L. Parsons

Malformation risks of antiepileptic drugs in pregnancy: a prospective study from the UK Epilepsy and Pregnancy Register

Objective: To assess the relative risk of major congenital malformation (MCM) from in utero exposure to antiepileptic drug (AEDs). Methods: Prospective data collected by the UK Epilepsy and Pregnancy Register were analysed. The presence of MCMs recorded within the first three months of life was the main outcome measure. Results: Full outcome data were collected on 3607 cases. The overall MCM rate for all AED exposed cases was 4.2% (95% confidence interval (CI), 3.6% to 5.0%). The MCM rate was higher for polytherapy (6.0%) (n = 770) than for monotherapy (3.7%) (n = 2598) (crude odds ratio (OR) = 1.63 (p = 0.010), adjusted OR = 1.83 (p = 0.002)). The MCM rate for women with epilepsy who had not taken AEDs during pregnancy (n = 239) was 3.5% (1.8% to 6.8%). The MCM rate was greater for pregnancies exposed only to valproate (6.2% (95% CI, 4.6% to 8.2%) than only to carbamazepine (2.2% (1.4% to 3.4%) (OR = 2.78 (p<0.001); adjusted OR = 2.97 (p<0.001)). There were fewer MCMs for pregnancies exposed only to lamotrigine than only to valproate. A positive dose response for MCMs was found for lamotrigine (p = 0.006). Polytherapy combinations containing valproate carried a higher risk of MCM than combinations not containing valproate (OR = 2.49 (1.31 to 4.70)). Conclusions: Only 4.2% of live births to women with epilepsy had an MCM. The MCM rate for polytherapy exposure was greater than for monotherapy exposure. Polytherapy regimens containing valproate had significantly more MCMs than those not containing valproate. For monotherapy exposures, carbamazepine was associated with the lowest risk of MCM.

Malformation risks of antiepileptic drug monotherapies in pregnancy: updated results from the UK and Ireland Epilepsy and Pregnancy Registers

Objectives Antiepileptic drug (AED) exposure during pregnancy increases the risk of major congenital malformations (MCMs). The magnitude of this risk varies by AED exposure. Here we provide updated results from the UK Epilepsy and Pregnancy Register of the risk of MCMs after monotherapy exposure to valproate, carbamazepine and lamotrigine. Methods Fifteen-year prospective observational study from 1996 until 2012. The main outcome measure is the MCM rate. Results Informative outcomes were available for 5206 cases. 1290 women were exposed to valproate monotherapy, 1718 to carbamazepine monotherapy and 2198 to lamotrigine monotherapy. The MCM risk with valproate monotherapy exposure in utero was 6.7% (95% CI 5.5% to 8.3%) compared with 2.6% with carbamazepine (95% CI 1.9% to 3.5%) and 2.3% with lamotrigine (95% CI 1.8% to 3.1%). A significant dose effect was seen with valproate (p=0.0006) and carbamazepine (p=0.03) exposed pregnancies. A non-significant trend towards higher MCM rate with increasing dose was found with lamotrigine. MCM rate for high-dose lamotrigine (>400 mg daily) was lower than the MCM rate for pregnancies exposed to <600 mg daily of valproate, but this was not significant (3.4% vs 5.0%, p=0.31). Conclusions In utero exposure to valproate carries a significantly higher MCM risk than lamotrigine (p=0.0001) and carbamazepine (p=0.0001) monotherapy. In contrast to prior findings, high-dose lamotrigine was associated with fewer MCMs than all doses of valproate. While lamotrigine has a favourable profile compared with valproate for adverse pregnancy outcomes, the requirements for seizure control should not be overlooked.

Folic acid use and major congenital malformations in offspring of women with epilepsy. A prospective study from the UK Epilepsy and Pregnancy Register.

