Alison Hitchcock

Critical relationship between sodium valproate dose and human teratogenicity: results of the Australian register of anti-epileptic drugs in pregnancy

UNLABELLED To compare the incidence of foetal malformations (FMs) in pregnant women with epilepsy treated with different anti-epileptic drugs (AED) and doses, and the influence of seizures, family and personal history, and environmental factors. A prospective, observational, community-based cohort study. METHODS A voluntary, Australia-wide, telephone-interview-based register prospectively enrolling three groups of pregnant women: taking AEDs for epilepsy; with epilepsy not taking AEDs; taking AEDs for a non-epileptic indication. Four hundred and fifty eligible women were enrolled over 40 months. Three hundred and ninety six pregnancies had been completed, with 7 sets of twins, for a total of 403 pregnancy outcomes. RESULTS 354 (87.8%) pregnancy outcomes resulted in a healthy live birth, 26 (6.5%) had a FM, 4 (1%) a death in utero, 1 (0.2%) a premature labour with stillbirth, 14 (3.5%) a spontaneous abortion and 4 lost to follow-up. The FM rate was greater in pregnancies exposed to sodium valproate (VPA) in the first trimester (16.0%) compared with those exposed to all other AEDs (16.0% vs. 2.4%, P < 0.01) or no AEDs (16.0% vs. 3.1%, [Formula: see text] ). The mean daily dose of VPA taken in pregnancy with FMs was significantly greater than in those without (1,975 vs. 1,128 mg, P < 0.01). The incidence of FM with VPA doses >or= 1,100 mg was 30.2% vs. 3.2% with doses <1,100 mg (P <0.01). CONCLUSIONS There is a dose-effect relationship for FM and exposure to VPA during the first trimester of pregnancy, with higher doses of VPA associated with a significantly greater risk than with lower doses or with other AEDs. These results highlight the need to limit, where possible, the dose of VPA in pregnancy.

Foetal malformations and seizure control: 52 months data of the Australian Pregnancy Registry.

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.

The Australian Register of Antiepileptic Drugs in Pregnancy: the first 1002 pregnancies.

Background:  Prospective studies are needed to assess the maternal and fetal hazards of antiepileptic drug (AED) therapy in pregnancy.

The teratogenic risk of antiepileptic drug polytherapy.

Purpose:  To compare the risks of fetal malformation during pregnancy associated with antiepileptic drug (AED) polytherapy and monotherapy.

Seizure control in antiepileptic drug-treated pregnancy

This brief report covers an analysis of 7 years outcome data from the Australian Register of Antiepileptic Drugs in Pregnancy. In studying the control of antiepileptic drug‐treated epileptic seizures during pregnancy, it was found that pregnancy had little influence on antiepileptic drug‐treated epileptic seizure disorders. Seizures during pregnancy occurred in 49.7% of 841 antiepileptic drug (AED) treated pregnancies in women with epilepsy. Epilepsies that were active in the year before pregnancy tended to increase the risk of intrapartum and postpartum seizures. The risk of seizures during pregnancy was 50–70% less if the prepregnancy year was seizure free, and decreased relatively little more with longer periods of prepregnancy seizure control. Once there had been 1 years freedom from seizures there seemed relatively little further advantage in deferring pregnancy to avoid seizures returning while pregnant.

Is lamotrigine a significant human teratogen? Observations from the Australian Pregnancy Register

Lamotrigine (LTG) is increasingly being prescribed in pregnancy for women with epilepsy in place of valproate (VPA), because of the teratogenic risks associated with the latter. It is therefore important to know the teratogenic hazard associated with LTG, relative to VPA and to other commonly used antiepileptic drugs (AEDs). Data from the Australian Register of Antiepileptic Drugs in Pregnancy was examined to determine the incidence of teratogenicity determined 1 year from completion of pregnancy in women who took AEDs in monotherapy during pregnancy. Compared with a 3.4% malformation incidence in women who took no AEDs (N = 118), the incidences for LTG (N = 243), carbamazepine (CBZ) (N = 302) and VPA (N = 224) were, respectively, 4.9%, 5.3% and 15.2%, the latter statistically significantly greater than the risk for no AED therapy in pregnant women with epilepsy. Logistic regression analysis showed no tendency for foetal hazard to increase with increasing LTG dose in pregnancy, unlike the situation for VPA. However, seizure control in pregnancy tended to be not as good in the women taking LTG compared with those taking VPA, though the data examined were not adequate to permit definite conclusions regarding this matter. We conclude that LTG monotherapy in pregnancy is safer than valproate monotherapy from the point of view of foetal malformations, and no more hazardous in this regard than therapy with other commonly used AEDs.

