Introduction

The administration of valproic acid (VPA) medication as a single therapy during the first trimester of pregnancy was linked to teratogenic effects such as neural tube defects (NTDs), cleft lip and palate, cardiovascular abnormalities, genitourinary defects, developmental delay, endocrinological disorders, limb defects, and autism, compared with the risk without the use of antiepileptic drugs (AEDs). This occurs in mothers who take valproic acid as a treatment for epilepsy during pregnancy. Valproic acid or Sodium valproate is an efficacious drug used in the treatment of epilepsy, bipolar disorder and migraines. When an unborn baby is exposed to valproate during the first trimester of pregnancy, it leads to fetal valproate syndrome.¹

Symptoms

• The symptoms may occur at different ages in a single age range or during several age ranges. Major facial characteristics commonly identified in infants exposed to valproate acid include the following 2-3
• A flat nasal bridge 
• An elongated upper lip with a relatively shallow groove above it
• Prominent eye folds merging with an infraorbital crease or groove 
• A thin upper vermilion border, and a small mouth with downturned corners. 
• Limb defects
• Neural tube defects
• Minor musculoskeletal abnormalities
• Congenital heart defects

Other abnormalities associated with FVS include

• Malformed nails of the toes and fingers
• separation of the rectus muscle of the abdominal wall
• softening of the windpipe
• Club foot
• Children are prone to a high chance of developmental problems such as reduced cognitive function, attention deficit disorder, learning difficulties, and communication problems of autism disorder²

Prevalence

In the United Kingdom, it is estimated that over 20,000 children are affected by the spectrum of conditions associated with VPA exposure based on the number of women prescribed VPA during pregnancy and the estimated percentage of those children who develop symptoms. However, the exact figure remains unknown. Despite the widespread use of VPA for treating epilepsy and bipolar disorder over several decades, the number of exposed children at the population level is relatively low. Consequently, clinicians often have limited experience with the condition.

According to the Genetic and Rare Diseases Information Center (GARD), fewer than 50,000 people in the USA have this disease.

Aetiology and pathophysiology

The disease is due to exposure of the unborn baby to valproic acid within the first trimester of pregnancy. Valproic acid crosses the placenta and disrupts the normal development of the fetus, leading to developmental malformations. Additionally, it causes changes in the genetic material (DNA).³

Clinical manifestations of FVS 

There are many cases of fetal valproate syndrome as a result of mothers who took valproic acid during pregnancy for the treatment of epilepsy. The clinical presentations of the FVS in the affected children include the following;

• Speech delay
• Gross motor delay
• Pulmonary stenosis
• Small hand contractures and toe overlapping
• Ventricular septal defect  
• Opening of the urethra on the underside of the penis instead of at the tip (hypospadias)
• Neurodevelopmental difficulties⁴

Diagnosis

There is no diagnostic testing that can identify fetal valproate syndrome; rather, diagnosis is made using the clinical presentations in an infant linked to exposure to valproic acid during pregnancy.

These presentations include:

• Heightened risk of spina bifida following prenatal VPA exposure
• Facial dysmorphism and impaired development 
• Increased neural tube defects 
• Congenital heart disease
• Cleft palate 
• Radial limb defects 
• Eye problems
• Genitourinary malformation
• Groin hernia
• High risk for attention deficit hyperactivity disorder
• Increased risk of autism spectrum disorder
• Overlapping toes 
• Scalp defects⁵

Diagnostic advances

Significant progress is being made in the development of diagnostic tools and techniques for fetal valproate syndrome. These include:

• Innovations in prenatal imaging, such as high-resolution ultrasound and fetal magnetic resonance imaging (MRI) are improving early detection of physical anomalies linked to fetal valproate syndrome
• Advances in genetic screening are helping earlier identification of fetuses at risk for fetal valproate syndrome, potentially allowing for more informed decision-making during pregnancy
• Researchers are focused on discovering biomarkers that could facilitate early diagnosis and monitoring of fetal valproate syndrome⁶

Current research on FVS

Current research in genetics and molecular biology aims to unravel the precise mechanisms of actions by which VPA induces teratogenic effects. These studies include:

• Epigenetic Modifications: VPA alters DNA methylation and histone acetylation, potentially disrupting normal gene expression during fetal development
• Gene Expression Studies: Research explores how VPA affects key developmental genes and identifies altered genetic pathways
• Genetic Susceptibility: Studies aim to identify biomarkers that predict susceptibility to VPA’s teratogenic effects
• Epidemiological Studies: Investigate FVS incidence, prevalence, risk factors, and long-term developmental outcomes to understand disease progression

Therapeutic advances and management

• New strategies for preventing and managing FVS are being developed and implemented. These involve
• Preventive measures like guidelines for the use of VPA in women of childbearing age are being refined to reduce the risk of FVS 
• Microarray analysis and Fragile X studies should be undertaken, and other syndromic diagnoses suggested by history and clinical findings should be ruled out 
• Folic acid should be taken from 2 to 3 months before conception and continued until 12 weeks.
• Ultrasound scans should be carried out at around 13 and 20 weeks, depending on the country
• Medical treatments to mitigate the effects of FVS are ongoing, with some studies bioprospecting the use of antioxidants and other neuroprotective agents
• Supportive therapies involving behavioural interventions and educational programs are aimed at enhancing the quality of life for individuals affected by FVS²

Ethical and social considerations

Current research further addresses the ethical and social implications of FVS. These include 

The significant role of informed consent and patient education for women taking VPA, spotlighting the need for comprehensive counselling on the risks of VPA during pregnancy. Possible genetic causes for the mother’s seizures should be considered and investigated if appropriate. Research is ongoing to examine the broader social impact of FVS, including the stigma associated with the condition and the importance of social support for affected families.⁷

Future directions in FVS research

In prospect, several emerging areas of research hold potential for advancing the understanding and management of FVS, such as:

• Personalized medicine: Advances in genomics and personalized medicine may lead to individualized risk assessments and tailored therapeutic approaches for women who require VPA treatment.
• Collaborative research: International collaborations and enough funding for FVS research are essential for making significant strides in understanding and addressing this disease condition.
• Innovative therapies: Ongoing research into novel therapeutic modalities, including gene therapy and stem cell therapy, could potentially offer new treatments for FVS in the future. 

Summary

Fetal Valproate Spectrum Disorder (FVSD) is caused by in utero exposure to valproic acid, leading to malformations such as clubfoot, speech delays, and heart defects. Affected children may face cognitive and developmental challenges. Current research aims to improve diagnostics, preventive measures, and therapies, emphasizing informed consent and social support. Progressive and continued research is paramount for improving our understanding of Fetal valproate syndrome and developing effective strategies to prevent and manage this condition. As we key into in-depth research, our knowledge grows and the potential for better desired therapeutic results for affected individuals and their families.