Accepted Manuscript Title: Prediction Of The Hazard Of Foetal Malformation In Pregnant Women With Epilepsy Author: F.J.E. Vajda T.J. O’Brien J Graham C.M. Lander M.J. Eadie PII: DOI: Reference:

S0920-1211(14)00121-1 http://dx.doi.org/doi:10.1016/j.eplepsyres.2014.04.005 EPIRES 5140

To appear in:

Epilepsy Research

Received date: Revised date: Accepted date:

7-8-2013 19-2-2014 27-4-2014

Please cite this article as: Vajda, F.J.E., O’Brien, T.J., Graham, J., Lander, C.M., Eadie, M.J.,Prediction Of The Hazard Of Foetal Malformation In Pregnant Women With Epilepsy, Epilepsy Research (2014), http://dx.doi.org/10.1016/j.eplepsyres.2014.04.005 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

PREDICTION OF THE HAZARD OF FOETAL MALFORMATION

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IN PREGNANT WOMEN WITH EPILEPSY

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F J E Vajda 1, TJ O’Brien 1, J Graham 1, CM Lander 2, M J Eadie 2

Department of Medicine and Neurosciences, Royal Melbourne Hospital and University of

Melbourne, Parkville, Victoria, 3050,

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Royal Brisbane and Women’s Hospital and University of

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Professor FJE Vajda

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Corresponding Author:

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Queensland, Brisbane, Queensland, 4027, AUSTRALIA

Address: Department of Medicine and Neurosciences, Royal Melbourne Hospital and University of Melbourne, Parkville, Australia 3050 Telephone: E-mail:

61(3).98193056

[email protected]

Word Count:

2097

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Abstract The data collected in the Australian Register of Antiepileptic drugs in pregnancy have been studied in the hope of defining simple items of information that could be recorded at initial interview of pregnant women with epilepsy, and which might allow estimation of the risk of the

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pregnancy resulting in a malformed foetus. Analysis of the data showed that dose of valproate, but not intake of other commonly used antiepileptic drugs, in the current pregnancy, and a past history of a pregnancy involving a malformed foetus, statistically significantly increased the

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malformation hazard in the current pregnancy, and that continuing alcohol intake might decrease it. Plotting the hazard against valproate dose in monotherapy, with or without histories of (i)

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previous pregnancies with foetal malformations (FMs), and (ii) continuing alcohol intake, provided quantitative information concerning the degree of increased risk. It is hoped that this information may help in advising about the risk of foetal malformation (FM) in individual

Key Words:

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pregnancies.

alcohol; antiepileptic drugs; foetal malformations; spina bifida; teratogenesis;

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valproate

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Introduction Women with epilepsy (WWE) who are treated with anti-epileptic drugs (AEDs) are known to have an increased risk of bearing children with FMs. This risk is believed to vary depending on

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the type of AED and the dose that is taken (Tomson et al 2011), as well as other factors such as a family and personal history of carrying previous babies with FMs (Campbell et al 2012; Vajda et

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al, 2012). Nevertheless, in clinical practice determining the degree of risk for the individual AEDtreated woman considering pregnancy and in early pregnancy is currently difficult and imprecise. It seemed possible that the information already collected in the Australian Register of

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Antiepileptic Drugs in Pregnancy, data which have previously been used primarily to study the relationships between intrauterine exposure to individual AEDs and the hazards of FMs, might be

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analysed to try to develop a predictive tool to help assess the chance of the individual woman with epilepsy bearing a malformed foetus . If available, such a tool would assist in advising WWE

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who are considering becoming pregnant.

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2. Materials and Methods

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2.1 The Australian Pregnancy Register

Details of the nature and data collecting and storage methods and ethics oversight of the Australian Pregnancy Register have been described previously (Vajda et al 2009, 2010, 2011).

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Ethical oversight of the Register has been in the hands of the Ethics Research Committees of

St. Vincent’s Hospital, Melbourne, the Monash Medical Centre, and the Royal Melbourne Hospital, as the Register’s site of housing has changed with time. Participation in the Register’s databank is at the instigation of the individual pregnant woman, most of whom are taking antiepileptic drugs (AEDs). The Register, which has been active since 1999, is estimated to be capturing 8 to 9% of all Australian pregnancies in WWE (Vajda et al - submitted). In the present paper, only material relating to WWE is used, whereas earlier papers from the Register have included data from the small number of women treated with AEDs for disorders other than epilepsy. The information used in the present analysis, except for the outcomes of the current pregnancy, was that provided at the structured interview at recruitment of the pregnancy into the Register. The material analysed comprised 1558 pregnancies exposed to AEDs, these agents being used as monotherapy in 73.2% of the pregnancies. The drugs used in at least 10 pregnancies were lamotrigine, in 533; carbamazepine, in 515; valproate, in 436;

