Teratogenic potential of third-generation antiepileptic drugs: Current status and research needs

Singh, K. P.; Verma, Niharika

doi:10.1016/j.pharep.2019.01.011

Cited by 13 publications

(11 citation statements)

References 71 publications

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“…The greatest concern for WWE is the teratogenicity of AEDs. Accumulating evidence suggests that different AEDs and dosages have different teratogenic risks [23][24][25], and that the newer generation AEDs such as LTG, LEV, and OXC are not associated with significantly increased risks of congenital malformations compared with no AED exposure control [15,16]. In this study, we found that more than 50 % of pregnancies in the unplanned pregnancy group were not prescribed AEDs during pregnancy, which may be because those patients feared drug teratogenicity and had rarely consulted epileptologists before and during pregnancy for relevant knowledge of epilepsy and AED compliance.…”

Section: Discussionmentioning

confidence: 99%

Clinical characteristics and fetal outcomes in women with epilepsy with planned and unplanned pregnancy: A retrospective study

Zhang¹,

Song²,

Wang

et al. 2020

Seizure

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To compare the antiepileptic drug (AED) treatment patterns, seizure control, and folic acid supplementation between planned and unplanned pregnancy in women with epilepsy (WWE) and to investigate the effects of planned pregnancy on fetal outcomes. Methods: A prospectively collected database including WWE with pregnancy from Feb 2010 to Dec 2018 was retrospectively analyzed. Planned pregnancy was defined as WWE being regularly supervised by epileptologists from the time of intended pregnancy until delivery. Clinical characteristics and fetal outcomes were compared between the planned and unplanned pregnancy groups. Logistic regression was used to identify modifiable factors associated with adverse fetal outcomes. Results: A total of 188 planned pregnancies and 289 unplanned pregnancies were enrolled in our study. Among planned pregnancies, 66.0 % took AED monotherapy, and 32.4 % received polytherapy. Among unplanned pregnancies, 58.1 % didn't take AEDs, 28.0 % took monotherapy, and 12.8 % received polytherapy. The planned pregnancies had less generalized tonic-clonic seizures (P = 0.002) and higher proportion of being seizure-free (41.0 % vs. 22.8 %; P < 0.001). All planned pregnancies took folic acid while 39.8 % of unplanned pregnancies never took it (P < 0.001). The planned pregnancies had less rates of induced abortions (2.7 % vs. 13.5 %; P < 0.001), preterm births (3.3 % vs. 20.4 %; P < 0.001), and major congenital malformations (1.6 % vs. 7.5 %; P = 0.016). Pregnancy planning was independently associated with adverse fetal outcomes (adjusted OR, 0.14; 95 % CI, 0.08−0.27; P < 0.001). Conclusion:Planned pregnancy in WWE contributes to more optimized AED pattern, better seizure control, more appropriate folic acid supplementation, and less adverse fetal outcomes.

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Section: Discussionmentioning

confidence: 99%

Clinical characteristics and fetal outcomes in women with epilepsy with planned and unplanned pregnancy: A retrospective study

Zhang¹,

Song²,

Wang

et al. 2020

Seizure

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“…More recently, second-and third-generation anticonvulsants have been developed. Some of these, such as lamotrigine, appear to be less teratogenic (Pariente et al 2017), others are no better than the older drugs (e.g., topiramate; Vajda et al 2019), and comprehensive clinical studies are yet to be completed for others (Singh and Verma 2019). The mechanism by which these drugs affect heart development is not well understood as few animal studies have been carried out.…”

Section: Anticonvulsantsmentioning

confidence: 99%

Environmental Risk Factors for Congenital Heart Disease

Kalisch-Smith

Ved

Sparrow

2019

Cold Spring Harb Perspect Biol

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Congenital heart disease (CHD) has many forms and a wide range of causes. Clinically, it is important to understand the causes. This allows estimation of recurrence rate, guides treatment options, and may also be used to formulate public health advice to reduce the population prevalence of CHD. The recent advent of sophisticated genetic and genomic methods has led to the identification of more than 100 genes associated with CHD. However, despite these great strides, to date only one-third of CHD cases have been shown to have a simple genetic cause. This is because CHD can also be caused by oligogenic factors, environmental factors, and/or gene-environment interaction. Although solid evidence for environmental causes of CHD have been available for almost 80 years, it is only very recently that the molecular mechanisms for these risk factors have begun to be investigated. In this review, we describe the most important environmental CHD risk factors, and what is known about how they cause CHD.

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“…Still, evaluations of tolerability crudely focus on motor toxicity, which itself may poorly correlate with complaints of somnolence or fatigue 65 . Similarly, animal studies on teratogenicity focus primarily on structural malformations, and standardized assessments of neurodevelopmental behavioral toxicity have been consistently deferred and/or ignored 66 . In this study, we asked whether detailed automated evaluations of home-cage behavior would be sensitive enough to detect anticonvulsant psychotropic effects, and further, reveal features of pervasive neurodevelopment (if any) in mice exposed to that anticonvulsant prenatally.…”

Section: Discussionmentioning

confidence: 99%

On the Digital Psychopharmacology of Valproic Acid in Mice

Bass

Tuo²,

Ton³

et al. 2020

Preprint

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ObjectiveAntiepileptic drugs (AEDs) require daily ingestion for maximal seizure prophylaxis. Adverse psychiatric consequences of AEDs present as: (i) reversible changes in mood, anger, anxiety and/or irritability that often necessitate drug discontinuation, and (ii) autism and/or cognitive/psychomotor developmental delays following fetal exposure. Technical advances in quantifying naturalistic rodent behaviors may provide sensitive preclinical estimates of AED psychiatric tolerability and neuropsychiatric teratogenicity.MethodsUsing instrumented home-cage monitoring, we assessed how valproic acid (VPA, dissolved in sweetened drinking water) alters home-cage behavior in adult C57BL/6J mice and in the adult offspring of VPA-exposed breeder pairs. By utilizing a pup open field assay, we also examined how prenatal VPA exposure impacts early spontaneous exploratory behavior.ResultsAt 500-600mg/kg/d, chronic VPA produced hyperphagia and increased wheel-running without impacting sleep, activity and measures of risk aversion. When applied chronically to breeder pairs of mice, VPA prolonged the latency to viable litters without affecting litter size. Two-week old VPA-exposed pups displayed open field hypoactivity without alterations in thigmotaxis. As adults, prenatal VPA-exposed mice displayed active state fragmentation, hypophagia and increased wheel running, together with subtle alterations in home-cage dyadic behavior.InterpretationThrough automated home-cage assessments of C57BL/6J mice, we capture an ethologically centered psychopharmacological profile of enterally administered VPA that is aligned with human clinical experience. By characterizing the effects of pangestational VPA exposure, we discover novel murine expressions of pervasive neurodevelopment. Incorporating rigorous comprehensive assessments of neuropsychiatric tolerability may inform the design of future AEDs with improved neuropsychiatric safety profiles, both for patients and their offspring.

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Teratogenic potential of third-generation antiepileptic drugs: Current status and research needs

Cited by 13 publications

References 71 publications

Clinical characteristics and fetal outcomes in women with epilepsy with planned and unplanned pregnancy: A retrospective study

Clinical characteristics and fetal outcomes in women with epilepsy with planned and unplanned pregnancy: A retrospective study

Environmental Risk Factors for Congenital Heart Disease

On the Digital Psychopharmacology of Valproic Acid in Mice

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