Anne Sabers

Dose-dependent risk of malformations with antiepileptic drugs: an analysis of data from the EURAP epilepsy and pregnancy registry

BACKGROUNDnPrenatal exposure to antiepileptic drugs is associated with a greater risk of major congenital malformations, but there is inadequate information on the comparative teratogenicity of individual antiepileptic drugs and the association with dose. We aimed to establish the risks of major congenital malformations after monotherapy exposure to four major antiepileptic drugs at different doses.nnnMETHODSnThe EURAP epilepsy and pregnancy registry is an observational cohort study representing a collaboration of physicians from 42 countries. We prospectively monitored pregnancies exposed to monotherapy with different doses of four common drugs: carbamazepine, lamotrigine, valproic acid, or phenobarbital. Our primary endpoint was the rate of major congenital malformations detected up to 12 months after birth. We assessed pregnancy outcomes according to dose at the time of conception irrespective of subsequent dose changes.nnnFINDINGSnAfter excluding pregnancies that ended in spontaneous abortions or chromosomal or genetic abnormalities, those in which the women had treatment changes in the first trimester, and those involving other diseases or treatments that could affect fetal outcome, we assessed rates of major congenital malformations in 1402 pregnancies exposed to carbamazepine, 1280 on lamotrigine, 1010 on valproic acid, and 217 on phenobarbital. An increase in malformation rates with increasing dose at the time of conception was recorded for all drugs. Multivariable analysis including ten covariates in addition to treatment with antiepileptic drugs showed that the risk of malformations was greater with a parental history of major congenital malformations (odds ratio 4·4, 95% CI 2·06-9·23). We noted the lowest rates of malformation with less than 300 mg per day lamotrigine (2·0% [17 events], 95% CI 1·19-3·24) and less than 400 mg per day carbamazepine (3·4% [5 events], 95% CI 1·11-7·71). Compared with lamotrigine monotherapy at doses less than 300 mg per day, risks of malformation were significantly higher with valproic acid and phenobarbital at all investigated doses, and with carbamazepine at doses greater than 400 mg per day.nnnINTERPRETATIONnThe risk of major congenital malformations is influenced not only by type of antiepileptic drug, but also by dose and other variables, which should be taken into account in the management of epilepsy in women of childbearing potential.nnnFUNDINGnEisai, GlaxoSmithKline, Janssen-Cilag, Novartis, Pfizer, Sanofi-Aventis, UCB, Netherlands Epilepsy Foundation, Stockholm County Council, and ALF.

Oral contraceptives reduce lamotrigine plasma levels

The mean steady-state plasma concentration of lamotrigine (LTG) was 13 μmol/L in 22 women taking LTG in combination oral contraceptives (OC) compared with 28 μmol/L among 30 women on LTG who did not take OC (p < 0.0001). The LTG dose/body weight/plasma concentration was 2.1 L/kg/day in women on OC compared with 0.8 L/kg/day in women without OC (p < 0.0001), indicating that LTG plasma levels are reduced by >50% during OC co-medication. It is advisable to monitor LTG plasma levels in conjunction with initiation or withdrawal of OC in women on LTG therapy.

Lamotrigine plasma levels reduced by oral contraceptives

Although it is known that the use of oral contraceptives (OCs) can induce glucuronide conjugating enzymes, currently no data exists as to the potential that the elimination of the glucuronidated drug lamotrigine (LTG) is increased by OCs. We present seven cases in whom the plasma levels of LTG were significantly decreased by OCs (mean 49%, range 41-64%). The interaction was of clinical relevance in most of the patients who either experienced increased seizure frequency/recurrence of seizures after OCs had been added, or adverse effects following withdrawal of OCs.

Oral contraceptives induce lamotrigine metabolism: Evidence from a double-blind placebo-controlled trial.

Summary:u2002 Purpose: This study evaluates the effect of oral contraceptives on lamotrigine (LTG) plasma concentrations and urine excretion of LTG metabolites in a double‐blind, placebo‐controlled, crossover study in patients with epilepsy.

Seizure control and treatment changes in pregnancy: Observations from the EURAP epilepsy pregnancy registry

To analyze seizure control, dose adjustments, and other changes of antiepileptic drug (AED) treatment during pregnancy in a large cohort of women with epilepsy entering pregnancy on monotherapy with carbamazepine, lamotrigine, phenobarbital, or valproate.

