Fetal valproate spectrum disorder

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Fetal valproate spectrum disorder
Other namesFetal valproate syndrome (FVS), fetal valproic acid syndrome, valproic acid embryopathy
Facial Features Associated With Valproate Exposure at Different Ages.webp
Facial features associated with valproate exposure at different ages
Specialty Medical genetics, pediatrics
Symptoms Neural tube defects, distinctive facial features, congenital heart defects, limb abnormalities, developmental delays, autism spectrum disorder [1] [2] [3]
Complications Intellectual disability, cognitive impairments, physical disabilities
Usual onsetPrenatal
DurationLifelong
CausesPrenatal exposure to valproic acid (VPA)
Diagnostic method Based on clinical features, history of VPA exposure, diagnostic imaging, genetic counseling
Differential diagnosis Other antiepileptic drug-related fetopathies, fetal alcohol spectrum disorder
PreventionAvoiding valproic acid during pregnancy, using alternative medications, folic acid supplementation
TreatmentMultidisciplinary management including regular monitoring, early intervention therapies, surgical correction of anomalies, supportive therapies
Prognosis Variable; depends on severity and type of anomalies
FrequencyRare; exact prevalence unknown, fewer than 50,000 cases in the U.S. [1]
Minor limb malformations seen after valproate exposure Minor Limb Malformations Seen After Valproate Exposure.webp
Minor limb malformations seen after valproate exposure

Fetal valproate spectrum disorder (FVSD), previously known as fetal valproate syndrome (FVS), is a rare disease caused by prenatal exposure to valproic acid (VPA), a medication commonly used to treat epilepsy, bipolar disorder, and migraines. This exposure can lead to a range of neurodevelopmental and physical symptoms, including cognitive impairments, developmental delays, autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), and congenital malformations. [1] [2] [3]

Contents

Overview

Valproate causes birth defects; [4] exposure during pregnancy is associated with about three times as many major abnormalities as usual, mainly spina bifida with the risks being related to the strength of medication used and use of more than one drug. [5] [6] " Fetal Valproate Syndrome " (FVS) has been used to refer to the effects of valproate exposure in utero. [7] However, similar to the discussion about the adverse effect of exposure to alcohol in utero (" fetal alcohol spectrum disorder "), a 2019 study proposed the term " Fetal valproate spectrum disorder " (FVSD) because valproate exposure can lead to a wide range of possible presentations, which can be influenced by various factors (including dosage and timing of exposure). The dysmorphic features associated with VPA exposure can be subtle and age-dependent, making it challenging to designate individuals as having the characteristic dysmorphism or not, especially for those with limited expertise in the area. While the presence of typical facial dysmorphism is suggestive of the condition, it is not required for diagnosis. This change in terminology to FVSD would benefit individuals affected by the neurodevelopmental effects of VPA exposure without significant malformations, since they can experience impairments in their everyday functioning similar to those with classical FVS. [8] Characteristics of valproate syndrome may include facial features that tend to evolve with age, including a triangle-shaped forehead, tall forehead with bifrontal narrowing, epicanthic folds, medial deficiency of eyebrows, flat nasal bridge, broad nasal root, anteverted nares, shallow philtrum, long upper lip and thin vermillion borders, thick lower lip and small downturned mouth. [9] While developmental delay is usually associated with altered physical characteristics (dysmorphic features), this is not always the case. [10]

Children of mothers taking valproate during pregnancy are at risk for lower IQs. [11] [12] [13] Maternal valproate use during pregnancy increased the probability of autism in the offspring compared to mothers not taking valproate from 1.5% to 4.4%. [14] A 2005 study found rates of autism among children exposed to sodium valproate before birth in the cohort studied were 8.9%. [15] The normal incidence for autism in the general population in 2018 was estimated at 1 in 44 (2.3%). [16] An updated March 2023 report estimates the number increased to 1 in 36 in 2020 (approximately 4% of boys and 1% of girls). [17] A 2009 study found that the 3-year-old children of pregnant women taking valproate had an IQ nine points lower than that of a well-matched control group. However, further research in older children and adults is needed. [18] [19] [20]

