Management of Epilepsy During Pregnancy
Management of Epilepsy During Pregnancy
The large prospective European and International Registry of Antiepileptic Drugs in Pregnancy (EURAP) study provided reassuring information that the frequency of seizures during pregnancy will not change in most (50–83%) WWE. But approximately 20–33% of patients will have an increase in their seizures and 7–25% have a decrease in seizures. In addition, the 2009 AAN Practice Parameter Update also concluded that seizure freedom for at least 9 months prior to pregnancy is associated with a 80–90% likelihood of seizure freedom during pregnancy. Though some older studies reported worsening of seizure control in the first and last trimesters, findings from the EURAP study noted better seizure control in second and third trimesters compared with the first. Similarly, smaller single-site studies noted seizure worsening most prominent during the 4th through 7th months of pregnancy, especially in association with a 35% or greater decrease in AED levels from preconception baseline levels.
Prospective data from the Kerala Registry of Epilepsy and Pregnancy cohort in India outlined some predictors that were associated with risk for seizure relapse during pregnancy. These included the type of seizures (partial seizures more than generalized seizures), AED polytherapy (although this may be confounded by more severe disease), and most importantly, the occurrence of seizures in the prepregnancy month.
Nevertheless, a single breakthrough seizure may be disastrous during pregnancy, not only due to the harm to the mother and fetus but also because of its implications on driving, family dynamics and emotional burden. Generalized tonic-clonic convulsions can cause maternal and fetal hypoxia and acidosis, fetal heart rate decelerations, fetal intracranial hemorrhage, miscarriages and stillbirths. Effects of nonconvulsive seizures during pregnancy still remain unclear though isolated case reports on complex partial seizures noted prolonged uterine contractions with fetal heart rate deceleration.
Various physiological changes in sex hormone concentrations, changes in AED metabolism, sleep deprivation and new stresses also affect the seizure frequency. Patients often have misconceptions about the danger of AEDs during pregnancy and thus may abruptly stop them, as soon as they know about their pregnancy. This re-emphasizes the role of adequate education of the patient along with her family members regarding the importance of medication compliance and monitoring, the current evidence on safety regarding her AEDs and the risks involved with the occurrence of seizures, especially generalized tonic clonic convulsions.
Several physiologic changes during pregnancy affect the pharmacokinetics of AEDs. Increased clearance of AEDs occurs with every successive week of gestation due to many factors, including changes in absorption, protein-binding, volume of distribution, increased metabolism through induction of various hepatic pathways and enhanced excretion through kidneys, resulting in wide variations in the drug levels (Box 2). For optimal seizure control during pregnancy, AED doses should be titrated to an appropriate serum level within the patient's therapeutic range (therapeutic drug monitoring). This level should be determined during the prepregnancy period.
The 2009 AAN/American Epilepsy Society (AES) Practice Parameter Update concluded the following: pregnancy probably causes an increase in the clearance and a decrease in the concentration of LTG, phenytoin (PHT), and to a lesser extent carbamazepine (CBZ), and possibly decreases the level of LEV and the active OXC metabolite, the monohydroxy derivative. The authors went on to state that monitoring of LTG, PHT and CBZ should be considered during pregnancy and monitoring of LEV and the OXC metabolite may be considered. As OXC quickly undergoes keto-reduction to an active monohydroxy derivative (MHD), the concentration of MHD should be measured rather than the parent drug. Since the writing of this practice parameter update, two small studies reported that there was significant increase in clearance of topiramate during pregnancy, although levels did not clearly correlate with seizure frequency. Thus the authors concluded that following levels during pregnancy might be of value. CBZ is another AED that has mixed reports with only modest changes in the clearance of total and free carbamazepine and its active metabolite, carbamazepine-10,11-epoxide and lack of correlation between levels and seizure control. Thus, monthly monitoring may not be necessary for carbamazepine, especially if the patient has relatively easy to control seizures and resources for therapeutic drug monitoring are limited.
