Expert consensus on neurodevelopmental outcomes in pregnancy pharmacovigilance studies.

Background: Exposure in utero to certain medications can disrupt processes of fetal development, including brain development, leading to a continuum of neurodevelopmental difficulties. Recognizing the deficiency of neurodevelopmental investigations within pregnancy pharmacovigilance, an international Neurodevelopmental Expert Working Group was convened to achieve consensus regarding the core neurodevelopmental outcomes, optimization of methodological approaches and barriers to conducting pregnancy pharmacovigilance studies with neurodevelopmental outcomes. Methods: A modified Delphi study was undertaken based on stakeholder and expert input. Stakeholders (patient, pharmaceutical, academic and regulatory) were invited to define topics, pertaining to neurodevelopmental investigations in medication-exposed pregnancies. Experts were identified for their experience regarding neurodevelopmental outcomes following medicinal, substances of misuse or environmental exposures in utero. Two questionnaire rounds and a virtual discussion meeting were used to explore expert opinion on the topics identified by the stakeholders. Results: Twenty-five experts, from 13 countries and professionally diverse backgrounds took part in the development of 11 recommendations. The recommendations focus on the importance of neurodevelopment as a core feature of pregnancy pharmacovigilance, the timing of study initiation and a core set of distinct but interrelated neurodevelopmental skills or diagnoses which require investigation. Studies should start in infancy with an extended period of investigation into adolescence, with more frequent sampling during rapid periods of development. Additionally, recommendations are made regarding optimal approach to neurodevelopmental outcome measurement, comparator groups, exposure factors, a core set of confounding and mediating variables, attrition, reporting of results and the required improvements in funding for potential later emerging effects. Different study designs will be required depending on the specific neurodevelopmental outcome type under investigation and whether the medicine in question is newly approved or already in widespread use. Conclusion: An improved focus on neurodevelopmental outcomes is required within pregnancy pharmacovigilance. These expert recommendations should be met across a complementary set of studies which converge to form a comprehensive set of evidence regarding neurodevelopmental outcomes in pregnancy pharmacovigilance.

Cognitive disorders in epilepsy II: Clinical targets, indications and selection of test instruments.

This is the second of two narrative reviews on cognitive disorders in epilepsy (companion manuscript: Cognitive disorders in epilepsy I: Clinical experience, real-world evidence and recommendations). Its focus is on the clinical targets, indications, and the selection of neuropsychological test instruments. Cognitive assessment has become an essential tool for the diagnosis and outcome control in the clinical management of epilepsy. The diagnostics of basic and higher brain functions can provide valuable information on lateralized and localized brain dysfunctions associated with epilepsy, its underlying pathologies and treatment. In addition to the detection or verification of deficits, neuropsychology reveals the patient's cognitive strengths and, thus, information about the patient reserve capacities for functional restitution and compensation. Neuropsychology is an integral part of diagnostic evaluations mainly in the context of epilepsy surgery to avoid new or additional damage to preexisting neurocognitive impairments. In addition and increasingly, neuropsychology is being used as a tool for monitoring of the disease and its underlying pathologies, and it is suited for the quality and outcome control of pharmacological or other non-invasive medical intervention. This narrative review summarizes the present state of neuropsychological assessments in epilepsy, reveals diagnostic gaps, and shows the great need for education, homogenization, translation and standardization of instruments.

Cessation of gamma activity in the dorsomedial nucleus associated with loss of consciousness during focal seizures.

RATIONALE: Impaired consciousness during seizures may be mediated by ictal propagation to the thalamus. Functions of individual thalamic nuclei with respect to consciousness, however, are largely unknown. The dorsomedial (DM) nucleus of the thalamus likely plays a role in arousal and cognition. We propose that alterations of firing patterns within the DM nucleus contribute to impaired arousal during focal seizures. METHODS: Electroencephalograph data were collected from electrodes within the left DM thalamus and midcingulate cortex (MCC) in a patient undergoing seizure monitoring. Spectral power was computed across ictal states (preictal, ictal, and postictal) and level of consciousness (stupor/sleep vs. awake) in the DM nucleus and MCC. RESULTS: Eighty-seven seizures of multifocal left frontal and temporal onsets were analyzed, characterized by loss of consciousness. At baseline, the left DM nucleus demonstrated rhythmic bursts of gamma activity, most frequently and with greatest amplitude during wakefulness. This activity ceased as ictal discharges spread to the MCC, and consciousness was impaired, and it recurred at the end of each seizure as awareness was regained. The analysis of gamma (30-40Hz) power demonstrated that when seizures occurred during wakefulness, there was lower DM ictal power (p<0.0001) and higher DM postictal power (p<0.0001) relative to the preictal epoch. This spectral pattern was not evident within the MCC or when seizures occurred during sleep. CONCLUSIONS: Data revealed a characteristic pattern of DM gamma bursts during wakefulness, which disappeared during partial seizures associated with impaired consciousness. The findings are consistent with studies suggesting that the DM nucleus participates in cognition and arousal.

