Fetal hydantoin syndrome

The pharmacokinetics of valproic acid (VPA) and several metabolites were measured in 11 epileptic mothers and their 12 newborns. VPA was found in higher concentrations in cord serum than in maternal serum [(factor 1.7 +/- 0.6; (n = 6)]. VPA was excreted in the neonates with a mean half-life of 47 +/- 15 hr (n = 8) which is approximately 4 times the mean value found in adult epileptics. Maternal comedication (primidone and phenytoin) resulted in slightly reduced half-lives. The transplacental kinetics of the two main VPA metabolites in blood were similar to those of VPA...

Eleven per cent of infants exposed to hydantoins in utero have a recognizable pattern of abnormalities with serious clinical consequences. This report of a child born to a mother taking diphenylhydantoin emphasized the ocular findings. At birth and subsequent 8-month exam, a girl was noted to have microphthalmus, prominent iris vessels, and an inferior iris and choroidal colobma. Relation of these anomalies to teratogenic properties of diphenylhydantoin is discussed.

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A six-year-old child, whose mother had been taking Hydanphen tablets for 14 years, is presented. The child had a harelip and some other symptoms of the fetal hydantion syndrome. The mother became pregnant again, no abortion was advised, and she gave birth to a healthy child. A possible teratogenic effect of anticonvulsants is discussed.

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The authors report a case of the Coffin Siris syndrome which associates a ungueo-digital syndrome (special by the bilateral aplasia or severe hypoplasia of nails and third phalanx of fifth toes and fingers) to other anomalies: facies with thinly fine hairs contrasting with bushy and dense eyebrows and body hypertrichosis, hypotonia and mental retardation. The connections of the Coffin Siris syndrome with the trisomy 9 p+ syndrome and the fetal hydantoïn syndrome are discussed.

Controversy over the existence of a fetal hydantoin syndrome continues in medical literature despite numerous recent clinical studies describing additional patients with a characteristic pattern of abnormalities. Resistance to its acceptance as a clinical entity seems to stem from the variability of the component malformations seen in this syndrome. To examine this variability in a controlled experimental situation, we utilized data obtained in previously reported studies of a mouse model of the fetal hydantoin syndrome...

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Four siblings exposed to phenytoin or primidone or both in utero are reported. Each has craniofacial features consistent with fetal hydantoin syndrome. Two of the siblings were exposed to primidone alone, indicating that phenytoin and primidone may have similar teratogenic effects.

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A baby with the fetal hydantoin syndrome was found to have acne vulgaris of the face. Hydantoin taken by epileptic women during pregnancy may cause neonatal acne in the offspring.

The effects of fetal exposure to the anticonvulsant drugs and their clinical, diagnostic and therapeutic problems have been considered. The authors have reported five cases of newborns from addicted mothers. Particularly discussed are some clinical and pathologic correlations involved in the exposure to the Hydantoin and to the Sodium Valproate.

Serum folate concentrations, blood counts, and antiepileptic drug concentrations were measured during 133 pregnancies of 125 women with epilepsy. There was an inverse correlation between serum folate concentrations and concentrations of phenytoin and phenobarbitone. The number of epileptic seizures during pregnancy showed no association with serum folate concentrations. No cases of maternal tissue folate deficiency or fetal damage attributable to low maternal serum folate were observed. Maternal serum folate concentrations for infants with structural birth defects, "fetal hydantoin syndrome," or perinatal death were similar to those for healthy babies...

Fetal hydantoin syndrome (FHS), a characteristic pattern of altered growth and development, has been well described in recent years in offsprings of epileptic mothers taking phenytoin or other hydantoin anticonvulsants during the gestational period. Recent reports of neuroblastoma in three patients with the FHS further raise the questions of the "oncogenic effect " of hydantoin compounds. A case of melanotic neuroectodermal tumor of infancy (MNTI) has been studied clinically and pathologically including light microscopy, histochemistry, and electron microscopy...

An infant with moderate growth retardation, convulsions, cranio-facial dysmorphia, absence deformity of limbs and vertebral segmentation defect is described. She was born to a young mother who had taken castor oil seed (Ricinus communis) orally as a contraceptive for eight weeks after conception. No other drugs were taken during pregnancy. The features of this case partially resemble Fetal Hydantoin Syndrome.

Three experiments were performed in order to develop a murine model of the postnatal functional defects recently described in humans as the fetal anticonvulsant syndromes. In the first experiment, the lower end of the malformation dose-response curves for diphenylhydantoin (DPH), trimethadione (TMD) and phenobarbital (PB) were established. Using this information, doses of each drug were selected for the postnatal behavioral teratology experiments that did not significantly increase the malformation rate. In experiment 2, all three drugs produced some evidence of postnatal dysfunction at the highest nonmalforming doses tested (DPH at 200, TMD at 250 and PB at 80 mg/kg, administered on days 7-18 of gestation)...

The anticonvulsant diphenylhydantion (DPH) causes embryonic folate antagonism in the animal model of the fetal hydantoin syndrome. Thus, comparisons were made between the metabolic effects of the teratogens DPH and 9-methyl pteroylglutamic acid (9-methyl PGA), a folate antagonist. The DPH inhibited ornithine decarboxylase (ODC), the rate-limiting enzyme in putrescine biosynthesis, and caused reduced levels of this precursor diamine as well as the resultant polyamines, spermidine and spermine. In contrast, embryos from rats treated with 9-methyl PGA had ODC activity similar to controls and increased levels of putrescine, spermidine, and spermine...

A large body of literature indicates that prenatal exposure to hydantoin anticonvulsant drugs can be teratogenic and therefore result in offspring with congenital malformations [6, 10-12, 18, 27, 30]. Literature discussing the actual etiologic agent responsible for the malformation and the types of anomalies typical of hydantoin-induced teratogenicity is contradictory [3, 10, 11, 35]. The majority of published cases of the fetal hydantoin syndrome have been associated with maternal ingestion of the most widely prescribed of all the hydantoin anticonvulsants, phenytoin (Dilantin; Parke, Davis) [11]...

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