Cognitive Function at 3 Years of Age after Fetal Exposure to AntiEpileptic Drugs

Valproate should not be used as a first-choice drug in women of childbearing potential

Cognitive Function at 3 Years of Age after Fetal Exposure to Antiepileptic Drugs
The New England Journal of Medicine is the world’s leading medical journal and website

BACKGROUND:
Fetal exposure of animals to antiepileptic drugs at doses lower than those required to produce congenital malformations can produce cognitive and behavioral abnormalities, but cognitive effects of fetal exposure of humans to antiepileptic drugs are uncertain.

METHODS:
Between 1999 and 2004, we enrolled pregnant women with epilepsy who were taking a single antiepileptic agent (carbamazepine, lamotrigine, phenytoin, or valproate) in a prospective, observational, multicenter study in the United States and the United Kingdom. The primary analysis is a comparison of neurodevelopmental outcomes at the age of 6 years after exposure to different antiepileptic drugs in utero. This report focuses on a planned interim analysis of cognitive outcomes in 309 children at 3 years of age.

RESULTS:
At 3 years of age, children who had been exposed to valproate in utero had significantly lower IQ scores than those who had been exposed to other antiepileptic drugs. After adjustment for maternal IQ, maternal age, antiepileptic-drug dose, gestational age at birth, and maternal preconception use of folate, the mean IQ was 101 for children exposed to lamotrigine, 99 for those exposed to phenytoin, 98 for those exposed to carbamazepine, and 92 for those exposed to valproate. On average, children exposed to valproate had an IQ score 9 points lower than the score of those exposed to lamotrigine (95% confidence interval [CI], 3.1 to 14.6; P=0.009), 7 points lower than the score of those exposed to phenytoin (95% CI, 0.2 to 14.0; P=0.04), and 6 points lower than the score of those exposed to carbamazepine (95% CI, 0.6 to 12.0; P=0.04). The association between valproate use and IQ was dose dependent. Children’s IQs were significantly related to maternal IQs among children exposed to carbamazepine, lamotrigine, or phenytoin but not among those exposed to valproate.

CONCLUSIONS:
In utero exposure to valproate, as compared with other commonly used antiepileptic drugs, is associated with an increased risk of impaired cognitive function at 3 years of age. This finding supports a recommendation that valproate not be used as a first-choice drug in women of childbearing potential.

Read full study: Cognitive Function at 3 Years of Age after Fetal Exposure to Antiepileptic Drugs, New England Journal Medicine, 16 April 2009

Exposure to AntiEpileptic Drugs in Utero and Child Development

Prospective population-based study, 2013

Abstract

Exposure to antiepileptic drugs in utero and child development: a prospective population-based study
Exposure to antiepileptic drugs during pregnancy is associated with adverse development at 18 and 36 months of age, measured as low scores within key developmental domains rated by mothers

PURPOSE:
Antiepileptic drugs may cause congenital malformations. Less is known about the effect on development in infancy and childhood. The aim of this study was to examine whether exposure to antiepileptic drugs during pregnancy has an effect on early child development.

METHODS:
From mid-1999 through December 2008, children of mothers recruited at 13-17 weeks of pregnancy were studied in the ongoing prospective Norwegian Mother and Child Cohort Study. Information on birth outcomes were obtained from the Medical Birth Registry (108,264 children), and mothers reported on their child’s motor development, language, social skills, and autistic traits using items from standardized screening tools at 18 months (61,351 children) and 36 months (44,147 children) of age. The relative risk of adverse outcomes in children according to maternal or paternal epilepsy with and without prenatal exposure to antiepileptic drugs was estimated as odds ratios (ORs), using logistic regression with adjustment for maternal age, parity, education, smoking, depression/anxiety, folate supplementation, and child congenital malformation or low birth weight.

KEY FINDINGS:
A total of 333 children were exposed to antiepileptic drugs in utero. At 18 months, the exposed children had increased risk of abnormal scores for gross motor skills (7.1% vs. 2.9%; OR 2.0, 95% confidence interval [CI] 1.1-3.7) and autistic traits (3.5% vs. 0.9%; OR 2.7, CI 1.1-6.7) compared to children of parents without epilepsy. At 36 months, the exposed children had increased risk of abnormal score for gross motor skills (7.5% vs. 3.3%; OR 2.2, CI 1.1-4.2), sentence skills (11.2% vs. 4.8%; OR 2.1, CI 1.2-3.6), and autistic traits (6.0% vs. 1.5%; OR 3.4, CI 1.6-7.0). The drug-exposed children also had increased risk of congenital malformations (6.1% vs. 2.9%; OR 2.1, CI 1.4-3.4), but exclusion of congenital malformations did not affect the risk of adverse development. Children born to women with epilepsy who did not use antiepileptic drugs had no increased risks. Children of fathers with epilepsy generally scored within the normal range.

