Handbook of Genetic Counseling/Fetal Valproate Syndrome

Fetal Valproate Syndrome

Valproic Acid and Antiepileptic Drugs During Pregnancy
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Fact Sheet

 * valproate is chemical present in depakote (commonly used to treat seizures or bipolar)
 * Valproate can negatively affect fetal growth and development, but is still used during pregnancy because maternal seizures can be dangerous to both mom and baby
 * Valproate crosses the placenta and dose fetus is exposed to may be higher than maternal dose
 * Valproic acid was released in 1967 in Europe and in 1978 in the United States to treat epilepsy
 * Epilepsy affects approximately 1 % of the population, and an estimated 1.1 million women in the United States with epilepsy are in the childbearing age range
 * Approximately 11,500 epileptic women become pregnant each year, many of which use valproic acid
 * One in two hundred pregnant women is epileptic
 * By 1980, publications began linking malformed children to in utero exposure to valproic acid (greater than 500 mg/day)

Adverse Outcomes

 * While risks have not been established for all of the various outcomes there is data for many.
 * stillbirth rates 1.3 - 14 % (ref 3)
 * perinatal mortality 1.4 - 7.8 %. (ref 3)
 * Congenital anomalies in babies born to mothers with epilepsy is estimated to be 2-3X's higher than general population (ref 1 and 2)which would mean about 6-15% others estimate below 10% (ref 3)
 * Some studies report association with autism and speech and language difficulties
 * Learning difficulties and mental retardation in approximately 29% of those with fetal valproate syndrome (ref 1)
 * malformations most likely related to first trimester exposure in a dose dependent fashion
 * Some of these adverse outcomes are associated with early first trimester phenomena (congenital malformations), others such as developmental delay are more likely to be associated with an exposure of greater duration, or during the third trimester.
 * Causal relationship of cleft lip and palate with valproic acid has not been established, but it has been associated with most anticonvulsants (p. 1093v) HOWEVER, in the study below they found 3 cases of cleft palate rate of 4% or 40 X's that in general population. In contrast to various studies that report no association. (ref 1)
 * A total of 69 cases that were solely exposed to VPA with adequate phenotypic description were identified.
 * The clinical manifestations of FVS encompass a wide spectrum of abnormalities: consistent facial phenotype, multiple systemic and orthopedic involvement, central nervous system dysfunction, and altered physical growth.
 * Twelve percent of affected children died in infancy and 29% of surviving patients had developmental deficits/mental retardation.
 * 30% had minor skin anomalies most common were hemangiomas and nipple abnormalities
 * respiratory tract abnormalities seen in 16% of patients (tracheomalacia was most common and etiology is unknown, but frequently seen with TEF)

Characteristic Features

 * In humans, VPA has been associated with an increased frequency of congenital malformations
 * VPA use during gestation has been associated with an increase risk of spina bifida. Several human studies have suggested that use of VPA during pregnancy increases the risk of neural tube defects (NTD) 20-40X, to approximately 1-2%, as compared to the general population risk of 0.05% (comparable to that of a woman who has a previous child with a NTD)
 * midfacial hypoplasia (flat nasal bridge with a broad base)
 * distinctive facial appearance
 * deficient orbital ridge
 * inferior epicanthal folds
 * anteverted nostrils
 * shallow philtrum
 * thin upper lip with a thick lower lip
 * prominent forehead
 * long thin overlapping fingers and toes, and hyper-convex nails have also been described
 * congenital heart disease
 * decreased postnatal growth.
 * increased risk of radial limb reduction defects and hypospadias in male fetuses
 * However, it is important to point out that several of the mothers in the studies were on multiple medications and it is difficult to assign causal effect as a result
 * proposed mechanism of action is that valproic acid influences folate metabolism, thereby altering the closure of the spinal column resulting in spina bifida

Review of the Literature
(1978-2000) (ref 1)
 * A total of 69 cases that were solely exposed to VPA with adequate phenotypic description were identified.
 * The clinical manifestations of FVS encompass a wide spectrum of abnormalities: consistent facial phenotype, multiple systemic and orthopedic involvement, central nervous system dysfunction, and altered physical growth.
 * The facial appearance is characterized by a small broad nose, small ears, flat philtrum, a long upper lip with shallow philtrum, and micro/retrognathia.
 * In this review, 62% of the patients had musculoskeletal abnormalities, 30% had minor skin defects, 26% had cardiovascular abnormalities, 22% had genital abnormalities, and 16% had pulmonary abnormalities.
 * Less frequently encountered abnormalities included brain, eye, kidney, and hearing defects.
 * Neural tube defects were seen in 3% of the sample.
 * Twelve percent of affected children died in infancy and 29% of surviving patients had developmental deficits/mental retardation.
 * Although 15% of patients had growth retardation, an overgrowth pattern was seen in 9%.