Antiepileptic drug clearance and seizure frequency during pregnancy in women with epilepsy.

The aims of the study were to characterize the magnitude of clearance changes during pregnancy for multiple antiepileptic drugs (AEDs) and to assess seizure frequency and factors increasing seizure risk in pregnant women with epilepsy. A retrospective analysis was performed for 115 pregnancies in 95 women with epilepsy followed at the Emory Epilepsy Center between 1999 and 2012. Antiepileptic drug blood levels (ABLs) obtained during routine clinical practice were used to calculate AED clearance at multiple points during pregnancy. Antiepileptic drug doses and seizure activity were also recorded. The data were analyzed for changes in clearance and dose across pregnancy and for an association between ABL and changes in seizure frequency. Significant changes in clearance during pregnancy were observed for lamotrigine (p<0.001) and levetiracetam (p<0.006). Average peak clearance increased by 191% for lamotrigine and 207% for levetiracetam from nonpregnant baseline. Marked variance was present across individual women and also across repeat pregnancies in individual women. Despite increased AED dose across most AEDs, seizures increased in 38.4% of patients during pregnancy. Seizure deterioration was significantly more likely in patients with seizures in the 12 months prior to conception (p<0.001) and those with localization-related epilepsy (p=0.005). When ABL fell >35% from preconception baseline, seizures worsened significantly during the second trimester when controlling for seizure occurrence in the year prior to conception. Substantial pharmacokinetic changes during pregnancy occur with multiple AEDs and may increase seizure risk. Monitoring of AED serum concentrations with dose adjustment is recommended in pregnant women with epilepsy. Further studies are needed for many AEDs.

Differential effects of antiepileptic drugs on neonatal outcomes.

Offspring of women with epilepsy (WWE) on AEDs are at increased risks for major congenital malformations and reduced cognition. They may be at risk for other adverse neonatal outcomes. Women with epilepsy on carbamazepine (CBZ), lamotrigine (LTG), phenytoin (PHT), or valproate (VPA) monotherapy were enrolled in a prospective, observational, multicenter study of the neurodevelopmental effects of AEDs. The odds ratio for small for gestational age (SGA) was higher for VPA vs. PHT, VPA vs. LTG, and CBZ vs. PHT. Microcephaly rates were elevated to 12% for all newborns and at 12 months old, but normalized by age 24 months. Reduced Apgar scores occurred more frequently in the VPA and PHT groups at 1 min, but scores were near normal in all groups at 5 min. This study demonstrates increased risks for being born SGA in the VPA and CBZ groups, and transiently reduced Apgar scores in the VPA and PHT groups. Differential risks among the AEDs can help inform decisions about AED selection for women during childbearing years.

Effects of fetal antiepileptic drug exposure: outcomes at age 4.5 years.

OBJECTIVE: To examine outcomes at age 4.5 years and compare to earlier ages in children with fetal antiepileptic drug (AED) exposure. METHODS: The NEAD Study is an ongoing prospective observational multicenter study, which enrolled pregnant women with epilepsy on AED monotherapy (1999-2004) to determine if differential long-term neurodevelopmental effects exist across 4 commonly used AEDs (carbamazepine, lamotrigine, phenytoin, or valproate). The primary outcome is IQ at 6 years of age. Planned analyses were conducted using Bayley Scales of Infant Development (BSID at age 2) and Differential Ability Scale (IQ at ages 3 and 4.5). RESULTS: Multivariate intent-to-treat (n = 310) and completer (n = 209) analyses of age 4.5 IQ revealed significant effects for AED group. IQ for children exposed to valproate was lower than each other AED. Adjusted means (95% confidence intervals) were carbamazepine 106 (102-109), lamotrigine 106 (102-109), phenytoin 105 (102-109), valproate 96 (91-100). IQ was negatively associated with valproate dose, but not other AEDs. Maternal IQ correlated with child IQ for children exposed to the other AEDs, but not valproate. Age 4.5 IQ correlated with age 2 BSID and age 3 IQ. Frequency of marked intellectual impairment diminished with age except for valproate (10% with IQ <70 at 4.5 years). Verbal abilities were impaired for all 4 AED groups compared to nonverbal skills. CONCLUSIONS: Adverse cognitive effects of fetal valproate exposure persist to 4.5 years and are related to performances at earlier ages. Verbal abilities may be impaired by commonly used AEDs. Additional research is needed.

