FVS is characterized by a distinctive facial appearance, a cluster of minor and major anomalies and central nervous system dysfunction
Fetal valproate syndrome (FVS) results from prenatal exposure to valproic acid.
It is characterized by a distinctive facial appearance, a cluster of minor and major anomalies and central nervous system dysfunction.
We describe a 2-month-old male infant with the typical dysmorphic features characteristic of FVS. He had a persistent left superior vena cava draining into a dilated coronary sinus and mild pulmonary hypertension. There was a history of maternal intake of sodium valproate during pregnancy.
Valproic acid (VPA) is a widely used antiepileptic drug and mood stabilizer. It was first introduced for use as an antiepileptic drug in 1964 and is still a commonly used antiepileptic drug (AED) worldwide. A description of the teratogenic effect of the drug was first published in 1980. Since then many potential teratogenic and dysmorphogenic effects of VPA have been reported. We report a case of fetal valproate syndrome (FVS) in a 2-month-old male infant born of an epileptic mother who was taking sodium valproate during pregnancy.
Topiramate, Valproate Special reminder on risk of neurodevelopmental delay in children following maternal use—not for use in pregnancy
New advice on switching between different manufacturers’ products for a particular drug
Different antiepileptic drugs (AEDs) vary considerably in their characteristics, which influences the risk of whether switching between different manufacturers’ products of a particular drug may cause adverse effects or loss of seizure control. AEDs have been divided into three risk-based categories to help healthcare professionals decide whether it is necessary to maintain continuity of supply of a specific manufacturer’s product. Read more via the PDF link below.
Special reminder on risk of neurodevelopmental delay in children following maternal use—not for use in pregnancy
There is new evidence on neurodevelopmental delay in children following maternal use of sodium valproate. A European review is underway to evaluate all currently available evidence on the association between fetal valproate exposure and neurodevelopmental delay or autism spectrum disorder. Healthcare professionals are reminded that sodium valproate should not be used during pregnancy and in women of childbearing potential unless clearly necessary. Read more via the PDF link below.
Janssen’s Topamax Users blame Drug for Birth Defects
” Johnson & Johnson’s (JNJ) Janssen Pharmaceuticals failed to inform expectant mothers of risks that its epilepsy drug Topamax could cause birth defects, a lawyer for the mother of a Virginia 6-year-old told a jury. April Czimmer wouldn’t have taken Topamax for more than six months had she known the risks associated with the drug, her attorney Tommy Fibich said in opening statements today in state court in Philadelphia. Czimmer blames the drug for her son’s cleft palate and lip and claims Janssen negligently failed to inform patients about its risks until the U.S. Food and Drug Administration ordered stronger warnings in 2011. ”
Children of mothers who took valproate during their pregnancy are at a significantly greater risk for a diagnosis of ADHD
The Neurodevelopmental Effects of Antiepileptic Drugs (NEAD) study is a prospective observational multicenter study in the USA and UK, which enrolled pregnant women with epilepsy on antiepileptic drug (AED) monotherapy from 1999 to 2004. The study aimed to determine if differential long-term neurodevelopmental effects exist across four commonly used AEDs (carbamazepine, lamotrigine, phenytoin, and valproate).
In this report, we examine fetal AED exposure effects on adaptive and emotional/behavioral functioning at 6 years of age in 195 children (including three sets of twins) whose parent (in most cases, the mother) completed at least one of the rating scales. Adjusted mean scores for the four AED groups were in the low average to average range for parent ratings of adaptive functioning on the Adaptive Behavior Assessment System-Second Edition (ABAS-II) and for parent and teacher ratings of emotional/behavioral functioning on the Behavior Assessment System for Children (BASC). However, children whose mothers took valproate during pregnancy had significantly lower General Adaptive Composite scores than the lamotrigine and phenytoin groups. Further, a significant dose-related performance decline in parental ratings of adaptive functioning was seen for both valproate and phenytoin. Children whose mothers took valproate were also rated by their parents as exhibiting significantly more atypical behaviors and inattention than those in the lamotrigine and phenytoin groups. Based upon BASC parent and teacher ratings of attention span and hyperactivity, children of mothers who took valproate during their pregnancy were at a significantly greater risk for a diagnosis of ADHD.
The increased likelihood of difficulty with adaptive functioning and ADHD with fetal valproate exposure should be communicated to women with epilepsy who require antiepileptic medication. Finally, additional research is needed to confirm these findings in larger prospective study samples, examine potential risks associated with other AEDs, better define the risks to the neonate that are associated with AEDs for treatment of seizures, and understand the underlying mechanisms of adverse AED effects on the immature brain.
Many women of childbearing potential take antiepileptic drugs, but the cognitive effects of fetal exposure are uncertain. We aimed to assess effects of commonly used antiepileptic drugs on cognitive outcomes in children up to 6 years of age.
In this prospective, observational, assessor-masked, multicentre study, we enrolled pregnant women with epilepsy on antiepileptic drug monotherapy (carbamazepine, lamotrigine, phenytoin, or valproate) between October, 1999, and February, 2004, at 25 epilepsy centres in the UK and the USA. Our primary outcome was intelligence quotient (IQ) at 6 years of age (age-6 IQ) in all children, assessed with linear regression adjusted for maternal IQ, antiepileptic drug type, standardised dose, gestational birth age, and use of periconceptional folate. We also assessed multiple cognitive domains and compared findings with outcomes at younger ages. This study is registered with ClinicalTrials.gov, number NCT00021866.