Risk Assessment for Seizures and Schizophrenia

 * Risk of children having epilepsy based on moms history is about 4% (Practical Genetic Counseling 4th edition 1993)
 * Risk of Schizophrenia 3-5% (from same source as above risk)

Other Antiepleptic Drugs (AED)
(and effects during pregnancy) (Taken primarily from information contained in a website by ©1998 Dr. Mark Yerby, North Pacific Epilepsy Research. ) six clinical AED syndromes have been reported in the medical literature
 * Fetal Trimethadione Syndrome
 * Children exposed to this drug in utero were more likely to be short in stature, microcephalic, have V-shaped eyebrows, epicanthal folds, low set ears, anteriorally folded helices, and irregular teeth. Inguinal hernias, hypospadias, and simian creases were also frequently observed.
 * A retrospective study of trimethadiaone exposures in 53 pregnancies revealed fetal loss or major malformations in 87 % of the pregnancies (Feldman et al. 1977).
 * Follow-up studies have reported significant rates of mental retardation among the exposed infants (Goldman et al. 1986).
 * Trimethadione, introduced in the 1940's for the treatment of absence epilepsy, has been largely supplanted by less toxic-more effective compounds and is seldom used in the treatment of epilepsy.
 * Fetal Hydantoin Syndrome (FHS)
 * Among the many dysmorphic findings associated with this syndrome, hypoplasia and irregular ossification of the distal phalanges was originally believed to be the single most characteristic feature.
 * Of the five children described by Hanson and Smith, only one was exposed to phenytoin monotherapy. The infants displayed facial dysmorphism including: epicanthal folds, hypertelorism, broad flat nasal bridges, an upturned nasal tip, wide prominent lips, and in addition distal digital hypoplasia (DDH), intrauterine growth retardation and mental retardation.
 * Subsequently, Hanson et al. (1976), reported a prevalence of FHS of 11%, with an additional 30% of the in utero exposed children expressing some of the syndrome's features.
 * He also suggested that these children are at greater risk for the development of neural crest tumors, although subsequent prospective studies have failed to verify this initial observation.
 * A prospective study from the University of Helsinki, examined 121 infants of mothers with epilepsy, 82 exposed to phenytoin, found no cases of FHS.
 * Hypertelorism and distal digital hypoplasia were the only dysmorphic features associated with phenytoin exposure in this study (Gaily et al. 1988).
 * As with the Fetal Alcohol Syndrome, it is now common nomenclature to consider children presenting with a more limited pattern of anomalies secondary to in utero hydantoin exposure to be expressing Fetal Hydantoin Effects (FHE; Hanson, 1986).
 * Primidone Embryopathy
 * Affected children present with hirsute foreheads, thick nasal roots, anteverted nostrils, long philtrums, straight thin upper lips, and DDH. These children tend to be small for dates, have an increased risk for psychomotor retardation and heart defects (Rudd and Freedom 1979, Gustavson and Chen 1985).
 * A case report of a family in whom all 4 siblings had clinical features of the FHE demonstrates the complexity involved in evaluating affected children.
 * The first 2 children in this family were exposed to both phenytoin and primidone in utero. In an attempt to prevent dysmorphism in subsequent pregnancies, the phenytoin was discontinued.
 * Unfortunately, the third and fourth children had the same dysmorphic features as their elder siblings having been exposed to primidone monotherapy (Krauss et al. 1984).
 * phenobarbital
 * facial dysmorphism, pre- and post-natal growth deficiency, developmental delay, and minor anomalies
 * clinical features were similar to those seen with in utero exposure to both phenytoin and alcohol, hence the author felt that it should not be classified as a separate syndrome (Seip 1976).
 * He also noted that all three of these compounds can result in folate deficiency and hypothesized that such a deficiency could be the common mechanism for the dysmorphism seen with such in utero teratogen exposures.
 * valproic acid embryopathy (see above information)
 * Fetal Carbamazepine Syndrome
 * described by a single group of investigators (Jones et al. 1989)
 * Dysmorphic features include: up slanting palpebral fissures, epicanthal folds, short nose, long philtrum, DDH and microcephaly. Developmental delay was also found in 20 % of exposed children, although the authors used one standard deviation from the mean as the cut-off for abnormality, rather than the customary two standard deviations.
 * Applying the conventional definitions to their data, eliminates any increased risk for developmental delay in the carbamazepine exposed children.
 * Reduction in fetal head circumference has been reported in carbamazepine exposed children (Hiilesmaa et al. 1981). Although smaller than controls, the head sizes were still within the normal range and the differences between the IME and controls disappeared as the children matured.

Difficulty Determining Risks

 * clinicians are uncertain how much of the adverse outcome difficulty is secondary to AED, maternal seizures, or simply the genetics of having epilepsy
 * In one large study, The Teratogenicity of Anticonvulsant Drugs. N Engl J Med 2001; 344: 1 132-8 (April 12) showed that women with seizures who were not on AED's were not at an increased risk of having children with birth defects while those that were treated with AED's were at a significant increased risk (However, possible confounding because women not treated with meds are likely to have less severe seizure disorder)
 * Controversy remains regarding the causes of the increased risk of adverse outcomes of pregnancy. AED are suspected of contributing to an increase in the risk of congenital malformations and dysmorphic features. Yet increased generalized convulsive seizures are associated with premature labor and fetal death.
 * Facial dysmorphism can be difficult to quantify and is certainly not specific to any one anticonvulsant drug. Infants of epileptic mothers with similar dysmorphic features have been described in the pre-anticonvulsant era (Baptisti 1938, Philbert and Dam 1982).
 * The long-term outcome and significance of these anomalies remain unclear
 * In those few cases which have been followed into early childhood, the dysmorphic features tend to disappear as the child grows older in some, but not all instances (Janz 1982)