Review
Valproic acid in pregnancy: How much are we endangering the embryo and fetus?

https://doi.org/10.1016/j.reprotox.2009.02.014Get rights and content

Abstract

Valproic acid (VPA) is a known human teratogen. Exposure in pregnancy is associated with approximately three-fold increase in the rate of major anomalies, mainly spina bifida and only rarely anencephaly (NTD), cardiac, craniofacial, skeletal and limb defects and a possible set of dysmorphic features, the “valproate syndrome” with decreased intrauterine growth. This was demonstrated by prospective and retrospective studies. There is also, mainly in the children with the “valproate syndrome”, a significant increase in the rate of developmental problems, manifested by decreased verbal intelligence often with communication problems of the autistic spectrum disorder (ASD). VPA is teratogenic in most animal species tested, but the human embryo seems to be the most susceptible. A daily dose of 1000 mg or more and/or polytherapy are associated with a higher teratogenic risk. It seems that several other AEDs potentiate the teratogenic effects of VPA. Thus, when valproate cannot be avoided in pregnancy, the lowest possible effective dose should be prescribed in 2–3 divided doses, preferably as monotherapy. Women exposed to valproate in pregnancy should be given periconceptional folic acid and followed up in a high risk pregnancy clinic. Appropriate ultrasonographic and other examinations, focusing on the possible different anomalies described with this agent, should be carried out. The specific inhibition by VPA of histone deacetylase and changes in gene expression may explain the teratogenicity of this drug. Other possible explanations are: increased fetal oxidative stress induced by VPA, with the brain being more susceptible to oxidative tress in comparison to other fetal organs, or the folic acid inhibitory action of this drug.

Section snippets

Introduction—basic principles in teratology

The human conceptus undergoes 3 major developmental periods: The pre-organogenetic period during the first 2.5 weeks after fertilization, active organogenesis from weeks 3 to 8 post fertilization and afterwards the fetal period. It is commonly accepted that in the first period the developing embryo is generally not susceptible to teratogens. If the damage caused by a teratogen is very severe, the pregnancy may end in a spontaneous abortion or fetal death. Although the most sensitive period to

Teratogenic effects of antiepileptic drugs—general comments

Antiepileptic drugs (AEDs) are used to control various types of convulsive disorders or as mood stabilizers. However, many of these drugs are teratogenic as their use by the pregnant mother has been associated with an increased risk of major congenital abnormalities in the embryo and fetus [3], [5], [6], [7], [8], [9], [10]. These anomalies are anatomical and/or functional and may also have neurological, behavioral and cognitive effects. Yet, in the majority of epileptic women planning a

Effects of valproic acid (VPA) in pregnancy—neural tube defects (NTD) and major congenital anomalies (MCA)

VPA is on the market as an anticonvulsant since 1974, and is used in many countries because of its efficiency against several types of epilepsy and as a mood stabilizer. One of its main actions is the increase in the level of gamma amino butyric acid (GABA) in the brain. GABA is an important inhibitor of seizures, and reduction of GABA levels may potentiate seizures. For seizure control, the daily doses range between 300 mg to 2 g, aiming to achieve therapeutic plasma levels of 50–100 μg/mL. Lower

Valproic acid syndrome (or AED syndrome)

A specific set of facial dysmorphic features related to the effects of VPA on the developing embryo and fetus was first described by DiLiberti et al. in 1984 in seven infants [23]. This syndrome was later corroborated by many authors describing additional children exposed in utero to VPA and exhibiting similar facial features [10], [24], [34], [38], [54], [55]. The main clinical findings include intrauterine growth retardation (IUGR), a long and thin upper lip, shallow philtrum, epicanthal

VPA—neurodevelopmental problems

As of today, the intellectual abilities of about 250 children exposed in utero to VPA have been studied [10], [38], [48], [56], [57], [58], [59], [60], [61], [62], [63], [64], [65], [66], [67]. Developmental delay, including reduced cognitive function, attention deficit disorder and learning difficulties have been repeatedly described among offspring of VPA treated mothers. It was mostly associated with the typical facial dysmorphic features of the “valproate syndrome”. For example, Koch et al.

