Pregnancy & Lactation : הריון/הנקה

4.6   Fertility, pregnancy and lactation
Pregnancy and women of childbearing potential

Treatment of epilepsy
• Valproate is contraindicated during pregnancy, unless there is no suitable alternative treatment.
• Valproate is contraindicated in women of childbearing potential, unless the conditions of the pregnancy prevention program are fulfilled (see sections 4.3 and 4.4).


Treatment of Bipolar disorder
• Valproate is contraindicated during pregnancy.
• Valproate is contraindicated in women of childbearing potential, unless the conditions of the pregnancy prevention programme are fulfilled (see sections 4.3 and 4.4).

Teratogenicity and developmental effects from in utero exposure

Pregnancy Exposure Risk related to valproate
In females, both valproate monotherapy and valproate polytherapy including other antiepileptics are frequently associated with abnormal pregnancy outcomes. Available data show an increased risk of major congenital malformations and neurodevelopmental disorders in both 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 section 5.2).
Teratogenic effects have been demonstrated in mice, rats and rabbits (see section 5.3).

Congenital malformations from in utero exposure
A meta-analysis (including registries and cohort studies) showed that about 11% of children of epileptic women exposed to valproate monotherapy during pregnancy had major congenital malformations. This is greater than the risk of major malformations in the general population (about 3 %).
The risk of major congenital malformations in children after in utero exposure to antiepileptic drug polytherapy including valproate is higher than that of anti-epileptic drugs polytherapy not including valproate.
This risk is dose-dependent in valproate monotherapy, and available data suggest it is dose-dependent in polytherapy. However, 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 to 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.

In utero exposure to valproate may result in eye malformations (including coloboma and microphthalmia), that have been reported in conjunction with other congenital malformations. These eye malformations can affect vision.

Neurodevelopmental disorders from in utero exposure
Data have shown that exposure to valproate in utero can have adverse effects on mental and physical development of the exposed children. The risk of neurodevelopmental disorders (including autism) seems to be dose-dependent when valproate is used in monotherapy, but a threshold dose below which no risk exists cannot be established based on available data.
When valproate is administered in polytherapy with other anti-epileptic drugs during pregnancy, the risks of neurodevelopment disorders in the offspring were also significantly increased as compared with those in children from general population or born to untreated epileptic mothers.
The exact gestational period of risk for these effects is uncertain and the possibility of a risk throughout the entire pregnancy cannot be excluded.

When valproate is administered in monotherapy, 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.

If a woman plans a pregnancy
For the indication epilepsy, 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 (see section 4.4). If switching is not possible, the woman should receive further counselling regarding the valproate risks for the unborn child to support her informed decision making regarding family planning.
For the indication bipolar disorder if a woman is planning to become pregnant a specialist experienced in the management of bipolar disorder must be consulted and treatment with valproate should be 
discontinued and if needed switched to an alternative treatment prior to conception, and before contraception is discontinued.

Pregnant women
Valproate as treatment for bipolar disorder is contraindicated for use during pregnancy. Valproate as treatment for epilepsy is contraindicated in pregnancy unless there is no suitable alternative treatment (see sections 4.3 and 4.4).
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 mother and the unborn child.
If, despite the known risks of valproate in pregnancy and after careful consideration of alternative treatment, in exceptional circumstances 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 (see section 4.2).

All patients with a valproate exposed pregnancy and their partners should be referred to a Teratology center for evaluation and counselling regarding the exposed pregnancy. Specialized 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 which may occur in all pregnancies. However, the available evidence does not suggest that it prevents the birth defects or malformations due to valproate exposure.

Serum concentrations of valproic acid should be checked regularly, as they apparently fluctuate considerably in the course of a pregnancy, even if the dose remains constant. After remaining roughly the same for the first and second trimester, a three-fold increase in the concentration of free valproic acid in the third trimester up to the delivery date has been observed.

Women of childbearing potential
Estrogen-containing products
Estrogen-containing products, including estrogen-containing hormonal contraceptives, may increase the clearance of valproate, which would result in decreased serum concentration of valproate and potentially decreased valproate efficacy (sections 4.4 and 4.5).

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, hypofibrinogenaemia and/or to a decrease in other coagulation factors.
Afibrinogenaemia 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, hyperexcitability, 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.

Breast-feeding

Valproate is excreted in human milk with a concentration ranging from 1 % to 10 % of maternal serum levels. Haematological disorders have been shown in breast-fed newborns/infants of treated women (see section 4.8).

A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Depalept Chrono therapy, taking into account the benefit of breast feeding 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 section 4.8). Valproate administration may also impair fertility in men (see section 4.8).
Fertility dysfunctions are in some cases reversible at the least 3 months after treatment discontinuation. Limited number of case reports suggest that a strong dose reduction may improve fertility function. However, in some other cases, the reversibility of male infertility was unknown.