Among the newer AEDs, lamotrigine is extremely susceptible to changes in levels during pregnancy. This is because of its primary elimination via hepatic glucuronidation that is directly affected by rising sex steroid hormone levels. Recent data from the EURAP pregnancy registry on a large cohort reported that the pregnancies exposed to lamotrigine were less likely to be seizure-free and were more likely to require an increase in drug load. The mean dose increase was highest for the lamotrigine group at 26%. The Class I data from a prospective, observational study showed that both free and total LTG clearance were increased during all three trimesters, with peaks of increases by 94% (total) and 89% (free) in the third trimester. This study also examined therapeutic drug monitoring and seizure frequency, and empiric postpartum taper to avoid toxicity. The authors reported that increased seizure frequency in the second trimester was associated with a decline in the LTG level to 65% or less of the preconceptional individualized target LTG concentration. A retrospective analysis combining all AEDs also found that seizure worsening in the second trimester of pregnancy was associated with a decline in the AED level to 65% or less of the preconception baseline.
A recent study on LTG identified two subpopulations who exhibited different LTG clearances during pregnancy that differed by tenfold. The majority of women (77%) had higher clearance whereas 23% of women had modest clearance of the drug. This information could have therapeutic implications as this influences the titration regimen in a particular group based on their presumed different pharmacogenomic profiles. However, future studies are needed to identify the genetic differences to allow preconceptional testing to identify into which subpopulation an individual fits.
LEV levels in pregnancy are also significantly affected, as the primary mode of elimination is excretion through kidneys (66%). Levels are decreased by 38–60% during the 3rd trimester because of increased renal blood flow and glomerular filtration rate. Though no prospective systemic studies are currently available to address the direct relation between drop in LEV level and seizure frequency, the retrospective analysis by Reisinger et al. did indicate that seizure was more likely to worsen if the LEV level fell below 65% of the preconception baseline. Therefore, therapeutic drug monitoring during pregnancy should be considered to maintain the individual's target concentration. Interestingly, a recent analysis from the Australian Register of Antiepileptic Drugs reported that levetiracetam controlled seizures more effectively than lamotrigine and topiramate with results that are comparable to older antiepileptic drugs (OR: 0.87) like carbamazepine and valproic acid. Decisions about the use of serum AED levels and any adjustments in dose were made individually by the patient's treating physician.
Despite the lack of standard trials on many newer agents, it is reasonable to adjust doses for those that have high renal clearance (pregabalin, vigabatrin) and/or undergo glucuronidation (eslicarbazepine) to avoid lower levels. As the AED concentrations during pregnancy may be affected, not only by the pharmacokinetic changes but also from the possibility of noncompliance, some experts recommend at least monthly monitoring of all AED concentrations.
The teratogenic potential of seizures directly is extremely unlikely, and there are a few clinical studies in the last decade that did not show increased risk of major malformations in women who had generalized seizures during their first trimester. There are various proposed mechanisms of teratogenicity caused by AEDs. Oxidative stress causing release of free radicals, formation of toxic epoxide intermediates, altered folate metabolism and histone deacetylase inhibition are thought to be some of the mechanisms, though enough evidence does not exist. In addition, not much is known about the mechanisms of teratogenicity of newer AEDs in particular.
MCM is defined as an abnormality of an essential anatomical structure present at birth that interferes significantly with function and/or requires major intervention. The MCMs that are most commonly reported at a higher rate with AED exposure compared with the general population include congenital heart defects, cleft lip/palate, urogenital defects, skeletal defects and neural tube defects (for valproic acid [VPA] and CBZ). The reported MCM rates in the general population vary between 1.6 and 3.2%. As per the results of a meta-analysis from 2004, the risk for MCMs in the offspring of women with untreated epilepsy was not higher than among nonepilepsy controls (odds ratio [OR]: 1.92; 95% CI: 0.92–4.00), but higher in offspring of mothers who received AEDs (OR: 3.26; 95% CI: 2.15–4.93) (Table 2).
