|Year : 2018 | Volume
| Issue : 1 | Page : 39-43
Levetiracetam use during pregnancy in women with epilepsy: Preliminary observations from a tertiary care center in Northern India
Ramandeep Bansal1, Vanita Suri1, Seema Chopra1, Neelam Aggarwal1, Pooja Sikka1, Subhas Chandra Saha1, Manoj Kumar Goyal2, Praveen Kumar3
1 Department of Obstetrics and Gynecology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
2 Department of Neurology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
3 Department of Paediatric Medicine, Postgraduate Institute of Medical Education and Research, Chandigarh, India
|Date of Submission||02-Jan-2018|
|Date of Acceptance||09-Apr-2018|
|Date of Web Publication||30-Apr-2018|
Department of Obstetrics and Gynecology, Postgraduate Institute of Medical Education and Research, Chandigarh
Source of Support: None, Conflict of Interest: None
INTRODUCTION: Data on efficacy and safety of levetiracetam (LEV) during pregnancy is still limited. We analyzed efficacy and safety of LEV during pregnancy in North Indian women with epilepsy (WWE) which is being presented here.
PATIENTS AND METHODS: This retrospective study included 99 WWE (on treatment with a single antiepileptic drug [AED]) who were evaluated in medical-surgical disorder antenatal clinic of the department of obstetrics and gynecology at a tertiary care teaching hospital and referral center in North India. All the obstetric and fetal data as well as data pertaining to epilepsy were noted meticulously.
RESULTS: In this study (n = 99), 35 women received carbamazepine, 28 received LEV, 15 received valproate (VPA), 13 received phenytoin (PHT), three each received oxcarbazepine and lamotrigine, respectively, and two received clobazam. Although the use of VPA was associated with significantly better control of seizures compared to LEV, its use was associated with higher risk of major congenital malformations (13.3%). The incidence of gestational hypertension was lower while incidence of fetal distress was significantly higher in WWE receiving PHT during pregnancy. None of the child born to pregnant women receiving LEV had any congenital malformation.
CONCLUSION: LEV is a first-line AED during pregnancy. Future prospective studies using therapeutic drug monitoring during pregnancy may further help in establishing its role during pregnancy.
Keywords: Levetiracetam, pregnancy, women with epilepsy
|How to cite this article:|
Bansal R, Suri V, Chopra S, Aggarwal N, Sikka P, Saha SC, Goyal MK, Kumar P. Levetiracetam use during pregnancy in women with epilepsy: Preliminary observations from a tertiary care center in Northern India. Indian J Pharmacol 2018;50:39-43
|How to cite this URL:|
Bansal R, Suri V, Chopra S, Aggarwal N, Sikka P, Saha SC, Goyal MK, Kumar P. Levetiracetam use during pregnancy in women with epilepsy: Preliminary observations from a tertiary care center in Northern India. Indian J Pharmacol [serial online] 2018 [cited 2021 May 10];50:39-43. Available from: https://www.ijp-online.com/text.asp?2018/50/1/39/231479
| » Introduction|| |
Despite decades of research, choice of antiepileptic drugs (AEDs) during pregnancy in women with epilepsy (WWE) continues to be debated, the main reason being the fact that both epilepsy and its treatment (AEDs) can have deleterious effects on mother and neonate. Most of the conventional AEDs are associated with harmful teratogenic effects on the fetus. Thus, there is an urgent need of AEDs which are both (a) effective in seizure control and (b) free from teratogenic side effects. Levetiracetam (LEV) is one such AED which is supposed to be effective in controlling seizures during pregnancy and relatively free of teratogenic side effects. However, data on its efficacy and teratogenicity during pregnancy are limited. More specificity, there are no data in this regard from the North Indian population. Thus, we conducted this study to analyze efficacy and safety of LEV during pregnancy in North Indian WWE.
