Limb And Digit Malformations In Foetal Valproate Syndrome

Overview

Foetal Valproate Syndrome (FVS) is a condition that occurs in a developing baby when it is exposed to valproic acid during pregnancy.¹ Valproic acid is a medication often prescribed for epilepsy and some psychiatric conditions.² During pregnancy, it can cross the placental membrane and reach the foetus, causing issues during development. The risk is especially high during the first trimester, a critical period when the organ templates are forming.² This exposure can lead to a range of serious birth defects and developmental issues. One of the most concerning effects is the potential for limb and digit malformations, such as underdeveloped or missing fingers and toes, or deformities in the arms and legs.² These physical challenges can cause serious motor difficulties, potentially resulting in long-term emotional and social difficulties. Research exploring the connection between valproic acid and these birth defects is being undertaken with clinical trials too, thus helping physicians to make informed decisions and to advise during or prior to pregnancy while taking this medication.² The following article will dive into the deformities caused by FVS, focusing specifically on the causes of limb and digit issues in FVS and how they can be treated.

Causes

FVS is caused when the developing foetus is exposed to valproic acid during pregnancy. Due to its molecular makeup, this antiepileptic drug can cross the placental membrane, thereby disrupting normal organogenesis in the foetus.² There are a number of ways it can do this, which we will now explore in more detail.

Firstly, it inhibits special enzymes called histone deacetylases (HDACs). Our DNA is wrapped around histone proteins, which allows it to coil up tightly in our cells, with methylation and acetylation controlling how tightly the DNA is wrapped. Looser wrapping allows specific genes to be exposed and copied into proteins that can affect cellular function and differentiation. By inhibiting HDACs, valproic acid can affect gene expression, interfering with tissue formation and cellular differentiation, thus resulting in birth defects.³

Another serious impact of valproic acid during pregnancy is its impact on folate. Folate, a crucial B-vitamin, plays a key role in creating new DNA, which is essential throughout pregnancy as the baby grows. However, valproic acid interferes with this process by interacting with the vital enzyme called methylenetetrahydrofolate reductase (MTHFR).⁴ This enzyme controls the transformation of folic acid from the nucleotide-use form into the epigenetic-modification form. Overactivation of this in FVS can lead to a lack of folate available for DNA.⁴ This shortage might cause serious problems with the baby's nervous system growth, DNA synthesis and control of gene expression.⁴

An additional cause of birth defects during pregnancy is the generation of reactive oxygen species (ROS) when the valproic acid is metabolised in the mother’s liver by cytochrome p450 enzymes.⁵ These ROS are very reactive, and as they circulate they are capable of causing DNA damage in lots of cells. These ROS circulate in the mother’s bloodstream, and due to the increased perfusion to the uterus during pregnancy, they can damage the placental membrane.⁵ Consequently, harmful substances can pass through the placenta and to the foetus, including the ROS, which can go on to cause DNA damage to the child’s organs, thus multiplying malformations by disrupting development.

Ultimately, these mechanisms all contribute to the spectrum of congenital defects seen in FVS, highlighting the importance of careful management of your medical conditions during pregnancy.

Symptoms

Foetal Valproate Syndrome (FVS) presents a range of symptoms that can affect a child's development and well-being, manifesting through both physical and cognitive challenges. These include:^1,6,7

Craniofacial abnormalities

• Children with FVS may have distinct facial features, including a smaller head size (microcephaly), a broad nasal bridge, and a thin upper lip. These features are often evident at birth and may become more pronounced as the child ages

Limb and digit deformities

Limb and digit deformities are particularly concerning in FVS, and their severity can vary.

