Preventing Teratogenicity in Women with Epilepsy.

Over the last 50 years there has been a significant increase in our understanding of the issues faced by women with epilepsy, in both planning and undertaking pregnancy. The risks of teratogenicity associated with antiseizure medications have emerged slowly. The major pregnancy registers have substantially contributed to our knowledge about teratogenic risk associated with the commonly used antiseizure medications. However, there are substantial gaps in our knowledge about the potential risks associated with many third-generation drugs. The remit of the pregnancy registers and the wider research focus has moved beyond anatomical major congenital malformations. Increasingly neurodevelopmental and behavioral abnormalities have been investigated after in utero exposure to antiseizure medications. Public health approaches can help reduce the risk of teratogenicity. However, neurologists still have a vital role in reducing the risk of teratogenicity at an individual level for women attending their clinic. They also have responsibility to ensure that women with epilepsy are aware of the rationale for the different available options.

Epilepsy and pregnancy: identifying risks.

Pregnancy is a time of physical, physiological and psychological challenge. For women with epilepsy, as well as its potential for joy and fulfilment, pregnancy may bring additional risks and difficulties. Clinicians must anticipate and prevent these complications, ensuring that pregnancy, delivery and motherhood proceed without obstetric or medical complications, using available evidence to balance individual risks of undertreatment and overtreatment. Here we review epilepsy management in pregnancy, identifying some of the known effects of epilepsy and its treatment on gestation, fetal malformation, delivery, and neurocognitive and behavioural development. We outline strategies to reduce obstetric and fetal complications in women with epilepsy, while recognising the sometimes competing need to maintain or improve seizure control. We reinforce the importance of identifying those at highest risk, who may require additional measures or safeguards.

Changing antiepilepsy drug-prescribing trends in women with epilepsy in the UK and Ireland and the impact on major congenital malformations.

OBJECTIVES: After 20 years of data collection, pregnancy registers have informed prescribing practice. Various populations show trends for a reduction in valproate prescribing, which is associated with an increased risk of anatomical teratogenesis and neurodevelopmental effects in those exposed in utero. Our aim was to determine if any shifts in prescribing trends have occurred in the UK and Ireland Epilepsy and Pregnancy Register cohort and to assess if there had been any change in the overall major congenital malformation (MCM) rate over time. METHODS: The UK and Ireland Epilepsy and Pregnancy Register, a prospective, observational, registration and follow-up study established in 1996, was used to determine the changes in antiepileptic drugs (AEDs) utilised during pregnancy and the MCM rate between 1996 and 2016. Linear regression analysis was used to assess changes in AED utilisation, and Poisson regression was used for the analysis of trends in the MCM rates. RESULTS: Outcome data for 9247 pregnancies showed a stable percentage of monotherapy to polytherapy prescribing habits over time. After Bonferroni correction, statistically significant (p<0.003) changes were found in monotherapy prescribing with increases in lamotrigine and levetiracetam and decreases in valproate and carbamazepine use. Between 1996 and 2016, the total MCM rate showed a 2.1% reduction per year (incidence risk ratio 0.979 (95% CIs 0.956 to 1.002) but Poisson regression analysis showed that this was not statistically significant p=0.08). CONCLUSION: Significant changes are seen in the prescribing habits in this cohort over 20 years, but a statistically significant change in the MCM rate was not detected. This work should be replicated on a larger scale to determine if significant changes are occurring in the MCM rate, which would allow a robust economic estimate of the benefits of improvements in prescribing practice and the personal effect of such changes.

Non-convulsive status epilepticus: mimics and chameleons.

Non-convulsive status epilepticus (NCSE) is an enigmatic condition with protean manifestations. It often goes unrecognised, leading to delays in its diagnosis and treatment. The principal reason for such delay is the failure to consider and request an electroencephalogram (EEG), although occasional presentations have no scalp or surface electroencephalographic correlate. In certain settings with limited EEG availability, particularly out-of-hours, clinicians should consider treating without an EEG. Patients need a careful risk-benefit analysis to assess the risks of neuronal damage and harm versus the risks of adverse effects from various intensities of therapeutic intervention. Specialists in EEG, intensive care or epilepsy are invaluable in the management of patients with possible NCSE.

