Fetal Hydantoin Syndrome

Hanson, Josiah F.; Smith, Dale E.

doi:10.1016/s0140-6736(76)92805-1

Cited by 78 publications

(84 citation statements)

References 8 publications

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“…Fetal exposure to phenytoin has been suspected to cause cognitive impairment since Hanson and Smith [63] described the fetal hydantoin syndrome in five unrelated children of WWE. Four children had been exposed to 100-400 mg of phenytoin (one monotherapy, three combined with barbiturates, one also to phensuximide) and one to 300 mg of mephenytoin during the fetal period.…”

Section: Phenytoinmentioning

confidence: 99%

Cognitive/behavioral teratogenetic effects of antiepileptic drugs

Meador

Baker

Cohen

et al. 2007

Epilepsy & Behavior

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The majority of children of mothers with epilepsy are normal, but they are at increased risk for developmental delay. Antiepileptic drugs (AEDs) appear to play a role. Our current knowledge is reviewed, including research design issues and recommendations for future research. In animals, exposure of the immature brain to some AEDs can produce widespread neuronal apoptosis and behavioral deficits. The risks of AEDs in humans are less clear, but recent studies raise concerns, especially for valproate. There is a critical need for well-designed systematic research to improve our understanding of AED effects on the fetal brain. KeywordsAntiepileptic drugs; Anticonvulsant drugs; Pregnancy; Teratogenesis; Development; Cognition; Behavior Animal studies on behavioral effects of in utero AED exposureAnimal studies have demonstrated that in utero antiepileptic drug (AED) exposure can produce behavioral as well as anatomical defects, which can occur at dosages lower than those required to produce somatic malformations [1,2]. Gestational or neonatal exposure to benzodiazepines can affect brain chemistry and behavior causing hyperactivity or learning deficits [3,4]. Despite the common use of carbamazepine in humans, very few neurobehavioral studies in animals have been conducted with this AED. In utero carbamazepine exposure did not produce hyperexcitability in primates [5]. Perinatal phenobarbital exposure in rats reduces brain weight [6]. Mice exposed prenatally to phenobarbital have neuronal deficits, reduced brain weight, and impaired development of reflexes, open-field activity, schedule-controlled behavior, spatial learning, and cate-cholamine brain levels [7][8][9][10][11][12]. Gestational or neonatal exposure to phenytoin reduces brain weight [13,14], alters neuronal membranes in the hippocampus [15], delays neurodevelopment [16], and impairs spatial learning and motor coordination [17][18][19][20][21][22][23][24][25]. Hyperactivity has been observed in rats and primates following prenatal exposure to phenytoin [5,23,25]. Gestational primidone in rats produces learning deficits and reduces open-field activity [26]. In utero valproate exposure can alter neuronal membranes [27], decrease brain weight in mice [28], and result in adverse neurobehavioral effects [29,30].

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Section: Phenytoinmentioning

confidence: 99%

Cognitive/behavioral teratogenetic effects of antiepileptic drugs

Meador

Baker

Cohen

et al. 2007

Epilepsy & Behavior

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“…In a chronic mouse exposure study, PHT added to drinking water prior to and throughout pregnancy resulted in a pattern of congenital defects in the offspring that was comparable to those observed in the human FHS [Finnell, 1981, Hanson andSmith, 1975]. The most consistently observed visceral malformations included: dilated or immaturely developed cerebral ventricles, renal agenesis, hydronephrosis, cutaneous and renal hemorrhage, and cardiac, digital and ocular abnormalities.…”

Section: Antiepileptic Drugsmentioning

confidence: 96%

“…Infants with FHS displayed facial dysmorphism including epicanthal folds, hypertelorism, broad depressed nasal bridge, an upturned nasal tip, wide prominent vermilion of the lips and additionally, digital hypoplasia, intrauterine growth restriction and intellectual disability. Subsequently, Hanson et al 1976 reported a prevalence of FHS in 11% of exposed infants, with an additional 30% of the in utero-exposed children expressing some of the syndrome's features. It is now common to consider children presenting with a more limited pattern of dysmorphic characteristics secondary to in utero hydantoin exposure to be expressing fetal hydantoin effects [Hanson and Smith, 1986].…”

Section: Antiepileptic Drugsmentioning

confidence: 99%

Antiepileptic Drugs and Pregnancy Outcomes

Wlodarczyk

Palacios

George³

et al. 2012

Obstetrical &Amp; Gynecological Survey

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The treatment of epilepsy in women of reproductive age remains a clinical challenge. While most women with epilepsy require anticonvulsant drugs for adequate control of their seizures, the teratogenicity associated with some antiepileptic drugs is a risk that needs to be carefully addressed. Antiepileptic medications are also used to treat an ever broadening range of medical conditions such as bipolar disorder, migraine prophylaxis, cancer and neuropathic pain. Despite the fact that the majority of pregnancies of women with epilepsy who are receiving pharmacological treatment are normal, studies have demonstrated that the risk of having a pregnancy complicated by a major congenital malformation is doubled when comparing the risk of untreated pregnancies. Furthermore, when antiepileptic drugs (AEDs) are used in polytherapy regimens, the risk is tripled, especially when valproic acid (VPA) is included. However, it should be noted that the risks are specific for each anticonvulsant drug. Some investigations have suggested that the risk of teratogenicity is increased in a dose-dependent manner. More recent studies have reported that in utero exposure to AEDs can have detrimental effects on the cognitive functions and language skills in later stages of life. In fact, the FDA just issued a safety announcement on the impact of VPA on cognition (Safety Announcement 6-30-2011). The purpose of this document is to review the most commonly used compounds in the treatment of women with epilepsy, and to provide information on the latest experimental and human epidemiological studies of the effects of antiepileptic drugs in the exposed embryos.

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“…Valproic acid and carbamazepine may be associated with a higher risk of neural tube defects, especially if there is a positive family history of neural tube defects (49-51). The highest rate of congenital anomalies is found after exposure to multiple antiepileptic medications (52,53). This may be due to accumulation of epoxide metabolites (52).…”

Section: Considerations In Special Populationsmentioning

confidence: 99%

Advances in pharmacotherapy: recent developments in the treatment of epilepsy

Graves

Leppik

1993

J Clin Pharm Ther

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SUMMARY Epilepsy is a disorder of the central nervous system in which the clinical symptoms are recurrent seizures. An increased understanding of the underlying mechanism of seizures and more definitive diagnostic procedures have improved the care of the patient with epilepsy. An improved classification of various seizure types, including specific epilepsy syndromes has helped optimize use of the standard antiepileptic drugs. Research on the mechanism of seizures has led to new antiepileptic drugs. More definitive diagnostic procedures have led to more accurate identification of patients likely to benefit from epilepsy surgery. This review focuses on these areas.

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Fetal Hydantoin Syndrome

Cited by 78 publications

References 8 publications

Cognitive/behavioral teratogenetic effects of antiepileptic drugs

Cognitive/behavioral teratogenetic effects of antiepileptic drugs

Antiepileptic Drugs and Pregnancy Outcomes

Advances in pharmacotherapy: recent developments in the treatment of epilepsy

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