Overview

Fetal valproate syndrome (FVS) is a condition that arises in unborn babies when the mother is exposed to valproic acid or sodium valproate in the first trimester of pregnancy, which are components of drugs used to treat migraines, seizures and bipolar disorder. This exposure leads to congenital malformations in the child, such as abnormal and characteristic facial features and skeletal abnormalities.¹ Other than these, neurodevelopmental abnormalities lead to cognitive and social impairments during the child’s growth. In this article, essential information regarding fetal valproate syndrome will be discussed, as well as the evidence of a link between the syndrome and autism spectrum disorder.

Causes

Fetal valproate syndrome is a neurodevelopmental syndrome which arises when the unborn child in the womb is exposed to valproic acid or sodium valproate, which is a compound that the child’s mother could be in contact with, as it is an active ingredient in some anticonvulsants, so as antiepileptic drugs, and drugs are given to people with migraine, bipolar disorder and other mental health issues.² After April 2018, the Pharmacovigilance Committee of the European Medicines Agency allows prescribing sodium valproate only to pregnant women who are epileptic and do not respond to other treatments, in order to protect the mother’s well-being.² The risk of congenital malformation in the unborn child in case of exposure to sodium valproate is around 11%, however this percentage reaches 24% in case the prescription is of a higher dose.² 

In terms of diagnosis of the syndrome in children, although the widespread use of sodium valproate to treat bipolar disorder and epilepsy, the syndrome is a quite rare condition that affects a small number of babies; therefore it cannot be seen often by clinicians, and therefore its diagnosis is not fully standardised.² This said the major signs of fetal valproate syndrome involve facial and skeletal abnormalities, as well as cognitive and social impairment later in life.

Skeletal abnormalities that appear during the diagnosis of FVS include spinal defects, like spina bifida, neural tube defects, congenital heart abnormalities or genitourinary abnormalities.² Other minor abnormalities include inguinal hernia, scalp defects, or overlapping toes.² The facial characteristics are: short and broad nasal bridge, which leads to forward-facing nostrils, small and thin mouth and lips and peculiar eyebrows.² 

The neurodevelopmental consequences, other than the congenital physical defects, lead to a range of different cognitive symptoms, which have been either related to ADHD (Attention deficit hyperactivity disorder) or ASD (Autism spectrum disorder).² 

It is important to notice that fetal valproate syndrome can be diagnosed by its cognitive symptoms, even in the absence of major physical defects.² In fact, lower doses of sodium valproate intake by the mother, while the child is in the womb, correlate to a lower risk of the major physical defects of the syndrome, while the cognitive symptoms can appear more frequently as they arise at lower doses.² At the same time, the major physical defects, lower IQ and higher probability of developing ASD and ADHD symptoms, arise at higher dose levels.² 

It would therefore be of benefit, in the future, to better understand the relation between the major physical defects and the cognitive deficits during the development in the womb and afterwards on the children exposed to sodium valproate.

Treatment and management of the syndrome

Unless major physical defects are present at birth, the neonatal period of infants who were exposed to sodium valproate during the mother’s pregnancy is usually normal.² Sodium valproate, in case the mother starts assuming the drugs containing the compound again, does not pass through the milk in large quantities during breastfeeding, but it is important to discuss with a clinician the situation before starting to take the medicines again.² During childhood years, it is important to check with clinicians the development of the child, to detect the presence of both previously unnoticed physical birth defects, as well as to assess cognitive abilities.²

Syndromes like fetal valproate syndrome, which originates from birth defects, cannot be reversed, but each of the symptoms, both physical and cognitive, can be treated separately.² Some of the physical and congenital symptoms can be treated as soon as they are detected by clinicians, while the cognitive symptoms need to be assessed throughout life.² Especially in the transition between childhood and early adulthood, it is important for practitioners to understand the situation of the cognitive development of the child.²

Following the neuropsychological assessment, often symptoms of ADHD or ASD are diagnosed as cognitive impairments, so the treatments are as the ones for these conditions.² 

We can conclude that the treatment of fetal valproate syndrome is not unique, both because the condition is quite rare, leading to a non-sufficient number of observed cases to standardise a treatment protocol, but more importantly because the range of physical and neurodevelopmental symptoms that can appear can vary through a vast range of symptoms, therefore cases are better assessed on a single-case basis.

Link with autism spectrum disorder

Autism spectrum disorder is a condition which originates from neurodevelopmental impairments and affects the social, communicative and cognitive life of those who are affected.³ Often the disease is found together with other conditions, such as metabolic disorders, neurological abnormalities linked with skin abnormalities, chromosomal abnormalities, and often the mother of the unborn child was exposed to infectious diseases like rubella and meningitis or other teratogenic factors, such as alcohol drinking during pregnancy.³ 

Several case studies are linking sodium valproate exposure to the unborn child to risk the development of autism, as there are reported cases in which the two conditions are diagnosed together.³ Animal studies and autopsies of human brain analysis are able to define correlations between the two conditions in order to define the common developmental pathway of the two conditions to understand them both in a more complete manner.³ However, until now, it is not possible to clearly define the link between the two, and especially to determine the causality in their relationship.³ 

Summary

Fetal valproate syndrome is a life-impairing syndrome that arises to the baby in the womb when the mother is in contact with sodium valproate or valproic acid: these substances are active ingredients in drugs for epilepsy, bipolar disorder and migraines. The administration of these drugs needs, therefore, to be suspended immediately during pregnancy, as they can be harmful to the baby, especially in the first trimester. The suspension of the drugs containing the compound happens in every case where the life of the mother is not threatened, therefore there are some exceptions, such as in cases of epilepsy where the mother does not respond to any other drug. 

If the child is exposed to low doses, around 11% are estimated to develop fetal valproate syndrome, while around 24% develop the syndrome when higher doses are given. 

The symptoms of the syndrome are both physical and neurodevelopmental and include skeletal and facial abnormalities, as well as congenital physical conditions and cognitive impairments that lead to developing ASD and ADHD symptoms and to obtain lower IQ test scores during neuropsychological assessments. The variety of symptoms is vast and each patient exhibits a different range of them. Therefore, treatment is targeted towards the particular symptoms that are detected during the child's development after birth. 

Fetal valproate syndrome is an example of the detrimental effects that exposition towards certain substances during pregnancy: it is therefore recommended to consult a clinician in case one is suspecting or planning a pregnancy while at the same time being prescribed drugs that contain sodium valproate in order to define the best and most safe solution for both the mother’s health and the child’s development. 

Read on: Fetal valproate syndrome and neural tube defects

Why does sodium valproate cause birth defects? The relation between the effects of the substance and its effects is not entirely clearly defined in terms of how neurodevelopment is impacted. 

However, it has been seen that sodium valproate causes low levels of folic acid. This deficiency causes problems in the child’s development in the womb as the neural tube is not able to close properly, causing the spine-related abnormalities and the physical defects that are associated with neural tube closure. The other effects could likely be a consequence of this, or the neurodevelopmental issues could be a separate effect of exposure to the drug. 
The causal link between these two effects needs to be studied in the coming years to best prevent damage in the baby in case of exposure to sodium valproate while in the womb.⁴