Individual changes in lamotrigine plasma concentrations during pregnancy

Eleven pregnant women on lamotrigine (LTG) monotherapy were retrospectively reviewed. A significant decrease in the ratio of plasma LTG concentration-to-dose by 65.1% was observed during the second trimester (TM2) (p=0.0058) and by 65.8% during TM3 (p=0.0045) compared to pre-pregnancy values. Five patients experienced seizure deterioration during pregnancy. The pharmacokinetic changes display marked inter-patient variation, which stresses the importance of evaluating each woman individually by closely monitoring LTG concentrations until term.

EURAP: An International Registry of Antiepileptic Drugs and Pregnancy

Editor’s note—Several pregnancy registries presently are collecting data on pregnancy outcomes in women with epilepsy. Such registries have inherent limitations of selection bias and incomplete information. Data from the registries cannot easily be combined to achieve greater statistical power, since each registry differs from the other in methodology. Nevertheless, in the likely continued absence of randomised prospective trials in this field, the registry information comprises a potentially useful data set. Epilepsia therefore, at the suggestion of Dr. Martha Morrell, has agreed to publish occasional updates on the Epilepsy and Pregnancy Registries, submitted in summary form by the registries. The following material is the first such update.

Pharmacokinetic interactions between contraceptives and antiepileptic drugs

The occurrence of bi-directional drug interactions between antiepileptic drugs (AEDs) and combined oral contraceptives (OCs) pose potential risks of un-intended pregnancy and as well as seizure deterioration. It is well established that several of the older AEDs (carbamazepine, phenytoin and phenobarbital), are strong inducers of the hepatic cytochrome P450 (CYP) 3A4 enzyme system, and are associated with increased the risk of contraceptive failure. In addition, it is demonstrated that also some of the newer AEDs, oxcarbazepine and topiramate influence on the pharmacokinetics of OCs, which is thought to be due to a more selective induction of subgroups of the hepatic enzyme system. Estrogens containing OCs induce the glucuronosyltransferase and may reduce the plasma levels and the effect of AEDs cleared by glucuronidation. This has been most intensively studied for lamotrigine but also other AEDs, which undergoes glucuronidation processes, such as valproate and oxcarbazepine, may be affected by OCs. The magnitude of the drug-drug interactions show in general wide inter-individual variability and the change in the elimination rate is often unpredictable and can be influenced by a number of co-variants such as co-medication of other drugs, as well as genetic and environmental factors. It is therefore recommended that change in OC use is assisted by AED monitoring whenever possible.

Managing antiepileptic drugs during pregnancy and lactation.

Purpose of reviewThis review discusses data on the pharmacokinetics of antiepileptic drugs (AEDs) in pregnancy and lactation, and the clinical consequences thereof, thus providing a basis for a rational management of AEDs during pregnancy and lactation. Recent findingsStudies have confirmed that the elimination of lamotrigine and the active metabolite of oxcarbazepine is enhanced during pregnancy. It has been established that the increased clearance of lamotrigine is caused by induction of glucuronidation. Also, the plasma concentrations of levetiracetam decline in pregnancy but the mechanism for this effect is yet to be explored. Lamotrigine is eliminated slowly in breast-fed infants, but although lamotrigine concentrations in the infant can reach pharmacological levels, no studies have reported clinically relevant adverse effects caused by lactation. SummaryKnowledge of the pharmacokinetics of AEDs in pregnancy and during lactation is important to enable optimal treatment. Gestation induced alterations in pharmacokinetics vary with the AED but also between patients and are difficult to predict. Therapeutic drug monitoring is, therefore, advisable during pregnancy and the use of the individual patients optimal prepregnancy drug level is recommended as reference. Breastfeeding is in general safe but needs appropriate observation of the nursing infant.

Oxcarbazepine concentrations during pregnancy: a retrospective study in patients with epilepsy.

We assessed the concentration of the oxcarbazepine metabolite 10-hydroxycarbazepine (MHD) in nine pregnancies among seven women before, during, and after pregnancy. The mean dose-corrected concentration of MHD was decreased during pregnancy (analysis of variance, p = 0.0016), being 72% (SD = 13%) in the first trimester, 74% (SD = 17%) in the second trimester, 64% (SD = 6%) in the third trimester, and 108% (SD = 18%) after pregnancy vs the dose-corrected concentration before pregnancy.