International Notes
Valproic Acid and Spina Bifida: A Preliminary Report -- France
Valproic acid use during the first trimester of pregnancy has
been
reported among an unusually high proportion of mothers of infants
with
spina bifida. During 1976 and from 1978 through September 1982,
the
birth defects surveillance system at the Institut Europeen des
Genomutations in Lyon, France, ascertained 146 cases of spina
bifida
aperta. Among these cases, nine (6.2%) of the mothers had epilepsy
and had taken valproic acid during the first trimester at dosages
between 400 mg and 2,000 mg per day. Five of the nine patients
with
spina bifida were exposed to valproic acid alone, and four were
exposed to additional anticonvulsants. Twenty-one (0.32%) of the
mothers of the 6,616 infants in the surveillance system with other
malformations had taken the drug (Table 1). These data show a
highly
statistically significant odds ratio of 20.6.* To isolate the
effect
of valproic acid from the possible effects of seizure disorders and
other drug therapy, the analysis was then confined to the 71
epileptic
mothers. Nine (90%) of the 10 such mothers of spina bifida infants
had taken valproic acid, compared with 21 (34.4%) of the 61 mothers
of
infants with other defects (Table 2). The odds ratio of 17.1 is
statistically significant.
Reported by E Robert, MD, Institut Europeen des Genomutations,
Lyon,
France; Epidemiology Development Br, Div of Drug Experience, Food
and
Drug Administration; Birth Defects Br, Chronic Diseases Div, Center
for Environmental Health, CDC.
*The odds ratio is an estimation of relative risk in case-control
studies.
Editorial Note
Editorial Note: A woman who requires treatment for epilepsy during
pregnancy is at increased risk of having a baby with a birth
defect.
The American Academy of Pediatrics Committee on Drugs offers the
following recommendation on alerting women to the risk: "When a
woman
who has epilepsy and requires medication asks about pregnancy, she
should be advised that she has a 90% chance of having a normal
child,
but that the risk of congenital malformations and mental
retardation
is two to three times greater than average because of her disease
or
its treatment" (1). The new data from Lyon do not change this
general
advice.
While the Lyon data suggest that valproic acid taken during the
first trimester of pregnancy is associated with spina bifida, other
anticonvulsants (phenytoin and trimethadione) have also been
associated with increased risk of specific congenital defects
(2,3).
Selection of therapy for a seizure patient who may become pregnant
is
a complex decision and requires careful consideration of the
clinical
situation. All anticonvulsants, including valproic acid, carry a
warning of potential human teratogenicity in their labeling.
It has been estimated that, in the United States, 700-1,000
pregnant women take valproic acid each year. Given the United
States'
spina bifida rate of approximately six per 10,000 births (4) and a
relative risk of 20.6 (as indicated by the French data), the
estimated
risk of valproic acid-exposed women having children with spina
bifida
is approximately 1.2%. This risk is similar to that for women who
have had previous children with neural-tube defects (anencephaly or
spina bifida). The United States has prenatal counseling centers
for
women at increased risk of having children with spina bifida.
Women
who may be exposed to valproic acid during pregnancy should contact
their physicians for further counseling.
A registry of women currently taking valproic acid during
pregnancy is being established in order to better define the risk
of
such therapy. Physicians of women who are taking valproic acid
during
pregnancy are urged to report to this registry as soon as possible
by
calling (404) 452-4080 on weekdays between 8:00 a.m. and 4:30 p.m.,
Eastern time, or by writing Birth Defects Branch, Center for
Environmental Health, Centers for Disease Control, Atlanta, Georgia
30333.
References
American Academy of Pediatrics Committee on Drugs.
Anticonvulsants
and pregnancy. Pediatrics 1979;63:331-3.
Hanson JW, Myrianthopoulos NC, Harvey MA, Smith DW. Risks to
the
offspring of women treated with hydantoin anticonvulsants, with
emphasis on the fetal hydantoin syndrome. J Pediatr
1976;89:662-8.
CDC. Congenital malformations surveillance, January-December
1980. Atlanta: CDC, February 1982:8.
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