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Objective: To study seizure control and rates of foetal malformation in pregnancies of women with epilepsy treated with antiepileptic drug polytherapy. Methods: The use of conventional statistical methods to analyse the Australian Pregnancy Register records of 1810 pregnancies in women with epilepsy, 508 treated with antiepileptic drug polytherapy. Results: Polytherapy‐treated pregnancies were less often seizure free than monotherapy‐treated ones, for both focal (36.0% vs 51.9%: P < .05) and primary generalized epilepsies (41.1% vs 69.3%; P < .05). Drug combinations with dissimilar and similar mechanisms of action achieved similar rates of seizure freedom during pregnancy (36.3% vs 38.3%). The increased rate of malformed foetuses in polytherapy pregnancies depended on valproate or topiramate being in the drug combinations. The combinations of lamotrigine and levetiracetam offered the chance of seizure control and foetal safety. Conclusions: In pregnancy, the use of antiepileptic drug combinations is not necessarily disadvantageous to mother and foetus if valproate and topiramate are avoided. [ABSTRACT FROM AUTHOR]

Objective To clarify whether anti-epileptic drug exposure during pregnancy is associated with an increased risk of intrauterine foetal death. Methods Analysis of data from 2064 pregnancies with known outcomes included in the Australian Register of Antiepileptic Drugs in Pregnancy, 170 of the pregnancies being unexposed to the drugs in at least the first half of pregnancy. Results The relative risk (6.46; 95% C.I. 0.90, 46.22) of intrauterine death appeared higher, though not statistically significantly higher, in drug-exposed pregnancies compared with unexposed ones (3.44% vs 0.59%). There was no statistically significantly increased hazard associated with AED polytherapy as compared with monotherapy. Logistic regression analysis showed a statistically significantly increased and dose-related hazard of intrauterine death in relation to carbamazepine exposure. Conclusions Intrauterine exposure to anti-epileptic drugs, particularly carbamazepine, may be associated with an increased risk of foetal death during pregnancy. [ABSTRACT FROM AUTHOR]

Background: Some recent studies have found an association between foetal malformations in earlier antiepileptic drug (AED)-exposed pregnancies and an increased hazard of such malformations in subsequent pregnancies. We investigated this matter further, and also considered the possible role of spontaneous abortions in previous pregnancies, in this situation. Methods: Analysis of foetal malformation data for current and previous pregnancies in women taking AEDs and women with untreated epilepsy in the Australian Register of Antiepileptic Drugs in Pregnancy (APR) from 1999 to late 2014. Results: Antiepileptic drug-treated women with either a malformed foetus or a spontaneous abortion in their previous pregnancy had a statistically significant twofold to threefold increased risk of foetal malformation in their next pregnancy, compared with similarly treated women with normal offspring in their previous pregnancy. This was not seen in the same circumstances in women with untreated epilepsy. On AED treatment, the women were more likely to have spontaneous abortions than in their previous untreated pregnancies. Possibly some of the increased abortion rate resulted from drug-related malformations that were incompatible with continuing intrauterine survival. Conclusions: In assessing the hazard of an AED-treated woman having a malformed foetus, it is important to know both the AEDs being taken and, if there had been a previous pregnancy, whether a foetal malformation or a spontaneous abortion occurred in it. [ABSTRACT FROM AUTHOR]

Objective To determine whether being pregnant in its own right alters epileptic seizure control. Materials/Methods Study of 148 pregnancies in women who took no antiepileptic drugs before pregnancy and in at least the earlier half of pregnancy, 69 taking none throughout pregnancy. Results More women ( P < 0.01) had seizures of any type during pregnancy (45.9%) than in the prepregnancy year (34.5%), and also convulsive seizures (30.4% vs 12.3%). After excluding potential confounding factors, viz. late prepregnancy drug withdrawal, treatment resumption in pregnancy possibly preventing seizure recurrence, the figures became seizures of any type 56.6% during and 35.5% before pregnancy and convulsive seizures 39.4% during and 18.2% before pregnancy (both P < 0.01). There was a non-statistically significant greater tendency for seizure control to be lost during pregnancy in genetic generalized than in focal epilepsies (54.2% vs 35.5%). Conclusions Irrespective of its effects on antiepileptic drug disposition, being pregnant per se seems to impair epileptic seizure control. [ABSTRACT FROM AUTHOR]

