Teratogenicity of valproic acid

Dalens, B; Raynaud, E. J.; Gaulme, J

doi:10.1016/s0022-3476(80)80517-8

Cited by 137 publications

(52 citation statements)

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“…Exposure in pregnancy is associated with approximately a three-fold increase in the rate of major malformations, mainly spina bifida, and only rarely, in increased risk for anencephaly, cardiac, craniofacial, skeletal and limb defects, and a possible set of dysmorphic features called the "valproate syndrome" associated with decreased intrauterine growth [17][18][19][20][21][22][23] . Intrauterine growth restriction associated with the maternal use of both VPA monotherapy and combination therapy have been described [24][25][26][27][28][29] . However, normal birth weights, lengths, and head circumferences have been observed in infants born to mothers receiving VPA monotherapy [30][31][32][33] .…”

Section: Introductionmentioning

confidence: 99%

Serum levels of valproic acid during delivery in mothers and in umbilical cord - correlation with birth length and weight

Kacířová¹,

Grundmann²,

Brozmanová³

2015

BIOMED PAP

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Aims. The data on the valproic acid transplacental transfer and risk to the fetus of exposure, remain sparse and only a limited number of studies have reported umbilical cord blood levels. Materials and Methods. Maternal and umbilical cord serum levels were analyzed at delivery in a cohort of 58 women, between the years 1991 -2013. The request forms for routine therapeutic drug monitoring were used as the data source. Maternal levels and dosing information were used for estimating the maternal apparent oral clearance and the paired umbilical cord and maternal levels for estimation of umbilical cord/maternal level ratios. Results. The levels varied from 5.3 -59.5 mg/L in maternal and 5.4 -72.1 mg/L in umbilical cord serum. The umbilical cord/maternal level ratios ranged from 0.64 -2.49. Significant correlation was found between maternal and umbilical cord levels. Significant inverse correlations were found between birth length, and both maternal and umbilical cord levels in monotherapy.Conclusions. There were large individual variations in umbilical cord/maternal level ratios of valproic acid. Neonatal length and weight were inversely related to maternal and umbilical cord levels, but not to dose. Therefore, therapeutic drug monitoring in mothers is more useful than the given dose for the estimation of fetal exposure and minimization of the risk of fetal effects.

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Section: Introductionmentioning

confidence: 99%

Serum levels of valproic acid during delivery in mothers and in umbilical cord - correlation with birth length and weight

Kacířová¹,

Grundmann²,

Brozmanová³

2015

BIOMED PAP

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“…Today, most of the literature seems to agree that valproic acid has a potential terato genic effect [1][2][3][4][5][6][7][8] and that it should be careful ly administered during pregnancy [9]. In addi tion to neural tube defect, other abnormalities such as dysmorphic facial features, minor limb defects and radial ray reduction have been reported [10,11], The latter anomaly is generally found in association with other mal formations.…”

Section: Introductionmentioning

confidence: 99%

Isolated Fetal Bilateral Radial Ray Reduction Associated with Valproic Acid Usage

Langer¹,

Haddad²,

Gasser

et al. 1994

Fetal Diagn Ther

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The authors describe the first case of an isolated bilateral radial ray reduction occurring in a fetus exposed in utero to valproic acid; the diagnosis was made by ultrasound during the second trimester. This case of an isolated radial ray reduction associated with valproic acid use in pregnancy is a reminder for sonographers to carefully examine not only the cardiac and neurologic system, but also the extremities, when a fetus is exposed in utero to valproic acid.

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“…Although VPA, as a carboxylic acid, is structurally unrelated to other kinds of anticonvulsant drugs, prenatal exposure to it, like other prenatal anticonvulsant exposures, has been associated with congenital malformations in laboratory animals [Brown et al, 1980;Kao et al, 1981: Diaz andShields, 1981;Bruckner et al, 1983;Paulson et al, 19851. VPA is known to cross the human placenta and is present in higher concentration in the infant than in the mother [Dickinson et al, 1979;Nau et al, 19811. Single case reports of birth defects occurring in offspring of women taking VPA during pregnancy have been published since 1980 suggesting that VPA might have teratogenic properties in humans as well [Dalens et al, 1980;Gomez, 1981;Thomas and Buchanan, 1981;Clay et al, 1981;Stanley andChambers, 1982: Bailey et al, 1983;Blaw and Woody, 1983;Bantz, 1984: Garden et al, 1985Tein and MacGregor, 19851. In September, 1982, utilizing data from the Birth Defects Surveillance Program in Lyon, France, for the years 1976and 1978 that an unusually high proportion of infants with spina bifida were born to women with epilepsy treated with VPA.…”

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confidence: 99%

Verification of the fetal valproate syndrome phenotype

et al. 1988

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We have evaluated 19 children who were exposed to valproic acid (VPA) in utero to look for manifestations of a fetal valproate syndrome (FVS), as proposed by Di Liberti et al. [1984]. We found no consistent alterations of pre- or postnatal growth with exposure to VPA monotherapy. Postnatal growth deficiency and microcephaly were present however, in two thirds of children exposed to VPA in combination with other anticonvulsants. Developmental delay or neurologic abnormality was found in 71% of those exposed to VPA monotherapy, and in 90% of those exposed to VPA and other anticonvulsants. Craniofacial anomalies, which can be seen with other anticonvulsant exposures, including midface hypoplasia, short nose with a broad and/or flat bridge, epicanthal folds, minor abnormalities of the ear, philtrum or lip, and micrognathia were also found in infants whose mothers used VPA. Prominent metopic ridge and outer orbital ridge deficiency or bifrontal narrowing and certain major anomalies such as tracheomalacia, talipes equinovarus (with intact spine) and lumbosacral meningomyelocele seem to be peculiar to infants with VPA exposure. Other defects such as urogenital anomalies, inguinal or umbilical hernias, and minor digital anomalies that are common to other prenatal anticonvulsant exposures are also occasionally found in those exposed to VPA. Heart defects have been found in infants exposed to nearly every class of anticonvulsant although the types of defects associated with maternal VPA use may be clarified when classified by pathogenetic mechanism. Our findings overall are in agreement with the report of Di Liberti et al. [1984].

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Teratogenicity of valproic acid

Cited by 137 publications

References 1 publication

Serum levels of valproic acid during delivery in mothers and in umbilical cord - correlation with birth length and weight

Serum levels of valproic acid during delivery in mothers and in umbilical cord - correlation with birth length and weight

Isolated Fetal Bilateral Radial Ray Reduction Associated with Valproic Acid Usage

Verification of the fetal valproate syndrome phenotype

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