Introduction

Valproate also known as valproic acid or sodium valproate is a first-line agent in the treatment of seizures. It has also found its use in the management of bipolar disorders and the prevention of migraine. It was first approved by the Food and Drug Association(FDA) for the treatment of seizures in 1978. 

However, there is a drawback to its use in women of childbearing age. This is because when babies are exposed to valproate before birth, there is an increased risk of developing major congenital malformations. This could range from major organ abnormalities to cognitive dysfunction. Because of this, restrictions have been put on its use in girls and women of childbearing age. Therefore, there is a need to have an alternative for women with these conditions.

How does valproate work?

Valproate works through a variety of mechanisms.¹ These include:

Inhibition of voltage-gated channels in neurons

The inhibition of the channels leads to the reduction of sodium entry into the cells, thereby leading to reduced excitability and firing rate. This prevents the transmission of abnormal impulses in the nerves.

Inhibition of gamma-aminobutyric acid (GABA) transaminase

GABA is an important inhibitory transmitter in the brain. The GABA transaminase is responsible for degrading GABA. When the enzyme is inhibited, it increases the level and the inhibitory activity of  GABA on the nerves.

Increased GABA synthesis

The drug stimulates the synthesis of GABA by enhancing the conversion of Glutamate, another neurotransmitter into GABA.

Inhibition of HDACs

The drug inhibits Histone Deacetylase(HDAC) enzymes in the brain. These enzymes are involved in gene expression. This process causes the transcription of genes responsible for the protection, transmission and formation of nerves. This transcription has been suggested as one of the possible mechanisms for the development of congenital anomalies.

Modulation of calcium channels

Valproic acid inhibits calcium channels through complex mechanisms. These are channels that help in nerve signalling, the release of neurotransmitters and cell survival. 

Risks of valproate in childbearing-age women

Valproate can cross the placenta and can cause damage to the unborn baby(teratogenesis). ² The risk is greatest in the first trimester of pregnancy.

However, the exact mechanism of teratogenesis is not known. Some of the suggested mechanisms include:

• Folic acid deficiency through the inhibition of the enzyme methylene-tetrahydrofolate reductase, which is involved in folic acid production
• Increased free oxygen radicals 
• DNA transcription through the inhibition of Histone Deacetylase(HDAC) enzymes in the brain

This leads to a condition known as fetal valproate syndrome.³ The syndrome is characterised by:

• Major birth defects in the brain and spinal cord eg-Spina bifida and anencephaly. The risk is up to 7-10 times the baseline risk in the general population^1,4
• Other malformations are in the face, skeleton(limbs), heart, blood vessels, and genitals. The affected babies have a distinctive facial feature marked by a vertical fold of skin on either side of the nose (epicanthal folds) and a small flat, upturned nose. It is also characterised by a small mouth(microstomia) with a thin, upper lip and minor abnormalities in the ears
• Developmental disorders like cognitive impairment, behavioural disorders and autism

Valproate has other effects on the baby that are not directly related to malformations(non-teratogenic effects)

These include:

• Growth restriction
• Liver toxicity
• Abnormal heart rate of the baby in labour(fetal distress)

It can excreted in breastmilk leading to drowsiness, irritability, poor feeding, weight loss, low platelet count, or liver damage in breastfed infants. This is more common in infants less than 2 months.

Because of the risk of major congenital abnormalities with the use of valproate, the use of the drug has been restricted in women of childbearing age by some regulatory bodies like the French National Agency for the Safety of Medicines and Health Products and the United Kingdom(UK) Medicines and Healthcare Devices Regulatory Agency.⁴ 

Alternatives to valproate in women of childbearing age

Considering the risks associated with valproate, it is important for women of childbearing age who have epilepsy or bipolar disease to have alternatives. While some of these alternatives can be used to manage both epilepsy and bipolar, others can only manage either disease.

This section of the article discusses the use of the first-line medications( lamotrigine and levetiracetam) as well as some second-line medications.

First-line medications

The World Health Organization(WHO) recommends lamotrigine and levetiracetam as the first-line treatment for epilepsy in women of childbearing potential.

