Change in antiepileptic drug prescription patterns for pregnant women with epilepsy over the years: Impact on pregnancy and fetal outcomes.

AIMS AND
OBJECTIVES: The objectives of the study were: (1) to determine if there is a change in pattern of antiepileptic drug (AED) prescription during pregnancy in women with epilepsy (WWE) attending a tertiary care institute in North India and (2) to determine if change in AED prescription pattern has resulted in improved fetal and maternal outcomes in WWE. PATIENTS AND METHODS: The current study was a retrospective analysis of records of WWE attending a medical and surgical disorder clinic of obstetrics and gynecology department of a tertiary care teaching hospital in North India. We retrospectively collected data of all the patients during the 5-year period from 2011 to 2015 (Group A) (n = 177) and compared it with our previously published data during the years 1987-1994 (Group B) (n = 219).
RESULTS: There was significantly higher use of (i) levetiracetam (LEV) in Group A compared to Group B when women on monotherapy were compared (P<0.0001) and (ii) LEV (P<0.0001), clobazam (P<0.0001) and lamotrigine (P=0.0004) in Group A compared to Group B when women on polytherapy were compared. A significantly higher (P=0.02) number of women were using more than two antiepileptic drugs simultaneously in Group A compared to Group B. There was a significantly higher incidence (P = 0.001) of small for gestational age babies in Group A.
CONCLUSION: Although there is an increase in the use of newer AEDs in WWE during pregnancy in North Indian population, it has not resulted in improved maternal and fetal outcomes. (2) to determine if change in AED prescription pattern has resulted in improved fetal and maternal outcomes in WWE.

Introduction

The management of epilepsy in women during pregnancy poses a special challenge as both seizures and antiepileptic drugs (AEDs) can have harmful effects on mother and fetus.[1] This is well exemplified by known teratogenic effects of some of the most commonly used conventional AEDs such as valproate (VPA) and phenytoin (PHT).[2] During the past two decades, several newer AEDs (levetiracetam [LEV] and lamotrigine [LTG]) have been introduced which are considered to be much less teratogenic than the conventional drugs.[123] Accordingly, worldwide, there is an increase in the usage of newer AEDs (LEV, LTG, zonisamide, clobazam (CLB), clonazepam, and oxcarbazepine), whereas the use of conventional AEDs (VPA, PHT, phenobarbitone, and carbamazepine [CBZ]) has declined.[456] However, the type of newer AEDs used varies from place to place.[7]

Although there is ample evidence that there is a change in AED prescriptions during pregnancy in women with epilepsy (WWE), the impact of this change with respect to maternal and fetal outcomes in pregnancy is not well studied.[6] This is especially true for developing countries where conventional AEDs continue to be prescribed primarily for their lower cost and lack of knowledge about newer AEDs. Thus, we conducted this study to determine the current pattern of AED prescription in WWE in our tertiary care institute and extent of change in maternal and fetal outcomes brought about by this change.

Aims and objectives

To determine if there is a change in pattern of AED prescription during pregnancy in WWE attending a tertiary care institute in North India

To determine if change in AED prescription pattern has resulted in improved fetal and maternal outcomes in WWE.

Patients and Methods

The current study was a retrospective analysis of records of WWE attending the obstetrics and gynecology department of a tertiary care teaching hospital in North India. The department runs a medical and surgical disorder clinic where all WWE are enrolled. Once enrolled, all WWE undergo detailed evaluation, and relevant findings are noted down in a predesigned pro forma. All the obstetric and fetal data (e.g., antenatal visit records, antenatal history, blood pressure, ultrasonographic findings, intrauterine growth retardation, seizures during pregnancy, premature rupture of membranes, antepartum hemorrhage, intrapartum events, fetal distress [FD], need and indication for cesarean section, postpartum hemorrhage, birth weight, major congenital malformations [MCMs], and laboratory data) as well as data pertaining to epilepsy (e.g., type, duration, and frequency of seizures and type, number, dose, and duration of AEDs) are noted by trained obstetricians in the pro forma. All the WWE are also seen by a neurologist with experience in epilepsy, and seizures are managed according to standard guidelines.[3]

We retrospectively collected data of all the patients for the past 5 years (n = 177) and compared it with our previously published data (n = 219).[8] We compared all the relevant data between the two groups.

Statistical analysis

The statistical analysis was done using SPSS version 21 (IBM Corp., Armonk. NY). The data were expressed as mean ± standard deviation and median. The categorical variables were compared using parametric tests (Student's t-test and Chi-square test), whereas the continuous variables were compared using nonparametric Mann–Whitney test. Two-tailed P < 0.05 was taken as statistically significant.

Results

Demographic profile

In the current study, we retrospectively analyzed maternal and fetal outcomes as well as data pertaining to epilepsy among WWE during the 5-year period from 2011 to 2015 (Group A) and compared it with our previously published experience during the years 1987–1994 (Group B). The mean age was 26.78 years in Group A and it was 25.14 years in Group B. In comparison, the mean age was found to be significantly higher (P < 0.001) in Group A compared to Group B. Group B consisted of 93 (42.7%) primigravida, whereas Group A consisted of 74 (41.8%) primigravida. In comparison, this difference was statistically insignificant (P = 0.62) [Table 1].

