Comparative safety of antiepileptic drugs during pregnancy

Hernández–Dı́az, Sonia; Smith, C. R.; Shen, Albert Yuh-Jer; Mittendorf, Robert; Hauser, W. Allen; Yerby, Mark S.; Holmes, Lewis B.

doi:10.1212/wnl.0b013e3182574f39

Cited by 552 publications

(489 citation statements)

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“…In 2012, the North American AED Pregnancy Registry (NAAPR) released findings comparing the risk of MCM among infants exposed to different AED monotherapies during the first trimester, as well as to an unexposed reference group [6]. The LTG monotherapy group was chosen as the exposed reference group for the other AEDs because of a low MCM rate and tight confidence intervals [CIs; 2.0 % (95 % CI 1.4-2.8)].…”

Section: Major Congenital Malformationsmentioning

confidence: 99%

“…Findings for specific polytherapy combinations are discussed above. The NAAPR reported on 450 first trimester LEV monotherapy exposures, and the MCM rate was 2.4 % (95 % CI 1.2-4.3) [6].…”

Section: Levmentioning

confidence: 99%

“…The NAAPR did report a MCM rate of 0.7 % with fairly wide 95 % CIs (0.02-3.80), given that only 145 pregnancies were captured [6]. The prospective AED pregnancy registries are structured to capture WWE better than women with other neuropsychiatric indications.…”

Section: Gabapentinmentioning

confidence: 99%

“…In the six women on CBZ monotherapy with adequate seizure diaries and blood sampling, seizure worsening did not correspond to a ratio to baseline concentration of < 0.65 for total or free CBZ or CBZ-EPO. The authors concluded that for focal-onset seizures when AED blood levels are not readily available, CBZ may be a particularly good choice as it is reasonable to not perform therapeutic drug monitoring during pregnancy and because of its relatively low structural teratogenic risk [6,45], and the normal neurocognitive profiles of the children following prenatal exposure [21]. Gestational-induced pharmacokinetic data are lacking for many of the newer AEDs (e.g., pregabalin, lacosamide, eslicarbazepine acetate, rufinamide, clobazam), in part because prescriptions in pregnant women are often delayed until some teratogenic safety data are available.…”

Section: Role Of Therapeutic Drug Monitoring In Maintaining Seizure Cmentioning

confidence: 99%

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Use of Antiepileptic Drugs During Pregnancy: Evolving Concepts

Pennell

2016

Neurotherapeutics

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Although prenatal exposure to antiepileptic drugs (AEDs) is known to impart relatively higher risks of major congenital malformations, prospective studies have provided refined data that allow us to differentiate the risks of different types and doses of AEDs. As the number of AED prescriptions has dramatically increased in reproductive-aged women with a variety of neuropsychiatric indications, the evolving concepts learned from studies in women with epilepsy can be applied to a much larger group of pregnant women to improve child outcomes while maintaining maternal disease control. In addition to careful selection of the type of medication, the amount of fetal exposure at conception and in the first trimester probably matters across all AEDs. Some AED polytherapy regimens are not associated with a higher risk of malformations, although other outcomes have not yet been formally studied. The individual woman's drug target concentration should be established preconception and maintained during pregnancy, to prevent seizure worsening. Substantial pharmacokinetic changes occur with many of the medications during pregnancy and postpartum, and interindividual variability supports the use of therapeutic drug monitoring for most AEDs. During pregnancy, vigilance and close monitoring should also include intrauterine fetal growth, obstetric complications, and neonatal complications. Breastfeeding can provide additional neurodevelopmental benefit and should be an option for women on AEDs. Knowledge of these key principles enhances our ability to make treatment recommendations with resultant improved maternal and child outcomes. Additional prospective studies are needed to further define the risk-benefit ratio across a variety of medications, dosing strategies, and neuropsychiatric disorders.

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Section: Major Congenital Malformationsmentioning

confidence: 99%

“…Findings for specific polytherapy combinations are discussed above. The NAAPR reported on 450 first trimester LEV monotherapy exposures, and the MCM rate was 2.4 % (95 % CI 1.2-4.3) [6].…”

Section: Levmentioning

confidence: 99%

Section: Gabapentinmentioning

confidence: 99%

Section: Role Of Therapeutic Drug Monitoring In Maintaining Seizure Cmentioning

confidence: 99%

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Use of Antiepileptic Drugs During Pregnancy: Evolving Concepts

Pennell

2016

Neurotherapeutics

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“…As a result, many animal studies focused on the time of neural tube closure in early pregnancy [3,31]. However, despite initial evidence that embryotoxicity following VPA exposure may be even higher in late gestation [32], the effects of late exposure VPA have received scant attention since.…”

Section: Introductionmentioning

confidence: 99%

A single low dose of valproic acid in late prenatal life alters postnatal behavior and glutamic acid decarboxylase levels in the mouse

