SOJ Pharmacy & Pharmaceutical Sciences

Valproic acid is a molecule known for 50 years, initially indicated in epilepsy, its use was later extended to bipolar disorder [1]. The benefit / risk of the molecule compared to existing treatments, has quickly positioned itself as a first-line treatment for generalized idiopathic epilepsy, but also other forms of epilepsy [2]. During the 1980s to 1990s, scientific publications increasingly documented more specifically congenital malformations, attributable to antiepileptics and mainly sodium valproate [3]. Later, from the 2000s, the observations of developmental delays and autism spectrum disorders affecting some children exposed in utero, motivate prospective studies [4]. The results confirm then the over-risk of cognitive and behavioral development disorders of valproate.

To date, knowledge about valproate is still incomplete, its mechanism of action is still partially misunderstood [5]. Many questions remain unanswered about the impact in utero fetal exposure to the molecule and, more specifically, of its interaction with the genome. The evolution of knowledge on the side effects of valproate salts and the appearance of new molecules, offering therapeutic alternatives, regularly supplement information to reassess the benefit / risk balance of the treatment.

However, the suspension of use of this drug for women of childbearing potential does not does not seem to be a feasible option in the context of its two indications: epilepsy and bipolar disorders. Indeed, valproate and its derivatives sometimes remain the only option therapeutic. Eviction during pregnancy also seems complicated, the risk of disrupting the stabilization of pathology can have serious consequences for the mother, with a higher risk than the risk of malformation.

Discovery of the teratogenicity of valproate
In the early days of the marketing of specialties based on valproic acid and derivatives, few side effects are observed by reports antiepileptic first generation. The sodium valproate drug was therefore prescribed, as soon as it was placed on the market, to pregnant women [6].

Three types of side effects for children have been gradually identified by the scientific literature:
- congenital malformations (documented from 1982);
- neurodevelopmental disorders, characterized by a decrease in IQ, (decrease estimated at about ten IQ points from the age of one year, 40% of children exposed);
- autism spectrum disorders, five to six times more frequent than in the general population.

The analysis of the literature shows that early safety signals back more than 30 years ; indeed a query of the “Medline” database, on the keywords “Pregnancy” and “valproic acid”, shows 934 references and reveals a very significant increase in publications at the beginning of the 80s, and from 2005 (between 30 and 40 per year), with a peak at 60 in 2013, probably in connection with the dissemination of new knowledge. Currently, almost all large cohort studies on the risks of valproic acid and its derivatives for pregnancy, relate to women suffering epilepsies. Thus, the following discussion presents mostly studies for this population.

A large retrospective cohort study conducted in 1999 (the SAMREN study)[7], provides evidence of a significant teratogenic dose-effect relationship for valproate. The year next, the MADRE study (58) identifies and quantifies the specific risks of birth defects associated with the main antiepileptics. It will, however, be necessary wait until the end of the 2000s for the results of prospective studies to attribute with deleterious effects to cognitive development on valproate behavioral development of children exposed in utero.

In 2006, the MEADOR study made it possible to quantify the frequency of serious adverse on the fetus of each antiepileptic: 8.2% for carbamazepine, 1% for lamotrigine, 10.7% for phenytoin, and… 20.3% for valproate [8].

Last observation achieved on the relationship, finally proven in 2013, between exposure to valproate and a form of autism. [9,10]. As is often the case in matters of birth defects by exposure to toxic, understanding of the pathophysiology of in utero exposure to valproate remains “incomplete “. Certain observations suggesting an increased risk if an unexposed sibling has developed a neurodevelopmental disorder, the notion of genetic susceptibility is mentioned. The hypothesis of a possible risk to the offspring of a father treated with valproate sodium and derivatives is also raised.

• Loss of pregnancy, fetal death:
There is little or no data on pregnancy loss in patients suffering from bipolar disorder treated with valproate and drifts, but studies in the context of epilepsy are numerous and rich in information. Several studies have confirmed a higher rate of miscarriages than the population normal in children of mothers with epilepsy. The cause is probably multifactorial, but we know that antiepileptic treatments are the main reason for the increased risk. The estimated rate of spontaneous abortions among women under antiepileptic drugs is difficult, much spontaneous abortions are associated with chromosomal abnormalities, anomalies that have not been studied in populations affected epilepsy [11,12].

