Table 2.

VPA-induced neurocognitive deficits in children.

Authors, Ref. Number.	Main Findings	Comments
Bromley et al. [9]	Cochrane Library review demonstrating a high rate of neurodevelopmental problems following prenatal VPA.	A review that covers data from many studies.
Kini et al. [11]	A high percentage of the 63 VPA-exposed children had a high rate of dysmorphic features and a low verbal intelligence quotient.	VPA-exposed were compared to carbamazepine- and phenytoin-exposed children.
Bromley et al. [22]	Thirty-one individuals with fetal valproate syndrome; IQ was 19 points lower than controls and 26% had an IQ lower than 70.	The group consisted of children, adolescents, and adults.
Rithman et al. [24]	Comparison of neurodevelopment in 30 preschool children exposed to VPA and lamotrigine. Those exposed to VPA had lowest scores and increased rate of preschool ADHD.	Relatively small sample.
Cohen et al. [25]	Children prenatally exposed to VPA monotherapy had lower adaptive abilities and lower learning abilities, especially difficulties in auditory verbal and visual non- verbal functions, in a dose–response manner. They also had a high rate of ADHD.	Worse performance compared to carbamazepine, phenytoin and lamotrigine.
Christianson et al. [68]	Two twin pairs with fetal valproate syndrome and global developmental delay.	Case reports.
Moore et al. [63]	Children with fetal valproate syndrome of which 34 were exposed only to VPA and most had neurodevelopmental delay, many with some autistic features.	Among the first to describe autistic features resulting from prenatal VPA.
Dean et al. [65]	General notice that VPA exposure (and other AEDs induce learning difficulties and behavioral problems.	Gives criteria for the definition of AEDs syndrome.
Koch et al. [66]	Forty children exposed to AEDs. VPA-exposed had the worse neurodevelopmental outcome.	Relatively few exposed children.
Nicolai et al. [67]	A review defining the neurodevelopmental effects of prenatal exposure to AEDs. The worst of all is VPA.	A summary of several studies.
Daugaard et al. [76]	A total of 580 children exposed to VPA; hazard ratio of 4.48 for intellectual disabilities compared to controls.	Some increased risk for intellectual disabilities also in children exposed to carbamazepine, oxcarbazepine and clonazepam.
Dean et al. [69]	A total of 299 children exposed to AEDs, of which 47 were exposed to VPA. MCMs were found in 10.6% and developmental delay was found in 28%, the highest rate among all AEDs.	Many had typical dysmorphic features of the anticonvulsant drug syndrome.
Vinikainen et al. [70]	A need for educational support in 62% of 13 VPA-exposed children.	Small number of children.
Adab et al. [71]	Evaluated the educational risk of children prenatally exposed to AEDs. VPA exposure induced a high need of educational support, with an odds ratio of 3.4 compared to non-exposed.	Exposure to VPA had the worst effect in comparison to other AEDs.
Adab et al. [72]	Retrospective study of 41 school-age children exposed to VPA monotherapy. They had lower mean verbal IQ compared to those with exposure to other AEDs. A negative correlation was found between verbal IQ and dysmorphic features.	Retrospective study showing similar findings to prospective studies.
Tomson et al. [77]	Meta-analysis of prospective studies. Increased risk of cognitive impairment and autistic traits with VPA.	The risk for anomalies and intellectual impairment with VPA is the highest among several AEDs tested.
Shallcross et al. [78]	A comparison of neurodevelopmental outcomes in infants younger than two-years old with exposure to levetiracetam versus VPA. VPA induced in 40% of infants a DQ of less than 84.	Levetiracetam exposure did not reduce the DQ of infants.