Treating women with juvenile myoclonic epilepsy.

Epilepsy has special implications for women, especially during their childbearing years, and particularly when pregnancy is contemplated. Being aware of the relevant issues is therefore essential. For anyone with juvenile myoclonic epilepsy and other idiopathic generalised epilepsies, valproate is generally regarded as the gold standard treatment against which other antiepileptic drugs are compared. However, information from pregnancy registers consistently show valproate to be associated with the highest risk for major congenital malformations, and studies exploring cognitive and behavioural development of offspring also show that valproate has an adverse impact. This creates a significant headache when trying to choose the "right" drug for most women with a generalised epilepsy syndrome.

Antiepileptic drugs and intrauterine death: A prospective observational study from EURAP.

OBJECTIVE: To compare the risk of spontaneous abortions and stillbirth associated with maternal use of different antiepileptic drugs (AEDs). METHODS: The EURAP registry is an observational international cohort study primarily designed to determine the risk of major congenital malformations (MCMs) after prenatal AED exposure. Using EURAP data, we prospectively monitored pregnancies exposed to the 6 most common AED monotherapies and to polytherapy. Intrauterine death (spontaneous abortion and stillbirth combined) was the primary endpoint. RESULTS: Of 7,055 pregnancies exposed to monotherapy with lamotrigine (n = 1,910), carbamazepine (n = 1,713), valproic acid (n = 1,171), levetiracetam (n = 324), oxcarbazepine (n = 262), or phenobarbital (n = 260), and to polytherapy (n = 1,415), 632 ended in intrauterine deaths (592 spontaneous abortions and 40 stillbirths). Rates of intrauterine death were similar across the different monotherapies (8.2%; 95% confidence interval [CI] 7.5%-8.9%), higher with polytherapy (12.1%; 95% CI 10.5%-13.9%), but showed no relationship with AED dose in monotherapy at conception. Multivariable analysis including 11 covariates in addition to the different AED exposures showed that the risk was greater with polytherapy vs monotherapy (risk ratio [RR] 1.38; 95% CI 1.14-1.66), parental history of MCMs (RR 1.92; 1.20-3.07), maternal age (RR 1.06; 1.04-1.07), and number of previous intrauterine deaths (RR 1.09; 1.00-1.19). The risk was greater with early enrollment and decreased with later gestational week at enrollment (RR 0.84; 0.82-0.86). CONCLUSIONS: The most important risk factors for intrauterine death in pregnancies of women with epilepsy include maternal exposure to AED polytherapy and the presence of MCMs in at least one of the parents.

Anti-epileptic drugs in pregnancy: current safety and other issues.

Women with epilepsy of child-bearing years have their own considerations, which must be taken into account if management of their epilepsy is to be optimised. The main issues to consider include the effects of: female hormones on seizure control, anti-epileptic drugs (AEDs) on hormonal methods of contraception, epilepsy and AEDs on fertility, epilepsy and AEDs on pregnancy itself, pregnancy on AEDs and seizure control and epilepsy, seizures and AEDs on the developing embryo/fetus. Whereas previous studies have concentrated on the increased risk of major congenital malformations from prenatal AED exposure, the effects on cognitive and behavioural development are increasingly being explored. This article looks at the evidence currently available for all of the above issues, taking into account the increased number of AEDs which are now available.

Do lamotrigine and levetiracetam solve the problem of using sodium valproate in women with epilepsy?

Women with epilepsy, especially those of child-bearing age, are faced with difficult choices when it comes to choosing the most suitable antiepileptic drug (AED). This is particularly so for those with idiopathic generalized epilepsies, or those for whom seizure syndrome is not immediately apparent, where sodium valproate is still considered the drug of choice. While with treatment most might expect to become seizure free, without any adverse effects, other considerations for women mean that valproate is usually initially avoided, with other AEDs such as lamotrigine or levetiracetam being chosen in preference. Based on current information, this article attempts to provide an overview on whether or not the availability of these and other broad-spectrum AEDs have solved the difficulties of using valproate in women of child-bearing age.