Several studies show that AED polytherapy regimens substantially increase the risk of congenital malformations, but only with specific combinations of AEDs. Data from the North American Pregnancy registry showed that the women were only at an increased risk of fetal MCMs when taking lamotrigine or carbamazepine in combination with valproic acid while other polytherapy combinations were safe (Table 3). This urges better preconceptional planning using AED monotherapy or safe regimens of AED polytherapy.
Pregnancy registries from various parts of the world and ongoing prospective studies on WWE provide a significant fund of knowledge about specific AEDs, and thus the ability to lower the teratogenicity risk in WWE. Conclusions about intrauterine first trimester exposure and risk for MCMs through an evidence based approach from the 2009 AAN Practice Parameter Updates on "Management issues for women with epilepsy – focus on pregnancy" are as follows:
It is highly probable that valproic acid exposure poses a higher risk of MCMs than carbamazepine, and possibly higher compared with phenytoin or lamotrigine; compared to untreated WWE, valproic acid probably as part of polytherapy and possibly as monotherapy contributes to the development of MCMs; AED polytherapy as compared with monotherapy regimens probably contributes more to the development of MCMs; carbamazepine probably does not substantially increase the risk of MCMs in the offspring of WWE and there is probably a dose-dependent relationship between valproic acid and lamotrigine and the risk of development of MCMs in the offspring of WWE.
Some specific types of MCM associations are also reported:
Phenytoin possibly contributes to the risk of cleft palate; carbamazepine possibly contributes to the risk of posterior cleft palate; valproic acid probably contributes to neural tube defects and facial clefts and possibly contributes to hypospadias and phenobarbital exposure in utero possibly contributes to cardiac malformations (Figure 2).
(Enlarge Image)
Figure 2.
Specific major congenital malformations associated with different antiepileptic drug monotehrapies (combined data from 21 prospective studies).
Reproduced with permission from [44].
Since these practice parameter updates, major epilepsy pregnancy registries and several prospective studies looked at various monotherapy and polytherapy combinations. These studies consistently showed higher risk of MCMs with valproic acid (Figure 3). Wlodarczyk et al. provide a detailed review of animal and human studies, including historical and updated information, about each of the AEDs.
(Enlarge Image)
Figure 3.
Number (%) and 95% CIs of major congenital malformations identified among infants exposed to a specific AED in monotherapy during the first trimester and among the internal comparison group of unexposed infants: North American Antiepileptic Drug Pregnancy Registry 1997–2011.
Data taken from [45].
Lamotrigine has been the most widely studied with promising findings in various international registries for about 20 years. Among 1558 first-trimester monotherapy exposures, 35 infants were noted to have MCMs (2.2%; 95% CI: 1.6–3.1%). These rates appear similar to the estimates from general population-based cohorts. Though the MCM rates were significantly higher at 10.7% among lamotrigine/valproate polytherapy exposure group, it was 2.8% among infants exposed to lamotrigine polytherapy without valproate. There is no specific MCM pattern consistently observed so far, although the North American AED Pregnancy Registry has reported higher rates for oral clefts, and further monitoring is ongoing through various registries and surveillance networks.
Data regarding MCMs related to topiramate exposure during pregnancy are available through the UK Epilepsy and Pregnancy Registry that had 203 pregnancies with 178 live births. The reported incidence was 9.0%, and 4.8% on monotherapy. MCMs like oral clefts (2.2%) and hypospadias (5.1%) were reported. In spite of the sample size being small and wide confidence intervals, caution should be noted with usage of topiramate as this incidence is 11 times the background rate. This risk has been replicated even in other studies. Based on North American Pregnancy Registry data, Hernandez-Diaz et al. reported a higher MCM rate of 4.2% (15 of 359) related to topiramate use, compared with that of reference population.
The results from the UK and Ireland epilepsy and pregnancy registry provide reassuring findings on first trimester exposure of levetiracetam, which is especially helpful given that it is a commonly prescribed AED including in women of child-bearing age. As a monotherapy agent, the MCM rate was 0.70%; CI: 0.19–2.51%. Polytherapy use of levetiracetam with lamotrigine had MCM rate of 1.77%; which is considerably less than combinations with valproate (6.90%) or carbamazepine (9.38%).