Topiramate dose effects on cognition: a randomized double-blind study.

BACKGROUND: Topiramate (TPM), a broad-spectrum antiepileptic drug, has been associated with neuropsychological impairment in patients with epilepsy and in healthy volunteers. OBJECTIVE: To establish whether TPM-induced neuropsychological impairment emerges in a dose-dependent fashion and whether early cognitive response (6-week) predicts later performance (24-week). METHODS: Computerized neuropsychological assessment was performed on 188 cognitively normal adults who completed a double-blind, placebo-controlled, parallel-group, 24-week, dose-ranging study which was designed primarily to assess TPM effects on weight. Target doses were 64, 96, 192, or 384 mg per day. The Computerized Neuropsychological Test Battery was administered at baseline and 6, 12, and 24 weeks. Individual cognitive change was established using reliable change index (RCI) analysis. RESULTS: Neuropsychological effects emerged in a dose-dependent fashion in group analyses (p < 0.0001). RCI analyses showed a dose-related effect that emerged only at the higher dosing, with 12% (64 mg), 8% (96 mg), 15% (192 mg), and 35% (384 mg) of subjects demonstrating neuropsychological decline relative to 5% declining in the placebo group. Neuropsychological change assessed at 6 weeks significantly predicted individual RCI outcome at 24 weeks. CONCLUSIONS: Neuropsychological impairment associated with TPM emerges in a dose-dependent fashion. Subjects more likely to demonstrate cognitive impairment after 24 weeks of treatment can be identified early on during treatment (i.e., within 6 weeks). RCI analysis provides a valuable approach to quantify individual neuropsychological risk.

Effects of breastfeeding in children of women taking antiepileptic drugs.

BACKGROUND: Breastfeeding is known to have beneficial effects, but there is concern that breastfeeding during antiepileptic drug (AED) therapy may be harmful to cognitive development. Animal and human studies have demonstrated that some AEDs can adversely affect the immature brain. However, no investigation has examined effects of breastfeeding during AED therapy on subsequent cognitive abilities in children. METHODS: The Neurodevelopmental Effects of Antiepileptic Drugs Study is an ongoing prospective multicenter observational investigation of long-term effects of in utero AED exposure on cognition. Between 1999 and 2004, we enrolled pregnant women with epilepsy who were taking a single AED (carbamazepine, lamotrigine, phenytoin, or valproate). We recently reported on differential AED effects on age 3 year cognitive outcomes. In this report, we focus on the effects of breastfeeding during AED therapy on age 3 cognitive outcomes in 199 children. RESULTS: A total of 42% of children were breastfed. IQs for breastfed children did not differ from nonbreastfed children for all AEDs combined and for each of the 4 individual AED groups. Mean adjusted IQ scores (95% confidence intervals) across all AEDs were breastfed = 99 (96-103) and nonbreastfed = 98 (95-101). Power was 95% to detect a half SD IQ effect in the combined AED analysis, but was inadequate within groups. CONCLUSIONS: This preliminary analysis fails to demonstrate deleterious effects of breastfeeding during AED therapy on cognitive outcomes in children previously exposed in utero. However, caution is advised due to study limitations. Additional research is needed to confirm this observation and extend investigations to other AEDs and polytherapy.

Is antiepileptic drug use related to depression and suicidal ideation among patients with epilepsy?

Depression and suicide are increased in patients with epilepsy. The U.S. Food and Drug Administration warns that antiepileptic drugs (AEDs) are associated with increased risk of suicidality. This study examines the relationship among depression, suicidal ideation, and AEDs in a prospective cohort of 163 patients with epilepsy from a registry at the University of Florida (January 2006 to August 2008). The Neurological Disorders Depression Inventory for Epilepsy (NDDI-E) was used to measure mood and suicidal ideation across two time points (median = 154 days). Groups included: (1) No AED Change, (2) New AED Added, (3) AED Dose Increased, (4) AED Reduced/Stopped, (5) Multiple AED Changes, and (6) Combined Any AED Change (groups 2-5 combined). No group had worsening mood or suicidal ideation. Significant improvements in proportions of depression and suicidal ideation were seen only for the No AED Change group, which differed only with the AED Dose Increased group with respect to suicidal ideation.

