The Australian Register of Antiepileptic Drugs in Pregnancy: Changes over time in the epileptic population

doi:10.1016/j.jocn.2013.11.049

Journal of Clinical Neuroscience

Volume 21, Issue 9, September 2014, Pages 1478-1482

https://doi.org/10.1016/j.jocn.2013.11.049 Get rights and content

Abstract

The demographic characteristics, details of pregnancies, epilepsies, and treatment of 855 pregnant women with epilepsy enrolled in the Australian Antiepileptic Drugs in Pregnancy Register during 1999–2005 were compared with the corresponding data for the 801 women enrolled from 2006–2012. We estimate that the Register captures approximately 1 in 12 of all pregnancies in Australian women with epilepsy. A number of statistically significant changes were found, with nearly all explained by factors such as re-enrolment of women who had enrolled earlier pregnancies, changes in general population behaviour, altered attitudes to prescribing valproate and using it in lower doses, and the advent of newer antiepileptic drugs which have displaced the use of older agents. It appears that the Register has continued to capture a reasonably representative sample of pregnant Australian women with epilepsy as time has passed.

Introduction

The Australian Register of Antiepileptic Drugs in Pregnancy was set up in 1999 with the intention of collecting information on the risks of foetal malformations associated with human intrauterine exposure to antiepileptic drugs (AED). Additionally, information was collected concerning various details of the characteristics of the female population whose pregnancies were being followed. This information to the end of the year 2005 was analysed to measure the inclusion of pregnant women with epilepsy (WWE) compared to the Australian population as a whole [1].

The current communication reassesses changes in the proportion and nature of participating women, and it is restricted to reporting only on WWE, comprising the vast majority of participants and a homogeneous group.

Section snippets

Materials and methods

Information about the existence of the Register and its contact details is provided to pregnant WWE by their treating medical practitioners, and by various lay organisations. After that, contact with the Register is left to the discretion of the women so informed. If they decide to participate, data concerning the present pregnancy are recorded in a computer database. With permission from the women involved, certain medical details are obtained from their treating medical practitioners.

All

Proportion of pregnant Australian WWE captured by the Register

Annual publications provide information on the number of WWE in Australia who have given birth each year, and on the total numbers of women in the country who have given birth. Data on WWE from the state of New South Wales were not available in the publications, and data from the state of Victoria are absent for some years. If the data for pregnant WWE from these two states (which were unavailable) and the available data for all women from Victoria who gave birth in the same period are omitted

Discussion

Now that more than 6 years have passed since the last analysis, it is of interest to reassess the Register population to determine if changes in its characteristics have occurred with the passage of time. Such changes might arise from changes in the characteristics of the general population, but could also be brought about by alterations in professional practice resulting from knowledge of findings derived from earlier analyses of the Register’s contents, and from the availability of new methods

Conflicts of Interest/Disclosures

The authors declare that they have no financial or other conflicts of interest in relation to this research and its publication.

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Cited by (33)

