Levetiracetam Use During Pregnancy in Women With Active Epilepsy: A Hospital-Based, Retrospective Study from a Tertiary Care Hospital in North Eastern INDIA
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.319234
Source of Support: None, Conflict of Interest: None
Keywords: Antiepileptic drugs, epilepsy, fetal malformation, levetiracetam, pregnancyKey Message: This study, in a meaningful number of exposed pregnancies confirmed a low risk of major congenital malformation with LEV monotherapy used in pregnancy. Long term prospective Neurologic and a cognitive follow-up study of children of WWAE is needed.
Management of women with active epilepsy (WWAE) is a complex task, given the potential influences on epilepsy of a women's biological state, the complicated interaction between antiepileptic drugs (AEDs) and female sex steroid hormones and hormonal contraception methods, and medication risks during any potential pregnancy. This is clearly a women's and societal health issue of major importance. Although definitive evidence based conclusions are still lacking for many of the management issues pertaining to WWAE, numerous studies published within the past two decades have suggested conventional AEDs are associated with harmful teratogenic effects on fetus. Prenatal exposure to AEDs increases the risk of a major congenital malformation (MCM) from the background risk of 1% to 2% to between 4% and 9%. However despite large number of new anticonvulsants available commercially in past two decades, no single best choice can be identified. Data from human pregnancies are sparse except for Lamotrigine. Information is limited on the recently available AEDs (vigabatrin, gabapentin, topiramate, tiagabine, oxcarbazepine, levetiracetam, pregabalin and zonisamide). With advances in treatment options for WWAE, it is important to know how various treatments and the epilepsy itself can influence pregnancy outcome in northeast India.
As it would be challenging to perform randomized controlled studies assigning WWAE to various anticonvulsant choices prior to pregnancy, most of available data regarding outcome of pregnancy on anticonvulsants come from matched cohort observational studies such as pregnancy registries. We conducted this study to analyze efficacy and safety of Levetiracetam (LEV) during pregnancy in northeastern matrilineal cultured population
We did a retrospective, descriptional analysis of all females cases of >18 years epileptic women with pregnancy that were managed in the hospital between June 2008 to June 2018. This institute is a tertiary care epilepsy Center in North East India. This study was carried out as extension of the anonymous registry of Epilepsy and Pregnancy. We encouraged all WWAE to enroll in this registry at the time of their marriage or as soon as possible, planning pregnancy or at least not planning to avoid conception. Enrolment was voluntary and there was no interference with any treating doctors individualized treatment. Each selected patient was subjected to a detailed neurological examination. An eyewitness account of seizure episodes was obtained either from a relative or a friend. All obstetrics parameters were studied in detail including fetal outcome. The obstetric data derived from pregnancy register were supplemented with detailed neurologic data retrieved from the medical records for the patients with epilepsy; information about the AED treatment and number and types of seizures and the course of epilepsy were obtained for WWAE. The seizures and epilepsy types were recorded according to the most recent classification of the international league against epilepsy. The pregnancies were divided into two groups according to the mother's epilepsy: - 1. Those with epileptic seizures occurring less than five years before conceiving (termed active epilepsy); 2. Those with seizures five years or more before conceiving (termed Non Active Epilepsy) were excluded. We identified the type of epilepsy according to the hospital case records made by a Neurologist. We classified epilepsy as either generalized or focal and as unspecified if the woman could not be assigned to either of these two groups. All geographic prevalent regional conditions and previous studies done in addition lead to predesigned Performa to be filled by trained obstetricians to gather comprehensive data.
WWAE were receiving levetiracetam monotherapy/polytherapy. Monotherapy was defined as exposure to LEV only, and polytherapy as exposure to LEV and at least one or more additional AED taken any time during pregnancy, whether concurrent or not. Changes in AED regimens did not affect eligibility for inclusion. In situations of seizure recurrence and/or AED toxicity, appropriate dosages adjustments were performed. Therapeutic drug monitoring of AED was not done.
Folate substitution was used before conception and during the pregnancy systematically in which the pregnancy was preplanned. During the entire study period, all new born received intramuscular injection of 1 mm vitamin K at birth to avoid coagulation affect. Premature delivery was defined as delivery before gestational week 37, and the post-term pregnancy lasting longer than 42 weeks. A small for gestational age new born were below the tenth percentile according to the normal tables of our population when adjusted to the gestational age and sex. Infants with birth weight less than 2500 grams were considered to have low birth weight.
