Overview 

Foetal valproate syndrome (FVS) is a rare condition caused by exposure of the unborn baby to valproic acid (VPA) or sodium valproate during the first three months of pregnancy (the first trimester). 

There is a significant correlation between abnormalities in some infants who are exposed to VPA without dose dependence and the common facial dysmorphic features and minor skeletal abnormalities. Such abnormalities may occur in cases of both low and high-dose VPA use.¹

Growth challenges 

Clayton-Smith and colleagues found that there is no difference in birth weight when comparing VPA-exposed children to control or unexposed children.³ A prospective cohort presented by Mawer et al. (2002), including 57 infants exposed to VPA monotherapy and 283 controls, did not identify significant differences in height, weight, or head circumference at the age of 6 years.² Regarding older individuals with Foetal Valproate Spectrum Disorder (FVSD), the consensus group has made personal observations that there might be an increase in weight from the time of puberty; therefore, this should continually be monitored along with the provision of dietary and lifestyle advice where needed. There are some reports of early puberty, but this has not been formally investigated.³

Neurodevelopmental disorders

A study by Bluett-Duncan and colleagues characterised the neurodevelopmental phenotype of older children and adults diagnosed with FVSD. Caregivers reported high levels of cognitive impairment, neurodevelopmental disorders, utilisation of services, and sensory difficulties. It was also reported that individuals with FVSD had more academic difficulties than non-VPA-exposed individuals, and higher levels of psychosocial challenges, including internalising and attention problems, but not externalising problems. Outcomes were not found to be significantly different for older (≥18 years) and younger (<18 years) participants, demonstrating that substantial neurodevelopmental impairment continues throughout adolescence and into adulthood for individuals with a diagnosis of FVSD.⁴

It has also been found that significant sensory difficulties are more prevalent in individuals with FVSD than has been found previously in the general population (80.6% vs 5–16%). This research is the first time this has been reported in the FVSD population. Sensory difficulties can lead to the impairment of the development of adaptive behaviours and have a significant impact on an individual's quality of life through their capacity for participation in education and social activities, thereby potentially limiting employment opportunities.

The prevalence of Autism Spectrum Disorder (ASD) in the group of individuals with a diagnosis of FVSD was found to be extremely high (62.9%). This is approximately 60 times the rate observed in the general population, and higher than the rates reported in populations exposed to FVSD. Similarly, high prevalence rates were reported for patients with intellectual disability, language disorders, sensory processing disorder, specific learning disorder, ADHD, and dyspraxia. There was a higher utilisation rate of specialist services such as speech therapy, occupational therapy and physiotherapy for the group with FVSD, as was the requirement for mental health care and emotional or behavioural therapy.

Scientific literature suggests that children who are exposed to VPA are at higher risk of neurodevelopmental difficulties, but it has also been observed that their rate of neurodevelopmental difficulties is lower than those diagnosed with FVSD. Therefore, it is proposed that a continuum of neurodevelopmental effects is found following valproate exposure, ranging from no observable effect through to severe disruption of neurodevelopmental functioning, with those with FVSD representing the moderate to severe end of the continuum. 

The risk of impaired neurodevelopmental outcomes was not statistically dose-dependent in individuals with a diagnosis of FVSD, with the exception of academic competence. Lower risk has been reported consistently for individuals exposed to <1000 mg/day of VPA for both congenital anomaly and neurodevelopmental risk.⁴

Symptoms

The types of symptoms experienced and the respective intensity may vary among people living with this condition. The symptoms include: 

• Depressed nasal ridge
• Downturned corners of the mouth
• Epicanthus

Nutritional challenges 

Owing to the risk of major congenital malformations, withdrawal symptoms, and poorer cognitive development later in life of the unborn baby, take place. Spina bifida aperta, cardiovascular and urogenital malformations, accompanied by defects in the skeletal system and specific facial malformations, are observed with VPA use during pregnancy. Withdrawal symptoms that can be observed include irritability, jitteriness, tone abnormalities, seizures, and feeding problems. Alternative treatment options for VPA in juvenile myoclonic epilepsy are neither always available nor effective.

For people assigned female at birth without the desire to become pregnant in the near future, VPA treatment can potentially be a very effective treatment option when combined with effective contraception. Untreated epilepsy during pregnancy is known to have an association with higher health risks for women and foetuses. Furthermore, a switch to another anti-epileptic drug may lead to additional risks of major congenital malformations and an elevation in maternal epileptic attacks. 