• Brachydactyly: This condition involves abnormally short fingers or toes, which can affect the child’s ability to grasp objects or maintain balance
• Syndactyly: In this condition, two or more fingers or toes are fused together, which can limit movement and make it challenging to perform tasks that require fine motor skills, like writing
• Polydactyly: Some children with FVS may be born with extra fingers or toes. These additional digits can be fully formed or appear as small, undeveloped nubs
• Oligodactyly: This is the presence of fewer than the normal number of fingers or toes, which can significantly impair the function of the hands or feet
• Camptodactyly: Fingers or toes which cannot be completely straightened, which can impact motor skills
• Clinodactyly: Irregularly curved fingers and toes which causes them to bend over one another. This can particularly impact fine motor skills
• Hypoplastic fingernails: The nails on the hands or the feet may be completely absent, or they may be smaller than expected, not covering the entire nail bed
• Radial Club Hand: Where the radial bone is missing or underdeveloped, causing the entire developed hand to bend in at an extreme angle towards the body in one or both hands

Developmental delays

• Children with FVS may struggle with speech and language development, motor skills, and learning. These delays are often recognised between birth and three years of age when developmental milestones are assessed by physicians

Behavioural issues

• Many children with FVS are at an increased risk for behavioural problems, including attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). These issues can affect social interactions, focus, and learning

Congenital heart defects

• Some children with FVS are born with heart defects that vary in severity. These defects may require surgical intervention or ongoing medical care to manage

Neural tube defects

• FVS can lead to neural tube defects such as spina bifida, where the spine does not form properly. This condition can result in varying degrees of physical and neurological impairment and often requires surgery and long-term medical care

Dose dependence

The main reason why FVS occurs is because valproate continues to be prescribed for its efficacy against seizures and mood disorders, rendering it vital for those suffering from various epileptic and bipolar disorders. Due to its high efficacy, it can sometimes be preferable to other medications, which may not meet the needs of the mother, which is why it is still prescribed during pregnancy in some cases.² However, it’s important to do your research and make informed decisions about your care, especially as this can also increase your chance of a miscarriage. Medications such as lamotrigine or levetiracetam are commonly considered for their decreased mutation potential during foetal development.

Research has also demonstrated that higher dosages of valproate often result in greater congenital malformations.² For example, one study showed that mothers taking daily valproate at doses higher than 1000mg had children with limb and finger defects, whereas those who were exposed to smaller amounts saw fewer defects of lower severity.²

Other studies have also confirmed this dose-dependent relationship. Some research declares that taking valproate during pregnancy increases the risk of defects seen in FVS by 20-fold, whereas other studies have seen that taking 700mg daily decreases the risk of congenital malformation by 25% more than those seen in mothers ingesting 1500mg/day.¹ This research underscores the need for healthcare physicians to carefully monitor the mother’s need for valproate during pregnancy, replacing it where possible or minimising the dose required to aid the likelihood of a healthy child being born. In addition to minimising the dose, folic acid supplements should also be prescribed to help buffer against the effects of valproate on foetal folate availability. Regular checkups and a personalised approach to treatment are crucial to balancing seizure control with the health of the developing foetus.

Treatments

While there is no cure for Foetal Valproate Syndrome (FVS), various interventions can help manage symptoms and improve a child's quality of life.²

Physical therapy

This can improve gross and fine motor skills in children, thus enabling children to carry out daily tasks to strengthen their muscles, despite a range of different limb defects which may span the nervous and skeletal system.

Speech therapy

This can improve children’s ability to communicate with others around them, in spite of any neurological or physical craniofacial issues.

Special educational needs programs

This can provide children with cognitive impairment with the extra support they require to help them catch up on both their education, social skills and ability to carry out daily tasks.

Medications

Medications may be prescribed to manage conditions like seizures, ADHD, or mood disorders.

Surgical options

In some cases, surgery may be needed to correct limb and digit deformities. This could include procedures to separate fused fingers (syndactyly), remove extra digits (polydactyly), or reconstruct malformed limbs.

Summary

FVS is a condition resulting from exposure to valproic acid during pregnancy, primarily used to treat epilepsy and mood disorders. This exposure can lead to a range of physical and developmental issues, including limb and digit malformations, such as shortened or fused fingers and toes, and broader craniofacial abnormalities. Additionally, children with FVS may experience developmental delays, learning disabilities, and behavioural challenges. The severity of these symptoms often correlates with the dosage of valproate taken during pregnancy, with higher doses posing greater risks. Management of FVS involves early intervention through therapies, possible surgical correction of physical deformities, special education, and behavioural therapy. Ongoing monitoring and support are crucial to address the diverse needs of affected children and enhance their quality of life.