Objective: In the general population, folic acid supplementation during pregnancy has been demonstrated to reduce the frequency of neural tube defects (NTDs) and other major congenital malformations (MCMs). It is recommended that women with epilepsy contemplating pregnancy take supplemental folic acid because of the known antifolate effect of some antiepileptic drugs (AEDs). Here the aim was to determine the effectiveness of this practice. Methods: This study is part of a prospective, observational, registration and follow-up study. Suitable cases are women with epilepsy who become pregnant and who are referred before outcome of the pregnancy is known. The main outcome measure is the MCM rate. Outcomes were analysed against folic acid exposure, malformation type and drug group for the most commonly used monotherapy AEDs. Results: In 1935 cases reported to have received preconceptual folic acid, 76 MCMs (3.9%; 95% CI 3.1 to 4.9) and eight NTDs (0.4%; 95% CI 0.2 to 0.8) were identified. For 2375 women who were reported to have received folic acid but not until later in the pregnancy (n = 1825) or not at all (n = 550), there were 53 outcomes with an MCM (2.2%; 95% CI 1.7 to 2.9) and eight NTDs (0.34%; 95% CI 0.2 to 0.7). Conclusions: The study supports the view that extrapolation from studies carried out in the general population to groups of women with epilepsy may be questionable. It may be that the increased risk of MCM recorded in this group occurs through mechanisms other than that of folic acid metabolism.

Recurrence risk of congenital malformations in infants exposed to antiepileptic drugs in utero.

Purpose:  Use of antiepileptic drugs in pregnancy is associated with congenital malformations and developmental delay. Previous studies have suggested that women who have had one child with a congenital malformation are at increased risk of having other children with malformations. We sought to confirm the magnitude of risk in a large cohort drawn from the United Kingdom Epilepsy and Pregnancy Register.

Valproate and the risk for congenital malformations: Is formulation and dosage regime important?

BACKGROUND Use of valproate in pregnancy, especially in doses over 1000mg a day, is known to be associated with a higher risk for major congenital malformations compared with other antiepileptic drugs. We sought to investigate whether the increased risk could be minimised by using controlled release or divided daily doses of valproate. METHODS The UK Epilepsy and Pregnancy Register is a prospective, observational and follow up study set up to determine the risks of major congenital malformations for infants exposed to antiepileptic drugs in utero. In this study we have extracted data for those pregnancies exposed to valproate in monotherapy. We have calculated malformation rates and relative risks as a function of valproate exposure. RESULTS Outcome data were available for 1109 pregnancies exposed to valproate in monotherapy. Exposure to 1000mg a day or more of valproate was associated with almost double the risk of major congenital malformation compared with daily valproate doses below 1000mg daily (8.86% vs 4.88%, RR: 1.7; 95% CI: 1.1-2.9). There were no differences in the risks for malformations between standard release valproate and controlled release valproate preparations (RR: 1.11; 95% CI: 0.67-1.83) or for those exposed to single or multiple daily administrations (RR: 0.99, 95% CI: 0.58-1.70). CONCLUSION Prescribing controlled release valproate or multiple daily administrations in pregnancy did not reduce the risk for malformations. Higher malformation rates observed with in utero exposure to valproate are more likely related to total daily dose, rather than peak serum levels.

PATH39 Malformation risks of antiepileptic drugs in pregnancy: an update from the UK Epilepsy and Pregnancy Register

Aim To assess the relative risk of major congenital malformations (MCM) from exposure to anti-epileptic drugs (AEDs) during pregnancy. Methods 15 year prospective observational study from 1996 until 2009. The outcome measure is the MCM rate. Results Informative outcomes were available for 5802 cases. The risk of MCM was significantly higher in women on AEDs during pregnancy (n=5376) in comparison to those on no treatment (n=426), RR: 1.55 (95% CI 1.13 to 2.14), and significantly higher in polytherapy (n=1183) than monotherapy (n=4193), RR: 1.60 (95% CI 1.19 to 2.15). The risk to those on valproate monotherapy was more than double that for those on either carbamazepine (RR 2.35, 95% CI 1.55 to 3.57) or lamotrigene (RR 2.40, 95% CI 1.57 to 3.68). 245 and 362 informative outcomes were obtained for topiramate and levetiracetam respectively, with MCM rates of 7.1% (95% CI 4.5 to 11.0%) and 2.5% (95% CI 1.3 to 4.7%). There were 3/83 cases of MCM in Topiramate monotherapy and 14/162 cases in polytherapy. There were no cases of MCMs in levetiracetam monotherapy and 9/229 cases levetiracetam polytherapy. Conclusions AED exposure during pregnancy increases the risk of MCM in the babies of women with epilepsy. Polytherapy exposure has a higher risk than monotherapy. Valproate exposure carries higher MCM risk than any other AED. Lowest risk is associated with carbamazepine or lamotrigene monotherapy. Results for levetiracetam, although numbers are small, look promising.

