ASMs and contraceptive options

For people taking hormonal contraceptives, the use of enzyme-inducing ASMs is associated with an elevated risk of unplanned pregnancies.

• Strong enzyme-inducing ASMs decrease the efficacy of most hormonal contraception. Carbamazepine, cenobamate, oxcarbazepine, perampanel, phenobarbital, phenytoin, and primidone are examples of strong enzyme-inducing ASMs.
• The effect of weak enzyme-inducing ASMs on hormonal contraception is less clear than that of the strong enzyme-inducing ASMs. Clobazam, eslicarbazepine, felbamate, lamotrigine, rufinamide and topiramate are examples of weak enzyme-inducing ASMs.
• Non-enzyme-inducing ASMs do not affect the efficacy of hormonal contraception. Brivaracetam, clonazepam, ethosuximide, gabapentin, levetiracetam, lacosamide, pregabalin, valproic acid and zonisamide are examples of non-enzyme-inducing ASMs.

The following hormonal contraceptives are preferred for people with epilepsy, especially if they are on enzyme-inducing ASMs.^[3]

• Hormone-eluting intrauterine devices (IUDs) (Mirena, Kyleena, Skyla, and Liletta) and copper IUD (Paragard). Hormone-eluting IUDs have a small amount of progesterone that predominantly works locally, unlike other hormonal contraceptives. The hormone-eluting IUDs will not affect seizure control and enzyme-inducing ASMs do not significantly affect their efficacy.
• Depo-medroxyprogesterone acetate (Depo-Provera, "Depo"). Depo-medroxyprogesterone may have benefits for catamenial epilepsy. Check seizure frequency and consider a shorter dosage interval (e.g., 10 weeks) if seizure frequency increases prior to the next dose (especially if on an enzyme-inducing ASM).
• Etonogestrel / progesterone implant. Overall, etonogestrel implants are a highly efficacious form of contraception, with unintended pregnancies of less than 1 per 100 women in a year. However, the efficacy may be lowered by enzyme inducers. The progesterone implant ("nexplanon") has higher efficacy than most other hormonal contraceptives, but enzyme-inducing ASMs could still influence efficacy.

Patients should avoid estrogen for the first six postpartum weeks to avoid deep vein thrombosis.

Epilepsy and heredity

For most patients with epilepsy, the risk of passing the disease to a child is only slightly higher than the risk of a member of the general population having a child with epilepsy (1–2%). Specifically, the hereditary rates for patients with:

• Any type of epilepsy is 3.5–6%
• Focal epilepsy is 1–5%
• Generalized epilepsy is 6–8%.^[5]

The above statistics do not apply if a person has a known genetic cause of their epilepsy. In those cases, the risks of passing on epilepsy to a child may be significantly higher. Some indications that epilepsy may have a genetic cause are:

• Periventricular nodular heterotopia (PVNH), a brain abnormality present in some individuals with epilepsy
• An intellectual disability or autism spectrum disorder in addition to epilepsy
• Sleep-related hypermotor epilepsy
• A strong family history of epilepsy, including having any first-degree relatives or more than one second-degree relative with epilepsy^[6]

In utero exposure to ASMs

Several studies^[7] following children exposed to ASMs during pregnancy found that:

• Lamotrigine exposure appears to carry a relatively low risk of adverse neurodevelopmental outcomes.
• Levetiracetam also carries a low risk, based on more limited data.
• The data on carbamazepine are mixed but generally suggest a low risk.
• The data on topiramate are more mixed and suggest negative effects.
• The data on valproic acid suggests highly elevated risk.

Valproic acid exposure during the first 13 weeks of pregnancy has been associated with adverse neurodevelopmental outcomes (cognitive and behavioral) in children when compared to children born to mothers without epilepsy and children born to mothers taking other ASMs. Specifically, children exposed to valproic acid during pregnancy may exhibit lower IQ, lower verbal abilities, and have an increased risk of autism spectrum disorder.^[8] Risk of major congenital malformations that exposure to valproic acid may impact is generally complete by 13 weeks of pregnancy.

Limited data is available about the neurodevelopment of children born to patients who take other ASMs during pregnancy.

Topiramate and zonisamide^[9] exposure during pregnancy has been linked to a risk of infants being born small for their gestational age.

ASMs during pregnancy

Research shows that different ASMs are associated with different levels of teratogenic risk. For best outcomes, people with epilepsy need to start planning for pregnancy with their clinician 12 months in advance, as it can take 3–12 months to switch or adjust their ASM if they are on an ASM with a higher level of teratogenic risk.^[2]

When switching ASMs or adjusting dosages, the goal is to identify the lowest effective ASM dosage that will pose the least teratogenic risk to the fetus while maintaining the patient's seizure control.^[12] This transition should start well before pregnancy — for those who will undergo major changes in their ASM regimen, this could be as much as 12 months before the patient attempts to become pregnant.

ASMs and breastfeeding

There is little evidence to suggest that ASM exposure from breast milk has clinical effects on newborns and several studies examined the neurodevelopment of babies exposed to ASMs via breast milk and the results were positive.

• Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) This study found blood concentrations in breastfed infants of mothers taking carbamazepine, oxcarbazepine, valproate, levetiracetam, and topiramate were quite low, especially in relationship to the mother's level and what the fetal level would have been during gestation. (Note: valproic acid is NOT a recommended ASM for patients with epilepsy who are considering having children.)
• Median lamotrigine levels in breastfed infants were 28.9% of the maternal levels.
• Median levetiracetam levels in breastfed infants were 5.3% of maternal levels.
• Neurodevelopmental Effects of Antiepileptic Drugs (NEAD): This study found that neurodevelopmental outcomes by age 6 were better in children who were breastfed compared to those who were not. This was true despite the breastfed children being continuously exposed to VPA, carbamazepine, lamotrigine, or phenytoin while in utero and during breastfeeding.
• Norwegian Mother and Child Cohort Study (MoBa): This study found that infant exposure to newer ASMs (cenobamate, perampanel, brivaracetam, eslicarbazepine, rufinamide, levetiracetam, topiramate, gabapentin, oxcarbazepine, lamotrigine, and vigabatrin) via breastmilk was not associated with negative neurodevelopment (such as lower IQ, autism, and autism spectrum disorder) at 36 months.

Babies of nursing parents who take benzodiazepines, barbiturates, and clobazam should be carefully monitored for wakefulness and growth. More testing is needed to determine the neurodevelopmental effects of these drugs on babies.

When a patient stops breastfeeding their ASM distribution levels may change; it is important to assess and carefully monitor ASM levels before, during, and after pregnancy.