SIGNIFICANCE:
Exposure to antiepileptic drugs during pregnancy is associated with adverse development at 18 and 36 months of age, measured as low scores within key developmental domains rated by mothers. Exposures to valproate, lamotrigine, carbamazepine, or multiple antiepileptic drugs were associated with adverse outcome within different developmental domains.

Sources: Exposure to antiepileptic drugs in utero and child development: a prospective population-based study
NCBI, July 2013

For Related Posts, see our Tags:
AEDsEpilepsyNCBIPregnancy
DrugsDépakineEpilimValproate

Valproate Anti-Seizure Products contraindicated in Pregnant Women

Reducing Epilepsy Drug Doses Key to Cutting Birth Defects

The FDA is advising health care professionals and women that the anti-seizure medication valproate sodium and related products, valproic acid and divalproex sodium, are contraindicated and should not be taken by pregnant women.

” The U.S. Food and Drug Administration (FDA) is advising health care professionals and women that the anti-seizure medication valproate sodium and related products, valproic acid and divalproex sodium, are contraindicated and should not be taken by pregnant women for the prevention of migraine headaches. Based on information from a recent study, there is evidence that these medications can cause decreased IQ scores in children whose mothers took them while pregnant.1 Stronger warnings about use during pregnancy will be added to the drug labels, and valproate’s pregnancy category for migraine use will be changed from “D” (the potential benefit of the drug in pregnant women may be acceptable despite its potential risks) to “X” (the risk of use in pregnant women clearly outweighs any possible benefit of the drug).
With regard to valproate use in pregnant women with epilepsy or bipolar disorder, valproate products should only be prescribed if other medications are not effective in treating the condition or are otherwise unacceptable. Valproate products will remain in pregnancy category D for treating epilepsy and manic episodes associated with bipolar disorder.
With regard to women of childbearing age who are not pregnant, valproate should not be taken for any condition unless the drug is essential to the management of the woman’s medical condition. All non-pregnant women of childbearing age taking valproate products should use effective birth control.
Valproate products include: valproate sodium (Depacon), divalproex sodium (Depakote, Depakote CP, and Depakote ER), valproic acid (Depakene and Stavzor), and their generics.
This alert is based on the final results of the Neurodevelopmental Effects of Antiepileptic Drugs (NEAD) study showing that children exposed to valproate products while their mothers were pregnant had decreased IQs at age 6 compared to children exposed to other anti-epileptic drugs (see Data Summary).1 The difference in average IQ between the children who had been exposed to valproate and the children who had been exposed to other antiepileptic drugs varied between 8 and 11 points depending on the drug to which valproate was compared.
FDA previously communicated initial findings about this risk in a June 2011 Drug Safety Communication. At that time, FDA also worked with valproate manufacturers to revise the drug labels after interim results from the NEAD study showed lower cognitive test scores at age 3 in children exposed to valproate compared to children exposed to other antiepileptic drugs.
Women who are pregnant and taking a valproate medication should not stop their medication but should talk to their health care professionals immediately. Stopping valproate treatment suddenly can cause serious and life-threatening medical problems to the woman or her baby.
It is not known whether there is a specific time period during pregnancy when valproate exposure can result in negative cognitive effects. Similarly, there is no known time during pregnancy in which exposure may be considered to have less risk for decreased IQ in children. Because the women in the NEAD study were exposed to antiepileptic drugs throughout pregnancy, whether the risk for decreased IQ was related to a particular time period during pregnancy could not be assessed.
FDA is working with manufacturers to change the drug labels for valproate products with this updated risk information. FDA continues to evaluate information about the potential risks of valproate use during pregnancy and will update the public as more information becomes available.
Pregnancy Category X means that studies in animals or humans have shown positive evidence of fetal risk, and the risk of the use of the drug in pregnant women clearly outweighs any possible benefits. Category D means there is positive evidence of risk to a baby based on data from studies or other experience in humans, but the potential benefits from the use of the drug in pregnant women may be acceptable despite its potential risks. ”

Sources: FDA Drug Safety Communication: Valproate Anti-seizure Products Contraindicated for Migraine Prevention in Pregnant Women due to Decreased IQ Scores in Exposed Children
Last Updated 13/05/2013 – PDF

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Dépakine : quelle efficacité pour quels effets secondaires?
Des résultats qui amènent à se demander s’il est réellement indiqué de recourir à un médicament assorti de tels effets secondaires !

Une étude suggère que la Dépakine, anticonvulsif à base de valproate de sodium et d’acide valproïque, pourrait diminuer les comportements répétitifs chez les personnes souffrant de troubles du spectre autistique.

D’autres études révèlent toutefois que ce médicament peut également présenter de nombreux effets secondaires dangereux, voire mortels.

Lire Dépakine : quelle efficacité pour quels effets secondaires?
Autism Research Institute, ARRI Vol. 19, No 4, 2005. Side Effects.

