Pregnancy & Lactation : הריון/הנקה

4.6   Fertility, pregnancy and lactation

Pregnancy
In animals (mice, rats, rabbits) oral administration of carbamazepine during organogenesis led to increased embryonic mortality at daily doses which caused maternal toxicity (above 200 mg/kg body weight daily, i.e. 10 to 20 times the usual human dosage). In the rat there was also some evidence of abortion at 300 mg/kg body weight daily. Near-term rat foetuses showed growth retardation, again at maternally toxic doses. There was no evidence of teratogenic potential in the three animal species tested, but, in one study using mice, carbamazepine (40 to 240 mg/kg body weight daily, orally) caused defects (mainly dilatation of cerebral ventricles) in 4.7% of exposed foetuses as compared with 1.3% in controls.

Risk summary
Offspring of epileptic mothers are known to be more prone to developmental disorders, including malformations. Although conclusive evidence from controlled studies with carbamazepine monotherapy is lacking, developmental disorders and malformations, including spina bifida and also other congenital anomalies, e.g. craniofacial defects, cardiovascular malformations, hypospadias and anomalies involving various body systems, have been reported in association with the use of Tegretol.
Based on data in a North American pregnancy registry, the rate of major congenital malformations, defined as a structural abnormality with surgical, medical, or cosmetic importance, diagnosed within 12 weeks of birth following maternal exposure to carbamazepine monotherapy in the first trimester was 3.0% (95% CI 2.1-4.2%). As compared to pregnant women not taking any antiepileptic drug, the relative risk was 2.7 (95% CI 1.1-7.0). There is evidence to suggest that the risk of malformation with carbamazepine may be dose-dependent.

Neurodevelopmental disorders have been reported among children born to women with epilepsy treated with carbamazepine alone or in combination with other antiepileptic drugs during pregnancy. Studies related to the risk of neurodevelopmental disorders in children exposed to carbamazepine during pregnancy are contradictory and a risk cannot be excluded.

Specialist medical advice regarding the potential risks to a foetus caused by both seizures and antiepileptic treatment should be given to all women of childbearing potential taking antiepileptic treatment, and especially to women planning pregnancy and women who are pregnant.

Clinical considerations
Taking these data into consideration:
• Pregnant women with epilepsy should be treated with special care.

•   If women receiving Tegretol become pregnant or plan to become pregnant, or if the need of initiating treatment with Tegretol arises during pregnancy, the drug's expected benefits must be carefully weighed against its possible hazards, particularly in the first 3 months of pregnancy.

•   In women of child-bearing potential Tegretol should, wherever possible, be prescribed as monotherapy, because the incidence of congenital abnormalities in the offspring of women treated with a combination of antiepileptic drugs is greater than in those of mothers receiving the individual drugs as monotherapy. The risk of malformations following exposure to carbamazepine as polytherapy may vary depending on the specific drugs used and may be higher in polytherapy combinations that include valproate.

•   Minimum effective doses should be given and monitoring of plasma levels is recommended. The plasma concentration could be maintained in the lower side of the therapeutic range 4 to 12 micrograms/mL provided seizure control is maintained (See Dosage and administration: Epilepsy). There is evidence to suggest that the risk of malformation with carbamazepine may be dose-dependent, i.e. at a dose < 400 mg per day, the rates of malformation were lower than with higher doses of carbamazepine.

•   Patients should be counseled regarding the possibility of an increased risk of malformations and given the opportunity of antenatal screening.

•   During pregnancy, an effective antiepileptic treatment should not be interrupted, since the aggravation of the illness is detrimental to both the mother and the foetus.

Monitoring and prevention
Folic acid deficiency is known to occur in pregnancy. Antiepileptic drugs have been reported to aggravate folic acid deficiency. This deficiency may contribute to the increased incidence of birth defects in the offspring of treated epileptic women. Folic acid supplementation has therefore been recommended before and during pregnancy. Folic acid supplementation (5 mg) should be commenced four weeks prior to and continue for twelve weeks after conception.

In the neonate
In order to prevent bleeding disorders in the offspring, it has also been recommended that vitamin K1 be given to the mother during the last weeks of pregnancy as well as to the neonate.

There have been a few cases of neonatal seizures and/or respiratory depression associated with maternal Tegretol and other concomitant anticonvulsant drug use. A few cases of neonatal vomiting, diarrhoea and/or decreased feeding have also been reported in association with maternal Tegretol use. These reactions may represent a neonatal withdrawal syndrome.

Lactation

Risk summary
Carbamazepine passes into the breast milk (about 25 to 60% of plasma concentrations). The benefits of breast-feeding should be weighed against the remote possibility of adverse effects occurring in the infant. Mothers taking Tegretol may breast-feed their infants, provided the infant is observed for possible adverse reactions (e.g. excessive somnolence, allergic skin reaction). There have been some reports of cholestatic hepatitis in neonates exposed to carbamazepine during antenatal and or during breast feeding. Therefore breast-fed infants of mothers treated with carbamazepine should be carefully observed for adverse hepatobiliary effects.

Females and males of reproductive potential

Contraception
Women of childbearing potential should use effective contraception during treatment with Tegretol and for 2 weeks after the last dose. Due to enzyme induction, Tegretol may result in a failure of the therapeutic effect of hormonal contraceptive drugs containing oestrogen and/or progesterone. Women of child-bearing potential should be advised to use alternative contraceptive methods while on treatment with Tegretol.

Fertility

There have been very rare reports of impaired male fertility and/or abnormal spermatogenesis.