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Teratogenicity and developmental effects: Pregnancy Exposure Risk related to valproate: Both valproate monotherapy and valproate polytherapy including other anti-epileptics are frequently associated with abnormal pregnancy outcomes. Available data suggest that anti-epileptic polytherapy including valproate may be associated with a greater risk of congenital malformations than valproate monotherapy and polytherapy compared to the population not exposed to valproate.
Valproate was shown to cross the placental barrier both in animal species and in humans (see Pharmacology: Pharmacokinetics under Actions).
In animals: teratogenic effects have been demonstrated in mice, rats and rabbits (see Pharmacology: Toxicology: Preclinical safety data under Actions).
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 below which no risk exists cannot be established.
Available data show an increased incidence of minor and major malformations. The most common types of malformations include neural tube defects, facial dysmorphism, cleft lip and palate, craniostenosis, cardiac, renal and urogenital defects, limb defects (including bilateral aplasia of the radius), and multiple anomalies involving various body systems.
In utero exposure to valproate may also result in hearing impairment or deafness due to ear and/or nose malformations (secondary effect) and/or direct toxicity on the hearing function. Cases describe both unilateral and bilateral deafness or hearing impairment. Outcomes were not
reported for all cases. When outcomes were reported, the majority of the cases did not recover.
Epilim IV: A meta-analysis (including registries and cohort studies) showed that approximately 11% of children of women with epilepsy exposed to valproate monotherapy during pregnancy had major congenital malformations.
The risk of major congenital malformations in children after in utero exposure to anti-epileptic drug polytherapy including valproate is higher than that of anti-epileptic drug polytherapy not including valproate.
In utero exposure to valproate may result in eye malformations (including colobomas, microphthalmos) that have been reported in conjunction with other congenital malformations. These eye malformations may affect vision.
Developmental disorders: Data have shown that exposure to valproate in utero can have adverse effects on mental and physical development of the exposed children. The risk seems to be dose-dependent but a threshold dose below which no risk exists, cannot be established based on available data. The exact gestational period of risk for these effects is uncertain and the possibility of a risk throughout the entire pregnancy cannot be excluded.
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.
Intelligence quotient (IQ) measured in school aged children (age 6) with a history of valproate exposure in utero was on average 7-10 points lower than those children exposed to other anti-epileptics. Although the role of confounding factors cannot be excluded, there is evidence in children exposed to valproate that the risk of intellectual impairment may be independent from maternal IQ.
There are limited data on the long-term outcomes.
Available data from a population-based study show that children exposed to valproate in utero are at increased risk of autistic spectrum disorder (approximately 3-fold) and childhood autism (approximately 5-fold) compared to the unexposed population in the study.
Available data from another population-based study show that children exposed to valproate in utero are at increased risk of developing attention-deficit/hyperactivity disorder (ADHD) (approximately 1.5-fold) compared to the unexposed population in the study.
Epilim IV: When valproate is administered in polytherapy with other anti-epileptic drugs during pregnancy, the risks of neuro-developmental disorders in the offspring were also significantly increased as compared with those in children from the general population or born to untreated women with epilepsy.
Female children and women of childbearing potential (see previously mentioned, Warnings and Precautions): Oestrogen-containing products: Oestrogen-containing products, including oestrogen-containing hormonal contraceptives, may increase the clearance of valproate, which would result in decreased serum concentration of valproate and potentially decreased valproate efficacy.
If a woman plans a pregnancy: If a woman is planning to become pregnant, a specialist experienced in the management of epilepsy must reassess valproate therapy and consider alternative treatment options. Every effort should be made to switch to appropriate alternative treatment prior to conception and before contraception is discontinued. If switching is not possible, the woman should receive further counselling regarding the risks of valproate for the unborn child to support her informed decision-making regarding family planning.
Pregnant women: Valproate as treatment for epilepsy is contraindicated in pregnancy unless there is no suitable alternative treatment. If a woman using valproate becomes pregnant, she must be immediately referred to a specialist to consider alternative treatment options.
During pregnancy, maternal tonic-clonic seizures and status epilepticus with hypoxia may carry a particular risk of death for the mother and the unborn child. If in exceptional circumstances, despite the known risks of valproate in pregnancy and after careful consideration of alternative treatment, a pregnant woman must receive valproate for epilepsy.
It is recommended to: Use the lowest effective dose and divide the daily dose of valproate into several small doses to be taken throughout the day; The use of a prolonged release formulation may be preferable to other treatment formulations in order to avoid high peak plasma concentrations.
All patients with valproate-exposed pregnancy and their partners should be referred to a specialist experienced in prenatal medicine for evaluation and counselling regarding the exposed pregnancy. Specialised prenatal monitoring should take place to detect the possible occurrence of neural tube defects or other malformations. Folate supplementation before the pregnancy may decrease the risk of neural tube defects common to all pregnancies. However, the available evidence does not suggest it prevents the birth defects or malformations due to valproate exposure.
Risk in the neonate: Cases of haemorrhagic syndrome have been reported very rarely in neonates whose mothers have taken valproate during pregnancy. This haemorrhagic syndrome is related to thrombocytopenia, hypofibrinogenemia and/or 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. Therefore, platelet count, fibrinogen plasma level, coagulation tests and coagulation factors should be investigated in neonates.
Cases of hypoglycaemia have been reported in neonates whose mothers have taken valproate during the third trimester of their pregnancy; Cases of hypothyroidism have been reported in neonates whose mothers have taken valproate during pregnancy; Withdrawal syndrome (such as, in particular, agitation, irritability, hyper-excitability, jitteriness, hyperkinesia, tonicity disorders, tremor, convulsions and feeding disorders) may occur in neonates whose mothers have taken valproate during the last trimester of their pregnancy.
Breastfeeding: Valproate is excreted in human milk with a concentration ranging from 1% to 10% of maternal serum levels. Haematological disorders have been shown in breastfed newborns/infants of treated women (see Adverse Reactions).
A decision must be made whether to discontinue breastfeeding or to discontinue/abstain from Epilim therapy taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman.
Fertility: Amenorrhoea, polycystic ovaries and increased testosterone levels have been reported in women using valproate (see Adverse Reactions). Valproate administration may also impair fertility in men (see Adverse Reactions). Case reports indicate that fertility dysfunctions are reversible after treatment discontinuation.
Epilim IV: Fertility dysfunctions are in some cases reversible at least 3 months after treatment discontinuation. Limited number of case reports suggest that a strong dose reduction may improve fertility function. However, in some cases, the reversibility of male infertility was unknown.