Tous nos posts taggés DépakineValproateAutism

Reducing Epilepsy Drug Doses Key to cutting Birth Defects

Epilepsy drug in pregnancy linked to baby’s higher autism risk

Epilepsy drug in pregnancy linked to baby's higher autism risk
Melissa Healy, LA Times science and medicine reporter

Pregnant women who took the anti-seizure drug valproate during pregnancy increased the odds that their baby would have autism, and were roughly twice as likely to give birth to a child who would go on to be diagnosed with an autism spectrum disorder, according to a large study that captured ten years of births in Denmark.

Read Epilepsy drug in pregnancy linked to baby’s higher autism risk, by Melissa Healy, 24 April 2013

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Les anti-épileptiques, le Valproate de Sodium

Reportage 3013 RTL-TV sur le syndrome du valproate avec témoignage de membres de l’APESAC. La Dépakine, anti-épileptique très connu et très répandu dans les années 80, causerait des malformations sur les fœtus chez les femmes épileptiques et enceintes.

Les médicaments, en savoir plus:

Valproate Epilepsy Drug linked to increased Risk of having a Baby with Spina Bifida or Hypospadias

Epilepsy drug dosage linked to specific birth defects

Researchers discover link between epilepsy drug and risk of having baby with birth defects
Epilepsy experts at The Royal Melbourne Hospital discovered the link

According to new research, the medical journal of the American Academy of Neurology, epilepsy experts at The Royal Melbourne Hospital have discovered a link between high doses of common epilepsy drug valproate and the increased risk of having a baby with spina bifida or hypospadias.

Abstract

 

Objective
To study the relationships between maternal valproate dose in pregnancy and the pattern of various fetal malformations.
Methods
Analysis of data in the Australian Register of Antiepileptic Drugs in Pregnancy collected from 1999 to 2012. The specific type of fetal malformation in offspring exposed to valproate in utero was correlated with the dose of valproate taken by the mother in the first trimester.

Results
Compared with other malformations, the mean dose of valproate taken during the first trimester was higher in mothers whose offspring had spina bifida (2,000 ± 707 vs 1,257 ± 918 mg/d) and hypospadias (2,417 ± 1,320 vs 1,235 ± 715 mg/d) (both p < 0.05). The overall mean maternal valproate dosage taken by women in the Register decreased over the last 5 years of the study period. This was paralleled by a statistically significant decrease in the rate of occurrence of spina bifida and hypospadias, but not other malformations.

Conclusions
Human fetal malformations associated with valproate exposure during pregnancy do not all seem to bear the same quantitative relationship to drug dose, and reduction in valproate dose in earlier pregnancy is likely to offer greater dividends in protecting against spina bifida and hypospadias than against other types of fetal malformations.

Read Epilepsy drug dosage linked to specific birth defects,
26 Aug 2013.

Related post: Researchers discover link between epilepsy drug and risk of having baby with birth defects, News Medical, 26 Aug 2013.

Epilim Sodium Valproate in Pregnancy

BBC1 Interview with Emma Friedmann of FACSaware

BBC1 East Midlands talks to Emma Friedmann, FACSaware, about the Flawed Warning System and the MHRA Protest

  • Video by jocozens1, Published on 31 Jul 2013
  • FACSaware aims to raising global awareness of Fetal Anti Convulsant Syndromes and other Teratogen related syndromes. The Fetal AntiConvulsant Trust (F.A.C.T.) was set up in 2011 to campaign for responsibility from the government and drug company.

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Increase in Birth Defects with Topiramate and Valproate Drugs

14-fold increase in birth defects in those taking topiramate in pregnancy

UK Pregnancy Study Finds Slight Increase in Birth Defects with Topiramate
There was a 14-fold increase in birth defects in those taking topiramate with other antiseizure medications

Researchers in the United Kingdom reported in a study – Topiramate in pregnancy: preliminary experience from the UK Epilepsy and Pregnancy Register – an increase in birth defects among children born to mothers taking the antiseizure medications  valproate and/or topiramate (Topomax) – also widely prescribed in the US for migraine.

Read UK Pregnancy Study Finds Slight Increase in Birth Defects with Topiramate, Neurology Today, 2009.

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L’exposition in-Utero au médicament antiépileptique Valproate et effets sur le cerveau des fœtus

Les résultats sont clairs, le Valproate agit sur l’intelligence des fœtus

Le cerveau des fœtus atteint par un antiépileptique, le Valproate
Le Valproatet cause, chez environ 10% des enfants exposés, des défauts congénitaux dès la naissance

Une étude publiée le 16 avril 2009 dans le New England Journal of Medicine conclut que des enfants âgés de trois ans, exposés au Valproate lorsqu’ils étaient dans l’utérus de leur mère, ont des scores de QI neufs points plus faibles que d’autres enfants du même âge exposés à d’autres antiépileptiques.

Il a été démontré que le médicament cause, chez environ 10% des enfants exposés, des défauts congénitaux et ce dès la naissance.

Lisez: Le cerveau des fœtus atteint par un antiépileptique, le Valproate
par Alain Rusterholtz, Pharmacien, LaRechercheClinique, 21 Avr 2009.