Overview of Epilepsy and Pregnancy

Epilepsy is a condition that can affect people from birth to people over 60 years of age. It causes  repetitive seizures due to the overactive electrical activity that momentarily stops brain function. 

Usually as an individual ages, seizures tend to occur less with less severity and become easier to handle.

Epilepsy can vary per person in intensity making it a spectrum disorder. This also means that symptoms range from mild to severe. Symptoms include:¹

• Seizures 
• Epileptic fits - usually uncontrollable shaking from the surge of electrical activity in the brain 
• Dissociation or staring off into the distance or losing concentration 
• Severe stiffness in muscles 
• Unusual stimuli in the 5 senses (odd taste in the mouth , smells in the nose, tingling sensations in the hand, vision slightly blurred or shaking

Purpose and scope of the article

This article will aim to convey how valproate affects maternal epilepsy. Specifically, how the drug affects the foetus during pregnancy and any associated consequences (both positive and negative.)

Introduction to Valproate and epileptic drugs

Common use of valproate and other drugs in epilepsy treatment

When a healthcare provider first sees signs of epilepsy, they will assess the type of seizures and what type of epilepsy the patient is exhibiting, then the suitable anti-epileptic drug is prescribed to treat the seizures. 

Valproate (also known as Epilim), is prescribed for epileptic seizures. They can be taken in many different forms, 

• Tablet
• Capsule 
• Liquid that is swallowed
• In an emergency situation valproate can be injected

Common side effects to this drug include:

• Stomach pains or nausea
• Gum swellings
• Dry mouth 
• Unusual or uncontrollable shakes or twitches in the body (usually exhibited in the eyelid)
• Fatigue
• Weight gain 
• Changes in hair texture, colour, or thickness

Valproate has the highest number of epileptic users compared to other anti-epileptic drugs; all of these drugs are anti-epileptic because they aim to prevent generalised seizures which most patients suffer from. The special thing about valproate is that it is also used for bipolar disorder too.²

Maternal Epilepsy

Effects of Epilepsy on Pregnancy

Epilepsy during pregnancy means that there are certain risks and factors that are applicable such as:

• Gestational diabetes
• Pre-eclampsia
• Intrauterine growth restriction 
• Placental abruption
• Premature birth or Stillbirths 
• Lower birth rate 
• Preterm labour
• Slow foetal heart rate
• Oxygen deprivation during seizures
• Maternal trauma ( leads to damage to the foetus)

Managing Epilepsy During Pregnancy

Regulating and managing epilepsy and seizures particularly during pregnancy is important because there is a large risk to the foetus. There is a balance that needs to be reached between seizures which need to be controlled and teratogenic (foetal) risks. This is where seizure control is applied.⁵

Importance of seizure control and balancing medication with pregnancy safety

Valproate (as already established) is a common drug used to regulate and manage seizures in epileptic individuals, however, there are gestational risks of taking this drug. There is a 2-3 times higher risk of a child having a birth defect because of women taking valproate when the child is in utero. 

This means that considering seizure control medication with the safety of the pregnancy is a bit harder due to the risks the medications can introduce.³

Different dosages of Valproate affects foetal development to different extent. Generally, it is seen that the higher the dosage of valproate, the higher the teratogenic risk.

To combat this, the lowest effective dosage of any anti-epileptic drug before conception needs to be found and continued during the pregnancy. This way seizures are controlled and there is a decreased risk to the foetus.³

Medication of any kind will pose a risk to the foetus during pregnancy, however, the risk is not significantly increased if the drug concentration is constantly monitored by healthcare professionals and the foetus is closely examined to regulate and maintain the foetus.³

Valproate Use in Pregnancy

Mechanism of Action of Valproate and how it controls seizures

In epilepsy, there is an unnatural surge of electrical activity in the brain, triggering a seizure because many neurons in the brain are overworked. Valproate predominantly works in two ways in the brain to stop seizures during an epileptic fit:⁴

• Valproate counteracts this by stopping activation of neurons by neurotransmitters that cause this surge. This prevents seizures by decreasing neuron electrical activity
• Valproate increases a chemical neurotransmitter in the brain that reduces electrical activity: gamma-aminobutyric acid (GABA.) Valproate stops the enzyme that breaks GABA down thus enhancing the blocking effect

Risks Associated with Valproate Use

There are more severe teratogenic side effects and risks of taking valproate during pregnancy for epilepsy. These include congenital malformations, developmental delays and cognitive impairment.