A 2008 study in India compared a population of women with epilepsy and women witnesses of the general population. It has been observed that the abortion rate spontaneous is higher in women with epilepsy (4%) than in controls (2%). This abortion rate observed in the study, although not significant (odds ratio (OR) 1.57; 95% CI 0.37 to 6.72), still remains higher among women than under antiepileptic women with epilepsy but not treated. The risk observed is greater with exposure to valproate (8%) than with other antiepileptics (1% with phenobarbital, 6% with lamotrigine)[13]. This result is supported by another prospective observational study, conducted on the records of the EURAP (the European Registry of Antiepileptic Drugs and Pregnancy) and by Tomson al. in 2015. This study assessed at 8.1% the risk of fetal death associated with pregnancy in valproic acid [14].

Combination therapy and a history of fetal death in utero are aggravating factors. In this contrary to previous results, the risk of fetal mortality linked to valproate is equivalent to that associated with other AEDs. Another research work on the teratogenic effects of valproic acid and its derivatives, assesses risks fetal death: the result is 2 of 69 fetal deaths in the group exposed to acid valproic [15].

Intra uterine growth retardation is more common in newborns of women epilepsy, as well as prematurity [16]. Compared to infants not exposed to antiepileptic drugs in utero, it is observed a higher proportion of neonates a small head circumference, among those exposed to anticonvulsants (polytherapy’s and monotherapies) including valproate [17]. Greater risk of low birth weight and lower APGAR score (which measures newborn vitality and its adaptation to ectopic life), are noted. These data should be taken with caution because if confirmed by some authors, they are also challenged by others ...

- Regarding the course of pregnancy, obstetric complications are found related to sodium valproate and derivatives, with more premature delivery, pre-eclampsia, retro placental hematoma, hemorrhages and caesarean section [18]. These observations, although confirmed, with published data very close, are discussed by certain studies which do not found no significant differences. This information is therefore also taken with caution. Carnitine deficiency is suggested on long-term use of valproic acid, but supplementation was not proposed.

Valproic acid has metabolic consequences in the neonatal period, it promotes occurrence of hypoglycemia by two mechanisms: decrease in endogenous production of glycogen and dysfunction in the way of glycolysis [19]. It has also been reported from rare cases of neonatal hyperammonemia in newborns of mothers treated with strong valproate doses and found no other etiology.

- A withdrawal syndrome has also been described with valproic acid, with irritability, hypertonia, agitation, seizures, eating disorders, hypoglycemia, vomiting, correlated with valproate doses taken in the 3rd quarter [20].
- Certain progressive organic diseases or symptoms may be linked to exposure in utero with valproic acid (non-exhaustive list):

§ Inguinal and umbilical hernias, tracheomalacia
§ Musculoskeletal disorders (hyperlaxity, very frequent scoliosis)
§ Sensory disorders (ophthalmological and auditory)
§ Frequent otorhinolaryngology infections in early childhood.

Many researchers have described an association between exposure to certain antiepileptic drugs and dysmorphic features of the child, sometimes in combination with major malformations and learning and behavior. Such syndromes have been described for phenytoin, carbamazepine and valproate. Distinctive facial features in children, caused by exposure to valproate, have been suggested to be markers of the severity of the syndrome.

A specific set of facial dysmorphic features linked to the effects of acid valproic on the developing embryo and fetus was first described in 1984. This syndrome was then corroborated by many authors describing other children exposed in utero to valproic acid and has similar facial features [21].

The main clinical findings include intrauterine growth restriction (IUGR), a long, thin upper lip, shallow philtrum, spiky folds (folds covering the inner corner of the eye) and hypoplasia (insufficient growth) of the face average manifested by a flat nasal bridge, small nose and returned back angles mouth.

However, there are also facial dysmorphic abnormalities described in children exposed in utero to other antiepileptic drugs, such as phenytoin, carbamazepine, phenobarbital, trimethadione or even primidone. These craniofacial anomalies attributed to these different antiepileptic drugs, can overlap with those observed after exposure to valproate in utero. So, it would seem that fetal valproate is not so distinct from the antiepileptic drug syndrome [22].

How difficult it is to diagnose a teratogenic effect of valproic acid only from the appearance of the face, the history of the exhibition, other anomalies major and / or developmental delay are essential in the diagnosis [23].

In the general population, approximately 2 to 3% of children are born with a malformation. A teratogen increases the overall frequency, or only that of a specific type deformity. Major birth defects are generally defined like structural abnormalities, which will be surgical, medical, functional or cosmetic.