VPA and autistic spectrum disorder (ASD)

A possible association between in utero VPA exposure and ASD was apparently first observed by Christianson et al. [67] who described four children exposed in utero to VPA; all demonstrated developmental delay and one of these children also had ASD. Later, Williams and Hesh [68] described an additional child with the typical facial features of VPA embryopathy who also developed the typical findings of Autism, and several year later additional 5 children [69]. Many reports appeared thereafter in

VPA and folic acid administration

Many antiepileptic drugs interfere with folic acid absorption (phenytoin, barbiturates, carbamazepine and lamotrigine) or metabolism (VPA) [43]. It is therefore recommended to treat women on AEDs at preconception and in the first 2–3 months of pregnancy with folic acid that protects human and animals from NTD. Although the use of folic acid supplementation has been shown to generally decrease the incidence of NTD in humans, there is disagreement as to the benefit of folic acid in reducing the

VPA-transplacental passage, secretion into milk and into semen

A basic principle for the action of any teratogenic agent is its ability to cross the placenta. Valproic acid is known to cross the human placenta, and the clearance of VPA is increased during pregnancy [76], [77]. Valproic acid levels in cord serum are often higher than in the mother and may be up to 5 times higher than the levels in maternal serum at term, with mean ratios of 1.4–2.4. This increased concentration in the fetus may impose a specific increased risk, and has been attributed to a

VPA and polytherapy (Tables 1–3)

AEDs polytherapy was reported in many studies to increase the rate of major congenital anomalies or of developmental delay [6], [8], [28], [30], [41], [56], [58]. When AEDs are given in combination, it may be difficult to point to the drug with the major contribution to the abnormal outcome, whenever it is found. This may also relate to the combinations of VPA with other AEDs, raising the question as to which is the major contributor. However, there are a number of studies demonstrating that

Malformations in children of untreated epileptic women

Since most antiepileptic drugs seem to be teratogenic in man and in experimental animals, the question often asked is whether epilepsy may cause an increase in the rate of major congenital anomalies (MCA) without any relation to treatment. This is in spite of the fact that the studies carried out in experimental animals which demonstrate AEDs teratogenicity, are carried out on non-epileptic animals, and that there are differences in the rate of specific anomalies in the offspring of epileptic

VPA and animal studies

Many animal studies were carried out in order to mimic the effects of VPA on the human embryo and elucidate the mechanism of its teratogenic action [71], [72], [73], [74], [88], [89], [90], [91], [92], [93], [94], [95], [96], [97], [98]. In most animals the drug was teratogenic but the effective teratogenic doses differed widely. VPA induced malformations of multiple organs in mice, rats, and gerbils, renal and skeletal defects in rabbits, neural tube defects in mice and hamsters, craniofacial

Folic acid deficiency

Older theories on the mechanism of action of AEDs-induced birth defects with anti-folate activity, focused on the reduction in folic acid levels that often occurs after treatment with VPA and other AEDs. Whereas other AEDs reduce intestinal absorption of folic acid, VPA acts specifically as an antimetabolite to folic acid [43], [73], [74].

Reduced embryonic folic acid may disrupt gene expression, increase embryonic oxidative stress and induce changes in protein synthesis [73], [74]. This is the

Conclusions

Valproic acid seems to be a highly teratogenic antiepileptic drug and therefore, if possible, should be avoided in pregnancy. Because NTD is induced in the third week post fertilization, it may be too late to stop the medication while pregnancy is first diagnosed. Therefore, VPA treated women at childbearing age should use contraceptives and stop the medication before any planned pregnancy. This seems to be possible in most epileptic women and in women taking VPA for any other indication

Conflict of interest statement

None.

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