How can a future parent be certain that what they are doing is best for their future child? Did you know that there are many medications that can harm your unborn child if taken during pregnancy? Such drugs are known as teratogens, and unfortunately, many medications used to treat life-threatening conditions, such as epilepsy, cancer and hypertension, can cause birth defects. One such medication is valproate, an anticonvulsant drug causing the so-called fetal valproate syndrome. In this article, we will delve into the relationship between prenatal valproate exposure and the development of birth defects. By understanding this problem, healthcare providers can minimise the risks associated with valproate and optimise outcomes for both mothers and their children.

What is the use of valproate in pregnancy?

Valproate belongs to a class of medications known as anticonvulsants, i.e. medications used for the treatment of epileptic seizures. The most common form of valproate is sodium valproate, which, in chemical terms, is a sodium salt of valproic acid. Its primary use is in the treatment of epilepsy, more specifically, in complex partial seizures. It is also used for bipolar disorder and migraine prophylaxis.¹ Valproate acts by inhibiting the metabolism of GABA in the brain, which is the primary inhibitory neurotransmitter. By increasing the levels of GABA, valproate suppresses the excitatory stimuli in the brain, preventing the onset of epileptic seizures. A second possible mechanism by which valproate might act is the direct inhibition of excitatory sodium channels in neurons.²

The human body may react to pregnancy in different ways. In some cases, women with epilepsy experience an increase in epileptic seizures after getting pregnant.³ Epileptic seizures are associated with a higher risk of birth complications and the need for surgical intervention (Caesarean section).⁴ In some cases, epilepsy in pregnant women can be a symptom of an underlying condition known as eclampsia, which is life-threatening for both the baby and the mother. Eclampsia is usually preceded by pre-eclampsia, which is characterised by hypertension, protein in the urine, and changes in complete blood count.⁵

Fetal valproate syndrome

Fetal valproate syndrome, also known as fetal valproate spectrum disorder, is a spectrum of physical and cognitive birth defects caused by prenatal exposure to valproate. Fetal valproate syndrome is considered a rare disorder, even in children born from mothers taking valproate, however, the exact prevalence remains unknown.⁶ Symptoms include:

Neural tube defects

The neural tube is a precursor to the central nervous system in the developing fetus. Failure of the neural tube to close properly can lead to neural tube defects such as spina bifida and encephalocele - sac-like protrusions of the spinal cord and brain, respectively.⁷ Valproate can cause neural tube defects by interfering with folate (folic acid) transport and bioactivation⁸ and possibly by preventing the binding of folate to its receptors in the neural tube.⁹ Additional supplementation with folate in pregnant women on valproate has not been shown to prevent the development of neural tube defects.

Craniofacial abnormalities

Children born with fetal valproate syndrome might have a degree of abnormal facial features affecting the nose, mouth, forehead, and ears.¹⁰

Limb abnormalities

Valproate can cause a range of limb abnormalities, such as missing bones leading to limbs bending abnormally inwards - a condition known as postural talipes.¹¹

Heart defects

Children with fetal valproate syndrome might be born with a congenital ventricular septal defect, i.e. a hole in the wall separating the heart’s ventricles, which leads to chronic fatigue, abnormal heart rate and breathing problems that worsen with age.⁶

Cognitive impairments

In utero exposure of children to valproate has shown to cause brain development retardation and cognitive impairment. Fetal valproate syndrome is associated with a higher risk for the development of autism spectrum disorders and attention deficit disorders.¹² A study shows that almost half of children with fetal exposure to valproate have ADHD.¹³

Facial abnormalities in fetal valproate syndrome

A child with fetal valproate syndrome may present with a mixture of the following craniofacial features:

Disorders of the forehead

• Tall¹⁰ and/or broad forehead¹⁴
• Trigonocephaly - a triangular forehead caused by the premature closure of the metopic suture that separates the two frontal bones at birth^10,15
• Thin arched or deficient eyebrows⁶