Objective To assess the risk of teratogenicity from maternal intake of the more widely used newer antiepileptic drugs, especially lamotrigine, levetiracetam and topiramate. Materials and methods Use of confidence interval and regression methods to compare risks of foetal malformation in pregnancies in women exposed ( n = 1572) and in women with epilepsy not exposed ( n = 153) to antiepileptic drugs in the first trimester. Results Compared with the foetal malformation rate in women with epilepsy who were untreated in the first trimester (3.3%), the malformation rates for lamotrigine (4.6%), levetiracetam (2.4%) and topiramate (2.4%), all in monotherapy, were not statistically significantly different. However, the malformation rates for topiramate as part of polytherapy (14.1%) and for valproate in both monotherapy (13.8%) and polytherapy (10.2%) were statistically significantly higher. Regression analysis of combined monotherapy and polytherapy data showed no statistically significant increased risk of teratogenesis associated with lamotrigine or levetiracetam, but a statistically significant and dose-related risk for first trimester topiramate ( P = 0.01) and valproate ( P < 0.0001) exposure. Conclusions Evidence from this and other studies suggests that lamotrigine and levetiracetam have low risk for teratogenesis, but that topiramate exposure early in pregnancy may be associated with dose-related anatomical teratogenesis, as valproate is already known to be. [ABSTRACT FROM AUTHOR]

Objective To study associations between patterns of fetal malformation and individual antiepileptic drugs taken during pregnancy. Methods Multiple variable logistic regression and other statistical analyses of data relating to 1733 fetuses from 1703 pregnancies (147 of which were not exposed to antiepileptic drugs during pregnancy). Results There were statistically significant ( P < 0.05) associations between (i) valproate exposure and spina bifida, malformations of the heart and great vessels, digits, skull bones, and brain, but not hypospadias, cleft palate/lip and mouth abnormalities, (ii) topiramate exposure and hypospadias and brain maldevelopments, and (iii) carbamazepine (CBZ) exposure and renal tract abnormalities. Conclusions The valproate findings are mostly in keeping with the published literature, but the topiramate finding regarding hypospadias and the association between CBZ exposure and various renal tract abnormalities raise questions of organ specific teratogenesis. More extensive data are desirable, particularly in relation to topiramate, which is being used increasingly as a migraine prophylactic in women of childbearing potential. [ABSTRACT FROM AUTHOR]

Vajda FJE, Graham J, Hitchcock AA, O'Brien TJ, Lander CM, Eadie MJ. Foetal malformations after exposure to antiepileptic drugs in utero assessed at birth and 12 months later: observations from the Australian pregnancy register. Acta Neurol Scand: 2011: 124: 9-12. © 2010 John Wiley & Sons A/S. In studies investigating foetal malformations associated with antiepileptic drug exposure during pregnancy, the common practice has been to assess the incidence and nature of the malformations at, or soon after, birth. The adequacy of this approach to determine the true incidence of the malformations has received little attention. To compare the incidence and natures of the foetal malformations recognized by, or soon after, birth with similar data for malformations recognized in the first post-natal year. Methods -Analysis of data from the Australian Register of Antiepileptic Drugs in Pregnancy. Up to 25% of the malformations recognized by the end of the first post-natal year had not been detected by, or soon after, birth. There was a tendency for the late-recognized malformations to differ from the early-recognized ones in relation to the body parts involved. Early assessment and delayed assessment of infants for the presence of foetal malformations are complementary, with the latter resulting in finding a higher incidence of malformations. However, omission of an early post-natal assessment may result in biases because of loss of subjects to follow-up. [ABSTRACT FROM AUTHOR]

Vajda FJE, Hollingworth S, Graham J, Hitchcock AA, O’Brien TJ, Lander CM, Eadie MJ. Changing patterns of antiepileptic drug use in pregnant Australian women. Acta Neurol Scand: 2010: 121: 89–93. © 2009 The Authors Journal compilation © 2009 Blackwell Munksgaard. Objective – To trace the pattern of antiepileptic drug (AED) use in pregnant Australian women annually from 1999 to 2007, and correlate it with the pattern of AED use in the wider community. Methods – Analysis of data from the Australian Register of AEDs in Pregnancy, related to Australian population data for AED prescriptions. Results – Over the study period, prescribing of carbamazepine, phenytoin and valproate for pregnant women decreased, and prescribing of lamotrigine, topiramate and levetiracetam increased. These changes tended to parallel prescribing trends in the wider community, except for valproate, whose prescribing in the overall community increased as its prescribing, and its dosage prescribed, decreased in pregnancy. Concomitant with this, there was a trend towards fewer births of foetuses with abnormalities. Conclusions – While otherwise following national AED prescribing trends, Australian prescribers are reducing the use and dose of valproate in pregnant women, likely in recognition of the teratogenic hazards of this drug. [ABSTRACT FROM AUTHOR]