Recent data from other pregnancy registries also noted that the malformation risk is dose-dependent. Investigators from the EURAP analyzed MCM rates by dose at the time of conception. Doses later in pregnancy were not accounted for in this analysis. The MCM rates were lowest with lamotrigine at less than 300 mg per day (2.0%; 95% CI: 1.19–3.24) and carbamazepine at less than 400 mg per day (3.4%; 95% CI: 1.11–7.71). Compared with lamotrigine monotherapy at doses less than 300 mg per day, risks of malformation were higher with carbamazepine at doses greater than 400 mg per day and significantly higher with valproic acid and phenobarbital at all doses (Table 4). Therefore, reduction of the dose prior to conception while maintaining seizure control can further reduce the risk of structural teratogenicity. Determining the women's individual target concentration preconception can also be a valuable tool for therapeutic drug monitoring during pregnancy.
A population-based cohort study from Denmark on newer generation AEDs showed that among 1532 infants exposed to lamotrigine (n = 1019), OXC (n = 393), topiramate (n = 108), gabapentin (n = 59) or levetiracetam (n = 58) during the first trimester, 49/3.2% were diagnosed with a major birth defect compared with 19,911/2.4% of the 836,263 who were not exposed to an AED (95% CI: 0.72–1.36). However, this study did not distinguish polytherapy from monotherapy. In a small prospective comparative cohort study involving gabapentin exposed pregnancies, the rates of major malformations appeared to be similar in both exposed and unexposed groups.
It is important to note that reproductive safety information is still lacking for many newer AEDs (often referred to as third-generation AEDs), and many of the second-generation AEDs do not yet have long-term neurodevelopmental data (see below), although prospective studies are underway. AEDs without reproductive safety information should be avoided when possible in women with epilepsy during pregnancy, unless they are the only medications that provided seizure control for that individual.
A multidisciplinary approach is essential for women on AEDs during pregnancy, and if possible, during preconceptional planning. Many women with epilepsy on AEDs will be referred to a perinatologist/maternal fetal medicine specialist in addition to her general obstetrician, but this varies greatly by region of practice. The important principle is that she be offered prenatal testing including a detailed structural ultrasound. Many regions have genetic counselors that are part of this multidisciplinary team, either early in the process or if a malformation is suspected. It is important to rule out other potential contributing factors such as genetic. If a malformation is identified, this not only allows the woman and her family to make decisions about termination, but also to provide in utero and neonatal treatment options if the pregnancy will continue. Additionally serial surveillance may be considered for fetal growth under the guidance of an obstetrician.
Gestational Period
Seizure Control
The large prospective European and International Registry of Antiepileptic Drugs in Pregnancy (EURAP) study provided reassuring information that the frequency of seizures during pregnancy will not change in most (50–83%) WWE. But approximately 20–33% of patients will have an increase in their seizures and 7–25% have a decrease in seizures. In addition, the 2009 AAN Practice Parameter Update also concluded that seizure freedom for at least 9 months prior to pregnancy is associated with a 80–90% likelihood of seizure freedom during pregnancy. Though some older studies reported worsening of seizure control in the first and last trimesters, findings from the EURAP study noted better seizure control in second and third trimesters compared with the first. Similarly, smaller single-site studies noted seizure worsening most prominent during the 4th through 7th months of pregnancy, especially in association with a 35% or greater decrease in AED levels from preconception baseline levels.
Prospective data from the Kerala Registry of Epilepsy and Pregnancy cohort in India outlined some predictors that were associated with risk for seizure relapse during pregnancy. These included the type of seizures (partial seizures more than generalized seizures), AED polytherapy (although this may be confounded by more severe disease), and most importantly, the occurrence of seizures in the prepregnancy month.
Nevertheless, a single breakthrough seizure may be disastrous during pregnancy, not only due to the harm to the mother and fetus but also because of its implications on driving, family dynamics and emotional burden. Generalized tonic-clonic convulsions can cause maternal and fetal hypoxia and acidosis, fetal heart rate decelerations, fetal intracranial hemorrhage, miscarriages and stillbirths. Effects of nonconvulsive seizures during pregnancy still remain unclear though isolated case reports on complex partial seizures noted prolonged uterine contractions with fetal heart rate deceleration.