Disorders of the eyes and vision

• A prominent infraorbital groove¹⁶
• Epicanthic folds - skin folds on the upper eyelids covering the inner corner of the eye⁶
• Nystagmus - rapid, uncontrollable eye movements¹⁷
• Vision problems such as refractive error, lazy eyes, and strabismus (crossed eyes)¹⁸
• Cataracts - opacification of the eye lens, which over time leads to vision loss progressing from cloudy eyesight to complete blindness¹⁹

Disorders of the mouth

• Cleft lip and/or cleft palate - a split opening respectively of the upper lip and of the hard palate (the mouth root) caused by incomplete tissue fusion during fetal development. People with cleft palate might be missing some teeth and might experience some degree of speech impairment and poor feeding²⁰
• Crooked mouth angles
• Thin and/or long upper lip
• Thick lower lip
• Shallow philtrum - the groove between the nose and the upper lip’s border⁶

Disorders of the nose and ears

• Flat nasal bridge
• Small upturned nose with clearly visible nostrils when viewed from the front
• Broad nasal base^16,17
• Low-set ears - the ears are positioned lower than normal¹⁴

How to prevent fetal valproate syndrome?

Teratogenic risk counseling

Healthcare providers that prescribe valproate should perform active counselling with women on the teratogenic potential of the medication with all potential consequences for their reproductive health. Effective contraception should be recommended to girls and women of child-bearing age taking valproate. Effective contraception methods include abstinence from intercourse, condoms, birth control pills, intrauterine devices, and implants. If a girl or woman taking valproate has any suspicion of pregnancy, she should immediately consult with her physician about the potential reproductive health risk.²¹

Pregnancy monitoring

An 18-20-week (second trimester) obstetric ultrasound scan, also known as the morphology scan, is commonly performed on pregnant women to assess the morphological features of the developing fetus and exclude any abnormalities by using high-definition, three-dimensional ultrasound.²² In case of suspected developmental defects, a second ultrasound scan in the third trimester can be performed to visualise malformations of the facial features. This method can be used to diagnose teratogenicity in fetuses exposed to valproate before birth.²³

Alternative medication options

All convulsants are generally considered to be teratogenic to some degree. The development of safe anticonvulsants that can be taken throughout a full-term pregnancy is still a challenge. Does this mean that pregnant women with epilepsy should choose between one poison and another? Actually, even though all anticonvulsants have been proven to interfere with normal fetal development, some of them are actually considered safer than others. Specifically, two anticonvulsants, lamotrigine and levetiracetam, are not associated with major developmental disorders of the fetus and are recommended over other medications for epilepsy in pregnant women.²⁴ In some cases, epileptic seizures are so severe that they don’t respond to other anticonvulsants. Despite there being strong evidence for severe congenital malformations in some children exposed in utero to valproate, the devastating consequences of severe epileptic seizures towards both the baby and the mother justify the use of this medication in some specific cases after weighing the benefits and potential risks.²⁵

Other teratogenic risk management measures

Fetal development is not consistent throughout all stages of pregnancy. This is a dynamic process, and different organs develop more rapidly than others during specific periods. The most important period in fetal development is the first 12 gestational weeks (first trimester), as that is when the major organs begin to form. The first organ traces of the neural tube, heart, facial features, and limbs (organs affected in fetal valproate syndrome) form between weeks 3 and 8. This is a critical period for the baby, and its organs are highly susceptible to the disruptive actions of teratogens.

Since body parts have more or less formed completely in the second and third trimesters and are only growing and maturing from there on, the risk of birth defects when taking valproate during this period is much lower.²⁶ If possible, valproate should be avoided during the first trimester or at least the first 8 weeks to minimise its teratogenic potential.

Summary

Fetal valproate syndrome is a severe congenital disorder that affects the quality of life in affected individuals. Active prenatal counselling, use of effective contraception, optimising the treatment regimen of every pregnant woman specifically, and close monitoring of the developing fetus are crucial strategies for mitigating the risk of fetal valproate syndrome and protecting the health of both mothers and their children.