As before, the main studies around the valproate risk pregnancy found in the scientific literature have been conducted almost exclusively on women pregnant with epilepsy. The following section therefore presents the results of studies by cohort based on this pathology and antiepileptic treatments. We already know that children exposed in utero to antiepileptics have more great risks of presenting such malformations: it is indeed three times more important than children of healthy mothers. However, the results of many recent cohorts on several thousand patients we learn epileptic pathology itself has no proper role in the occurrence malformations during pregnancy and that the malformation risk is mainly linked to treatment. This risk is different according to antiepileptics, and polytherapy is not in itself an important risk factor unless it includes valproic acid [24].

Valproic acid causes polymalformative syndrome in 9 to 15% of cases average. This risk is significantly high compared to other antiepileptic or mood stabilizers, also high relative to the risk in women with epilepsy processed and that of the general population. Nearly 10% of children born to mothers treated with valproate during pregnancy present deformities, against 2% to 3% of children in the general population, which is equivalent to a frequency about 4 to 5 times higher than that observed in the general population [25].

A summary of the in-utero exposure to valproic acid in France identified the major congenital malformations arising [26]. These malformations have been identified from the list of the European network of Population registers for monitoring congenital anomalies EUROCAT (European surveillance of congenital anomalies), in consultation with the Reference Center on Teratogenic Agents (ARCT). A total of 26 major birth defects of the EUROCAT identifiable from the list information available in SNIIRAM has been selected:
- Central nervous system anomalies: Anencephaly, Spina bifida, Microcephaly
-Cardiovascular anomalies: Inter-ventricular communication, Inter-auricular communication, Tetralogy of Fallot, Atresia of the pulmonary artery, Hypoplasia of the left ventricle, Hypoplastic right heart, Ebstein disease, and malposition of Transposition large vessels Aortic coarctation
- Orofacial anomalies: Cleft lip / labial palate, Cleft palate
- Abnormalities of the digestive system: Diaphragmatic hernia, Esophageal atresia,
Atresia anorectal
- Renal anomalies: Bilateral renal agenesis, Cystic kidney disease
- Anomalies of the external genital organs: Hypospadias, Epispadias
- Abdominal wall anomalies: Laparoschisis, Omphalocele
- Limb anomalies: clubfoot, radial radius anomalies
- Other anomalies: Craniostenosis

Among these malformations, some are significantly more represented. A study combining the results of 8 cohort studies with EUROCAT data, gives an idea of the frequency of 14 malformations more frequently represented in exposed children in utero to valproic acid in the first quarter [27].

Thus, compared to the untreated control group, the use of valproic acid in monotherapy was associated with significantly increased risks for 6 of the 14 defects considered, namely spina bifida, atrial septal defect, cleft palate, hypospadias, polydactyly and craniosynostosis (or craniostenosis). To compare the teratogenic effect of valproic acid with other antiepileptics, different prospective studies have been put in parallel, they include information on heart defects, neural tube defects, hypospadias and lunges orofacial (cleft palate) according to an exposure to five different molecules in monotherapy [28].

Compared to other AEDs, the numbers vary, but all of the studies agree that valproate is the most teratogenic of the anticonvulsants and mood stabilizers.

- In a study that brings together data from 25 centers specializing in epilepsy in United States and the United Kingdom, totaling 333 mothers with their children, under treatment in carbamazepine monotherapy (n = 110), lamotrigine (n = 98), phenytoin (n = 56), and valproate (n = 69), the frequencies of serious undesirable effects were noted, that is to say major birth defects and fetal death. For each antiepileptic studied rates were: carbamazepine 8.2%, lamotrigine 1.0%, 10.7% and phenytoin valproate 20.3% [29].

- In another study from 2012, combining data from registers of Nordic countries, an evaluation of the rates of malformations after exposure to different antiepileptics was performed [28].This study was based on data from the medical birth register in Norway counts 2,861 children born to women diagnosed with epilepsy (0.8% of 372,128 deliveries). Among them 961 were exposed to antiepileptics. The increase in rate of major malformations was only reported for valproate (6%) or combination therapy (6%) compared to children of mothers without epilepsy (3%). Excluding pregnancies on valproate, it was observed that the rates of malformations were the same in infants of epileptic mothers exposed to other antiepileptic drugs (3%) than mothers with untreated epilepsy (3%).Excluding pregnancies on valproate, it was observed that the rates of malformations were the same in infants of epileptic mothers exposed to other antiepileptics (3%) than for mothers with untreated epilepsy (3%). Unfortunately, this study does not report the different rates of malformations according to the different monotherapies.