Various physiological changes in sex hormone concentrations, changes in AED metabolism, sleep deprivation and new stresses also affect the seizure frequency. Patients often have misconceptions about the danger of AEDs during pregnancy and thus may abruptly stop them, as soon as they know about their pregnancy. This re-emphasizes the role of adequate education of the patient along with her family members regarding the importance of medication compliance and monitoring, the current evidence on safety regarding her AEDs and the risks involved with the occurrence of seizures, especially generalized tonic clonic convulsions.
AED Management
Several physiologic changes during pregnancy affect the pharmacokinetics of AEDs. Increased clearance of AEDs occurs with every successive week of gestation due to many factors, including changes in absorption, protein-binding, volume of distribution, increased metabolism through induction of various hepatic pathways and enhanced excretion through kidneys, resulting in wide variations in the drug levels (Box 2). For optimal seizure control during pregnancy, AED doses should be titrated to an appropriate serum level within the patient's therapeutic range (therapeutic drug monitoring). This level should be determined during the prepregnancy period.
The 2009 AAN/American Epilepsy Society (AES) Practice Parameter Update concluded the following: pregnancy probably causes an increase in the clearance and a decrease in the concentration of LTG, phenytoin (PHT), and to a lesser extent carbamazepine (CBZ), and possibly decreases the level of LEV and the active OXC metabolite, the monohydroxy derivative. The authors went on to state that monitoring of LTG, PHT and CBZ should be considered during pregnancy and monitoring of LEV and the OXC metabolite may be considered. As OXC quickly undergoes keto-reduction to an active monohydroxy derivative (MHD), the concentration of MHD should be measured rather than the parent drug. Since the writing of this practice parameter update, two small studies reported that there was significant increase in clearance of topiramate during pregnancy, although levels did not clearly correlate with seizure frequency. Thus the authors concluded that following levels during pregnancy might be of value. CBZ is another AED that has mixed reports with only modest changes in the clearance of total and free carbamazepine and its active metabolite, carbamazepine-10,11-epoxide and lack of correlation between levels and seizure control. Thus, monthly monitoring may not be necessary for carbamazepine, especially if the patient has relatively easy to control seizures and resources for therapeutic drug monitoring are limited.
Among the newer AEDs, lamotrigine is extremely susceptible to changes in levels during pregnancy. This is because of its primary elimination via hepatic glucuronidation that is directly affected by rising sex steroid hormone levels. Recent data from the EURAP pregnancy registry on a large cohort reported that the pregnancies exposed to lamotrigine were less likely to be seizure-free and were more likely to require an increase in drug load. The mean dose increase was highest for the lamotrigine group at 26%. The Class I data from a prospective, observational study showed that both free and total LTG clearance were increased during all three trimesters, with peaks of increases by 94% (total) and 89% (free) in the third trimester. This study also examined therapeutic drug monitoring and seizure frequency, and empiric postpartum taper to avoid toxicity. The authors reported that increased seizure frequency in the second trimester was associated with a decline in the LTG level to 65% or less of the preconceptional individualized target LTG concentration. A retrospective analysis combining all AEDs also found that seizure worsening in the second trimester of pregnancy was associated with a decline in the AED level to 65% or less of the preconception baseline.
A recent study on LTG identified two subpopulations who exhibited different LTG clearances during pregnancy that differed by tenfold. The majority of women (77%) had higher clearance whereas 23% of women had modest clearance of the drug. This information could have therapeutic implications as this influences the titration regimen in a particular group based on their presumed different pharmacogenomic profiles. However, future studies are needed to identify the genetic differences to allow preconceptional testing to identify into which subpopulation an individual fits.