Stopping VPA before reaching the new steady-state concentrations of the new antiepileptic drug is valid regarding the additional risk for maternal epileptic attacks. If VPA dosages and serum levels are both as low as possible, combined with the clinical assessment of the neurologist, it can be used as a tool for treatment optimisation during pregnancy. This will, therefore, reduce the exposure of the unborn child.⁵

Gastrointestinal problems 

Common issues can involve gastroesophageal reflux disease (GERD), constipation and delayed gastric emptying.

In a study conducted by Ji-Woon Kim and colleagues (2013), the structural defect of mucosa and muscle in the ileum and stomach of the VPA-animal model of autism spectrum disorder (ASD) was reported, which may be linked to the impairment in gastrointestinal (GI) motility in the respective animal model. Although the exact mechanism and relevance between ASD and GI motility could not be identified and verified in the same study, the VPA-animal model may be successful in the provision of versatility for the purpose of an in-depth study of GI-tract issues in ASD.⁶

Management strategies 

A strongly supported system is required because multiple body systems are affected in FVSD. As the signs and symptoms vary with age in the disease, it is important to encompass preconception and prenatal management as well as management of the neonate, child, and adult. 

The management recommendations have been categorised according to the clinical setting and age at which individuals are observed or diagnosed.

Preconception care and advice

The European Medicines Agency endorsed new measures for the prevention of valproate exposure in pregnancy in April 2018. It is recommended that 0.4-5 mg folic acid should be taken daily in doses starting from two to three months before conception and should be continued until 12 weeks of pregnancy. Recommendations for the dose vary widely between countries and societies. The Medicines and Healthcare Regulatory Agency (MHRA) recently issued specific guidance to all women for whom VPA has been prescribed. There is a recommendation of a daily dose of 4-5 mg in case there is a family history of neural tube defects. The evidence of high-dose folic acid in the prevention of VPA teratogenesis is contradictory. It has been suggested by a recent low-power trial of whole pregnancy folate supplementation that it has psychological developmental benefits for children. However, it has been suggested that high doses are not recommended or justified after the first trimester.

Pregnancy

The risk of congenital malformations in VPA-exposed babies in pregnancy is of the order of 10–11% with an increase in the dose, and can be as high as 24%. The European Surveillance of Congenital Anomalies (EUROCAT) antiepileptic study database, gathering data from several congenital malformation registries, has suggested a relative risk for neural tube defects of 12.7. However, Weston et al. (2016) in the Cochrane review on malformations have identified a lower relative risk of around 5.3 from prospective observational studies.⁷

There is an increase in the risk of cardiac malformations by two to three-fold; that for cleft palate malformations is increased five-fold; that for craniosynostosis is six-fold, and that for genitourinary (GU) and hypospadias malformations is five-fold. Regarding limb malformations, more specifically radial ray defects, also show an elevation. These are dose-related effects. 

Considering this increased risk of malformations, it should be specifically sought on a routine detailed anomaly scan at 20 weeks, and the foetal medicine specialist or ultrasonographer carrying out the scan should be made aware of the history of VPA exposure. 

Neonatal period

The majority of VPA-exposed infants during pregnancy will have a normal neonatal period. Though the NEAD study⁸ failed to find any difference in Apgar scores across infants exposed to different antiepileptic drug (AED) monotherapy types, two studies have found approximately a doubling of the risk of having a lower Apgar score in infants exposed to VPA in larger cohorts.^9,10

A dose of 1 mg of Vitamin K is offered in many countries, given intramuscularly, to all infants after birth. Scientific evidence suggests that VPA does not pass through into breast milk in large concentrations. 

Following delivery, recommendations are that the mother should have a chance to meet with an epilepsy specialist nurse who should review her seizure management and provide practical advice on how to care for their baby, as an epileptic new mother, after they are discharged home. At the time of discharge, the paediatrician and the local midwife should be arranged for the baby, along with a health visitor or equivalent, made aware of the need for extra surveillance.³

Other management strategies can involve pediatric surveillance of the infant, preschool surveillance and school-age surveillance.

Summary

Foetal valproate syndrome (FVS) is a rare condition caused by exposure of the unborn baby to valproic acid (VPA) or sodium valproate during the first three months of pregnancy (the first trimester). 

Scientific evidence has not identified significant differences in height, weight or head circumference between VPA-exposed and unexposed infants. They also suffer from neurodevelopmental disorders accompanied by symptoms like a depressed nasal ridge, downturned corners of the mouth and epicanthus.

Nutritional challenges involve gastrointestinal issues, including gastroesophageal reflux disease (GERD), constipation and delayed gastric emptying.

Management strategies can involve preconception care and advice, advice during pregnancy, pediatric surveillance of the infant, pre-school surveillance and school-age surveillance.