Kola, I.

Pillans, P. I.

University of Queensland eSpace

SAMJ VOLUME 68 28 SEPTEMBER 1985 531
Drugs in Practice/~J1edisyne in die Praktyk
Teratogenic potential of valproate
Valproic acid, or dipropylacetic acid, and its salt, sodium
valproate, are used to treat a wide variety of seizure disorders.
Until recently there was no convincing evidence demonstrating
a teratogenic effect in humans. However, the association
between other anticonvulsant drugs and congenital malforma-
tions has been recognized for more than a decade,I,2 and this,
together witfI tbe lack of convincing data for valproate, may
have favoured the use of valproate during pregnancy.
Valproate is known to be teratogenic in rabbits, rats and
mice. ,-5 In the mouse, abnormalities include neural tube
defects, craniofacial deformities6 and dose-dependent growth
retardation and embryo lethality.5 We have confirmed a dose-
dependent increase in mouse embryo mortality both in the
pre- and post-implantation embryo, growth retardation and a
substantial incidence of exencephaly. We have also found
decreased esterase enzyme activity in pre-implantation embryos
and a decrease in brain acetylcholinesterase levels of treated
18-day mouse fetuses (unpublished data).
Valproate is known to cross the human placenta.7 Numerous
case reports associating a variety of birth defects with the drug
have been published;8'14 these include craniofacial abnormali-
ties, thoracic cage abnormalities, spina bifida, hydrocephalus,
diastasis recti abdominis, hernias, genito-urinary tract abnor-
malities and low birth weight. Recent reports suggest a sub-
stantial association between maternal valproate therapy and
neural tube defects/ 5,16 which must be taken seriously. In the
Rh6ne-Alpes region of France 72 cases of spina bifida were
notified between 1979 and 1982. Ten of the mothers were
epileptic, and 9 of them were receiving valproate (alone in 5,
combined in 4). Further data from this region supporting the
notion that valproate can cause spina bifida have been pre-
sented. 17,18 In the Netherlands 10 cases of spina bifida with
prenatal exposure to valproate have been found. 19 The higher
than expected number of spina bifida cases, the high rate of
valproate exposure among these cases, and the high proportion
of cases exposed to valproate only (6 out of 10) support an
association between valproate and spina bifida.
More recently a distinct fetal valproate syndrome has been
described.20 Seven children who had been exposed to valproate
in Ulero had a consistent facial phenotype consisting of epi-
canthic folds, flat nasal bridge, small upturned nose, long
upper lip with a relatively shallow philtrum, a thin upper
vermilion border, and downturned angles of the mouth. Other
birth defects noted in 4 of the children were hypospadias,
strabismus, psychomotor delay and low birth weight. Several
previous reports have also suggested that an abnormal facial
appearance might result from valproate.8,9,11,21,22 The descrip-
tions of the faces in these cases are suggestive of the findings
in the above group of 7 children.
Albendazole in hydatid disease
Until recently the only effective treatment for hydatid disease
caused by Echinococcus granulosus has been surgical removal of
cysts, but there have been obvious disadvantages to this.
The data that valproate is potentially teratogenic are im-
pressive and this should be borne in mind when prescribing
the drug in women of childbearing age. However, the relative
teratogenic risk is not accurately known, although it has been
reported that spina bifida occurs in about I% of births after
first-trimester valproate exposure. 15 Good control of seizures
in pregnancy is desirable and decisions on therapy must rest
on clinical judgement, balancing the benefits against the pos-
sible hazards. If women are exposed to valproate during the
first trimester they should be informed of the risk and offered
counselling and amniocentesis.
P. I. Pillans
I. Kola
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Mebendazole has been shown to have a beneficial effect but
prolonged courses of treatment for many months have failed to
improve the condition in some patients. Another benzimidazole


Teratogenic potential of valproate

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Teratogenic potential of valproate

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