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Anti-epileptic dosages associated with breakthrough seizures in pregnancy – MONEAD study

Blood levels of many commonly used anti-epileptic drugs drop dramatically in pregnancy, researchers from the University of Pittsburgh and the University of Minnesota have found, reinforcing the need to increase some anti-seizure medications and monitor blood levels carefully.

The findings, collected as part of the multicentre study Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD), explain why many people with epilepsy experience breakthrough seizures after conception.

When it comes to epilepsy, maintaining a fine-tuned medication regime is critical, according to the study, published in JAMA Neurology.

“Some people mistakenly believe that changes in the drugs’ blood concentration won’t occur until after 20 weeks of pregnancy, but our study shows how important it is to start monitoring and adjusting patients’ medication dosages early,” said lead author Dr Page Pennell, chair of neurology at the University of Pittsburgh and the principal investigator on the MONEAD trial. “Nearly half of all pregnancies in the United States are unplanned, so it is important to ensure that doctors have a clear picture of each patient’s baseline drug level even if they are not trying to conceive.”

Epilepsy is a life-altering neurological condition that affects children and adults alike, and two-thirds of cases do not have a known cause. In people with epilepsy, nerve cells in the brain are hyper-reactive, causing them to change the pattern of their electrical activity and become spontaneously active, millions of cells at a time. In people with epilepsy, that synchronous activation is manifested in seizures, which can make a person become disoriented, lose consciousness and, in some cases, experience limb movements or rigidity.

Clinical management of epilepsy has had a fraught medical history, compounded by myths and stigma over the centuries. Many people with epilepsy go undiagnosed or under-treated. Even though epileptic seizures can often be successfully controlled with medications, the first-generation drugs had a slew of dangerous side effects and were contraindicated for people who are trying to conceive.

Since then, safer medications have entered the market and become widely available, but clinicians started noticing a new problem – patients whose epilepsy was successfully managed with medications started having seizures soon after becoming pregnant.

“Identifying which anti-seizure medications may have changes in concentrations and at what point in pregnancy those changes occur is important for determining which patients may need to be monitored more closely during pregnancy and after delivery,” said senior author Angela Birnbaum, PhD, professor of experimental and clinical pharmacology at the University of Minnesota.

To get to the bottom of the mystery, Pennell and colleagues launched a study to analyse blood concentrations of 10 commonly used anti-seizure drugs and compare them across different stages of pregnancy and after childbirth.

The study found that blood levels of seven out of 10 of the medications they examined dropped dramatically, from 29.7% for lacosamide, a commonly prescribed anticonvulsant, and up to 56.4% for lamotrigine.

In addition, they noted that the drop in the drugs’ blood concentration occurred mere days after conception, long before most women have their first prenatal visit and before the pregnancy showed itself physically.

“Until now, we knew very little about how becoming pregnant impacted blood levels of most anti-epileptic medications,” said Vicky Whittemore, PhD, programme director at the National Institute of Neurological Disorders and Stroke (NINDS).

“This study lays the groundwork for a larger goal of the MONEAD study, which is to improve outcomes in women with epilepsy by better managing their medications over the course of pregnancy.”

Study details

Antiseizure Medication Concentrations During Pregnancy: Results From the Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) Study

Page Pennell, Ashwin Karanam, Kimford Meador et al.

Published in JAMA Neurology on 14 February 2022

Key Points
Question In women with epilepsy, which anti-seizure medications undergo concentration declines during pregnancy?
Findings In this cohort study of 430 participants, women with epilepsy taking lamotrigine, levetiracetam, lacosamide, oxcarbazepine, and zonisamide experienced significant decreases in dose-normalised concentrations during pregnancy. Although dose-normalised concentrations decreased for carbamazepine, they remained stable for unbound carbamazepine and carbamazepine-10,11-epoxide.
Meaning Results of this study suggest the need for higher doses of several antiseizure medications during pregnancy and support therapeutic drug monitoring beginning early in pregnancy.