Changes over 24 years in a pregnancy register – Teratogenicity and epileptic seizure control
2023, Epilepsy and Behavior
To trace (i) changes in Australian Pregnancy Register (APR) records concerning antiseizure medications (ASMs) prescribed for women with epilepsy (WWE) over the course of 24 years and correlate the changes with (ii) rates of occurrence of pregnancies involving foetal malformations, (iii) the body organs involved in the malformations, and (iv) freedom from epileptic seizures.
Use of valproate and carbamazepine decreased progressively, use of lamotrigine remained relatively static, and the use of levetiracetam increased progressively, whereas the use of topiramate first increased and then fell again, associated with a temporary increase in malformation-associated pregnancy rate. More serious malformations, such as spina bifida, became less frequent, whereas more trivial ones tended to increase, whereas epileptic seizure freedom rates improved.
The increasing use of newer ASMs in pregnant women has been associated with overall advantages in relation to the frequency and severity of foetal malformation and with advantages in relation to freedom from epileptic seizures.
Achieving neurologically desirable outcomes to pregnancy in women with epilepsy
2022, Epilepsy and Behavior
Citation Excerpt :
Women had become aware of the APR’s existence volunteered for inclusion either before or during their current pregnancy. It has been estimated that the APR has obtained information on about 8.7% of the relevant pregnancies that occurred in Australia over the period studied [14]. All contact between pregnant women and the APR has been via telephone.
To investigate possible factors that influenced whether pregnancy in women with epilepsy resulted in the desirable outcome of a live-born non-malformed infant and a mother whose pregnancy had been seizure free.
The desirable outcome, as defined, occurred in 46.3% of unselected pregnancies in the database of the Australian Register of Antiepileptic Drugs in Pregnancy (APR). The only factor investigated that had a statistically significant (P < 0.05) effect, increasing the chance of such a desirable outcome, was freedom from seizures in the pre-pregnancy year. However, anti-seizure medication (ASM) doses, particularly valproate doses, had been reduced prior to 15.6% of the pregnancies, and this may have concealed factors that otherwise may have adversely affected the desirable outcome rate. Analysis of data for monotherapy with the more commonly used ASMs appears to suggest that employing levetiracetam at the outset of antiseizure therapy may offer a better chance of a desirable outcome to future pregnancies than monotherapy with other ASMs, but this finding is not confirmed statistically.
In pregnancies where valproate use has already been minimized, seizure control throughout the pre-pregnancy year was associated with the best chance of a desirable outcome, as defined above. In most Australian women starting therapy for epilepsy initiating treatment with levetiracetam monotherapy may offer the best chance of such a desirable outcome to a future pregnancy, yet to be confirmed.
30 years of second-generation antiseizure medications: impact and future perspectives
2020, The Lancet Neurology
Citation Excerpt :
Another prospective study in 181 children aged 6–7 years reported behavioural problems, as assessed by parents, in 32% of children exposed to valproic acid, 14% exposed to carbamazepine, 16% exposed to lamotrigine, and 14% exposed to levetiracetam.69 In response to these findings and the regulatory restrictions on the use of valproic acid,70,71 prescription patterns for women with epilepsy have changed substantially during the past two decades.72–77 For pregnant women, the use of valproic acid and carbamazepine has substantially declined, and the use of lamotrigine and levetiracetam has substantially increased.74,77
Since 1989, 18 second-generation antiseizure medications have reached the market, resulting in a greatly increased range of treatment options for patients and prescribers. 30 years have passed and now is the time for an appraisal of the effect of these medications on clinical outcomes. Every antiseizure medication needs to be assessed individually, but overall second-generation drugs are less likely to cause pharmacokinetic interactions than their older counterparts. Some second-generation antiseizure medications have shown advantages in tolerability and safety, particularly in the treatment of older patients and women of childbearing potential. Disappointingly, however, none of these medications appear to be more efficacious than first-generation antiseizure medications, highlighting the need for novel strategies in epilepsy drug development. Although second-generation antiseizure medications have not substantially reduced the proportion of patients with pharmacoresistant epilepsy, their availability has enabled more opportunities to tailor treatment choice to the characteristics of the individual.
Valproate utilisation trends among girls and women from 2013 to 2018
2019, Seizure
To evaluate the change in the number of female valproate users in Lithuania from 2013 to 2018 and determine the presumed impact of two distinct European Medicines Agency (EMA) regulatory interventions on the observed trend.
