiepileptic
drugs, but this must be assessed on an individual basis. If treatment is
needed during pregnancy, carbamazepine seems to be the safest option.
While most authorities recommend either valproate or lamotrigine as
first line treatment for idiopathic generalised epilepsy, little
evidence exists to support this notion,w5 except that some types of
epilepsy-such as juvenile myoclonic epilepsy-may be exacerbated by
carbamazepine. Women already established on valproate or high dose
lamotrigine face a difficult decision when planning pregnancy. Their
options include maintaining current treatment, lowering the dose as far
as possible, or considering swapping to carbamazepine. Women taking more
than one drug should consider switching to monotherapy, although many do
not alter their antiepileptic drug regimen during pregnancy.w6 In
practice, many pregnancies are unplanned, so doctors and epilepsy nurses
should discuss this issue with all women of childbearing potential when
epilepsy is first diagnosed.
It remains to be seen whether any of the newer antiepileptic drugs will
prove to be less teratogenic. In the meantime, we should use the best
available evidence to guide our decisions and the advice we give to
women with epilepsy, and reassure them that they are likely to have a
successful uncomplicated pregnancy.
David P Breen, foundation year 2 doctor in colorectal surgery
Department of Colorectal Surgery, Western General Hospital, Edinburgh
EH4 2XU
(davebreen@lycos.com)
Richard J Davenport, consultant neurologist
Department of Clinical Neurosciences, Western General Hospital,
Edinburgh EH4 2XU
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Competing interests: RJD has received consultancy fees or speaker's
fees (or both) from Pfizer (gabapentin, phenytoin), GSK (lamotrigine),
Janssen Cilag (topiramate), and Sanofi (valproate).
References w1-w6 are on bmj.com
References
1. Commission on Genetics, Pregnancy and the Child, International
League against Epilepsy. Guidelines for the care of women of
childbearing age with epilepsy. Epilepsia 1993;34: 588-9.
2. Adab N, Tudur SC, Vinten J, Williamson P, Winterbottom J. Common
antiepileptic drugs in pregnancy in women with epilepsy. Cochrane
Database Syst Rev 2004;(3):CD004848.
3. Morrow JI, Russell A, Gutherie E, Parsons L, Robertson I, Waddell R,
et al. Malformation risks of anti-epileptic drugs in pregnancy: a
prospective study from the UK Epilepsy and Pregnancy Register. J Neurol
Neurosurg Psychiatry 2006;77: 193-8.
4. Vajda FJ, O'Brien TJ, Hitchcock A, Graham J, Cook M, Lauder C, et
al. Critical relationship between sodium valproate dose and human
teratogenicity: results of the Australian register of anti-epileptic
drugs in pregnancy. J Clin Neurosci 2004;11: 854-8.
5. Wyszynski DF, Nambisan M, Surve T, Alsdorf RM, Smith CR, Holmes LB.
Increased rate of major malformations in offspring exposed to valproate
during pregnancy. Neurology 2005;64: 961-5.
6. Holmes LB, Wyszynski DF, Lieberman E. The AED (Antiepileptic Drug)
Pregnancy Registry: a 6-year experience. Arch Neurol 2004;61: 673-8.