ACOG practice bulletin: Clinical management guidelines for obstetrician-gynecologists

Objective: To assess the relative risk of major congenital malformation (MCM) from in utero exposure to antiepileptic drug (AEDs). Methods: Prospective data collected by the UK Epilepsy and Pregnancy Register were analysed. The presence of MCMs recorded within the first three months of life was the main outcome measure. Results: Full outcome data were collected on 3607 cases. The overall MCM rate for all AED exposed cases was 4.2% (95% confidence interval (CI), 3.6% to 5.0%). The MCM rate was higher for polytherapy (6.0%) (n = 770) than for monotherapy (3.7%) (n = 2598) (crude odds ratio (OR) = 1.63 (p = 0.010), adjusted OR = 1.83 (p = 0.002)). The MCM rate for women with epilepsy who had not taken AEDs during pregnancy (n = 239) was 3.5% (1.8% to 6.8%). The MCM rate was greater for pregnancies exposed only to valproate (6.2% (95% CI, 4.6% to 8.2%) than only to carbamazepine (2.2% (1.4% to 3.4%) (OR = 2.78 (p Conclusions: Only 4.2% of live births to women with epilepsy had an MCM. The MCM rate for polytherapy exposure was greater than for monotherapy exposure. Polytherapy regimens containing valproate had significantly more MCMs than those not containing valproate. For monotherapy exposures, carbamazepine was associated with the lowest risk of MCM.

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Malformation risks of antiepileptic drugs in pregnancy: a prospective study from the UK Epilepsy and Pregnancy Register

Epilepsy is the most common neurological disorder of young humans. Each year 150,000 children in the United States experience their first seizure. Antiepileptic drugs (AEDs), used to treat seizures in children, infants, and pregnant women, cause cognitive impairment, microcephaly, and birth defects. The cause of unwanted effects of therapy with AEDs is unknown. Here we reveal that phenytoin, phenobarbital, diazepam, clonazepam, vigabatrin, and valproate cause apoptotic neurodegeneration in the developing rat brain at plasma concentrations relevant for seizure control in humans. Neuronal death is associated with reduced expression of neurotrophins and decreased concentrations of survival-promoting proteins in the brain. β-Estradiol, which stimulates pathways that are activated by neurotrophins, ameliorates AED-induced apoptotic neurodegeneration. Our findings present one possible mechanism to explain cognitive impairment and reduced brain mass associated with prenatal or postnatal exposure of humans to antiepileptic therapy.

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Antiepileptic drugs and apoptotic neurodegeneration in the developing brain.

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.

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

Each recommendation is identified as falling into one of three categories of endorsement, indicated by a bracketed Roman numeral following the statement. The three categories represent varying levels of clinical confidence regarding the recommendation: [I] Recommended with substantial clinical confidence. [II] Recommended with moderate clinical confidence. [III] May be recommended on the basis of individual circumstances.

https://focus.psychiatryonline.org/doi/pdf/10.1176/foc.1.1.64

Practice Guideline for the Treatment of Patients With Bipolar Disorder (Revision)

Background The frequency of major malformations, growth retardation, and hypoplasia of the midface and fingers, known as anticonvulsant embryopathy, is increased in infants exposed to anticonvulsant drugs in utero. However, whether the abnormalities are caused by the maternal epilepsy itself or by exposure to anticonvulsant drugs is not known. Methods We screened 128,049 pregnant women at delivery to identify three groups of infants: those exposed to anticonvulsant drugs, those unexposed to anticonvulsant drugs but with a maternal history of seizures, and those unexposed to anticonvulsant drugs with no maternal history of seizures (control group). The infants were examined systematically for the presence of major malformations, signs of hypoplasia of the midface and fingers, microcephaly, and small body size. Results The combined frequency of anticonvulsant embryopathy was higher in 223 infants exposed to one anticonvulsant drug than in 508 control infants (20.6 percent vs. 8.5 percent; odds ratio, 2.8; 9...

The teratogenicity of anticonvulsant drugs.

The Teratogenicity of Anticonvulsant Drugs

We report on a child with Duane anomaly, deafness, cervical spine, and radial ray abnormalities. A sister of the proposita had hemifacial microsomia, cervical abnormalities, and hypoplasia of the thenar eminence. Four relatives had hypoplasia of the thenar eminence. A fifth had preaxial polydactyly. Duane anomaly was present in two sixth-degree relatives. This appears to be an autosomal dominant trait. Singly or in combination the abnormalities seen in this family have all been described in association with Duane anomaly. Their occurrence in the same family suggests that they are not independent entities but represent pleiotropic effects of the same gene.

The Okihiro syndrome of Duane anomaly, radial ray abnormalities, and deafness

The basis for the apparent teratogenicity of maternal epilepsy is controversial. Is the critical factor the anticonvulsant drugs taken by the pregnant woman, or the genes which cause the mother's epilepsy? We describe a study design developed to assess these competing theories in a cohort study of newborn infants. We show the feasibility of ascertaining exposed and unexposed infants at several birthing hospitals in one urban area. Between 1986 and 1988, we identified 180 drug-exposed and 218 epilepsy-history infants among 49,403 infants. The rate of exposure to seizure medication was 0.36% and of maternal history of epilepsy was 0.44%. A significant number of infants could not be evaluated because they were missed, ineligible, or either the doctor, nurse or parent refused to participate. Overall, there was a significant increase in major malformations, microcephaly or growth retardation among the drug-exposed infants in comparison to both the epilepsy-history and the unexposed infants. The types of epilepsy and the apparent etiology were the same among women who took anticonvulsants and women with a history of epilepsy but no anticonvulsants during pregnancy. This study must be extended to include a sufficient number of infants exposed to each commonly used drug as mono-therapy to allow for a comparison of the effect of each drug on pregnancy outcomes; to provide a comparison of infants whose mothers had a strong family history of epilepsy with infants whose mothers had trauma-induced epilepsy; and to assess the possible impact of the severity of the mothers' disease on the infants. © 1994 Wiley-Liss, Inc.

Anticonvulsant teratogenesis: I. A study design for newborn infants.

Clinical assessments made with measuring devices are generally considered “objective” and “accurate” and are, therefore, more discriminating than subjective assessments. We show that the choice of measuring devices or non-standardized landmarks to be used with the measuring devices affect the “accuracy” of the “objective” findings. © 1994 Wiley-Liss, Inc.

Ailish M. Hayes

Papers

The teratogenicity of anticonvulsant drugs.

The Teratogenicity of Anticonvulsant Drugs

The Okihiro syndrome of Duane anomaly, radial ray abnormalities, and deafness

Anticonvulsant teratogenesis: I. A study design for newborn infants.

Lessons on objectivity in clinical studies.