**3. Valproic acid as an environmental risk factor in the development of autism**

After the VPA license for use in 1978, the first adverse report of a fetus exposed to the drug was published in 1980 [30]. Since then. particular attention has been directed to the occurrence of neural tube defects in infants exposed to VPA *in utero* [31, 32]. The critical period for exposure to teratogens shown to increase the risk of autism is early in the first trimester [33]. Some of the critical teratogens related to autism risk are maternal rubella infection [6], ethanol [34], thalidomide [35] and VPA [8, 9]. Approximately one in 250 pregnancies is known to be exposed to antiepileptic drugs [36] and a significant proportion of these are exposed to VPA, either as monotherapy or as part of a polytherapy drug regimen.

The timing for the teratogenic effect of VPA that increases the risk for autism cannot be estimated directly, as the drug is typically taken throughout the entire pregnancy [33]. Many children exposed *in utero* to VPA exhibit FVS, first described in 1984 [37] and characterized by a major and minor malformations and developmental and behavioral delays [8, 12, 38-40]. Specific impairments observed in FVS includes neural tube defects, trigonocephaly, radial ray defects, pulmonary abnormalities, coloboma of iris/optic disc, low verbal IQ and features of ASD [41] and has been reported in a number of sibling pairs [12, 21, 37, 42-44] with different degree of severity among affected siblings. Common facial features of FVS include epicanthal folds, broad nasal bridge, short nose with antiverted nares, long upper lip, and low set, posteriorly rotated ears [41].

The classical autism was first reported to be one of the behavioral outcomes of VPA exposure [41] through several case reports [12, 39, 45]. The first epidemiological study with drugs as environmental risk factors of autism was described in 2000, with 57 offspring of women taking anticonvulsants (see ref [46], summarized in Tables 3 and 4).


**Table 3.** Autism features in children exposed *in utero* to anticonvulsants.

**Target of action Biological effects Reference** HDAC (inhibition) Open DNA transcription [20] Mitochondria Energy metabolism impairment [21] Lymphocytes Modification of the epigenotype [22]

neural progenitor cells [26]

after spinal cord injury (SCI) [28]

[27]

Up-regulation of *CYP3A4* and *MDR1* gene expression

Neurons from *substantia nigra* Reduction in firing rate [23] c-Jun N-terminal kinase (JNK) Defective neurite formation [24] GSK3β inhibitor Promotion of hair re-growth [25]

PI3K/Akt/mTOR pathway Skeletal muscle hypertrophy [29]

**3. Valproic acid as an environmental risk factor in the development of**

After the VPA license for use in 1978, the first adverse report of a fetus exposed to the drug was published in 1980 [30]. Since then. particular attention has been directed to the occurrence of neural tube defects in infants exposed to VPA *in utero* [31, 32]. The critical period for exposure to teratogens shown to increase the risk of autism is early in the first trimester [33]. Some of the critical teratogens related to autism risk are maternal rubella infection [6], ethanol [34], thalidomide [35] and VPA [8, 9]. Approximately one in 250 pregnancies is known to be exposed to antiepileptic drugs [36] and a significant proportion of these are exposed to VPA, either as

The timing for the teratogenic effect of VPA that increases the risk for autism cannot be estimated directly, as the drug is typically taken throughout the entire pregnancy [33]. Many children exposed *in utero* to VPA exhibit FVS, first described in 1984 [37] and characterized by a major and minor malformations and developmental and behavioral delays [8, 12, 38-40]. Specific impairments observed in FVS includes neural tube defects, trigonocephaly, radial ray defects, pulmonary abnormalities, coloboma of iris/optic disc, low verbal IQ and features of ASD [41] and has been reported in a number of sibling pairs [12, 21, 37, 42-44] with different degree of severity among affected siblings. Common facial features of FVS include epicanthal folds, broad nasal bridge, short nose with antiverted nares, long upper lip, and low set,

Beta-catenin-Ras-ERK-p21Cip/WAF1 pathway Differentiation and inhibition of proliferation in

Matrix metalloprotease-9 inhibitor Attenuation of blood-spinal cord barrier (BSCB)

Constitutive androstane receptor (CAR) and pregnane X receptor (PXR)

146 Recent Advances in Autism Spectrum Disorders - Volume I

**Table 2.** Biochemical and biological effects of VPA

monotherapy or as part of a polytherapy drug regimen.

posteriorly rotated ears [41].

**autism**


**Table 4.** Congenital malformations in children exposed *in utero* to VPA

Fifty two children were ascertained through the Fetal Anticonvulsant Syndrome Association (FACS) and five were referred to the Aberdeen Medical Genetics Service (AMGS). The number of patients exposed *in utero* to each anticonvulsant alone was 34 (60%) to VPA, 4 (7%) to carbamazepine, 4 (7%) to phenytoin, and 15 (26%) to more than one anticonvulsant. The number of patients with behavioral problems was 46 (81%), with hyperactivity or poor concentration was 22 (39%) and with attention deficit and hyperactivity disorder 4 (7%). Autistic features were present in 34 patients (60%).