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levetiracetam, in 149; topiramate, in 114; clonazepam, in 105; phenytoin, in 82; gabapentin, in 31; oxcarbazepine, in 19; ethosuximide, in 15; vigabatrin, in 12. 2.2 Data analysis Items selected for potential inclusion in the proposed model were such that pregnant women could

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be expected to be able to provide information on at the time of an initial interview before

pregnancy, or in early pregnancy. The magnitudes, or frequencies of occurrence of these items in

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database pregnancies which resulted in, or did not result in, FMs were then compared, mainly in terms of Relative Risk (RR) values, using 95% confidence intervals to assess significance. Statistically significantly different items (P < 0.05), and also several items in which the RR was

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sufficiently different from 1.0 to suggest that further examination was warranted, were then studied by a series of multiple variable logistic regressions, progressively removing non-

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significant variables until only statistically significant ones remained. Malformation risks were then calculated based on the surviving variables, and the outcomes displayed graphically.

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1. Results 1.1 Relevant parameters

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The values and rates of occurrence of various variables of possible relevance recorded in the Register are shown in Table 1. Data for individual types of employment are not shown if fewer

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than 10% of pregnancies were involved in the occupation in question. No data applying to fathers were considered, as only paternal nationality and occupational details had been recorded. Further,

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issues of biological fatherhood might cause sensitivities at the time of data collection. Among the items involved in the individual parameter comparisons there was a statistically significantly increased chance of a pregnancy leading to a foetus with malformations only in women (i) from families on lower incomes, (ii) with primary generalised epilepsies, (iii) taking valproate (VPA), and (iv) who had previous pregnancies which had resulted in FMs. There was a statistically borderline increase chance in those of European ethnicity and those taking any AED. On the other hand, malformations were statistically significantly less frequent in those who had taken AEDs apart from VPA. There was an obvious dose related association between valproate exposure and malformed foetuses. The malformation risk at various ranges of valproate dose were: up to 400 mg per day, 6.7% in 104 –pregnancies, 401-800 mg per day, 9.9% in 131 pregnancies; 801-1200 mg per day, 7.1% in 112 pregnancies; 1201-1600 mg per day, 23.4% in 47 pregnancies; 1601-2000 mg per day, 33.3% in 24 pregnancies; 2001-2400 mg per day, 0% in 3 pregnancies; 2401-2800 mg per day, 42.9% in 14 pregnancies; > 2800 mg per day, 54.5% in 11 pregnancies.

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The association between malformation bearing pregnancy and primary generalised epilepsy may have related to the increased use of VPA in this group of epilepsies, and maternal intake of VPA in more than one pregnancy in the same woman may have contributed to the association between previous histories of FM and FM in the pregnancy under consideration. In view of the latter possibility, only women who had previous pregnancies that did not involve exposure to VPA (N =

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659) were considered, but the malformation rate remained statistically significantly higher if there had been a previous pregnancy with a malformation (14.3% versus 4.8%, R.R. = 2.97; 95% C.I. =

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1.23, 7.19). 1.2 Risk calculation

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The various parameters mentioned in the preceding two paragraphs, together with urban dwelling, alcohol intake in pregnancy, a history of FMs in pregnancies of other family members and

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exposure to individual AEDs which had been taken in more than 10 pregnancies, provided 20 independent variables then studied in a series of logistic regressions. The effects of VPA were investigated both in terms of simple exposure to the drug, and the VPA dosages in the individual

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pregnancies. Statistically non-significant variables were deleted in a step-wise manner in the series of regressions until the final regression of best fit (P 3 years Previous pregnancies Number of previous offspring • 0 • 1 • 2 • >2 Malformations in offspring

47.0

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Non-valproate AEDs

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This item excludes those dying with previously recognised malformations

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Highlights Predictive tool to help assess the risk of foetal malformations Prospective data collected by the Australian Pregnancy Register

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Risks; Lower income, primary generalised epilepsy, valproate, previous defects High valproate dose relates to increased risk

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Possibility of protective effect of alcohol – needs validation

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Prediction of the hazard of foetal malformation in pregnant women with epilepsy.

The data collected in the Australian Register of antiepileptic drugs in pregnancy have been studied in the hope of defining simple items of informatio...
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