Changes in Seizure Frequency and Antiepileptic Therapy during Pregnancy

Pennell, Page B.; French, Jacqueline A.; May, Ryan; Gerard, Elizabeth E.; Kalayjian, Laura A.; Penovich, Patricia; Gedzelman, Evan; Cavitt, Jennifer; Hwang, Sean; Pack, Alison; Sam, Maria; Miller, John W.; Wilson, Steffanie H; Brown, Carrie; Birnbaum, Angela K.; Meador, Kimford J.

doi:10.1056/nejmoa2008663

Cited by 68 publications

(48 citation statements)

References 24 publications

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“…While we cannot draw a direct quantitative comparison between our in vitro labetalol metabolism experiments and increased labetalol clearance in pregnant individuals, these results provide experimental evidence suggesting that induction of hepatic UGT1A1, not UGT2B7, protein concentrations underlies the increased hepatic labetalol metabolic clearance during pregnancy predicted by pharmacokinetic models (Fischer et al, 2014;Clark et al, 2015). Although future in vivo studies are needed to validate this hypothesis, and investigate other potential mechanisms that could increase labetalol oral clearance during pregnancy (e.g., intestinal UGT metabolism, hepatic transport), these effects are consistent with prior studies demonstrating a parallel in vitro induction of UGT1A4 expression and lamotrigine glucuronidation (a UGT1A4 substrate) by E2 in HepG2 cells (Chen et al, 2009) and an in vivo increase in lamotrigine glucuronide metabolite formation, oral clearance, and dose requirements in pregnant individuals (Ohman et al, 2008a;Ohman et al, 2008b;Pennell et al, 2020).…”

Section: Discussionsupporting

confidence: 86%

Pregnancy-Related Hormones Increase UGT1A1-Mediated Labetalol Metabolism in Human Hepatocytes

et al. 2021

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Pregnancy-related hormones (PRH) are recognized as important regulators of hepatic cytochrome P450 enzyme expression and function. However, the impact of PRH on the hepatic expression and function of uridine diphosphate glucuronosyltransferases (UGTs) remains unclear. Using primary human hepatocytes, we evaluated the effect of PRH exposure on mRNA levels and protein concentrations of UGT1A1, UGT2B7, and other key UGT enzymes, and on the metabolism of labetalol (a UGT1A1 and UGT2B7 substrate commonly prescribed to treat hypertensive disorders of pregnancy). Sandwich-cultured human hepatocytes (SCHH) from female donors were exposed to the PRH estradiol, estriol, estetrol, progesterone, and cortisol individually or in combination. We quantified protein concentrations of UGT1A1, UGT2B7, and four additional UGT1A isoforms in SCHH membrane fractions and evaluated the metabolism of labetalol to its glucuronide metabolites in SCHH. PRH exposure increased mRNA levels and protein concentrations of UGT1A1 and UGT1A4 in SCHH. PRH exposure also significantly increased labetalol metabolism to its UGT1A1-derived glucuronide metabolite in a concentration-dependent manner, which positively correlated with PRH-induced changes in UGT1A1 protein concentrations. In contrast, PRH did not alter UGT2B7 mRNA levels or protein concentrations in SCHH, and formation of the UGT2B7-derived labetalol glucuronide metabolite was decreased following PRH exposure. Our findings demonstrate that PRH alter expression and function of UGT proteins in an isoform-specific manner and increase UGT1A1-mediated labetalol metabolism in human hepatocytes by inducing UGT1A1 protein concentrations. These results provide mechanistic insight into the increases in labetalol clearance observed in pregnant individuals.

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Section: Discussionsupporting

confidence: 86%

Pregnancy-Related Hormones Increase UGT1A1-Mediated Labetalol Metabolism in Human Hepatocytes

et al. 2021

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“…What can we do to mitigate that risk and improve the chances for a healthy and seizure-free pregnancy? The highlighted study by Pennell et al 5 certainly provides some answers. imaging biomarker for secondary generalization of seizures.…”

Section: Commentarymentioning

confidence: 98%

“…While disentangling these analyses is not part of this commentary, for the purpose of better understanding their approach, we can briefly state that psychophysiologic interaction is a between regions connectivity analysis for fMRI data that is context-dependent. Graph theory analysis, as explained previously in great detail, 5 allows mathematical analysis and description of complex systems using terms such as "hubs," "centrality," and "betweenness." Finally, the term ROC-probably most recognized by neurologists-is a binary classifier that allows diagnostic discrimination between groups.…”

Section: Commentarymentioning

confidence: 99%

Like Mother, Like Child. Keeping Control of Seizures During Pregnancy

Bermeo‐Ovalle¹

2021

Epilepsy Curr

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“…In an encouraging comparative study, it was shown that, with the expanse of more frequent AED dosage changes (in 74% of pregnant WWE as compared to 31% of non pregnant WWE during the same period), no significant differences in seizure frequency were detected between the two groups [51]. This suggests that, with a good support and careful management, pregnancy may not be a complicated period for WWE.…”

Section: -Consider Seizures During Pregnancymentioning

confidence: 99%

Epilepsy and pregnancy: What should the neurologists do?

Vercueil

2021

Revue Neurologique

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Epilepsy is one of the most common chronic disorders affecting women of childbearing age. Unfortunately, many women with epilepsy (WWE) still report not receiving key information about pregnancy. They obviously need information about epilepsy and pregnancy prior to conception with a particular emphasis on effective birth control (i.e contraception), necessity to plan pregnancy, antiepileptic drugs optimization, and folate supplementation. The risks associated with use of antiepileptic drugs during pregnancy has to be balanced against fetal and maternal risks associated with uncontrolled seizures. This report reviews evidence-based counseling and management strategies concerning maternal and fetal risks associated with seizures, teratogenic risks associated with antiepileptic drug exposure with a special emphasis on developmental and behavioural outcomes of children exposed to intra utero antiepileptic drugs.

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Changes in Seizure Frequency and Antiepileptic Therapy during Pregnancy

Cited by 68 publications

References 24 publications

Pregnancy-Related Hormones Increase UGT1A1-Mediated Labetalol Metabolism in Human Hepatocytes

Pregnancy-Related Hormones Increase UGT1A1-Mediated Labetalol Metabolism in Human Hepatocytes

Like Mother, Like Child. Keeping Control of Seizures During Pregnancy

Epilepsy and pregnancy: What should the neurologists do?

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