Aims and objectives
The aim of this study is to determine the safety and efficacy of LEV in North Indian WWE.
| » Patients and Methods|| |
This study included retrospective analysis of WWE who were evaluated in medical-surgical disorder antenatal clinic of the department of obstetrics and gynecology at a tertiary care teaching hospital and referral center in North India. All the women who attend this clinic had their data filled in a predesigned pro forma by trained obstetricians. All the obstetric and fetal data (e.g., antenatal visit records, antenatal history, blood pressure, seizures during pregnancy, findings on ultrasonography, intrauterine growth retardation [IUGR], antepartum and postpartum hemorrhage [PPH], premature rupture of membranes [PROM], intrapartum events, presence of fetal distress [FD], need as well as indication for cesarean section [CS], major congenital malformations [MCMs], birth weight, and investigational records) as well as data pertaining to epilepsy (e.g., type, frequency, and duration of seizures and type, number, dose, and duration of AEDs) are entered in this pro forma at every visit and at completion of delivery. All the WWE are also seen by a neurologist with experience in epilepsy, and seizures were managed according to standard guidelines. All the neonates were examined carefully by a neonatologist.
We identified 28 WWE from January 2011 to December 2016 who received LEV monotherapy for control of their seizures. During this period, a total of 210 WWE were evaluated in our clinic out of whom 99 women were on monotherapy with single AED during their index pregnancy. LEV monotherapy was administered in 28/99 (28.3%) WWE making it one of the most commonly prescribed drugs at our center. All the data were collected retrospectively from the charts.
statistical analysis was done using SPSS version 22 (IBM SPSS Statistics for Windows, Armonk, NY: IBM Corp. released in 2013). The results were represented as mean, median, and standard deviation. Categorical variables were compared using Chi-square test while continuous variables were compared using Mann–Whitney test. P < 0.05 was taken as significant.
| » Results|| |
Profile of study group
This study included 99 WWE who were on AED monotherapy. Thirty-five WWE received carbamazepine (CBZ), 28 received LEV, 15 received valproate (VPA), 13 received phenytoin (PHT), three each received oxcarbazepine and lamotrigine, respectively, and two received clobazam.
Demographic profile of levetiracetam group (n
The mean age of patients in LEV group was 26.13 ± 3.9 years. The mean duration of seizures in LEV group was 97.9 ± 81.6 months. Mean interval between last seizure and pregnancy was 34.3 ± 36.1 months. Duration of epilepsy was >15 years in three and >5 years in 15 WWE. Twelve (42.9%) women had recurrence of seizures during pregnancy. Three (10.7%) women had preterm labor, 5 (17.9%) women needed CS (emergency = 4; elective = 1), 2 (7.1%) women had FD, 5 (17.9%) had low birth weight/IUGR, 2 (7.1%) had preeclampsia, while 7 (25%) women had gestational hypertension (HT). None of the women had ante or PPH, postpartum seizures, or abortion. None of the newborns had any MCM. These results are summarized in [Table 1].
|Table 1: Demographic profile and comparisons of various maternal and neonatal outcomes among women with epilepsy on monotherapy with levetiracetam, phenytoin, carbamazepine, and valproate|
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Comparison of levetiracetam with other antiepileptic drugs when used as monotherapy
In this study, we compared effects of various drugs (CBZ, VPA, and PHT) on maternal and neonatal outcomes with LEV. On comparison, while LEV and CBZ were comparable to each other in all aspects, there was significantly better control of seizures with VPA compared to LEV. However, there was a statistically insignificant (P = 0.1) higher risk of MCMs (13.3%) in children born to women receiving VPA. The risk of gestational HT was lower in WWE receiving PHT, but there was a significantly higher incidence of FD in WWE receiving PHT during pregnancy.
Factors determining occurrence of seizures in the entire cohort (n
In this study, we tried to determine if any of the factors (duration of epilepsy, parity, preconception control of seizures, type of drug used, poor past obstetrical history, age of the woman, etc.) can predict occurrence of seizures during pregnancy. Only factor which correlated with occurrence of seizure during pregnancy was poor preconception control of seizures defined as occurrence of seizures within 9 months before conception (P = 0.013). There was a better seizure control (P = 0.1) when VPA was used as AED compared to other AEDs though the difference was statistically insignificant.