Major congenital malformations were defined as structural defects present from birth causing significant functional impairment and/or leading to surgical intervention and were identified by the pediatrician, who examined the infants at birth and at discharge from the hospital.
The demographic characteristics of patients were collected. History and pertinent examination findings were recorded including obstetric complications and maternal prognoses. The study was approved by institutional ethics board, and the requirement for informed consent was waived because of the retrospective nature of the study and de identification of data. During this period approximately 73,340 antenatal women attended obstetric department for care. 143 women were found to had active epilepsy and were using AED before conception and through the whole pregnancy (WWAE). The other group included 163 pregnant women, in which the mother reported having seizures 5 years or more before conceiving but no need for AED at the time of pregnancy were termed nonactive epilepsy cases. This hospital caters to mainly high-risk maternal care and delivers approximately 1200 babies per year.
The mean age of patients was 23.6 years (range 18–45 years). Majority of our women (75) were multiparous (72.81%), as in Meghalaya grand multiparty is very common, 64 women (62.15%) were from low or rural stratum. [Table 1] From June 2008 to June 2018 complete outcome data were available for 103 pregnancies. Of these 47 pregnancies had been exposed to leviteracetam in monotherapy and 56 had been exposed to Levetiracetam in combination with at least one other AED. Mean gestational age at enrollment was 14 weeks (standard deviation 9.27 range 5 to 38 weeks). We observed 59 (57.2%) women with generalized epilepsy (absence or myoclonic seizures), 38 (36.89%), women with focal epilepsy (localization related) and 5.82% (n = 6) with unspecified epilepsy. [Figure 1] Monotherapy was used in most pregnancies (47 of 103, 45.6%), duo therapy in 37 (35.9%) cases and polytherapy with three drugs in 19 (18.4%) cases. [Table 2] Eighty-two of the mothers were seizure free during the pregnancy (,79.6%), and 21 (20.3%) of 103 women experienced seizures during pregnancy. The number of seizures during pregnancy was 2 to 4 seizures in (7%), 1 in (10%), and 10–20 in 7% of 103 cases. One patient experienced an increased in seizure frequency and status epileptics during pregnancy. Another patient experienced a flurry of seizures at late stage of pregnancy, and a cesarean section was performed because of this premonitory phase of status epileptics. Although, 63 (61.1%) of 103 continued to be seizure free during pregnancy, or their seizure frequency remained the same as that before pregnancy. Twelve (11.6%) of 103 lost their seizure freedom during pregnancy and seven (6.7%) of 103 experienced an increase in their seizure number compared with the year preceding the pregnancy. Conversly, the seizure frequency was reduced in 11 (10.6) of 103 patients, and 10 (9.7%) of 103 pregnancies became seizure free during time of pregnancy. In conclusion 61.1% of patients did not experience any change in seizure frequency, 20% experienced a change for better. A small but significant proportion of women (18%) experienced a change for worse in seizure control, and no specific reason could explain this exacerbation of seizures.
The mode of delivery (e.g., With regard to the complications related to pregnancy and delivery, no significant differences were noted for Forceps, vacuum) and the incidence of cesarean sections were equal. The mean gestation age of pregnancy was 37 weeks ± 4 days in women with active epilepsy. No significant interactions between parity or gestational age and epilepsy were found with respect to occurrence of induction, cesarean section and post partum hemorrhage. Regarding obstetric outcome in this study, there were 96 live births, 5 spontaneous abortions, 2 induced abortions, 1 stillbirth. [Table 3]
A significant number 12 (17.8%) of the children of WWAE were found to be small for gestational age (SGA). For monotherapy exposure, five (12.5%) infants had a low birth weight (<2500 g); these were exposed to an average dose of 1500 mg of levetiracetam per day. Four Infants were born less than 37 weeks gestation (9.09%). For polytherapy outcomes, 13 combination of at least an antiepileptic drug in addition to levetiracetam were recorded. Seven infants (17.5%) exposed to levetiracetam as part of polytherapy had a low birth weight, two with a very low birth weight (<1500 g) (two of these infants were twins born at 31 weeks) and one (1.7%) an extremely low birth weight (<1000 g). Twelve live infants exposed to levetiracetam as part of polytherapy regimen were born less than 37 weeks gestation (23.07%).