Sodium valproate has been associated with paroxysmal tonic upgaze of childhood, also known as Ouvrier–Billson syndrome, from childhood or fetal exposure. This condition resolved after discontinuing valproate therapy. [21] [22]

Women who intend to become pregnant should switch to a different medication if possible or decrease their dose of valproate. [23] Women who become pregnant while taking valproate should be warned that it causes birth defects and cognitive impairment in the newborn, especially at high doses (although valproate is sometimes the only drug that can control seizures, and seizures in pregnancy could have worse outcomes for the fetus than exposure to valproate). Studies have shown that taking folic acid supplements can reduce the risk of congenital neural tube defects. [24] The use of valproate for migraine or bipolar disorder during pregnancy is contraindicated in the European Union, Australia [25] , New Zealand [26] , the UK [27] and the United States, and the medicines are not recommended for epilepsy during pregnancy unless there is no other effective treatment available. [28]

Paternal exposure

A 2023 retrospective study of Norway, Denmark, and Sweden found a significantly increased risk of neurodevelopmental disabilities in the children of fathers exposed to valproate up to 3 months prior to conception, compared to offspring paternally exposed to lamotrigine/levetiracetam. [29] : 9  This led the EMA to recommend "the need to consider effective contraception, while using valproate and for at least 3 months after treatment discontinuation. Male patients should not donate sperm during treatment and for at least 3 months after treatment discontinuation." [29] : 26 

See also

Related Research Articles

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Valproate are medications primarily used to treat epilepsy and bipolar disorder and prevent migraine headaches. They are useful for the prevention of seizures in those with absence seizures, partial seizures, and generalized seizures. They can be given intravenously or by mouth, and the tablet forms exist in both long- and short-acting formulations.

Anticonvulsants are a diverse group of pharmacological agents used in the treatment of epileptic seizures. Anticonvulsants are also increasingly being used in the treatment of bipolar disorder and borderline personality disorder, since many seem to act as mood stabilizers, and for the treatment of neuropathic pain. Anticonvulsants suppress the excessive rapid firing of neurons during seizures. Anticonvulsants also prevent the spread of the seizure within the brain.

Teratology is the study of abnormalities of physiological development in organisms during their life span. It is a sub-discipline in medical genetics which focuses on the classification of congenital abnormalities in dysmorphology caused by teratogens. Teratogens are substances that may cause non-heritable birth defects via a toxic effect on an embryo or fetus. Defects include malformations, disruptions, deformations, and dysplasia that may cause stunted growth, delayed mental development, or other congenital disorders that lack structural malformations. The related term developmental toxicity includes all manifestations of abnormal development that are caused by environmental insult. The extent to which teratogens will impact an embryo is dependent on several factors, such as how long the embryo has been exposed, the stage of development the embryo was in when exposed, the genetic makeup of the embryo, and the transfer rate of the teratogen.

<span class="mw-page-title-main">Birth defect</span> Condition present at birth regardless of cause

A birth defect is an abnormal condition that is present at birth, regardless of its cause. Birth defects may result in disabilities that may be physical, intellectual, or developmental. The disabilities can range from mild to severe. Birth defects are divided into two main types: structural disorders in which problems are seen with the shape of a body part and functional disorders in which problems exist with how a body part works. Functional disorders include metabolic and degenerative disorders. Some birth defects include both structural and functional disorders.

<span class="mw-page-title-main">Fetal alcohol spectrum disorder</span> Group of conditions resulting from maternal alcohol consumption during pregnancy

Fetal alcohol spectrum disorders (FASDs) are a group of conditions that can occur in a person who is exposed to alcohol during gestation. FASD affects 1 in 20 Americans, but is highly mis- and under-diagnosed.

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<span class="mw-page-title-main">Generalized epilepsy</span> Epilepsy syndrome that is characterised by generalised seizures with no apparent cause

Generalized epilepsy is a form of epilepsy characterised by generalised seizures with no apparent cause. Generalized seizures, as opposed to focal seizures, are a type of seizure that impairs consciousness and distorts the electrical activity of the whole or a larger portion of the brain.

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<span class="mw-page-title-main">Pitt–Hopkins syndrome</span> Medical condition

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References

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