Introduction

Antiepileptic drugs (AEDs) are used to manage epilepsy, through the prevention, reduction or treatment of seizures and convulsions by controlling any abnormal electrical activity within the brain. They can also treat conditions such as nerve pain, migraines, fibromyalgia and bipolar disorder.¹ AEDs control seizures in around 70% of people suffering from epilepsy by changing the levels of the chemicals in the brain. Epilepsy can affect people of all ages, but typically starts in childhood or in those over 60 years, meaning the use of AEDs needs to be safe.^2,3 Research has demonstrated that if various types of AEDs are taken during pregnancy, there are increased risks and complications of the child not developing normally.⁴

Teratogenic effects of AEDs

AEDs have chronic and frequent teratogenic effects, which are when something causes an abnormality or defect after fetal exposure during pregnancy and particularly the first half of pregnancy. These effects are typically associated with the type of teratogen, the dose and duration of exposure. Unfortunately, teratogens are usually discovered after there is an increase in a certain birth defect and relationships between the cause and effect are found.⁵ Teratogenic effects can include conditions such as fetal valproate syndrome.⁶

Fetal valproate syndrome (FVS)

FVS is a condition that arises from exposure of a fetus to valproic acid or sodium valproate (VPA) in the first trimester of pregnancy. VPA is a type of AED. It is known that FVS is associated with a greater risk of cognitive and neurological abnormalities than other AEDs, hence it is not recommended for those that are pregnant.^1,6 VPA can be sold under the brand names Belvo, Depakote, Dyzantil, Convulex or Syonell.⁷ VPA has many mechanisms of action that are currently not fully understood, however, a suggested mechanism includes VPA obstructing the entry of sodium ions into neurons in the brain. This would lead to reduced neuron excitability and firing rate, leading to the prevention of abnormal electrical impulses and activities that are responsible for triggering seizures.⁸

Symptoms of FVS

The development of FVS can include major and minor malformations, which can be a 20x increase in neural tube defects such as cleft lip and palate, limb defects, spina bifida, genitourinary defects, developmental delays, endocrine disorders, autism and cardiovascular abnormalities. Spina bifida is one of the most common defects involving incomplete closure of the spine and occurs when the neural tube does not fuse fully during fetal development. This can lead to the spinal canal or parts of it protruding through the bifida cystica. Depending on the severity of the protrusion, both physical and neurological complications may occur. FVS can also cause certain distinctive facial features, including having a vertical fold of skin on the sides of the nose, a small mouth, and a small or upturned nose with a flat bridge. Other physical abnormalities and defects can include underdeveloped fingers and toenails, long and thin fingers, overlapping fingers or toes, softening of the windpipe and dislocation of the hip. Children who have FVS are more likely to develop problems such as attention deficit disorder, reduced cognitive function and autism.⁶

Risk factors of FVS

If an individual with epilepsy wishes to to have children, VPA should be avoided and substituted with a different or newer antiepileptic medicine. Despite this recommendation of avoidance, there are some instances when VPA is necessary. There is research to show there are dose-dependent risks of fetal abnormalities that arise from prenatal VPA exposure. Higher doses of VPA are shown to be associated with a greater risk of developing abnormalities when compared to a lower dose. VPA when combined with other AEDs may also increase the chances of developing fetal abnormalities and defects.⁶

Prevention and management of FVS

To prevent FVS, VPA should not be taken during pregnancy. However, if this is unavoidable, AEDs should be given as a single drug of the lowest dose possible. A healthcare professional should also constantly monitor the amount of the drug administered. It is recommended for someone who is pregnant or wishing to become pregnant to consume folic acid supplements to decrease the risk of abnormalities in their child. There is no direct treatment for FVS but instead is directed towards the various symptoms that arise in the child. This may involve contributions from multiple specialists, including oral surgeons, plastic surgeons, psychologists and paediatricians. Early developmental interventions can benefit a child through improving their speech and physical therapy. Treatment plans may also include measures to improve behavioural motions. Some children with spina bifida do not require surgery andsome do, depending on its severity.. Surgery can prevent the condition from worsening but will not restore the full function of the muscle, as well as having orthopaedic and physical therapy from an early age to prevent contractures from developing.⁶

Other AED syndromes

There are several types of AEDs that are used during epilepsy treatment that can vary in their teratogenic effects and therefore the risks that come with using them. Some other AEDs can include carbamazepine, lamotrigine, levetiracetam and topiramate.² The AED suited to you will depend on the nature of the seizure, age and whether you wish to become pregnant.⁹ Below is a comparison of FVS with various other AED syndromes.

Fetal carbamazepine syndrome (FCS)

FCS arises after the use of carbamazepine during pregnancy; however, case studies have shown it to be less teratogenic than VPA, meaning a child is less likely to develop malformations when compared to VPA exposure. The symptoms that can appear should a child still develop FCS can include congenital anomalies, facial dysmorphisms such as a short nose, full cheeks, a small chin, a small head, and various developmental delays. These are more minor malformations when compared to those associated with VPA use, making it one of the safer drugs to consume to treat seizures in pregnancy. Folic acid supplements can also be used during the use of the AED to further protect the fetus.¹⁰

Fetal hydantoin syndrome (FHS)

FHS affects children who were exposed to phenytoin during the fetal period. Phenytoin is a known teratogen, causing birth defects that are visible straight away and others that are less noticeable until childhood. The former can include malformations affecting the child’s face, fingers, toes and head, including hypertelorism, strabismus, cleft lip, flatter or wider nasal bridge and microcephaly. The latter includes intellectual disabilities and developmental delays, such as difficulties in learning and interacting and reaching developmental milestones later than other children. FHS affects only 5% to 11% of children exposed to phenytoin. This AED is once again less teratogenic than VPA but becomes more likely to contribute to developing abnormalities when used in combination with other antiepileptic medications.⁹

Lamotrigine and levetiracetam

Lamotrigine and levetiracetam are both AEDs that are generally safer options to take during pregnancy than VPA. Neither of these drugs is associated with an increased risk of major congenital malformations. They are also not associated with any increased risks of neurodevelopmental delays or disorders, however, there is limited data on it. Additionally, they have no links to fetal loss or prenatal growth restrictions, making these AEDs a better choice for antiepileptic medication if you wish to become pregnant.¹¹

Why are there symptomatic differences?

FVS has shown more severe symptoms associated with physical malformations and more significant neurodevelopmental disorders than other AED syndromes. As mentioned, the teratogenic effects vary among the AEDs but VPA shows the highest risk of complications in a child.¹² These varying teratogenic effects are linked to variations in the mechanism of action of the drug, as VPA affects the metabolism of folate and histones, but phenytoin affects oxidative stress.^12,13,14

Summary

AEDs are used to treat epilepsy but can pose a risk to the fetus during pregnancy. It is important to balance both the health of the mother and the fetus, as uncontrolled seizures can lead to complications for both individuals. Nevertheless, teratogenic risks to the child can lead to many other issues. A healthcare professional should then select the most suitable AED for the epileptic individual, aiming to optimise the dosage and duration of exposure. Newer AEDs such as lamotrigine and levetiracetam have shown potential in safely balancing these problems, however, there is limited data on long-term complications. VPA shows the largest risk of increasing fetal abnormalities and should therefore be avoided during pregnancy. If you have any questions about what medication is most suitable for you, consult your medical professional to optimise your care throughout your pregnancy.