We included 305 mothers and 311 children (six twin pairs) in the primary analysis. 224 children completed 6 years of follow-up (6-year-completer sample). Multivariate analysis of all children showed that age-6 IQ was lower after exposure to valproate (mean 97, 95% CI 94–101) than to carbamazepine (105, 102–108; p=0·0015), lamotrigine (108, 105–110; p=0·0003), or phenytoin (108, 104–112; p=0·0006). Children exposed to valproate did poorly on measures of verbal and memory abilities compared with those exposed to the other antiepileptic drugs and on non-verbal and executive functions compared with lamotrigine (but not carbamazepine or phenytoin). High doses of valproate were negatively associated with IQ (r=−0·56, p<0·0001), verbal ability (r=−0·40, p=0·0045), non-verbal ability (r=−0·42, p=0·0028), memory (r=−0·30, p=0·0434), and executive function (r=−0·42, p=0·0004), but other antiepileptic drugs were not. Age-6 IQ correlated with IQs at younger ages, and IQ improved with age for infants exposed to any antiepileptic drug. Compared with a normative sample (173 [93%] of 187 children), right-handedness was less frequent in children in our study overall (185 [86%] of 215; p=0·0404) and in the lamotrigine (59 [83%] of 71; p=0·0287) and valproate (38 [79%] of 40; p=0·0089) groups. Verbal abilities were worse than non-verbal abilities in children in our study overall and in the lamotrigine and valproate groups. Mean IQs were higher in children exposed to periconceptional folate (108, 95% CI 106–111) than they were in unexposed children (101, 98–104; p=0·0009).
Fetal valproate exposure has dose-dependent associations with reduced cognitive abilities across a range of domains at 6 years of age. Reduced right-handedness and verbal (vs non-verbal) abilities might be attributable to changes in cerebral lateralisation induced by exposure to antiepileptic drugs. The positive association of periconceptional folate with IQ is consistent with other recent studies.
Valproate should not be used as a first-choice drug in women of childbearing potential
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.
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.
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.
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.
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.
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.
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.
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.
Exposure to antiepileptic drugs (AEDs) in the first trimester of pregnancy has been associated with an increased risk of major congenital anomalies (MCAs) in offspring. Most of the studies, however, have been fraught with methodological shortcomings, and differences in ascertainment methods and classifications prevent meaningful data pooling. Individual studies lacked the statistical power to assess comparative risks associated with specific AEDs.
Several larger-scale studies, including collaborative multinational registries, have been set up to compare MCA risks associated with different treatments, including newer generation AEDs. Results have largely been consistent with the notion that monotherapy with the most commonly used AEDs is associated with an increase in risk of MCAs by two to three times, and that the magnitude of risk increases in offspring exposed to polytherapy. Available evidence does not suggest that epilepsy per se is associated with a major increase in the risk of MCAs. Almost all studies have suggested that exposure to valproic acid is associated with a greater incidence of MCAs than other AEDs. Valproic acid is also the only AED for which a dose-dependency has been confirmed in several studies: the increase in risk of MCAs, compared with other AEDs, is especially evident at doses above 800-1000 mg/day. Data from the North American registry have suggested that phenobarbital may also have a higher teratogenic risk compared with AEDs other than valproic acid, but evidence remains inconclusive. Information about effects on fetuses of newer generation AEDs other than lamotrigine and oxcarbazepine is scant. Although teratogenic effects of lamotrigine and oxcarbazepine have not been established with certainty, none of the investigations to date identified any statistically significant difference in rates of MCAs between infants exposed to lamotrigine or oxcarbazepine and infants exposed to carbamazepine. In the case of lamotrigine, moreover, a positive correlation between maternal dose and rates of MCAs has been identified.
Collaborative pregnancy registries worldwide are at work to fill remaining gaps in knowledge. Issues to be addressed include the comparative risks associated with phenobarbital, with low-dose valproic acid, with newer generation AEDs, and with specific AED combinations; the influence of potential confounders; and the interaction of AED-associated risks with other risk factors, such as genetic profiles. Large scale studies may also clarify whether individual AEDs differ in their ability to cause specific anomalies. Finally, studies are urgently needed to investigate other potential adverse effects of AED exposure, with special reference to effects on postnatal intellectual development.
Adverse birth outcomes after prenatal exposure to antiepileptic drugs
Fetal exposure to anti-epileptic drugs (AEDs) appears to carry risks beyond those congenital defects currently listed on the products’ labels, a Danish researcher said
There is limited knowledge of the effects of prenatal exposure to antiepileptic drugs and birth outcome.
To study birth outcome in newborn children after prenatal exposure to antiepileptic drugs.
Patients and methods:
From Danish registers, we identified all children born from 1997 to 2008 and linked this with information on the mother’s prescriptions for antiepileptic drugs during pregnancy. We used linear regression to study birth weight, gestational age and head circumference at birth, and binominal regression to study preterm birth (< 37 weeks) and “small for gestational age” (< 10 %). Estimates were adjusted for potential confounding factors. Furthermore, head circumference and birth weight were adjusted for gestational age, and gestational age was adjusted for birth weight.
We identified 679,762 newborn singletons. After adjustment for confounders, antiepileptic drugs exposure (n = 2928) was associated with reduced gestational age; -0.92 days (95% confidence interval (CI): -1.40 – -0.44), lower birth weight; – 31.96 g (95% CI: – 51.74 – – 12.18) and smaller head circumference -0.07 cm (95% CI: -0.14 – – 0.004) compared to non-exposed.
There was a higher risk of being born preterm (< 37 weeks) (adjusted Risk Ratio (aRR): 1.51 (95% CI: 1.32 – 1.72)) and a higher risk of being small for gestational age (aRR: 1.21 (95% CI: 1.10 – 1.34).
Prenatal exposure to antiepileptic drugs was associated with lower birth weight, reduced gestational age, decrease in head circumference, and increased risk of preterm birth and being small for gestational age.