Factors affecting maternal and neonatal complications in entire cohort (n
In this study, we also determined factors which could predict various maternal and neonatal outcomes. On analysis, a positive correlation was found between duration of illness >15 years and anemia during pregnancy (P = 0.037) as well as occurrence of seizures during pregnancy with preterm labor and (P = 0.013) and need for CS (P = 0.04). Although MCMs (n = 2, both neural tube defects) in newborns were seen only in WWE on VPA, the difference did not reach statistical significance.
| » Discussion|| |
Several studies , and reviews  have documented an increased risk of fetal malformations (4%–9% with AEDs compared to 1%–2% risk in general population) in WWE treated with conventional AEDs during pregnancy. In addition, recent studies have indicated risk of autism and poor cognitive abilities in children exposed to VPA in utero. However, data on risk of fetal and maternal outcomes in WWE who are exposed to newer AEDs are limited save for lamotrigine.
LEV was first approved by the Food and Drug Administration as an AED in 1999. It has several advantages over conventional AEDs, namely, complete oral bioavailability, linear pharmacokinetics, twice daily dosing, excretion through kidneys, minimal bindings to plasma proteins, and relative lack of drug-to-drug interactions. All the properties have made LEV more suitable as first-line AED for the treatment of epilepsy, and in fact, it is one of the commonly prescribed drugs for epilepsy in India. Even in this study, 28.3% of all WWE who were on monotherapy were taking LEV. Thus, it is imperative that safety profile of LEV in pregnant women should be studied in detail.
In this study, we retrospectively analyzed our data to determine safety profile of LEV in pregnancy. The demographic profile of study cohort (n = 99) was in accordance with previous studies , from the Indian subcontinent. The determinants of occurrence of seizures and MCMs during pregnancy were also in accordance with previous studies from the Indian subcontinent and across the globe.,,,
In this study, we did not find any fetal malformation in WWE who were exposed to LEV during pregnancy. Our results are similar to Australian pregnancy register  (no MCM in babies born to WWE on LEV; n = 22), UK and Ireland epilepsy pregnancy registers  (0.7% risk of MCM in babies born to WWE on LEV; n = 304), and a population-based cohort study from Denmark  (no MCM in babies born to WWE on LEV; n = 58). Thus, from our experience and other studies, it can be safely concluded that in utero, exposure to LEV is relatively safe in terms of occurrence of MCMs in neonates. On comparison with different AEDs, there was a higher risk of MCMs following in utero exposure to VPA compared to LEV though it did not reach significance. The main reason for this may be the lower sample size of this cohort.
The incidence of various maternal and neonatal complications in WWE on LEV (n = 28) in this study was in accordance with previous data. Compared to a study from Southern part of our country, incidence of gestational HT (25% vs. 6.4%), preeclampsia (7.1% vs. 3.8%), and instrumental delivery (10.7% vs. 2.7%) was higher in our cohort while incidence was lower for vaginal bleeding (1.1% vs. 1.6%), PROM (3.5% vs. 5.3%), and CS (17.8% vs. 30%). The reason for higher prevalence of gestational HT as well as other differences in reported rates of various maternal complications in our cohort is likely related to the fact that ours being a tertiary care institute, we often receive patients with severe complications compared to other centers. The incidence of LBW (i.e., <2500 gm) (17.8%) was higher in our cohort than reported by the western study. This is likely related to lower mean birth weight of Indian newborn babies compared to western babies.