Practice parameter update: management issues for women with epilepsy--focus on pregnancy (an evidence-based review): vitamin K, folic acid, blood levels, and breastfeeding: report of the Quality Standards Subcommittee and Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and American Epilepsy Society.

OBJECTIVE: To reassess the evidence for management issues related to the care of women with epilepsy (WWE) during pregnancy, including preconceptional folic acid use, prenatal vitamin K use, risk of hemorrhagic disease of the newborn, clinical implications of placental and breast milk transfer of antiepileptic drugs (AEDs), risks of breastfeeding, and change in AED levels during pregnancy. METHODS: A 20-member committee evaluated the available evidence based on a structured literature review and classification of relevant articles published between 1985 and October 2007. RESULTS: Preconceptional folic acid supplementation is possibly effective in preventing major congenital malformations in the newborns of WWE taking AEDs. There is inadequate evidence to determine if the newborns of WWE taking AEDs have a substantially increased risk of hemorrhagic complications. Primidone and levetiracetam probably transfer into breast milk in amounts that may be clinically important. Valproate, phenobarbital, phenytoin, and carbamazepine probably are not transferred into breast milk in clinically important amounts. Pregnancy probably causes an increase in the clearance and a decrease in the concentration of lamotrigine, phenytoin, and to a lesser extent carbamazepine, and possibly decreases the level of levetiracetam and the active oxcarbazepine metabolite, the monohydroxy derivative. RECOMMENDATIONS: Supplementing women with epilepsy with at least 0.4 mg of folic acid before they become pregnant may be considered (Level C). Monitoring of lamotrigine, carbamazepine, and phenytoin levels during pregnancy should be considered (Level B) and monitoring of levetiracetam and oxcarbazepine (as monohydroxy derivative) levels may be considered (Level C). A paucity of evidence limited the strength of many recommendations.

Practice parameter update: management issues for women with epilepsy--focus on pregnancy (an evidence-based review): obstetrical complications and change in seizure frequency: report of the Quality Standards Subcommittee and Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and American Epilepsy Society.

OBJECTIVE: To reassess the evidence for management issues related to the care of women with epilepsy (WWE) during pregnancy, including the risk of pregnancy complications or other medical problems during pregnancy in WWE compared to other women, change in seizure frequency, the risk of status epilepticus, and the rate of remaining seizure-free during pregnancy. METHODS: A 20-member committee including general neurologists, epileptologists, and doctors in pharmacy evaluated the available evidence based on a structured literature review and classification of relevant articles published between 1985 and February 2008. RESULTS: For WWE taking antiepileptic drugs, there is probably no substantially increased risk (greater than two times expected) of cesarean delivery or late pregnancy bleeding, and probably no moderately increased risk (greater than 1.5 times expected) of premature contractions or premature labor and delivery. There is possibly a substantially increased risk of premature contractions and premature labor and delivery during pregnancy for WWE who smoke. Seizure freedom for at least 9 months prior to pregnancy is probably associated with a high likelihood (84%-92%) of remaining seizure-free during pregnancy. RECOMMENDATIONS: Women with epilepsy (WWE) should be counseled that seizure freedom for at least 9 months prior to pregnancy is probably associated with a high rate (84%-92%) of remaining seizure-free during pregnancy (Level B). However, WWE who smoke should be counseled that they possibly have a substantially increased risk of premature contractions and premature labor and delivery during pregnancy (Level C).

Practice parameter update: management issues for women with epilepsy--focus on pregnancy (an evidence-based review): teratogenesis and perinatal outcomes: report of the Quality Standards Subcommittee and Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and American Epilepsy Society.