Apgar score at 5 minutes in children of WWAE was low, <7 in 6.25%, accordingly, the admission to the neonatal intensive Care Unit or neonatal ward were more prevalent in children of WWAE. The mean duration of follow-up in neonatal ward and in neonatal intensive care unit for the neonates of WWAE was 7.5 (+ - 5.5 days). The reason for admission was suspected infection (3 of 13.23%), hypoglycemia or other metabolic abnormality 4 of 13,30.7%%), respiratory distress (3 of 13.23%), low Apgar (2 of 13, 15.3%), preterm (1 out of 13 7.69%). Two of these neonates needed intensive care (i.e. intubation, ventilation, surgical intervention) and others were treated only with intravenous (IV) glucose or antibiotic and monitored. Most (11 of 13, (84.6%) of the children were discharged home without any long-term diagnosis or need for follow-up. [Table 4]
The frequency of major congenital malformation was 6.79% percent in the children of WWAE. In the general population, the rate of major congenital malformation due to spontaneous mutations has been found around 2%. In this study, 7 infants among 96 live births had major congenital malformation resulting in 7.2% for overall prevalence. [Table 5] shows detailed information about the seven infants with major congenital malformation.
As it is impossible for ethical reasons to perform controlled trials on the effects of antiepileptic drugs for pregnancy and neonates, it is essential to collect data on the outcome of pregnancies in human with epilepsy by observational community-based studies and by keeping up large scale pregnancy registries monitoring maternal exposures to different anti-epileptic drugs. The reason for getting high-risk pregnant women is likely that ours being a tertiary care institute, we often receive challenging patients with complications compared to other centres
Neurologist precision medicine prefererence the novel characteristic of new AED, (i.e. LEV), fuelling expectations that that this may be more suitable for managing difficult to treat epilepsy group.
LEV was first approved by the food and drug administration in 1999. It has several advantages over conventional AEDs, namely complete bioavailability, linear phrarmacokinetics, rapid onset of action, totally excreted by the kidneys, minimal bindings to plasma proteins, relative lack of drug to drug interactions, can be loaded intravenously or orally, is weight neutral, has no cognitive side effects, and doesn't require blood level monitoring.
Advantageous attributes have made LEV preferable first-line AED treatment for many neurologists, and in fact, it is one of the commonly prescribed drugs for epilepsy at our center. Currently many epileptologists try to switch to LEV during or before planned pregnancy because of its known relative safety during pregnancy. Moreover, in addition to its efficacy in focal epilepsy, LEV is an excellent AED to use in myoclonic epilepsies, whereas lamotigine which was considered to be safe in pregnancy may actually worsen the myoclonus and requires complex titration schedules and LTG level continues to drop drastically during pregnancy.
The percentages of patients with generalized epilepsy and focal epilepsy in our study are similar with the percentages observed in the EURAP Registry. However, other studies (UK, US), have not analyzed this variable, or report results that differ from ours (focal epilepsy in 48% of patients in Australian registry vs. 36.8% in this study). Such differences are very likely due to methodological reasons: the EURAP Registry gathered data recorded by Neurologists, whereas other registries gather patient-reported data. Data on the type of epilepsy is important, given that patients with generalized epilepsy are known to be more likely to remain seizure free during pregnancy than those with focal epilepsy., Even in this study, 46% of all WWAE who were on monotherapy were taking LEV thus, it is imperative that safety profile of LEV in pregnant women should be studied in detail
The demographic profile of study was in accordance with previous study. We were able to state the time of last seizure and hence divide the epilepsy population into active and non active groups. Women with active epilepsy and used levetiracetam monotherapy had the same obstetric risk as women with active epilepsy and used levetiracetam polytherapy in this study. The incidence of AED used in pregnancy in our study was equal to that in previous study of the total Norwegians cohort, where 0.3% of all women used AEDs during pregnancy. Seizures prior to pregnancy did not seem to affect the risk in our study. In this study, we retrospective analyzed our data to determined safety profile of LEV in pregnancy.