Table 1

Comparison of demographic data and seizure characteristics among the study groups

Parameter	Group A (n=177), n (%)	Group B (n=219), n (%)	P
Mean±SD age (years)	25.14±3.47	26.78±3.87	<0.001
Primigravida	74 (41.8)	93 (42.5)	0.62
Presence of generalized tonic-clonic seizures	163 (92.1)	203 (92.7)	0.87
Duration of epilepsy of >5 years	99 (99.9)	99 (45.2)	0.04
Onset of epilepsy during index pregnancy	9 (5.1)	25 (11.4)	0.02

Seizure characteristics

In Group A, 163 patients had generalized seizures, 2 had simple partial seizures, and 12 had complex partial seizures, whereas in Group B, 203 had generalized seizures, 13 had simple partial seizures, and 3 had complex partial seizures. Both the groups were comparable with respect to the occurrence of generalized seizures (P = 0.87). In Group A, 99 patients had epilepsy duration of >5 years, whereas 9 patients had their first seizure during index pregnancy. In Group B, 99 patients had epilepsy duration of >5 years, whereas 25 had onset of epilepsy during index pregnancy. A significant higher number of patients (P = 0.04) had duration of epilepsy of >5 years in Group A compared to Group B, whereas a significantly higher number of patients (P = 0.02) had onset of seizure during index pregnancy in Group B compared to Group A [Table 1].

Type of antiepileptic drugs

In Group B, 152 women received monotherapy, whereas in Group A, 103 received monotherapy. Thus, the higher number of women received one drug in Group B than Group A. The most commonly used drugs in Group A and Group B are shown in Table 2. Overall, there was significantly (P < 0.0001) higher use of LEV in Group A among the WWE on monotherapy and significantly higher use of LEV (P < 0.0001), CLB (P < 0.0001), and LTG (P = 0.0004) in Group A among WWE on polytherapy. There was significantly lower use of CBZ and PHT as monotherapy and PHT and phenobarbitone (PB) as a part of polytherapy regimens in Group A. Surprisingly, there was a trend toward the higher use of VPA both as monotherapy and as a part of polytherapy regimen in Group A compared to Group B. There was also significantly higher (P = 0.02) use of more than two drugs simultaneously in Group A [Table 2].

Table 2

Commonly used antiepileptic drugs during the years 2011-2015 (Group A) and 1987-1994 (Group B)

Monotherapy
Name of the drug	Group A (n=103)	Group B (n=152)	P
Conventional AEDs	67	152	<0.0001
CBZ	35	86	0.0005
PHT	13	52	0.0001
PB	4	13	0.2
VPA	15	1	<0.0001
Newer AEDs	36	Nil	<0.0001
LEV	32	Nil	<0.0001
CLB	2	Nil	0.16
OXC	1	Nil	0.40
LTG	1	Nil	0.40
Polypharmacy
Name of the drug	Group A (n=74)	Group B (n=67)	P
Conventional AEDs	67	67	0.01
CBZ	32	27	0.73
PHT	17	49	<0.0001
PB	6	44	<0.0001
VPA	9	2	0.06
Newer AEDs	73	0	<0.0001
LEV	21	Nil	<0.0001
CLB	37	Nil	<0.0001
OXC	5	Nil	0.06
LTG	12	Nil	0.0004
Zonisamide/clonazepam	2 each	Nil
Polytherapy (number of drugs)
Number of drugs	Group A (n=74), n (%)	Group B (n=67), n (%)	P
Two	68 (91.9)	67 (100)	0.02 for use of more than two drugs (n=6) in Group A compared to Group B
Three	5 (6.8)	Nil
Four	1 (1.3)	Nil

CBZ=Carbamazepine, PHT=Phenytoin, PB=Phenobarbitone, VPA=Valproate, LEV=Levetiracetam, CLB=Clobazam, OXC=Oxcarbazepine, LTG=Lamotrigine, AED=Antiepileptic drugs

Difference in seizure control during pregnancy between two groups

The seizure control during pregnancy among both the groups is illustrated in Table 3. There was no difference in recurrence of any seizure (P = 0.3), recurrence of more than two seizures (P = 0.57), or occurrence of status epilepticus (P = 0.23) among the two groups.

Table 3

Control of seizures in pregnancy during the years 2011-2015 (Group A) and 1987-1994 (Group B)

Parameter	Group A (n=177), n (%)	Group B (n=219), n (%)	P
Recurrence of seizures during pregnancy	95 (53.7)	67 (30.6)	0.30
Occurrence of status epilepticus during pregnancy	1 (0.6)	5 (2.3)	0.23
More than two seizures during pregnancy	19 (10.7)	12 (5.5)	0.57

Fetal and maternal outcomes among the two groups

The fetal and maternal outcomes between the two groups are compared in Table 4. There was a higher incidence (P = 0.001) of small for gestational age babies and a trend (P = 0.08) toward higher incidence of cesarean section for FD in Group A compared to Group B.