A 2014 prospective study, listing 5206 cases from 1996 to 2012, provides updated results from the UK Epilepsy and Pregnancy Register on the risk of malformation congenital major after monotherapy exposure to valproate (n = 1290), carbamazepine (n = 1718) and lamotrigine (n = 2198). The risk with exposure to valproate in monotherapy utero was 6.7% (95% CI 5.5% to 8.3%) compared to 2.6% for carbamazepine (95% CI 1.9% to 3.5%) and 2.3% for lamotrigine 3.1%. Exposure to valproate again shows a higher rate of major birth defects than other antiepileptics studied [30].

-decrease in IQ quotient:
The very first studies describing development delays and autism spectrum disorders in some children exposed in utero to antiepileptic drugs date from the 90s, in reports of observations of patients with malformations congenital [31]. These neurodevelopmental effects were revealed later, for several reasons. First, they appear at a distance from childbirth and the registers recording birth defects, in general, do not follow the fate of children beyond the first year of life. In addition, the potential confounding factors are multiple, making difficult the attribution to the treatment alone of the responsibility for the noted possible deficits.

In 2000, a retrospective British study, including 57 children, really highlights speech developmental delay, with changes in speech behavior in many children. It allows to objectify for the first time this likely link in children affected by anticonvulsant syndrome. At a small part of the children in the study, autistic characteristics are noted [32].

Then in 2001, another British study, assesses the needs additional educational support for children exposed to medication antiepileptics. These publications lead to the launch of prospective studies for better identify possible liability for the main antiepileptic treatments cognitive and behavioral development. [33]. Another 2004 review studies the potential side effects of antiepileptics by the Cochrane group. Although the meta-analysis is not conclusive, this time it emits serious suspicions of developmental delay due to sodium valproate and advise to favor monotherapy during pregnancy at the lowest dose allowing to control seizures. The following year, the same author publishes an article studying long-term differential effects on cognitive functioning in school-aged children exposed to antiepileptics in utero. A battery of neuropsychological tests was applied to “mother-child” pairs, in order to obtain a neuropsychological profile for each child. In total, the study has 249 children, ages 6 to 16. The results show that children exposed to valproate sodium have significantly lower verbal IQ compared to children exposed to other antiepileptic or unexposed drugs. These same children are also more likely to have an IQ below 69 and to have a memory impairment by compared to other groups [34].

A large multicenter study then provides a wealth of knowledge valproate, the NEAD study, (Neurodevelopmental Effects of Antiepileptic Drugs). Its objective is differentiating the relative risks and benefits, in terms of neurobehavioural outcomes, in children exposed to four most commonly used antiepileptic drugs used in women of childbearing potential: carbamazepine, lamotrigine, phenytoin and valproate. This is a prospective cohort study, which includes four groups of women pregnant with epilepsy, treated with antiepileptic monotherapy. In all, 25 specialized centers in the United States and the United Kingdom participate in the group’s work. At total, 330 women who received one of the four most common antiepileptic drugs during their pregnancy, were included in the cohort between October 1999 and February 2004. They were followed in their first quarter. The children were then followed until the age of 6 years, to determine whether long-term differential effects of neurodevelopment exist.

The first article of this study, from August 2006, exposes congenital malformations found in the year of birth, he identifies and lists them [29]. This study confirms that valproate is the most teratogenic of the antiepileptics. In April 2009, a new article by the NEAD study, studying the cognitive functions at 3 years of children exposed in utero to antiepileptic drugs, finds a significantly lower IQ for children exposed to valproate than those exposed to other antiepileptic drugs, with an average IQ score of 9 points less than the score of those exposed to lamotrigine [35]. In addition to the NEAD study, other articles compare the long-term effects of intrauterine exposure to antiepileptics on cognitive functioning. A meta-analysis Canadian, through bibliographic research started in April 2009, gathered data from all cohort studies that have studied cognitive functioning after an in utero with antiepileptics. Studies have assessed IQ as a measure of development cognitive (IQ assessed by the Wechsler, Bayley or McCarthy information scales according to age), differentiating between average IQ, verbal IQ and performance IQ. IQ scores means are all significantly lower in the valproic acid group by report to the unexposed group [36].