051 Valproate and the risk for congenital malformations; is formulation and dosage regime important?

Background Use of valproate in pregnancy, especially in doses over 1000mg a day, is known to be associated with a higher risk for major congenital malformations compared with other antiepileptic drugs. We sought to investigate whether the increased risk could be minimised by using controlled release or divided daily doses of valproate. Methods The UK Epilepsy and Pregnancy Register is a prospective, observational and follow-up study set up to determine the risks of major congenital malformations for infants exposed to antiepileptic drugs in-utero. In this study we have extracted data for those pregnancies exposed to valproate in monotherapy. We have calculated malformation rates and relative risks as a function of valproate exposure. Results Outcome data were available for 1109 pregnancies exposed to valproate in monotherapy. Exposure to over 1000 mg a day of valproate was associated with almost double the risk of major congenital malformation compared with daily valproate doses below 1000mg daily (8.86% vs 4.88%, RR: 1.7; 95% CI 1.1 to 2.9). There were no differences in the risks for malformations between standard release valproate and controlled release valproate preparations (RR: 1.11; 95% CI 0.67 to 1.83) or for those exposed to single or multiple daily administrations (RR: 0.99, 95% CI 0.58 to 1.70). Conclusion Prescribing controlled release valproate or multiple daily administrations in pregnancy did not reduce the risk for malformations. Higher malformation rates observed with in utero exposure to valproate are more likely related to total daily dose, rather than peak serum levels.

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.

The antiepileptic drugs in pregnancy—a register in the UK to determine the relative safety of each in this situation

Abstracts of papers and posters presented at ‘Epilepsy 1998-The Leading Edge’ annual scientific meeting of the British Branch of the International League against Epilepsy, Oxford, October 1998s of papers and posters presented at ‘Epilepsy 1998-The Leading Edge’ annual scientific meeting of the British Branch of the International League against Epilepsy, Oxford, October 1998 Is folic acid protective against neural tube defects in infants exposed to sodium valproate in utero? John J. Craig*, P. Morrison+, J.I. Morrow* & V.H. Patterson* *Department of Neurology, Royal Victoria Hospital, Belfast, UK; + Department of Medical Genetics, Be/fast City Hospital, Be/fast, UK The risk of neural tube defects (NTDs) in infants exposed to sodium valproate (VPA) in utero is estimated between 2% and 6%. Since this is similar to the risk of a recurrent NTD for a woman who has had a previous child with this condition, and high-dose folic acid (4 mg) has been shown to be protective in this situation, it has been suggested that a similar dose (5 mg daily) of folic acid should be prescribed periconceptually to women taking VPA. There is, however, no evidence to support this. We present the case of an infant born with an NTD to a woman taking VPA despite maternal high-dose periconceptual folic acid intake to highlight the difficulties in counselling women with epilepsy who become pregnant whilst taking VPA based on current information. We also present the data so far collected through the UK Register, which we have set up to assess the relative safety of the AEDs, to demonstrate the low-level of periconceptual folic acid intake in women taking VPA. Further randomized studies need to be done to compare the protective effect of low and high-dose folic acid in women taking AEDs. In the meantime, however, all those dealing with patients with epilepsy should ensure that folic acid is taken by their female patients who are planning a pregnancy. The antiepileptic drugs in pregnancy-a register in the UK to determine the relative safety of each in this situation John Craig*, Aline RussetIt, Patrick Morrison:, Linda Parsons” & Jim Morrow* * Department of Neurology, Royal Victoria Hospital, Be/fast, UK; + Department of Neurophysiology, Southern General Hospital, Glasgow, UK;

U.K. epilepsy and pregnancy group

Department of Genetics, Be/fast City Hospital, Be/fast, UK; s Department of Neurology, St A/bans, UK Counselling women with epilepsy as to the safest preparation in pregnancy has become more difficult in the last few years because of the ever increasing number of antiepileptic drugs (AEDs). This is because whilst the teratogenic potential of the older AEDs is well established, the situation for the newer drugs is unknown. Recognizing the problems with post-marketing surveillance in general, and existing registers in particular, we have established a register, in conjunction with the British Neurological Surveillance Unit, to which all pregnancies occurring in women with epilepsy in the UK can be reported. Since commencing the study approximately 30 months ago we have been informed of almost 400 cases, of which more than 80% have been prospectively reported, and have collected full follow-up details on almost half of these so far. We have therefore established an effective method of obtaining information, which in part, might allow the relative safety of each of the AEDs in pregnancy to be determined. We would therefore encourage all those dealing with women with epilepsy to refer suitable cases to the register so that this might be achieved. 1059-1311/98/010421 + 09