Lamotrigine

Efficacy

Lamotrigine functions by inhibiting voltage-gated channels thereby stabilizing the membranes of the nerves and inhibiting glutamate and aspartate increase.⁵

Evidence shows that lamotrigine and valproate are both effective in the control of seizures. Valproate, however, is more efficacious than lamotrigine but with more risks to the unborn baby.⁶ 

Lamotrigine is also approved for the treatment of bipolar disorders.

Safety profile in pregnancy

Lamotrigine is not associated with any major malformation in the baby. Though animal studies have demonstrated some effects, human studies have not shown any effect. It is categorised as Pregnancy class C.⁵ 

Data on thousands of exposed babies shows a malformation rate that is not greater than what is obtainable in the general population.² 

Levetiracetam

Efficacy

The mechanism of action of levetiracetam is unclear. It is believed to exert its action by modulating the action of pre-synaptic vesicle protein 2A. This inhibits neurotransmitter release. 

A study done in Iran that compared valproate and levitiracetam showed similar efficacy in the treatment of generalised seizures and juvenile epilepsy. Evidence shows that it is also effective as an adjunctive treatment for Bipolar disorders.

Safety profile in pregnancy

Children exposed to levetiracetam during pregnancy have a comparable rate of major malformations to unexposed children.^2,7 

There is limited data on the effect on cognitive function. The effect of levetiracetam is not dose-dependent and an insignificant amount is excreted in breastmilk.

Second-line medications

Some of the second-line medications have been associated with some abnormalities, though less than what is obtainable with valproate use. In some others, there is limited exposure data to arrive at substantial conclusions.

Since some of the alternatives are not altogether risk-free in pregnancy, The WHO recommends that women with epilepsy should have seizures controlled as much as possible with the minimum dose of anti-seizure medication, taken in monotherapy(as a single drug), whenever possible.

This recommendation also applies to the first-line medications.

These medications are: Carbamazepine

Carbamazepine is a first-line antiseizure drug that has been in use since the 1960s. It works by the blockage of the sodium channels in the nerve cells.

Efficacy

The results from a study showed that carbamazepine was as effective as valproate in the treatment of generalised seizures, though it may be better in the treatment of partial seizures. Carbamazepine is also FDA-approved for the treatment of bipolar disorders.

Safety profile in pregnancy

Studies show a dose-dependent increase in major malformations for exposed children and also an increase in minor malformations.

Cleft lips and palate and facial malformations were the most commonly associated malformations, though the difference between the exposed and unexposed babies was not significant. 

The drug may also cause an increased risk of maldevelopment of the brain and spinal cord(neural tube defect)  No significant cognitive deficit was reported in most studies.

Clobazam

Clobazam exerts its effects by partial inhibition of the GABA receptors, It is used for the adjunctive treatment of refractory seizures.

Efficacy

 Evidence shows that it is effective when used as an add-on after treatment failure with other anti-seizure medications. A study that evaluated the efficacy of clobazam as an add-on therapy in patients not responding to valproate showed that it was effective in reducing seizures.

Safety profile in pregnancy

Clobazam crosses the placenta but has not been linked to any major malformation. However, exposure to clobazam was found to be associated with restriction of growth and preterm delivery.

Clonazepam

Efficacy

Clonazepam is a benzodiazepine that acts by increasing the activity of GABA receptors. It is used in the treatment of many from of epileptic disease and seizures in adults. It is also used to treat mania and panic disorders. 

Safety profile in pregnancy

There is limited data on exposure in pregnancy. Exposure was found to be associated with a significantly increased risk of hypospadias, though there is limited data on other outcomes.⁸ Some other reports have also shown no increase in the risk of malformations. Use of clonazepam later in pregnancy can lead to withdrawal symptoms in the baby. 

Lithium

Lithium carbonate is a drug that is effective as a first-line treatment for bipolar and manic disorders.

Efficacy

Lithium carbonate is a mood-stabilizing agent and has been effective in the treatment of manic disorders since the 19th century.

The mechanism of action is not fully known but it is speculated to cause the depletion of inositol.

Safety in pregnancy

The association between lithium and malformations is still unclear. There are conflicting reports in the literature, though the drug has been linked to some cardiovascular disorders, notably Ebstein anomaly.⁹  Pregnancy in women on lithium should be closely monitored and this involves the monitoring of lithium levels in the blood.

