The Teratogenicity of Anticonvulsant Drugs

Holmes, Lewis B.; Harvey, Elizabeth A.; Coull, Brent A.; Huntington, Kelly B.; Khoshbin, Shahram; Hayes, Ailish M.; Ryan, Louise

doi:10.1056/nejm200104123441504

Cited by 587 publications

(206 citation statements)

References 36 publications

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“…In humans, the comparable period begins in the third trimester of gestation and extends to several years after birth. Apoptotic neurodegeneration triggered by AEDs during this critical stage of development can at least partly account for reduced head circumference and impaired intellectual skills observed in prenatally or postnatally exposed humans (6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16). The observation that combinations of AEDs cause more pronounced neurotoxic effects offers one possible explanation for the increased risk for cognitive impairment associated with AED polytherapy (11).…”

Section: Discussionmentioning

confidence: 99%

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Antiepileptic drugs and apoptotic neurodegeneration in the developing brain

Bittigau

Sifringer

Genz

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

712

627

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Epilepsy is the most common neurological disorder of young humans. Each year 150,000 children in the United States experience their first seizure. Antiepileptic drugs (AEDs), used to treat seizures in children, infants, and pregnant women, cause cognitive impairment, microcephaly, and birth defects. The cause of unwanted effects of therapy with AEDs is unknown. Here we reveal that phenytoin, phenobarbital, diazepam, clonazepam, vigabatrin, and valproate cause apoptotic neurodegeneration in the developing rat brain at plasma concentrations relevant for seizure control in humans. Neuronal death is associated with reduced expression of neurotrophins and decreased concentrations of survival-promoting proteins in the brain. ␤-Estradiol, which stimulates pathways that are activated by neurotrophins, ameliorates AED-induced apoptotic neurodegeneration. Our findings present one possible mechanism to explain cognitive impairment and reduced brain mass associated with prenatal or postnatal exposure of humans to antiepileptic therapy.survival ͉ epilepsy ͉ rat ͉ neurotrophins

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Section: Discussionmentioning

confidence: 99%

“…AEDs are among the most common causes of fetal malformations, developmental delay, and microcephaly (6)(7)(8)(9)(10)(11). Increasing maternal blood levels and combinations of AEDs impose an increased risk for harm to human infants (11).…”

mentioning

confidence: 99%

Antiepileptic drugs and apoptotic neurodegeneration in the developing brain

Bittigau

Sifringer

Genz

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

712

627

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“…In animals, estrogen administration decreases while progesterone increases seizure thresholds (13,(15)(16)(17)21,44); these differential steroid effects are med to explain the cycle dependent changes in seizure patterns in women. Indeed, the effects observed with progesterone fomi the basis for progesterone treatment of women with catemenial epilepsy (7,14,40,41,43,58,59,62).…”

Section: Discussionmentioning

confidence: 99%

Neuroprotection by Progesterone Through Simulation of Mitochondrial Gene Expression

Fiskum¹

2002

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“…42,43 Exposure to polytherapy is associated with a greater risk for MCMs, which increases the more AEDs are taken.…”

Section: Risks To the Fetusmentioning

confidence: 99%

Do lamotrigine and levetiracetam solve the problem of using sodium valproate in women with epilepsy?

Craig

2012

Obstet Med

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Summary: Women with epilepsy, especially those of child-bearing age, are faced with difficult choices when it comes to choosing the most suitable antiepileptic drug (AED). This is particularly so for those with idiopathic generalized epilepsies, or those for whom seizure syndrome is not immediately apparent, where sodium valproate is still considered the drug of choice. While with treatment most might expect to become seizure free, without any adverse effects, other considerations for women mean that valproate is usually initially avoided, with other AEDs such as lamotrigine or levetiracetam being chosen in preference. Based on current information, this article attempts to provide an overview on whether or not the availability of these and other broad-spectrum AEDs have solved the difficulties of using valproate in women of child-bearing age.

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The Teratogenicity of Anticonvulsant Drugs

Abstract: A distinctive pattern of physical abnormalities in infants of mothers with epilepsy is associated with the use of anticonvulsant drugs during pregnancy, rather than with epilepsy itself.

Cited by 587 publications

References 36 publications

Antiepileptic drugs and apoptotic neurodegeneration in the developing brain

Antiepileptic drugs and apoptotic neurodegeneration in the developing brain

Neuroprotection by Progesterone Through Simulation of Mitochondrial Gene Expression

Do lamotrigine and levetiracetam solve the problem of using sodium valproate in women with epilepsy?

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