A late 2010 Australian study, then studied cognitive impairment in school age children. Using the Wechsler Intelligence Scale for Children (4th edition), the results show extremely low IQs (<70) or borderlines (70-79). The article concluded on the negative impact of valproic acid on intellectual, verbal, as well only on working memory. This study suggests that the low scores observed among children exposed to antiepileptic combination therapies including valproate, would be properly attributed to the latter [37].

In February 2011, an observational cohort study demonstrated that exposure in utero with valproate and carbamazepine (monotherapy) has a significant harmful effect on the neurological development. 23 children (39.6%) exposed in utero to valproate, and 10 children (20.4%) exposed to carbamazepine show signs of mild developmental delay or significant, compared to 2 children in the control group (4.5%). Which is not the case for the lamotrigine (2.9%, or 1 child). Then in June of the same year, the NEAD study wanted to rule out possible biases on IQ results by identifying potential confounders: maternal IQ and level parent education that is correlated with the child’s IQ [38]. This allows to control the genetic and environmental influences when examining cognitive outcomes in children for whom clinical considerations preclude study randomization. This important point was raised in many studies during this period and will draw thereafter more certain conclusions. In October 2011, the Fetal antiepileptic drug exposure: motor, adaptive, and emotional / behavioral functioning at age 3 years confirms the negative effect of valproate and carbamazepine on the functioning and coping skills of children aged 3 years, exposed in utero. Compared to children exposed to other antiepileptic drugs, those whose mothers taking valproic acid have difficulties with social skills and the adaptive operation. These effects are associated with the dose of valproic acid. So, there are an increase in hyperactive behavior, with a risk for the development of attention deficit hyperactivity disorder [39]. NEAD study continues to track children, examines results at 4.5 compares them to younger ages. As the table below illustrates, the results show harmful cognitive effects from exposure to valproate in utero that persists at 4.5 years. These results are linked to performance at earlier ages [40]. The study confirms the dose-dependent effect of valproate for lowering IQ, already highlighted in many studies. This dose dependence is not found for the others antiepileptics. In addition, the frequency of marked intellectualdisabilities decreases with age, except for the valproate (10% with IQ <70 to 4.5 years). Then this study continued the full IQ monitoring at 6 years for these children exposed utero. The results then show, in 2013, an ever-lower IQ after exposure to valproate (on average 97), compared to carbamazepine (105), to lamotrigine (108), or phenytoin (108). These children exposed to valproate have, as before, poorer results on measures of verbal and memory skills, compared to children exposed to others antiepileptics. The same goes for nonverbal functions, the results are less good compared to lamotrigine (but not carbamazepine or phenytoin)[41].

These observations overlap with those of a 2015 cohort study, where the IQ mean found is 9.7 points lower for children exposed to a dose of valproate high (dose> 800mg per day). A similar significant effect on skills is noted. verbal, nonverbal, and spatial subscales. Children also have 8 times more need for academic support compared to the control children. However, exposure to valproate doses <800mg per day is not associated with an IQ reduced. Verbal skills are still impaired, with an increased need for tutoring (6 times more). In this study, in utero exposure to carbamazepine or lamotrigine did not had a significant effect on IQ. Carbamazepine has been associated with verbal abilities reduced and an increased frequency of IQ <85. [42].

ADHD is a concept that has evolved a lot over the years, according to the fifth version of the DSM (Diagnostic and statistical manual of mental disorders) and the American Psychiatric Association (APA) this is a persistent mode that interferes with the functioning or development, characterized by:
- inattention
-inattention and /or hyperactivity and impulsivity, knowing that this impulsivity is always a consequence of the attention deficit in the context of which “the action precedes thought” (this component is an essential element of the diagnosis).

These symptoms constitute an individualized clinical entity, both in children and in adults. ADHD is distinguished from “normal” by the number of symptoms, their severity and their disabling nature, leading to negative social consequences, psychological and educational. Symptoms do not occur exclusively during schizophrenia or another psychotic disorder and they are no better explained by another mental disorder (thymic disorder, anxiety disorder, dissociative disorder, personality disorder, poisoning by taken or stopped substance)[43].

Another risk for a child exposed in utero to valproic acid and derivatives is an Autism Spectrum Disorder (ASD). There are as many forms of autism as there are cases (fundamental). Previously classified as “pervasive developmental disorders”, according to DSM-V autism spectrum disorders now include both autism disorders, that Asperger’s syndrome or the pervasive developmental disorder – no specified. To define ASD, we speak of an “autistic triad”: communication disorder (verbal and nonverbal), impaired social interactions and behavioral anomalies (interests and activity of a restricted and repetitive nature). (95) (96).