Abstract

Importance During pregnancy in women with epilepsy, lower blood concentrations of anti-seizure medications can have adverse clinical consequences.
Objective To characterise pregnancy-associated concentration changes for several anti0seizure medications among women with epilepsy.

Design, Setting, and Participants Enrolment in this prospective, observational cohort study, Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD), occurred from December 19, 2012, to February 11, 2016, at 20 US sites. Enrolled cohorts included pregnant women with epilepsy and nonpregnant control participants with epilepsy. Inclusion criteria were women aged 14 to 45 years, an intelligence quotient greater than 70 points, and, for the cohort of pregnant women, a fetal gestational age younger than 20 weeks. A total of 1087 women were assessed for eligibility; 397 were excluded and 230 declined. Data were analysed from May 1, 2014, to June 30, 2021.

Exposure
Medication plasma concentrations in women taking monotherapy or in combination with noninteracting medications. The cohort of pregnant women was monitored through 9 months post partum, with similar time points for control participants.

Main Outcomes and Measures
Dose-normalised concentrations were calculated as total or unbound plasma medication concentrations divided by total daily dose. Phlebotomy was performed during 4 pregnancy study visits and 3 postpartum visits for the pregnant women and 7 visits over 18 months for control participants. The primary hypothesis was to test pregnancy changes of dose-normalised concentrations from nonpregnant postpartum samples compared with those of control participants.

Results
Of the 351 pregnant women and 109 control participants enrolled in MONEAD, 326 pregnant women (median [range] age, 29 [19-43] years) and 104 control participants (median [range] age, 29 [16-43] years) met eligibility criteria for this analysis. Compared with postpartum values, dose-normalised concentrations during pregnancy were decreased by up to 56.1% for lamotrigine (15.60 μg/L/mg to 6.85 μg/L/mg; P < .001), 36.8% for levetiracetam (11.33 μg/L/mg to 7.16 μg/L/mg; P < .001), 17.3% for carbamazepine (11.56 μg/L/mg to 7.97 μg/L/mg; P = .03), 32.6% for oxcarbazepine (11.55 μg/L/mg to 7.79 μg/L/mg; P < .001), 30.6% for unbound oxcarbazepine (6.15 μg/L/mg to 4.27 μg/L/mg; P < .001), 39.9% for lacosamide (26.14 μg/L/mg to 15.71 μg/L/mg; P < .001), and 29.8% for zonisamide (40.12 μg/L/mg to 28.15 μg/L/mg; P < .001). No significant changes occurred for unbound carbamazepine, carbamazepine-10,11-epoxide, and topiramate, although a decrease was observed for topiramate (29.83 μg/L/mg to 13.77 μg/L/mg; P = .18). Additionally, compared with dose-normalized concentrations from control participants, pregnancy dose-normalized median (SE) concentrations decreased significantly by week of gestational age: carbamazepine, −0.14 (0.06) μg/L/mg (P = .02); carbamazepine unbound, −0.04 (0.01) μg/L/mg (P = .01); lacosamide, −0.23 (0.07) μg/L/mg (P < .001); lamotrigine, −0.20 (0.02) μg/L/mg (P < .001); levetiracetam, −0.06 (0.03) μg/L/mg (P = .01); oxcarbazepine, −0.14 (0.04) μg/L/mg (P < .001); oxcarbazepine unbound, −0.11 (0.03) μg/L/mg (P < .001); and zonisamide, −0.53 (0.14) μg/L/mg (P < .001) except for topiramate (−0.35 [0.20] μg/L/mg per week) and carbamazepine-10,11-epoxide (0.02 [0.01] μg/L/mg).

Conclusions and Relevance
Study results suggest that therapeutic drug monitoring should begin early in pregnancy and that increasing doses of these anticonvulsants may be needed throughout the pregnancy.

 

JAMA Neurology article – Antiseizure Medication Concentrations During Pregnancy (Open access)

 

See more from MedicalBrief archives:

 

Poorer test results for children exposed to epilepsy drugs in the womb

 

Warnings on side effects of epilepsy drug came 40 years too late

 

Repeated febrile convulsions linked to epilepsy and psychiatric disorders — large Danish study

 

 

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