Pregnancy & Lactation : הריון/הנקה

4.6   Fertility, pregnancy and lactation
Pregnancy
Risk related to epilepsy and anti-epileptic drugs (AEDs) in general
Specialist advice regarding the potential risks to a foetus caused by both seizures and antiepileptic treatment should be given to women of childbearing potential, and especially to women planning for pregnancy and women who are pregnant. The need for treatment with AEDs should be reviewed when a woman is planning to become pregnant. In women being treated for epilepsy, sudden discontinuation of AED therapy should be avoided as this may lead to breakthrough seizures that could have serious consequences for the woman and the foetus. Monotherapy should be preferred whenever possible because therapy with multiple AEDs could be associated with a higher risk of congenital malformations than monotherapy, depending on the associated antiepileptics.

Risk related to topiramate
Topiramate is teratogenic in mice, rats and rabbits (see section 5.3). In rats, topiramate crosses the placental barrier.

In humans, topiramate crosses the placenta and similar concentrations have been reported in the umbilical cord and maternal blood.

Clinical data from pregnancy registries indicate that infants exposed in utero to topiramate monotherapy have:

Major congenital malformations and foetal growth restriction
•    An increased risk of congenital malformations (particularly cleft lip/palate, hypospadias, and anomalies involving various body systems) following exposure during the first trimester. The North American Antiepileptic Drug Pregnancy Registry data for topiramate monotherapy showed an approximate 3-fold higher prevalence of major congenital malformations (4.3%), compared with a reference group not taking AEDs (1.4%). Data from an observational population-based registry study from the Nordic countries showed a 2 to 3-fold higher prevalence of major congenital malformations (up to 9.5%), compared with a reference group not taking AEDs (3.0%). In addition, data from other studies indicate that, compared with monotherapy, there is an increased risk of teratogenic effects associated with the use of AEDs in combination therapy. The risk has been reported to be dose dependent; effects were observed in all doses. In women treated with topiramate who have had a child with a congenital malformation, there appears to be an increased risk of malformations in subsequent pregnancies when exposed to topiramate.
•    A higher prevalence of low birth weight (<2500 grams) compared with a reference group.
•    An increased prevalence of being small for gestational age (SGA; defined as birth weight below the 10th percentile corrected for their gestational age, stratified by sex). In the North American Antiepileptic Drug Pregnancy Registry, the risk of SGA in children of women receiving topiramate was 18% compared with 5% in children of women without epilepsy not receiving an AED. The long-term consequences of the SGA findings could not be determined.

Neurodevelopmental disorders
•    Data from two observational population-based registry studies undertaken in largely the same dataset from the Nordic countries suggest that there may be a 2 to-3-fold higher prevalence of autism spectrum disorders, intellectual disability or attention deficit hyperactivity disorder (ADHD) in almost 300 children of mothers with epilepsy exposed to topiramate in utero, compared with children of mothers with epilepsy not exposed to an AED. A third observational cohort study from the U.S.A. did not suggest an increased cumulative incidence of these outcomes by 8 years of age in approximately 1000 children of mothers with epilepsy exposed to topiramate in utero, compared with children of mothers with epilepsy not exposed to an AED.

Indication epilepsy


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•     Topiramate is contraindicated in pregnancy, unless there is no suitable alternative treatment (see sections 4.3 and 4.4).
•     The woman must be fully informed of and understand the risks of using topiramate during pregnancy. This includes discussion about the risks of uncontrolled epilepsy to the pregnancy.
•     If a woman is planning to become pregnant, efforts should be made to switch to an appropriate alternative treatment before contraception is discontinued.
•     If a woman becomes pregnant while taking topiramate, she should promptly be referred to a specialist to reassess topiramate treatment and consider alternative treatment options.
•     If topiramate is used during pregnancy, the patient should be referred to a specialist for evaluation and counselling regarding the exposed pregnancy. Careful prenatal monitoring should be performed.

Indication migraine prophylaxis
Topiramate is contraindicated in pregnancy (see sections 4.3 and 4.4).

Women of childbearing potential (all indications)
Topiramate is contraindicated in women of childbearing potential not using highly effective contraception. The only exception is a woman with epilepsy for whom there is no suitable alternative but who plans a pregnancy and who is fully informed about the risks of taking topiramate during pregnancy (see sections 4.4, 4.5 and 4.6).

At least one highly effective method of contraception (such as an intrauterine device) or two complementary forms of contraception including a barrier method should be used (see sections 4.3, 4.4 and 4.5) during treatment and for at least 4 weeks after stopping treatment with Topamax.

Alternative therapeutic options should be considered in women of childbearing potential.

Pregnancy testing should be performed before initiating treatment with topiramate in a woman of childbearing potential.

The patient must be fully informed and understand the risks related to the use of topiramate during pregnancy. This includes the need for specialist consultation if the woman is planning for pregnancy, and for prompt contact with a specialist if she becomes pregnant or thinks she may be pregnant and is taking topiramate.

For women with epilepsy, the risks of uncontrolled epilepsy to the pregnancy should also be taken into account (see sections 4.3 and 4.4).

For female children (see section 4.4).

Breast-feeding
Animal studies have shown excretion of topiramate in milk. The excretion of topiramate in human milk has not been evaluated in controlled studies. Limited observations in patients suggest an extensive excretion of topiramate into human milk. Effects that have been observed in breastfed newborns/infants of treated mothers, include diarrhoea, drowsiness, irritability and inadequate weight gain. Therefore, a decision must be made whether to suspend breast-feeding or to discontinue/abstain from topiramate therapy taking into account the benefit of breast-feeding for the child and the benefit of topiramate therapy for the women (see section 4.4).

Fertility
Animal studies did not reveal impairment of fertility by topiramate (see section 5.3). The effect of topiramate on human fertility has not been established.