Fetal anticonvulsant syndrome

Introduction
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By C P Panayiotopoulos MD PhD

Fetal anticonvulsant syndrome is also known as or subsumes Fetal hydantoin syndrome, Fetal phenobarbital syndrome, Fetal primidone syndrome, Fetal trimethadione syndrome, and Fetal valproate syndrome. -ed

Fetal anticonvulsant syndrome is a nonfortuitous cluster of a variety of congenital malformations in infants exposed to antiepileptic drugs (AEDs) in utero. These include major congenital malformations such as cardiac and neural tube defects, oro-facial clefts, and hypospadias, minor malformations such as craniofacial dysmorphisms (hypertelorism, flat nasal ridge, low­set ears, microcephaly, short neck) and digital anomalies (hypoplasia of the distal phalanges or nails), as well as cognitive and behavioral disturbances and intrauterine growth retardation. Many investigators have described a specific association between exposure to certain antiepileptic drugs and dysmorphic features of the child, sometimes in combination with major congenital malformations and learning and behavioral problems. Such syndromes with specific patterns of fetal malformations attributed to single antiepileptic drug exposure have been reported, and these are fetal trimethadione syndrome, fetal hydantoin syndrome, fetal barbiturate syndrome, fetal carbamazepine syndrome, and fetal valproate syndrome. However, though some of these congenital abnormalities may be more prominent in association with 1 antiepileptic drug compared with another, it is now generally accepted that the separation of the various syndromes of embryo­fetal exposure to antiepileptic drugs is not as clear­cut as previously thought. Like other teratogens, antiepileptic drugs produce a pattern of major congenital malformations with overlap among the individual antiepileptic drugs (Harden et al 2009b); there is a considerable overlap in facial features in children exposed to different antiepileptic drugs, and many of those features also frequently occur among unexposed children. Major congenital malformations seen more frequently with valproate, such as neural tube defects, can also occur following exposure to other antiepileptic drugs, demonstrating that this is not an antiepileptic drug­specific major congenital malformation.

Key points:

  • Fetal anticonvulsant syndrome is a nonfortuitous cluster of a variety of congenital malformations in infants exposed to antiepileptic drugs in utero.
  • Symptoms and signs of fetal anticonvulsant syndrome consist of major congenital malformations, minor malformations, cognitive and behavioral disturbances, and intrauterine growth retardation.
  • A specific association between exposure to certain antiepileptic drugs and dysmorphic features of the child, sometimes in combination with major congenital malformations and learning and behavioral problems, has been described particularly in relation to phenytoin, phenobarbital, and valproate.
  • It is now generally accepted that the separation of the various syndromes of embryo­fetal exposure to antiepileptic drugs is not as clear­cut as previously thought.
  • The highest risk of major congenital malformations and of adverse cognitive outcomes is with polytherapy (mainly combination of valproate and lamotrigine).
  • With monotherapy the highest risk of major congenital malformations is found with valproate followed by topiramate.
  • Monotherapy with lamotrigine, carbamazepine, and levetiracetam has a low risk of major congenital malformations, near 2.5%.
  • Folic acid taken at the time of conception decreases the risk of adverse outcomes.
  • The preconception management is the cornerstone for care of women with epilepsy who wish to become pregnant.

 

In This Article

Introduction
Historical note and nomenclature
Clinical manifestations
Clinical vignette
Etiology
Pathogenesis and pathophysiology
Epidemiology
Prevention
Differential diagnosis
Diagnostic workup
Prognosis and complications
Management
Pregnancy
References cited
Contributors