A workshop was held in Göteborg in June 2005 to discuss the place of valproate in treating adult epilepsies. Consensus positions were developed on the epilepsy types for which the drug is most suitable and the use of valproate in women of child-bearing age, in men and in patients with psychiatric comorbidity. Valproate was considered to be effective across a broad variety of epilepsy syndromes and seizure types and should be considered a suitable choice for first-line monotherapy of juvenile myoclonic epilepsy and other idiopathic generalized epilepsies. The use of valproate by women of child-bearing age is associated with potential harm to the foetus. A conservative approach to treatment is recommended in these patients whereby alternative antiepileptic drugs should be proposed to women planning pregnancies wherever satisfactory seizure control can be thereby maintained. In cases where valproate is used during pregnancy, either because the pregnancy was unplanned or because alternative treatment options of equivalent efficacy are unavailable, appropriate counselling, precautionary measures and monitoring should be provided. The evidence for an impact of valproate on male reproductive health is equivocal and considerations of male fertility should not be taken into account in deciding whether to prescribe valproate to men. Valproate can be proposed safely to patients with comorbid psychiatric disease or underlying psychiatric vulnerability. [ABSTRACT FROM AUTHOR]

The Australian Pregnancy Registry, affiliated European Register of Antiepileptic drugs in Pregnancy (EURAP), recruits informed consenting women with epilepsy on treatment with antiepileptic drugs (AEDs), those untreated, and women on AEDs for other indications. Enrolment is considered prospective if it has occurred before presence or absence of major foetal malformations (FMs) are known, or retrospective, if they had occurred after the birth of infant or detection of major FM. Telephone Interviews are conducted to ascertain pregnancy outcome and collect data about seizures. To date 630 women have been enrolled, with 565 known pregnancy outcomes. Valproate (VPA) above 1100 mg/day was associated with a significantly higher incidence of FMs than other AEDs ( P < 0.05). This was independent of other AED use or potentially confounding factors on multivariate analysis (OR = 7.3, P < 0.0001). Lamotrigine (LTG) monotherapy ( n = 65), has so far been free of malformations. Although seizure control was not a primary outcome, we noted that more patients on LTG than on VPA required dose adjustments to control seizures. Data indicate an increased risk of FM in women taking VPA in doses >1100 mg/day compared with other AEDs. The choice of AED for pregnant women with epilepsy requires assessment of balance of risks between teratogenicity and seizure control. [ABSTRACT FROM AUTHOR]

Vajda FJE, Eadie MJ. Maternal valproate dosage and foetal malformations. Acta Neurol Scand 2005: 112: 137–143. © Blackwell Munksgaard 2005. To study the possible dose dependence of the foetal malformation rate after exposure to sodium valproate in pregnancy Analysis of records of all foetuses in the Australian Registry of Antiepileptic Drugs in Pregnancy exposed to valproate, to carbamazepine, lamotrigine or phenytoin in the absence of valproate, and to no antiepileptic drugs. The foetal malformation rate was higher ( P < 0.05) in the 110 foetuses exposed to valproate alone (17.1%), and in the 165 exposed to valproate, whether alone or together with the other antiepileptic drugs (15.2%), than in the 297 exposed to the other drugs without valproate (2.4%). It was also higher ( P < 0.10) than in the 40 not exposed to antiepileptic drugs (2.5%). Unlike the situation for the other drugs, the malformation rate in those exposed to valproate increased with increasing maternal drug dosage ( P < 0.05). The rate was not altered by simultaneous exposure to the other drugs. Valproate doses exceeding 1400 mg per day seemed to be associated with a more steeply increasing malformation rate than at lower doses and with a different pattern of foetal malformations. Foetal exposure to valproate during pregnancy is associated with particularly high, and dose-dependent risks of malformation compared with other antiepileptic drugs, and may possibly involve different teratogenetic mechanisms. [ABSTRACT FROM AUTHOR]

1. The chemical characteristics of sodium valproate suggest that it might be absorbed from stomach as well as from intestine. 2. Absorption from these sites was assessed in rats by measuring plasma drug levels after administering [14C]-valproate or unlabelled valproate separately into (a) intact animals (by gavage), (b) ligated intestine, or (c) ligated stomach. 3. After gastric administration, mean plasma valproate at 1 h, and the mean area under the 0-3 h plasma radioactivity-time curves were 53% and 64% respectively, of the corresponding values after intestinal administration. 4. It is concluded that sodium valproate is absorbed from rat stomach, although at a slower rate than from the whole intestine.