Table 4

Fetal and maternal outcomes during the years 2011-2015 (Group A) and 1987-1994 (Group B)

Parameter	Group A (n=177), n (%)	Group B (n=160), n (%)	P
Mean±SD birth weight (g)	2757.65±441.04	2823.55±564.45	0.23
Low birth weight	33 (18.6)	25 (15.6)	0.47
Major congenital malformations	6 (3.4)	1 (0.62)	0.12
Small for gestational age	35 (19.8)	12 (7.5)	0.001
Stillbirth	Nil	1 (0.62)	0.47
Parameter	Group A (n=177), n (%)	Group B (n=157), n (%)	P
Need for CS	45 (25.4)	42 (26.8)	0.9
CS for fetal distress	30 (16.9)	16 (10.2)	0.08

Information on CS is available for 157 women only as rest delivered elsewhere. Information on neonatal data is available for 160 neonates. CS=Cesarean section

Discussion

The management of epilepsy in WWE during pregnancy requires special attention. While seizures do have deleterious effects on mother and fetus, antiseizure drugs are also associated with teratogenicity. Although newer AEDs are considered to be better in terms of fetal teratogenicity compared to conventional AEDs,[910] only a few studies have evaluated their overall impact on maternal and fetal outcomes in WWE. In the present study, we evaluated (a) changes in AED prescription trends in WWE during pregnancy and (b) impact of these changes on maternal and fetal outcomes. For this, we retrospectively analyzed our data from 2011 to 2015 (Group A: when the use of newer AEDs became common) and compared it with our previously published data[8](Group B: when only conventional AEDs were being used). The mean age in the current study was higher than our previously published data. This is in line with trends, wherein a gradual increase in age of marriage is reported among Indian women.[11] Both the study groups had a similar percentage of generalized tonic–clonic seizures.

There was a significantly higher use of newer AEDs among WWE during pregnancy. Among women on monotherapy, there was a significantly higher use of LEV during the years 2011–2015 than during the years 1987–1994. This is in accordance with recent studies.[61213] LEV is one of the safest drugs during pregnancy and thus its increased use augers well for WWE. However, in contrast to these studies,[612] we did not find an increase in usage of LTG in our cohort. The likely result for this discrepancy is the fact that LTG concentrations are known to fluctuate markedly during pregnancy[14] necessitating frequent serum drug level monitoring which is not feasible in developing nations. Among the women on polytherapy, there was a significantly higher use of newer AEDs including CLB, LEV, LTG, and oxcarbazepine (OXC). This is in accordance with published guidelines[3] wherein newer AEDs, being relatively free of drug interactions, are used much more frequently as add on agents.

A trend observed in the current study was an increase in the use of VPA in recent years. This is in contrast to most other studies[612] which report a decrease in the use of VPA during pregnancy. Among various conventional AEDs, VPA has maximum teratogenic potential. Furthermore, its use during pregnancy is associated with lower verbal IQ in children.[12] The Committee on Safety of Medicines[15] has cautioned against the use of VPA in pregnancy in 2003. The International League Against Epilepsy has also reported risk of teratogenicity and neurodevelopment abnormalities in children exposed to VPA in utero.[16] Keeping with these guidelines, all the WWE attending our institute are counseled regarding possible teratogenic effects of AEDs including VPA, and the use of VPA is avoided both as mono- and polytherapy. However, the use of VPA as AED is common in general practice. Many WWE on VPA visit our institute only after pregnancy when VPA cannot be stopped, and among them, many present only after 20 weeks of gestation. Thus, there is an urgent need to educate primary care physicians about possible teratogenic effects of VPA and encourage the use of other AEDs at least in women of childbearing age. In the current study, there was a significantly higher use of polytherapy with more than two drugs among WWE in Group A compared to Group B. All these patients presented first to us in the third trimester of pregnancy when there was a little chance of intervention.

The incidence of MCMs was higher in Group A compared to Group B, though the difference was statistically insignificant. Of six neonates with MCMs on Group A, two were on VPA monotherapy, whereas two were on polypharmacy with more than two drugs. The incidence of small for gestational age babies as well as cesarean section for FD was also higher in Group A compared to Group B. All these data indicate that an increase in the use of newer AEDs in WWE during pregnancy in North Indian population has not resulted in improved maternal and fetal outcomes. The likely reason for this observation is the fact that the use of newer AEDs has increased at the expense of CBZ, PHT, and PB (drugs with lower teratogenic potential) rather than VPA, the drug with maximum teratogenicity.[2] Results of the study suggest a need to formulate protocols and educate primary care physicians regarding administration of appropriate AEDs to WWE during the childbearing age.

The main limitation of this study is that being a tertiary care institute, the study population is not representative of general population. Future studies employing larger population and well-defined AED protocols will help in better delineation of the impact of newer AEDs on maternal and fetal outcomes in WWE.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.