Ethosuximide

Ethosuximide belongs to the class of drugs called succinimides.

Efficacy

It is indicated for the treatment of absence seizures. It works by blocking calcium channels in nerves.

Safety profile in pregnancy

There is limited data on exposure. Evidence from the available data however shows a higher risk of club foot and cleft lip/palate than in the unexposed group

Oxcarbazepine

Efficacy

Oxcarbazepine is a derivative of carbamazepine that is effective in the treatment of partial seizures. It functions by blocking the sodium channels and increasing the release of glutamate.

Safety profile in pregnancy

Animal studies found that it may be associated with an increased risk of birth defects. Evidence from humans shows that the reported incidence of major malformation was not higher than in patients exposed to low-dose lamotrigine and in the unexposed population.

There is no reported decline in cognitive development.

Phenobarbital

Efficacy

Phenobarbital belongs to the class of drugs called barbiturates. It acts on chloride channels to maintain them open, thereby stabilising them.  It is indicated for the treatment of epilepsy.

Safety in pregnancy

Evidence shows a higher risk of major malformations in babies compared to babies of women without epilepsy and those exposed to Lamotrigine. Levericetam and Gabapectin. However, no significant risk was shown when compared to those with untreated epilepsy. It is regarded as a pregnancy category D drug. The drug should be used when the benefits outweigh the risks.

Phenytoin

Efficacy

Phenytoin has been in use as an antiseizure drug since the 1930’s. It also works by blocking the Sodium channels. Evidence from a study shows that phenytoin is comparable to valproate in the treatment of generalised and partial seizures.

Safety profile in pregnancy

It has the highest drug interaction side effect profile when compared with the other medications. This has limited its use in current practice. Fosphenytoin, a prodrug has a better side effect and is used in place of phenytoin, especially in patients with unrelenting seizures.

Phenytoin is associated with a significantly increased risk of cleft palate and club foot. It is associated with the rare disorder, fetal hydrantoin syndrome. Data on cognitive effect is limited. The drug should only be used when the benefits outweigh the risks.

Zonisamide

Efficacy

Zonisamide is a sulfonamide that is used for the management of epilepsy.

It works by blocking the sodium channels

Safety profile in pregnancy

Animal data suggests a risk of malformations in the baby with the use of Zonisamide, Human data are limited but also suggest a risk of malformation and reduced birth weight.

Other second-line medications that can be used for bipolar disorder and epilepsy in women of childbearing age include drugs like olanzapine, quetiapine and gabapectin.

Preconception care and pregnancy management in women on these medications

Preconception care

In the pre-delivery period, women of childbearing age who need to be on any of these medications need to be reviewed by their health practitioner.

The components of the review include:

Counselling

There is a higher risk of congenital malformations in women with epilepsy and this increases with the use of some of these medications. Preconceptual genetic counselling on these risks should be given to the women and their partners.

Review of medications

To reduce the risk of malformations and depending on the clinical state of the patient, the drug regime may need to be modified.

The options include;

• Decreasing polytherapy to monotherapy
• Reducing the dose to the lowest possible dose
• Complete withdrawal of medications, if there has been absence of seizures for 2-5years
• Monitoring of the optimal blood level of the anti-epileptic medications needed to control seizures.

Folic acid supplementation

Folic acid supplementation is needed in all women desirous of conception, but higher doses of up to 5mg are needed in patients with any of these medications.

Care in pregnancy

The care in pregnancy will involve:

• Repeat genetic counselling
• Regular antenatal care visits
• Checking the levels of  antiepileptic drugs monthly
• Screening  for congenital malformations
• Multidisciplinary management

Summary

The need for effective and safe alternatives to valproate in women of childbearing age is paramount due to the significant risks of major malformations in the baby. Lamotrigine and levetiracetam are recommended as first-line treatments by the World Health Organization (WHO) for epilepsy in women of childbearing potential, offering a safer profile compared to valproate. Second-line medications have varying degrees of efficacy and safety and require careful consideration and personalised treatment plans. Women should be adequately counselled on the risks and benefits of each medication.