One of the most convincing initial reports on the association between intrauterine exposure to valproic acid and autistic disorders was presented by Bromley et al. in 2008. (97) This prospective study studies the children of women with epilepsy compared to a non-epileptic and untreated control group: 6.3% of children exposed to valproic acid have autism spectrum disorder or key symptoms of autism spectrum disorder autism, including language impairment, reduced attention and social relationships difficult compared to 0.9% of control children (an increase 7 times greater). Long-term follow-up of this cohort showed in 2013 that 6 of the 50 (12%) children exposed to valproate had neurodevelopmental disorders; 5 of them have troubles of the autism spectrum. (98)

In the same year, another article from the NEAD study studying adaptive functioning as well as the emotional and behavioral functioning of the children followed at the age of 6 years, concludes that children, whose mothers have taken valproate, have a significantly risk higher to have a diagnosis of attention deficit disorder with or without hyperactivity (ADHD). (99) For the four groups of antiepileptic drugs the scores are in the low to medium range. Children whose mothers took valproate during pregnancy have lower overall adaptive competence scores lamotrigine and phenytoin groups. A dose-dependent decrease is found in the performance of adaptive functioning for valproate and phenytoin. Children exhibit significantly more atypical and inattentive behaviors than those in groups lamotrigine and phenytoin. This finding provides additional support for asserting that exposure to valproate in utero can have an impact not only on cognitive development, but also on the daily adaptive functioning of children whose mothers took this antiepileptic medication, especially at higher doses. Children also received significantly higher parental ratings for attention deficit disorder and social immaturity of children of mothers who have taken lamotrigine or phenytoin. This finding also supports previous studies showing that children exposed to valproate in utero at greater risk of developing neurological development such as autism spectrum disorder. (100)(101)(102)

These results are then confirmed by a study on the Danish population carried out by 1996 to 2006, using national registers. Children exposed to valproate during pregnancy and diagnosed with autism spectrum disorder (childhood autism, Asperger Syndrome, atypical autism and other pervasive developmental disorders) have identified, the average age of children at the end of follow-up is 8.84 years. Out of 655,615 children born from 1996 to 2006, 5,437 were identified with a spectrum disorder autistic, including 2067 with childhood autism. The absolute risk for the population is 1.53% for autism spectrum disorder and 0.48% for childhood autism. In overall, the 508 children exposed to valproate have an absolute risk of 4.42% for autism spectrum disorder and an absolute 2.50% risk for childhood autism. By limiting the cohort to 6,584 children born to women with epilepsy, the risk autism spectrum disorder in 432 children exposed to valproate was 4.15%, and the absolute risk of autism in children was 2.95% compared to 2.44% for the disorder autism spectrum and 1.02% for autism in children among 6152 children not exposed to valproate. Maternal use of valproate during pregnancy is therefore associated with significantly increased risk of autism spectrum disorder and childhood autism in children the unborn child. (60 The few studies at 6 and over leave the current data open to criticism. It exists probably a dose effect and a therapeutic combination effect. Data on the distribution of autistic children and adults are very rare or even non-existent.

Finally, there is no such thing in the literature specific descriptions of other types of pervasive disorder of the development. This lack of clinical data hinders the understanding of behavior and social life of those affected. The association of malformities, morphological, cognitive, organic pathologies, sensory and behavioral in children exposed in utero to valproate and derivatives no equivalent in human pathology with another teratogen. It results in an infinity of combinations which are not yet all described. The occurrence of unusual pathologies for the age or for the evolution of the individual must give priority to thinking of a “delay” this exhibition. Descriptive epidemiology as currently used also does the impasse on hundreds of pregnancies of bipolar women, treated with valproate. They don’t are not part of a cohort and there are no articles on them. Retrospective studies are confirmed by prospective studies on the cognitive level. Neurocognitive impairment is 7 to 11 points lower in IQ in the cohorts exposed to valproate. When it comes to averages, it’s hard to appreciate the daily impact simple tutoring with proven deficiency. It is also known that the study of subtypes (especially verbal IQ) can show more severe impacts. But there is no study usable in adolescents or adults, no study shedding light on social adjustment, no study on the link between cognitive impairment and autism, whatever type, no scalability study. Much study will therefore still be necessary to guide us in patient care, and all skills must be put profit to work in this direction. [39]. On the other hand, an animal model of autism induced by prenatal exposure to valproic acid demonstrates important structural and behavioral features that can be observed in individuals with autism.

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