Statistically, 10% of babies have congenital malformations due to in utero exposure to valproate, but around 2-3% of babies in utero with unmedicated epileptic pregnant mothers are born with malformations.

Children who are born with these disorders or malformations have foetal valproate syndrome (FVS.)⁶ Some commonly seen issues include: 

• Neural tube defects such as Spina bifida
• Cleft lip 
• Cardiovascular abnormalities 
• Genitourinary defects 
• Developmental delay 
• Endocrine disorder 
• Limb defect 

Less common issues include:

• Underdevelopment of the nails, fingers and toes
• Dislocated hip
• Longer and thinner fingers and toes (arachnodactyly)
• First ribcage is missing 
• Penis underside has a urinary opening (hypospadias)
• Abnormally soft trachea (tracheomalacia)
• Club foot

Babies born with FVS have a higher likelihood of having less common disorders. Placental exposure to valproate which then travels into the developing foetus triggers FVS and causes developmental defects (as listed above.)⁶ 

Neurodevelopmental Impact from valproate

Neurodevelopmental risks in utero can progress into disorders or birth defects in the central nervous system (CNS) where the brain and spinal cord are developmentally damaged. 

Children exposed to valproate in utero manifest symptoms of neurodevelopmental conditions ranging in severity. Pre-birth intake of valproate is a large risk factor for developing and worsening these conditions.⁸

These neurodevelopmental disorders include learning and behavioural difficulties such as:

• Developmental delays like learning to walk and talk slower than the average child 
• Decreased IQ levels
• Difficulty articulating forms of communication (talking)
• Difficulty in recall (memory difficulties)

Furthermore, 40% of children exposed to valproate in utero are born with these developmental disorders.

Comparing neurodevelopmental impact from other anti-epileptic drugs on pregnancy and births

As established earlier, valproate is not the only drug available for epilepsy and seizure treatments, other drugs include:

• Lamotrigine
• Carbamazepine
• Topiramate
• Levetiracetam
• Clonazepam
• Oxcarbazepine
• Gabapentin
• Pregabalin

Lamotrigine is the most favourable anti-epileptic drug, because it has the lowest rate of risk for neurodevelopmental risks and more preferred outcomes. However, valproate has a range of less desirable neurodevelopmental outcomes resulting in post birth defects. 

Considering this, unless the mother is more attuned to the side effects of valproate pre-pregnancy, it should never be prescribed and taken as an antiepileptic, anti-migraine, or 

anti-bipolar medication during pregnancy. Long-term intake of valproate prior to pregnancy allows the body to acclimate and reduce harm and risk to the child during pregnancy.

According to professional recommendations from healthcare providers: Lamotrigine is the preferable drug treatment for epilepsy due to the decreased risks in pregnancy and preferred neurodevelopmental outcomes for the child, there should be no reason to alter the medication treatment to lamotrigine if the mother is already adapted to valproate before becoming pregnant.⁷

Regulatory guidelines 

Regulatory guidelines, in the UK dictate that Valproate should never be used or consumed during pregnancy. Furthermore, the medication should not be used to treat migraines or bipolar disorder. ,However, guidelines also emphasised that valproate consumption should not be stopped if the medication works and the individual has had it for a long period of time and it is effective. This is where monitoring the foetal response to it is important.

Monitoring valproate response during pregnancy

Generally, professionals will monitor foetal and maternal health via ultrasound to observe foetal development and maternal organ health. Another important method of measurement is via blood tests from the mother between 15 and 20 weeks of pregnancy to observe maternal serum alpha-fetoprotein. 

• Too high or low levels of fetoprotein indicate neural defects. Fetoprotein, produced from the mother’s liver is transported via the blood to the amniotic fluid which is directly in contact with the developing foetus in the amniotic sac.

Summary 

Valproate controls epileptic fits and seizures, but it has a significant health risk during pregnancy. These risks include congenital malformations and neurodevelopmental disorders in the foetus. Managing this neurological disorder requires a balance between the minimum effective dosage of valproate to prevent seizures as well as maximally reducing pregnancy risks. Alternative anti-epileptic medications such as Lamotrigine is preferable because there are less teratogenic risks. Furthermore, regulatory guidelines in the UK suggest that valproate usage should be avoided at all costs, especially if an individual plans on being pregnant in the future. The only reason to continue valproate during pregnancy is if it has been consumed for a long period of time and the mother is well attuned to the side effects. If this is the case, it is strongly advised to regularly visit a healthcare professional for closely monitoring foetal development and growth.