Wei

Lam

et al. 2016

Behavioural Brain Research

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Rationale Rodents exposed to valproic acid (VPA) in prenatal life exhibit post-natal characteristics analogous to autism spectrum disorder (ASD). Many previous studies used relatively high doses of VPA during early pregnancy, potentially confounding interpretation because the offspring are the "survivors" of a toxic insult. Low dose or late gestation exposure has not been widely studied. Objectives We examined the behavioral sequelae of late gestation exposure to low dose VPA in the mouse. We also examined postnatal levels of glutamic acid decarboxylase (GAD65 and GAD67) as markers for GABA neurons, because GABA pathology and subsequent excitatory/inhibitory imbalance is strongly implicated in ASD. Methods Pregnant C57BL/6N mice received a single subcutaneous injection of 100 or 200 mg/kg on gestation day 17. The control group received a saline injection on the same day. The offspring were tested in a battery of behavioral tests in adolescence and adulthood. Six brain regions were harvested and GAD65 and GAD67 were measured by western blotting. Results Compared to saline-exposed controls, adult mice exposed to prenatal VPA had impaired novel object exploration and fear conditioning anomalies. GAD67 was decreased in midbrain, olfactory bulb, prefrontal cortex and increased in cerebellum, hippocampus and striatum; GAD65 was decreased in all 6 regions. ConclusionsOur results suggest that a low dose of VPA in late pregnancy has persistent effects on brain development, and in particular the GABA system, which 3 may be relevant to ASD. Further attention to the impact of gestation time and dose of exposure in VPA-induced ASD models is encouraged.

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New-Onset Seizure in Adults and Adolescents

Gavvala

Schuele

2016

JAMA

113

102

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nance imaging (MRI) of the brain, 5,6 emphasizing the importance of access to and quality of additional testing. This review will focus on the evaluation of new-onset seizure in adults and adolescents, which includes history and physical examination, the differential diagnosis, characteristic features of each etiology, and features of a rational diagnostic workup. The choice of treatment includes discussion of the consideration of efficacy, adverse effects, dosing, and patient counseling. MethodsThe literature published through November 2016 was reviewed by searching PubMed. The following keywords were used: epilepsy, first time seizure, unprovoked seizures, first time unprovoked seizure, acute symptomaticseizure,antiepileptictreatment,seizureepidemiology,epilepsy epidemiology, women with epilepsy, epilepsy in the elderly, sudden unexplained death in epilepsy, and refractory epilepsy. No language restriction was applied. Review articles, primary literature, and meta-analysis were included in this review. Articles were reviewed if they were published between 1976 and 2016. Articles were rated using IMPORTANCE Approximately 8% to 10% of the population will experience a seizure during their lifetime. Only about 2% to 3% of patients go on to develop epilepsy. Understanding the underlying etiology leading to an accurate diagnosis is necessary to ensure appropriate treatment and that patients with low risk for recurrence are not treated unnecessarily.OBSERVATIONS Patients can present with new-onset seizure for a variety of reasons such as acute symptomatic seizures due to acute brain injury or metabolic derangements, or unprovoked seizures that are the initial manifestation of epilepsy. A patient history and physical examination may identify features more consistent with an epileptic event and laboratory studies and brain imaging can identify an acute insult contributing to the presentation. Patients diagnosed with first-time unprovoked seizure require electroencephalography and epilepsy protocol-specific magnetic resonance imaging of the brain, which includes thin-cut coronal slices to determine risk of recurrence and the need for long-term treatment. In patients who meet the criteria for diagnosis of epilepsy, a carefully selected antiepileptic medication with consideration of comorbidities, adverse effect profile, and type of epilepsy is essential along with appropriate counseling.CONCLUSIONS AND RELEVANCE Approximately 3% of the population will develop epilepsy but 2 to 3 times as many patients will experience a single seizure or seizure-like event. A diagnosis of epilepsy has significant medical, social, and emotional consequences. A careful patient history and physical examination, electroencephalography, and brain imaging are necessary to separate patients with acute symptomatic seizures, single unprovoked seizures, and nonepileptic events from those with new-onset epilepsy.

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Comparative safety of antiepileptic drugs during pregnancy

Abstract: AEDs such as valproate and phenobarbital were associated with a higher risk of major malformations than newer AEDs such as lamotrigine and levetiracetam. Topiramate was associated with an increased risk of cleft lip compared with that of a reference population.

Cited by 552 publications

References 40 publications

Use of Antiepileptic Drugs During Pregnancy: Evolving Concepts

Use of Antiepileptic Drugs During Pregnancy: Evolving Concepts

A single low dose of valproic acid in late prenatal life alters postnatal behavior and glutamic acid decarboxylase levels in the mouse

New-Onset Seizure in Adults and Adolescents

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