An interrupted time series analysis was performed using reimbursement data from the National Health Register Fund to detect changes in user trends after a selected regulatory event in time.
The absolute number of female patients under 50 using valproate is seen decreasing over time. After an EMA regulatory procedure in 2014, there was only a delayed decrease in female valproate users under 15 (a change in trend of -4.83, 95%CI = -9.45 to -0.22, P = 0.041, a decrease in level 15 months post-intervention of -40.06, 95%CI = -79.26 to -0.86, P = 0.046). An increase in new prescriptions for patients with epilepsy was noted post-intervention (change in trend 13.75, 95%CI = 6.03–21.48, P = 0.004). The EMA referral procedure in 2017–2018 was followed by a lasting decrease in female valproate users of reproductive age and older (level effect 3 months post-intervention: -201.28, 95%CI = -310.61 to -91.96, P = 0.001 and -170.60, 95%CI = -287.73 to -53.48, P = 0.007, respectively). However, the rate of new initiations on valproate for patients with either epilepsy or mood disorders remained constant.
The number of female patients under 50 using valproate is decreasing over time. The 2018 EMA referral procedure was followed by a notable reduction in female valproate users.
Valproate and female patients: Prescribing attitudes of Italian epileptologists
2019, Epilepsy and Behavior
Citation Excerpt :
Little data exist on the impact of such evidence and recommendations on practice patterns in women with epilepsy. Common trends in different countries are a reduced prescription of valproate overall and lower prescribed doses together with increased use of lamotrigine (LTG) and levetiracetam (LEV) rather than carbamazepine (CBZ) or VPA [23–25]. The decline in use likely began before the warning in women with epilepsy, as one Swedish study showed [26].
After the European Medicines Agency (EMA) warning on the use of valproate (VPA) in female patients, we explored the antiepileptic drug (AED) prescribing attitudes of Italian epileptologists with regard to sex and VPA use in patients with epilepsy.
A specifically designed 30-item questionnaire was distributed at the annual multicenter meeting of the Italian League Against Epilepsy (LICE), held in Rome on January 2018. One hundred and sixty-nine physicians answered the questionnaire.
In females, VPA was significantly less prescribed as first-choice AED in childhood absence epilepsy (22% females vs 64% males, p < 0.001), Dravet syndrome (54% vs 71%, p = 0.01), juvenile myoclonic epilepsy (JME) (2% vs 74%, p < 0.001), and undetermined epilepsy (0% vs 32%, p < 0.001). Ninety-six percent of the respondents inform teenage girls of the detrimental effects of intrauterine exposure to VPA; 74% recommend contraceptive measures when prescribing VPA. All the respondents stated that they were aware of the recommendations on VPA in female patients, and 64% claimed to have had difficulties in implementing them.
The main challenges were represented by women with JME, who were seizure-free on VPA and failed to respond to levetiracetam and lamotrigine, and by little girls for whom VPA was considered the best choice. According to many Italian epileptologists, the decision to withdraw VPA should be shared with the patient.
Changes in antiepileptic drug-prescribing patterns in pregnant women with epilepsy
2018, Epilepsy and Behavior
We analyzed current prescribing patterns for antiepileptic drugs (AEDs) in pregnant women with epilepsy (PWWE) at 20 USA tertiary epilepsy centers.
The Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) study is an NIH-funded, prospective, observational, multicenter investigation of pregnancy outcomes for both mother and child, which enrolled women from December 2012 to January 2016. Inclusion criteria for PWWE included ages 14–45 years and up to 20 weeks gestational age. Exclusion criteria included history of psychogenic nonepileptic spells, expected intelligence quotient (IQ) < 70, other major medical illness, progressive cerebral disease, and switching AEDs in pregnancy prior to enrollment.
Three hundred fifty-one PWWE were enrolled in the MONEAD study, which included 259 (73.8%) on monotherapy, 77 (21.9%) on polytherapy, and 15 (4.3%) on no AEDs. The most common AED monotherapy regimens were lamotrigine (42.1% of monotherapies), levetiracetam (37.5%), carbamazepine (5.4%), zonisamide (5.0%), oxcarbazepine (4.6%), and topiramate (3.1%). All other individual monotherapies were each < 1%. The most common AED polytherapy combination was lamotrigine + levetiracetam (42.9% of polytherapies), followed by lacosamide + levetiracetam (6.5%), lamotrigine + zonisamide (5.2%), and all other remaining combinations (each < 4%); only 5.2% of polytherapy subjects were on ≥ 3 AEDs (1.1% of total PWWE). Only four subjects (1.1%) were on valproate (1 monotherapy, 3 polytherapy).
The distribution of AED use likely reflects current prescribing patterns for PWWE cared for in USA tertiary epilepsy centers. This distribution has changed markedly since the turn of the century, but changes in the general population remain uncertain.

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ReviewThe Australian Register of Antiepileptic Drugs in Pregnancy: Changes over time in the epileptic population