OBJECTIVE: To reassess the evidence for management issues related to the care of women with epilepsy (WWE) during pregnancy. METHODS: Systematic review of relevant articles published between January 1985 and June 2007. RESULTS: It is highly probable that intrauterine first-trimester valproate (VPA) exposure has higher risk of major congenital malformations (MCMs) compared to carbamazepine and possible compared to phenytoin or lamotrigine. Compared to untreated WWE, it is probable that VPA as part of polytherapy and possible that VPA as monotherapy contribute to the development of MCMs. It is probable that antiepileptic drug (AED) polytherapy as compared to monotherapy regimens contributes to the development of MCMs and to reduced cognitive outcomes. For monotherapy, intrauterine exposure to VPA probably reduces cognitive outcomes. Further, monotherapy exposure to phenytoin or phenobarbital possibly reduces cognitive outcomes. Neonates of WWE taking AEDs probably have an increased risk of being small for gestational age and possibly have an increased risk of a 1-minute Apgar score of <7. RECOMMENDATIONS: If possible, avoidance of valproate (VPA) and antiepileptic drug (AED) polytherapy during the first trimester of pregnancy should be considered to decrease the risk of major congenital malformations (Level B). If possible, avoidance of VPA and AED polytherapy throughout pregnancy should be considered to prevent reduced cognitive outcomes (Level B). If possible, avoidance of phenytoin and phenobarbital during pregnancy may be considered to prevent reduced cognitive outcomes (Level C). Pregnancy risk stratification should reflect that the offspring of women with epilepsy taking AEDs are probably at increased risk for being small for gestational age (Level B) and possibly at increased risk of 1-minute Apgar scores of <7 (Level C).

Subjective perception of cognition is related to mood and not performance.

OBJECTIVE: Clinicians monitor cognitive effects of drugs primarily by asking patients to describe their side effects. We examined the relationship of subjective perception of cognition to mood and objective cognitive performance in healthy volunteers and neurological patients. METHODS: Three separate experiments used healthy adults treated with lamotrigine (LTG) and topiramate (TPM), adults with epilepsy on LTG or TPM, and patients with idiopathic Parkinson's disease. Correlations were calculated for change scores on and off drugs in the first two experiments and for the single assessment in Experiment 3. RESULTS: Across all three experiments, significant correlations were more frequent (chi(2)=259, P < or = 0.000) for mood versus subjective cognitive perception (59%) compared with subjective versus objective cognition (2%) and mood versus objective cognitive performance (2%). CONCLUSIONS: Subjective perception of cognitive effects is related more to mood than objective performance. Clinicians should be aware of this relationship when assessing patients' cognitive complaints.

Pregnancy registries in epilepsy: a consensus statement on health outcomes.

Most pregnant women with epilepsy require antiepileptic drug (AED) therapy. Present guidelines recommend optimizing treatment prior to conception, choosing the most effective AED for seizure type and syndrome, using monotherapy and lowest effective dose, and supplementing with folate. The Epilepsy Therapy Project established the international Health Outcomes in Pregnancy and Epilepsy (HOPE) forum to learn more about the impact of AEDs on the developing fetus, particularly the role of pregnancy registries in studying AED teratogenicity. The primary outcome of interest in these registries is the occurrence of major congenital malformations, with some data collected on minor malformations. Cognitive and behavioral outcomes are often beyond the timeframe for follow-up of these registries and require independent study. The HOPE consensus report describes the current state of knowledge and the limitations to interpretations of information from the various sources. Data regarding specific risks for both older and newer AEDs need to be analyzed carefully, considering study designs and confounding factors. There is a critical need for investigations to delineate the underlying mechanisms and explain the variance seen in outcomes across AEDs and within a single AED.

Applicability of NINDS-sponsored studies to community-based physician involvement.

BACKGROUND: The National Institute of Neurological Disorders and Stroke (NINDS) Clinical Trials Group established the Clinical Research Collaboration (CRC) Project in 2005 to increase community-based physician involvement in NINDS-sponsored research. METHODS: We assessed a random sample of 112 of the more than 1,000 current NINDS-sponsored clinical research studies to determine which could involve community physicians in enrollment or follow-up. Scoring factors were based on the premise that participation is feasible for noninvasive studies with simple screening, and follow-up criteria and visit frequency consistent with usual care. Scored studies included 26 Phase III, 31 Phase I/II, and 55 nonclinical trials. RESULTS: Overall, 41% of the sampled research studies were considered conducive to community physician participation that exceeds referral only; 21% with participation in all study activities and 20% with ability to provide some follow-up. Specialized neuropsychological or neurologic scale testing was judged to exclude community physician participation in 16% of studies. CONCLUSION: Many National Institute of Neurological Disorders and Stroke studies are available in which community-based physicians could participate. Involving community physicians may increase efficiency of completing clinical research and encourage application of research findings in community practices.

Neuropsychological and neurophysiologic effects of carbamazepine and levetiracetam.