Changing patterns of antiepileptic drug use in pregnant Australian women

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

Australian Pregnancy Registry of Women Taking Antiepileptic Drugs

Established in 1999, the Australian Registry enrolls women with epilepsy treated with antiepileptic drugs (AEDs), untreated women with epilepsy, and those taking AEDs for other indications. It is a centralized observational study, with ethical committee approval and patient consent. Data from patients fulfilling the criteria for enrollment also are fed into the EURAP database, coordinated by the center in Milan by Professor Dina Battino, supervised by a Board (T. Tomson, Chair). Four telephone interviews are conducted. Patients are enrolled prospectively as well as retrospectively. To date, 830 women have contacted the Registry; 630 have been enrolled, and 565 pregnancies reached completion, including 10 sets of twins. Live births with no defect composed 89%; live births with defect, 5%; spontaneous abortions, 3%; and stillbirths, induced abortion with defect, and lost to followup, 1% each. The reason for AED intake was predominantly for epilepsy (542 of 555 women). Folic acid intake before conception was noted in 378, and no folate in 187. Truly prospective enrollment (before any tests for malformation) comprised 233, with prospective, 252; and retrospective, 80 patients. Primary generalized epilepsy was present in 253 women, partial in 266, the remainder were unclassified. Drug therapy outcomes were related to valproate (VPA) in monotherapy, with a statistically significant increase over untreated patients in incidence of malformations on monotherapy treated (16.1%), and combined groups treated with monotherapy and polytherapy (15.1%) over untreated. patients (2.5%: p < 0.05).

Changing Australian prescribing patterns for antiepileptic drugs in pregnancy and their possible consequences

We report progress in the accumulation of data by the Australian Pregnancy Register over 64 months, confirming the rise in enrollment and the predominantly epileptic indication for taking antiepileptic drugs. Eighty percent of the enrollment was prospective. The focus of the current report is the observation that as a possible result of education and dissemination of information about the risks of exposure to high-dose valproate, there has been a decline in the drugs doses prescribed in Australia, as well as a decline in the proportion of patients prescribed this drug in pregnancy. The risk of teratogenicity associated with valproate in doses in excess of 1100 mg/day was confirmed, and the incidence of lamotrigine-related malformations was comparable to that associated with exposure to phenytoin and carbamazepine. Reporting of data for this paper took into account the 12 months follow-up period for each pregnancy outcome, thus in effect making the evaluation period 21 months for each pregnancy and its outcome.

The case for lamotrigine monitoring in pregnancy

Lamotrigine (LTG) is one of the so-called new generation of anticonvulsants, launched in Australia in 1994. It has become one of the major drugs in the treatment of epilepsy. Its mechanism of action is different from that envisaged at the time of its introduction, when it was postulated to act via an anti-folate mechanism. Subsequently it was shown to have a sodium channel blocking activity, sharing this property with carbamazepine, and phenytoin, amongst other antiepileptic drugs (AEDs). The drug has a different side-effect profile to the older AEDs, in that it has an alerting, so-called euthymic effect, which renders it suitable for patients experiencing the tiring, depressive effects of older medications. It also has an application in bipolar disorders, similar to that of certain other antiepileptic drugs. One of the early favourable features claimed for lamotrigine was the lack of a need to monitor its concentration in plasma. This claim arose from a number of considerations. First, there appeared to be no generally agreed plasma therapeutic range. Second, individual patients differed widely in the plasma level required to control their seizures. Third, other AEDs interact with lamotrigine. Enzyme inducers cause a fall in concentrations of lamotrigine, and phenytoin particularly has a profound effect on lowering LTG levels, necessitating increased LTG doses to control seizures. In contrast, valproate (VPA) causes a rise in LTG levels, and consequently smaller doses of LTG are required to control seizures and prevent neurotoxitiy. In addition VPA and LTG interact pharmacodynamically and the combination has been reported clinically to be more effec-