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Use in Pregnancy: SODIUM VALPROATE AGUETTANT should not be used in girls, female adolescents, women of childbearing age, and pregnant women except in case of inefficacy of or intolerance to drug alternatives. Women of childbearing age should use effective contraception during treatment.
In women planning to become pregnant, all efforts should be made to switch to appropriate alternative treatment prior to conception.
Risks associated with Exposure to Valproate During Pregnancy: The use of valproate, whether as monotherapy or as polytherapy is associated with abnormal pregnancy outcomes. Available data suggests that anti-epileptic therapy with multiple agents including valproate is associated with a higher risk of congenital malformations than valproate monotherapy.
Congenital Malformations: Data derived from a meta-analysis (including registries and cohort studies) has shown that 10.73% of children of epileptic women exposed to valproate monotherapy during pregnancy suffer from congenital malformations (95% CI: 8.16-13.29). This is a greater risk of major malformations than for the general population, for whom the risk is about 2-3%. The risk is dose-dependent but a threshold dose as follows which no risk exists cannot be established.
Available data shows an increased incidence of minor and major malformations. The most common types of malformations include neural tube defects (about 2-3% facial dysmorphism, cleft lip and palate, craniostenosis, cardiac, renal and urogenital defects (including hypospadias), limb defects (including bilateral aplasia of the radius), and multiple anomalies involving various parts of the body.
Neurodevelopmental Disorders: Studies show that valproate increases the risk of neurovedelopmental disorders in children exposed to it in utero. The risk seems to be dose-dependent but a threshold dose below which no risk exists cannot be established based on available data. The possibility of a risk throughout the entire pregnancy period cannot be ruled out.
Studies in preschool children exposed in utero to valproate show that up to 30-40% experience delays in their early development, such as talking and walking later, lower intellectual abilities, poor-language skills (speaking and understanding) and memory problems.
The Intelligence quotient (IQ) measured in school-age children (6 years) with a history of valproate exposure in utero was on average 7-10 points lower than those children exposed to other anti-epileptic agents. Although the role of confounding factors cannot be ruled out, there is evidence that the IQ impairment observed in children exposed to valproate in utero is independent of maternal IQ.
Data on the outcome of these disorders in the long-term is limited.
Available data shows that children exposed to valproate in utero are at increased risk of developing pervasive developmental disorders (autistic spectrum type disorders) (approximately 3 times more frequent) and childhood autism (approximately 5 times more frequent) as compared with the control population.
Limited data suggests that children exposed to valproate in utero are more likely to develop symptoms of attention deficit hyperactivity disorder (ADHD).
Female Children, Female Adolescents and Women of Childbearing Age (see previous text and Precautions): SODIUM VALPROATE AGUETTANT should not be used in girls, female adolescents, women of childbearing age and pregnant women except in case of inefficacy of or intolerance to drug alternatives. Women of childbearing age should use effective contraception during treatment.
In women planning to become pregnant or who are pregnant: Valproate therapy should be reassessed.
All efforts should be made to switch to appropriate alternative treatment prior to conception;
Pre-conception consultation is recommended.
Valproate therapy should not be discontinued without a re-assessment of the benefit/risk ratio of the treatment for the patient by a physician experience in the management of epilepsy. During pregnancy, tonic-clonic seizures and status epilepticus with hypoxia in the mother can lead to serious or even fatal consequences for mother and the foetus.
If, after careful assessment of the risks and benefits, valproate therapy must be absolutely maintained during pregnancy (no alternative). It is recommended to: Use the lowest effective dose and divide the daily dose into several small doses to be taken throughout the day. The use of a prolonged-release formulation may be preferable in order to avoid high peak plasma concentrations.
Folate supplementation before the pregnancy may decrease the risk of neural tube defects common to all pregnancies. However, the available data does not suggest that the action of folic acid prevents the malformations associated with valproate exposure.
Initiate specialised prenatal monitoring in order to detect the possible occurrence of neural tube defects or other malformations.
Before Delivery: Perform a coagulation investigation including platelet count, fibrinogen assay and clotting time (Activated Partial Thromboplastin Time, APTT) in the mother before delivery.
Risk in the Neonate: Cases of haemorrhagic syndrome have been reported very rarely in neonates of mothers treated with valproate during pregnancy. This haemorrhagic syndrome is related to thrombocytopenia, hypofibrinogenemia and/or to a decrease in other coagulation factors. Afibrinogenemia has also been reported and may be fatal. However, this syndrome must be distinguished from the decrease of the vitamin-K factors induced by phenobarbital and enzymatic inducers. A normal haemostasis assessment in the mother does not allow the elimination of abnormalities of haemostasis in the neonate. Therefor platelet count fibrinogen plasma level, coagulation tests and coagulation factors should be investigated in neonates.
Cases of hypoglycaemia have been reported in neonates of mothers treated with valproate during the third trimester of pregnancy.
Cases of hypothyroidism have been reported in neonates of mothers treated with valproate during pregnancy.
Withdrawal symptoms (particularly agitation, irritability, hyper-excitability, nervousness, hyperkinesia, tonicity disorders, tremors, convulsions and feeding disorders) may occur in neonates of mothers treated with valproate during the third trimester of pregnancy.
Use in Lactation: Valproate is excreted in human milk in a concentration ranging between 1% and 10% of maternal serum levels. Haematological disorders have been observed in neonates/infants breastfed by women on treatment (see Adverse Reactions).
The decision to suspend breastfeeding or discontinue treatment with SODIUM VALPROATE AGUETTANT must take account of the benefit of breastfeeding for the child and the benefit of therapy for the mother.
Fertility: Cases of amenorrhoea polycystic ovaries and increased testosterone levels have been reported in women treated with valproate (see Adverse Reactions). In men, the administration of valproate may also affect fertility (decreased sperm mobility in particular) (see Adverse Reactions). Case reports indicated that fertility disorders are reversible after discontinuation of treatment.