BACKGROUND: The relative effects of levetiracetam (LEV) and carbamazepine (CBZ) on cognitive and neurophysiologic measures are uncertain. METHODS: The effects of LEV and CBZ were compared in healthy adults using a randomized, double-blind, two-period crossover design. Outcome measures included 11 standard neuropsychological tests and the score from a cognitive-neurophysiologic test of attention and memory. Evaluations were conducted at screening, baseline pre-drug treatment, end of each maintenance phase (4 weeks), and end of each washout period after drug treatment. RESULTS: A total of 28 adults (17 women) with mean age of 33 years (range 18 to 51) completed the study. Mean maintenance doses (+/-SD) were CBZ = 564 mg/day (110) and LEV = 2,000 mg/day (0). CBZ was adjusted to mid-range therapeutic level. Mean serum levels (+/-SD) were CBZ = 7.5 mcg/mL (1.5) and LEV = 32.2 mcg/mL (11.2). An overall composite score including all measures revealed worse effects for CBZ compared to LEV (p

What constitutes high quality of care for adults with epilepsy?

BACKGROUND: Providers are increasingly being held accountable for the quality of care provided. While quality indicators have been used to benchmark the quality of care for a number of other disease states, no such measures are available for evaluating the quality of care provided to adults with epilepsy. In order to assess and improve quality of care, it is critical to develop valid quality indicators. Our objective is to describe the development of quality indicators for evaluating care of adults with epilepsy. As most care is provided in primary and general neurology care, we focused our assessment of quality on care within primary care and general neurology clinics. METHODS: We reviewed existing national clinical guidelines and systematic reviews of the literature to develop an initial list of quality indicators; supplemented the list with indicators derived from patient focus groups; and convened a 10-member expert panel to rate the appropriateness, reliability, and necessity of each quality indicator. RESULTS: From the original 37 evidence-based and 10 patient-based quality indicators, the panel identified 24 evidence-based and 5 patient-based indicators as appropriate indicators of quality. Of these, the panel identified 9 that were not necessary for high quality care. CONCLUSION: There is, at best, a poor understanding of the quality of care provided for adults with epilepsy. These indicators, developed based on published evidence, expert opinion, and patient perceptions, provide a basis to assess and improve the quality of care for this population.

In utero antiepileptic drug exposure: fetal death and malformations.

BACKGROUND: Pregnancy outcomes following in utero exposure to antiepileptic drugs (AEDs) are uncertain, limiting an evidenced-based approach. OBJECTIVE: To determine if fetal outcomes vary as a function of different in utero AED exposures. METHODS: This ongoing prospective observational study across 25 epilepsy centers in the USA and UK enrolled pregnant women with epilepsy from October 1999 to February 2004 to determine if differential long-term cognitive and behavioral neurodevelopmental effects exist across the four most commonly used AEDs. This initial report focuses on the incidence of serious adverse outcomes including major congenital malformations (which could be attributable to AEDs) or fetal death. A total of 333 mother/child pairs were analyzed for monotherapy exposures: carbamazepine (n = 110), lamotrigine (n = 98), phenytoin (n = 56), and valproate (n = 69). RESULTS: Response frequencies of pregnancies resulting in serious adverse outcomes for each AED were as follows: carbamazepine 8.2%, lamotrigine 1.0%, phenytoin 10.7%, and valproate 20.3%. Distribution of serious adverse outcomes differed significantly across AEDs and was not explained by factors other than in utero AED exposure. Valproate exhibited a dose-dependent effect. CONCLUSIONS: More adverse outcomes were observed in pregnancies with in utero valproate exposure vs the other antiepileptic drugs (AEDs). These results combined with several recent studies provide strong evidence that valproate poses the highest risk to the fetus. For women who fail other AEDs and require valproate, the dose should be limited if possible.

Adverse effects of antiepileptic drugs.

Adverse effects of antiepileptic drugs (AEDs) are common, can have a considerable impact on quality of life and contribute to treatment failure in up to 40% of patients. The adverse effect profiles of AEDs differ greatly and are often a determining factor in drug selection because of the similar efficacy rates shown by most AEDs. The most common adverse effects are dose dependent and reversible. Cognitive impairment is of particular concern, especially for patients who work or study. Idiosyncratic effects, such as skin rashes, and chronic effects, such as weight gain, can lead to high rates of treatment discontinuation and complicate clinical management. Nearly all conventional AEDs increase the risk of congenital malformations when taken during pregnancy, with valproate posing a potentially greater risk, whereas the potential teratogenicity of new generation AEDs is largely unknown. Most conventional AEDs have a poor record when it comes to drug interactions, largely because of their tendency to interfere with hepatic drug metabolism. Some newer AEDs have no effect on hepatic drug metabolizing enzymes and are renally excreted, resulting in a lower potential for drug interactions. However, further research is needed to confirm the apparent improvement in tolerability offered by some of the newer AEDs.