Valproate and the risk for congenital malformations: Is formulation and dosage regime important?

The University of Sheffield, Sheffield, England, United Kingdom
Seizure (Impact Factor: 1.82). 04/2012; 21(3):215-8. DOI: 10.1016/j.seizure.2012.01.005
Source: PubMed


Use of valproate in pregnancy, especially in doses over 1000mg a day, is known to be associated with a higher risk for major congenital malformations compared with other antiepileptic drugs. We sought to investigate whether the increased risk could be minimised by using controlled release or divided daily doses of valproate.
The UK Epilepsy and Pregnancy Register is a prospective, observational and follow up study set up to determine the risks of major congenital malformations for infants exposed to antiepileptic drugs in utero. In this study we have extracted data for those pregnancies exposed to valproate in monotherapy. We have calculated malformation rates and relative risks as a function of valproate exposure.
Outcome data were available for 1109 pregnancies exposed to valproate in monotherapy. Exposure to 1000mg a day or more of valproate was associated with almost double the risk of major congenital malformation compared with daily valproate doses below 1000mg daily (8.86% vs 4.88%, RR: 1.7; 95% CI: 1.1-2.9). There were no differences in the risks for malformations between standard release valproate and controlled release valproate preparations (RR: 1.11; 95% CI: 0.67-1.83) or for those exposed to single or multiple daily administrations (RR: 0.99, 95% CI: 0.58-1.70).
Prescribing controlled release valproate or multiple daily administrations in pregnancy did not reduce the risk for malformations. Higher malformation rates observed with in utero exposure to valproate are more likely related to total daily dose, rather than peak serum levels.

Download full-text


Available from: Henry Smithson, Oct 12, 2015
1 Follower
31 Reads
  • Source
    • "In recent years, the slow (controlled, sustained) release preparations have been replacing the immediate release forms more and more often. However , data from the British registry has shown that avoiding high peak doses of VPA with multiple dosing or using slow release preparations does not necessarily diminish the risk for MCMs (Mawhinney et al., 2012 "
    [Show abstract] [Hide abstract]
    ABSTRACT: Although a wide variety of antiepileptic drugs (AEDs) are available, counseling women of childbearing age with epilepsy is still a challenge.Are there treatment alternatives available for these women? Are there data in the studies and registries allowing women to use VPA under certain circumstances? Is there enough knowledge available to council women and how can this be done?For generalized and unclassified epilepsies, valproate (VPA) should still be considered the gold standard. In many cases, VPA cannot be replaced in patients suffering from idiopathic generalized epilepsy (IGE). There are many reasons for contraindicating the use of VPA in female patients, e.g. increasing risk for Major congenital malformations (MCM) and influence on cognition. These risks are dose dependent and there is evidence that low dose therapy reduces the risks considerable. If VPA proves to be indispensable, then administering the lowest dose possible is mandatory.
    Epileptology 03/2013; 1(1):43–45. DOI:10.1016/j.epilep.2013.01.002
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Antenatal antiepileptic drug (AED) use has been found to be associated with increased major congenital anomaly (CA) risks. However whether such AED-associated risks were different according to periconceptional high dose (5mg daily) folic acid supplementation is still unclear. We included 258,591 singleton live-born children of mothers aged 15-44 years in 1990-2013 from The Health Improvement Network, a large UK primary care database. We identified all major CAs according to the European Surveillance of Congenital Anomalies classification. Absolute risks and adjusted odds ratios (aOR) were calculated comparing children of mothers prescribed AEDs to those without such prescriptions, stratified by folic acid prescriptions around the time of conception (one month before conception to two months post-conception). CA risk was 476/10,000 in children of mothers with first trimester AEDs compared with 269/10,000 in those without AEDs equating to an aOR of 1.82, 95% confidence interval 1.30-2.56. The highest system-specific risks were for heart anomalies (198/10,000 and 79/10,000 respectively, aOR 2.49,1.47-4.21). Sodium valproate and lamotrigine were both associated with increased risks of any CA (aOR 2.63,1.46-4.74 and aOR 2.01,1.12-3.59 respectively) and system-specific risks. Stratification by folic acid supplementation did not show marked reductions in AED-associated risks (e.g. for CAs overall aOR 1.75, 1.01-3.03 in the high dose folic acid group and 1.94, 95%CI 1.21-3.13 in the low dose or no folic acid group); however, the majority of mothers taking AEDs only initiated high dose folic acid from the second month of pregnancy. Children of mothers with AEDs in the first trimester of pregnancy have a 2-fold increased risk of major CA compared to those unexposed. We found no evidence that prescribed high dose folic acid supplementation reduced such AED-associated risks. Although statistical power was limited, prescribing of folic acid too late for it to be effective during the organogenic period or selective prescribing to those with more severe morbidity may explain these findings.
    PLoS ONE 07/2015; 10(7):e0131130. DOI:10.1371/journal.pone.0131130 · 3.23 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Pregnancy is a state where pharmacokinetic changes are more pronounced and more rapid than during any other period of life. The consequences of such changes can be far reaching, not least in the management of epilepsy where the risks with uncontrolled seizures during pregnancy need to be balanced against potential teratogenic effects of antiepileptic drugs (AEDs). This article aims to review the literature on gestational effects on the pharmacokinetics of older and newer generation AEDs and discuss the implications for the treatment of epilepsy in women during pregnancy. Pregnancy can affect the pharmacokinetics of AEDs at any level from absorption, distribution, metabolism, to elimination. The effect varies depending on the type of AED. The most pronounced decline in serum concentrations is seen for AEDs that are eliminated by glucuronidation (UGT), in particular lamotrigine where the effect may be profound. Serum concentrations of AEDs that are cleared mainly through the kidneys, for example, levetiracetam, can also decline significantly. Some AEDs, such as carbamazepine seem to be affected only marginally by pregnancy. Data on pharmacokinetics during pregnancy are lacking completely for some of the newer generation AEDs: pregabalin, lacosamide, retigabine, and eslicarbazepine acetate. Where data are available, the effects of pregnancy on serum concentrations seem to vary considerably individually and are thus difficult to predict. Although large-scale systematic studies of the clinical relevance of the pharmacokinetic alterations are lacking, prospective and retrospective case series have reported an association between declining serum concentrations and deterioration in seizures control. The usefulness of routine monitoring of AED serum concentrations in pregnancy and of dose adjustments based on falling levels, are discussed in this review. We suggest that monitoring could be important, in particular when women have been titrated to the lowest effective AED dose and serum concentration before pregnancy, and when that individual optimal concentration can be used as reference.
    Epilepsia 01/2013; 54(3). DOI:10.1111/epi.12109 · 4.57 Impact Factor
Show more