General information on drug use in pregnancy: neurology drugs
A woman who has epilepsy and is taking antiepileptic medication has an increased risk of giving birth to an infant with an abnormality. This risk is about 2 to 3 times that of the general population and some of this risk is due to the antiepileptic drugs taken. Women taking more than one antiepileptic drug possibly have a higher risk of having a baby with a malformation.
All antiepileptic drugs are potentially teratogenic and there is no 'drug of choice' in pregnancy. However, many women with epilepsy need to be continued on antiepileptic drugs to prevent the potentially harmful effects of uncontrolled seizures to them, to their unborn child, and to others. In general, the best choice of treatment is the drug that best controls the epilepsy, at the lowest effective dose, in monotherapy if possible. Changes to the treatment regimen, including attempts to withdraw medications, are best done preconception.
Overall, the risk of teratogenicity is probably greatest with sodium valproate, particularly doses greater than 1200 mg/day, and phenobarbitone.
Sodium valproate has been associated with up to a ten-fold (0.2% to 2%) increased risk of spina bifida, as well as other serious malformations and coagulopathies. These effects are thought to be dose-related.
Carbamazepine has also been associated with significant increased risk of spina bifida in addition to developmental delay and craniofacial defects, although the risk is lower than with higher dose sodium valproate.
Data are now accumulating which suggest that lamotrigine (if taken alone) may not be associated with increased risk of congenital abnormalities if used in early pregnancy. Lamotrigine clearance may be increased by 50% in pregnancy requiring increased dose, with corresponding dose reduction after delivery (see below).
Phenytoin has been associated with distinctive craniofacial abnormalities, mental and growth deficiency and, less frequently, oral clefts and cardiac anomalies.
Primidone, phenobarbitone or methylphenobarbitone, alone or in combination with other antiepileptic drugs, can cause coagulation defects in the neonate, which may be preventable by the administration of vitamin K to the mother prior to delivery.
The newer antiepileptic drugs, with the exception of lamotrigine, do not have enough data available to inform on their risk profile for birth defects, and therefore a decision on whether to continue these in a woman planning to become pregnant needs to balance the potential risk versus the potential benefit in seizure control.
Women taking antiepileptic drugs should be offered counselling (preferably preconception) and prenatal screening (alpha-fetoprotein measurement and ultrasound examination). If a decision is taken to continue antiepileptics, authorities suggest that the risk of neural tube defects may be reduced if larger than the standard dose of folic acid is taken prior to pregnancy (ie 5 mg/day instead of 0.5 mg/day) although this is not established to definitely reduce the risk. Phytomenadione (vitamin K1), taken from 36 weeks of pregnancy (20 mg/day 'Konakion' chewable tablets) has also been suggested to reduce the risk of coagulopathies in women using medications that induce the liver drug metabolising enzymes (eg carbamazepine, phenytoin, phenobarbitone).
Dose adjustment and monitoring
Plasma antiepileptic drug concentrations may change during pregnancy, so concentrations should be measured preconception, during pregnancy, and over the first 3 months postpartum. Changes during and after pregnancy may be helpful in assessing the effect of the pregnancy on the woman's pharmacokinetic profile for the drug, and therefore help guide decisions about dose adjustment. This is particularly important for lamotrigine, as the kinetics of lamotrigine are altered to such an extent that dose adjustments are usually required during pregnancy.
Lamotrigine plasma levels decrease in pregnancy because of increased hepatic drug clearance, which is induced by physiological changes during pregnancy. Studies have shown that the ratio of dose to plasma concentration is 5.8 times higher at delivery and 3.6 times higher in late pregnancy as compared with 5 months postpartum.
It is recommended that a women's plasma level of lamotrigine be measured prior to conception, or as early as possible into the pregnancy, so that a baseline can be established. Thereafter, the plasma levels of lamotrigine should be measured at least bimonthly throughout the pregnancy, and dose adjustments guided by plasma levels. Following parturition, maternal lamotrigine kinetics normalise in 2 to 3 weeks.
Ergotamine and the triptans should be avoided throughout pregnancy.
For acute treatment, paracetamol is safe but often inadequate for severe attacks. Many women have used aspirin and ibuprofen in early pregnancy but safety cannot be assured. Both aspirin and ibuprofen (but particularly aspirin) should not be used in late pregnancy, as these drugs may inhibit closure of the fetal ductus arteriosus; aspirin may also affect platelet function. Parenteral opioids, such as morphine, are probably safe but should be reserved for severe attacks. Repeated doses of pethidine can lead to the accumulation of a toxic metabolite, with resultant confusion and seizures. Repeated doses of opioids can lead to dependency and withdrawal symptoms in the mother and newborn.
For prophylaxis, propranolol and metoprolol have also been used but again safety cannot be assured. Beta blockers in late pregnancy may be associated with fetal bradycardia, hypoglycaemia and respiratory depression.
Azathioprine and cyclosporin can cross the placenta and cause immunosuppression in the neonate. Interferon beta-1b and methotrexate can induce spontaneous abortions.
Amended February 2007. Amended September 2008 ©Therapeutic Guidelines Limited (etg31demo, July 2010)