Conflicting results maybe caused by methodological limitations with recruitment bias and small sample sizes, but could also be a result of new medications giving better seizure prevention with fewer side effects. In our study more than half 61.1% of the patients did not experience any change in their seizure frequency, 11.6% experience a change for the better and only 6.7% experienced a change for the worst in seizure control. Vajda et al. compare use of LEV to that of VPA, finding no significant differences between these two AEDs in terms of seizure control. However, that study provides no data on the percentage of patients with generalized epilepsy who received LEV or VPA, or on seizure occurrence in these patients during the year before pregnancy. Other studies directly or indirectly analyzing seizure frequency in patient receiving LEV show seizure occurrence rate no higher than those associated with the use of classic AEDs. This study does not give an answer as to whether it is advisable to increase the AED doses in pregnancy having seizures controlled on antiepileptics.
However, we found that the rate of small for gestational age infants was significantly higher in WWAE. Body dimensions of infants born to mothers with epilepsy have also been studied by Wide and colleagues showing that infants exposed to polytherapy were shorter and smaller than those exposed monotharapy. The incidence of low birth weight babies (i.e. <2500 grams) was higher 15.18% in our study than reported by western studies. This can also be explained as lower mean birth weight of Indian newborn babies compared to western babies. In our study, Apgar scores in children of WWAE were lower at 5 minutes. However, the need for neonatal care after birth was increased as compared to earlier studies. However, the outcome was favorable in most (84.6%) of the children, because they were discharged home without any long-term diagnosis or need for follow-up.
MCM occur at a rate of 2% in the general population; reported major malformation rates in children of WWAE range from 1.25 to 11.5%, with the pooled estimates yielding 4 to 6%. In this study we did not find any fetal congenital malformation in WWAE who were exposed to LEV monotherapy during pregnancy. Our results of are similar to Australian pregnancy Register [no MCM in babies born to WWE on LEV; n = 22, UK and Ireland epilepsy pregnancy Registry (0.7% risk of MCM in babies born to WWAE 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. There was a higher risk of MCMs following in utero exposure to polytherapy with LEV. The overall frequency of major congenial malformation in this study was 7.2%. The study population is too small to draw conclusions about frequency of malformations, but these results are in accordance with the previous studies. In our study, children with malformations were exposed to polytherapy (reflecting difficulty to treat epilepsy) or significant confounding factors were present (genetics susceptibility). Long-term prospective Neuruocognitive follow-up studies of children of WWAE have not been published, and therefore relatively little is known about the subsequent neurologic and cognitive development of these children. Some mainly retrospective reports have, however, suggested that a high prevalence of developmental delay and additional educational needs may exist in children exposed to AEDs in utero.,,
WWAE represents a particularly challenging population for Neurologists. Although guidelines on the management of pregnant women with epilepsy have been published, recent evidence suggests that antenatal care offered to women with epilepsy does not follow currently recommended optimum care practices. In this study, we confirmed that the pregnancy is uncomplicated and neonatal outcome is good in the majority of cases. Pregnancy outcome of women with earlier diagnosis of epilepsy did not differ in this study, indicating the important role of AEDs in causing the complications related to epilepsy. Re-evaluating the need for and those of AED therapy and initiating folate supplementation before conception was the cause for improvement in our outcome. Well-planned prenatal care, careful monitoring of AED treatment and prenatal testing for congenital malformations may increase the likelihood of a normal outcome in future study. Long-term prospective follow-up of the neurologic and cognitive development of the children of WWAE, together with evaluation of the contributing role of the possible risk factors like levetiracetam use, seizures or problems in intrauterine growth, is still needed.
Most of the WWAE had uneventful pregnancy and delivery. Major congenital malformation risk is high when LEV is taken as part of a polytherapy regimen. This study, in a meaningful number of exposed pregnancies confirmed a low risk of major congenital malformation with LEV monotherapy used in pregnancy. Moreover, the effect of LEV on neuropsychological and cognitive development remains unknown. Any interpretation of data however should be made with caution. As with all women who wish to start a family, the risk of teratogenesis due to continued treatment with medications should be carefully balanced against the risk of any potential harm to mother and embryo/fetus due to seizures if treatment is stopped.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]