A word of caution needs to be mentioned here. In this study, 12 (42.8%) WWE had recurrence of seizures during pregnancy. These rates were slightly higher than reported in a previous study. The occurrence of seizures during pregnancy was associated with higher risk of preterm birth and need for CS in this study. When compared, there was trend toward better control of seizures with VPA compared to LEV during pregnancy. This is probably related to fluctuations in levels of LEV during pregnancy. The serum concentrations of LEV are supposed to decrease by 60% during pregnancy (especially in the third trimester), owing to (a) increased renal clearance, (b) increase metabolism by nonhepatic esterases, (c) changes in oral absorption, and (d) increase in the volume of distribution. This is likely to affect seizure control during pregnancy. Thus, ideally, doses of LEV during pregnancy should be guided by therapeutic drug monitoring., However, facilities for serum LEV levels are currently not available at most centers in India and whether the dose of LEV should be increased empirically during pregnancy is not clear at the time of drafting this article. Future well-conducted prospective studies determining drug levels of LEV during pregnancy may help in providing answer to some of these questions.
| » Conclusion|| |
LEV continues to be a promising drug for use as first-line AED during pregnancy. The main limitation of this study was its small sample size resulting in small numbers of patients during subgroup analyses. Future prospective studies using therapeutic drug monitoring during pregnancy may further help in establishing its role as AED in WWE during pregnancy.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| » References|| |
Pennell PB. 2005 AES annual course: Evidence used to treat women with epilepsy. Epilepsia 2006;47 Suppl 1:46-53.
Longo B, Forinash AB, Murphy JA. Levetiracetam use in pregnancy. Ann Pharmacother 2009;43:1692-5.
Harden CL. Pregnancy and epilepsy. Continuum (Minneap Minn) 2014;20:60-79.
Meador KJ, Baker GA, Browning N, Clayton-Smith J, Combs-Cantrell DT, Cohen M, et al.
Cognitive function at 3 years of age after fetal exposure to antiepileptic drugs. N Engl J Med 2009;360:1597-605.
Hunt S, Craig J, Russell A, Guthrie E, Parsons L, Robertson I, et al.
Levetiracetam in pregnancy: Preliminary experience from the UK epilepsy and pregnancy register. Neurology 2006;67:1876-9.
Dooley M, Plosker GL. Levetiracetam. A review of its adjunctive use in the management of partial onset seizures. Drugs 2000;60:871-93.
Hovinga CA. Levetiracetam: A novel antiepileptic drug. Pharmacotherapy 2001;21:1375-88.
Koubeissi M. Levetiracetam: More evidence of safety in pregnancy. Epilepsy Curr 2013;13:279-81.
Thomas SV. Managing epilepsy in pregnancy. Neurol India 2011;59:59-65.
] [Full text]
Thomas SV, Sindhu K, Ajaykumar B, Sulekha Devi PB, Sujamol J. Maternal and obstetric outcome of women with epilepsy. Seizure 2009;18:163-6.
Borthen I, Eide MG, Daltveit AK, Gilhus NE. Obstetric outcome in women with epilepsy: A hospital-based, retrospective study. BJOG 2011;118:956-65.
Borthen I, Eide MG, Daltveit AK, Gilhus NE. Delivery outcome of women with epilepsy: A population-based cohort study. BJOG 2010;117:1537-43.
Vajda FJ, Graham J, Roten A, Lander CM, O'Brien TJ, Eadie M, et al.
Teratogenicity of the newer antiepileptic drugs – The Australian experience. J Clin Neurosci 2012;19:57-9.
Mawhinney E, Craig J, Morrow J, Russell A, Smithson WH, Parsons L, et al.
Levetiracetam in pregnancy: Results from the UK and Ireland epilepsy and pregnancy registers. Neurology 2013;80:400-5.
Mølgaard-Nielsen D, Hviid A. Newer-generation antiepileptic drugs and the risk of major birth defects. JAMA 2011;305:1996-2002.
Viinikainen K, Heinonen S, Eriksson K, Kälviäinen R. Community-based, prospective, controlled study of obstetric and neonatal outcome of 179 pregnancies in women with epilepsy. Epilepsia 2006;47:186-92.
Garrity LC, Turner M, Standridge SM. Increased levetiracetam clearance associated with a breakthrough seizure in a pregnant patient receiving once/day extended-release levetiracetam. Pharmacotherapy 2014;34:e128-32.
Thomas SV, Syam U, Devi JS. Predictors of seizures during pregnancy in women with epilepsy. Epilepsia 2012;53:e85-8.