LEV levels in pregnancy are also significantly affected, as the primary mode of elimination is excretion through kidneys (66%). Levels are decreased by 38–60% during the 3rd trimester because of increased renal blood flow and glomerular filtration rate. Though no prospective systemic studies are currently available to address the direct relation between drop in LEV level and seizure frequency, the retrospective analysis by Reisinger et al. did indicate that seizure was more likely to worsen if the LEV level fell below 65% of the preconception baseline. Therefore, therapeutic drug monitoring during pregnancy should be considered to maintain the individual's target concentration. Interestingly, a recent analysis from the Australian Register of Antiepileptic Drugs reported that levetiracetam controlled seizures more effectively than lamotrigine and topiramate with results that are comparable to older antiepileptic drugs (OR: 0.87) like carbamazepine and valproic acid. Decisions about the use of serum AED levels and any adjustments in dose were made individually by the patient's treating physician.
Despite the lack of standard trials on many newer agents, it is reasonable to adjust doses for those that have high renal clearance (pregabalin, vigabatrin) and/or undergo glucuronidation (eslicarbazepine) to avoid lower levels. As the AED concentrations during pregnancy may be affected, not only by the pharmacokinetic changes but also from the possibility of noncompliance, some experts recommend at least monthly monitoring of all AED concentrations.
Congenital Malformations
The teratogenic potential of seizures directly is extremely unlikely, and there are a few clinical studies in the last decade that did not show increased risk of major malformations in women who had generalized seizures during their first trimester. There are various proposed mechanisms of teratogenicity caused by AEDs. Oxidative stress causing release of free radicals, formation of toxic epoxide intermediates, altered folate metabolism and histone deacetylase inhibition are thought to be some of the mechanisms, though enough evidence does not exist. In addition, not much is known about the mechanisms of teratogenicity of newer AEDs in particular.
Major Malformations
MCM is defined as an abnormality of an essential anatomical structure present at birth that interferes significantly with function and/or requires major intervention. The MCMs that are most commonly reported at a higher rate with AED exposure compared with the general population include congenital heart defects, cleft lip/palate, urogenital defects, skeletal defects and neural tube defects (for valproic acid [VPA] and CBZ). The reported MCM rates in the general population vary between 1.6 and 3.2%. As per the results of a meta-analysis from 2004, the risk for MCMs in the offspring of women with untreated epilepsy was not higher than among nonepilepsy controls (odds ratio [OR]: 1.92; 95% CI: 0.92–4.00), but higher in offspring of mothers who received AEDs (OR: 3.26; 95% CI: 2.15–4.93) (Table 2).
AED Polytherapy
Several studies show that AED polytherapy regimens substantially increase the risk of congenital malformations, but only with specific combinations of AEDs. Data from the North American Pregnancy registry showed that the women were only at an increased risk of fetal MCMs when taking lamotrigine or carbamazepine in combination with valproic acid while other polytherapy combinations were safe (Table 3). This urges better preconceptional planning using AED monotherapy or safe regimens of AED polytherapy.
AED Monotherapy
Pregnancy registries from various parts of the world and ongoing prospective studies on WWE provide a significant fund of knowledge about specific AEDs, and thus the ability to lower the teratogenicity risk in WWE. Conclusions about intrauterine first trimester exposure and risk for MCMs through an evidence based approach from the 2009 AAN Practice Parameter Updates on "Management issues for women with epilepsy – focus on pregnancy" are as follows:
It is highly probable that valproic acid exposure poses a higher risk of MCMs than carbamazepine, and possibly higher compared with phenytoin or lamotrigine; compared to untreated WWE, valproic acid probably as part of polytherapy and possibly as monotherapy contributes to the development of MCMs; AED polytherapy as compared with monotherapy regimens probably contributes more to the development of MCMs; carbamazepine probably does not substantially increase the risk of MCMs in the offspring of WWE and there is probably a dose-dependent relationship between valproic acid and lamotrigine and the risk of development of MCMs in the offspring of WWE.
Some specific types of MCM associations are also reported:
Phenytoin possibly contributes to the risk of cleft palate; carbamazepine possibly contributes to the risk of posterior cleft palate; valproic acid probably contributes to neural tube defects and facial clefts and possibly contributes to hypospadias and phenobarbital exposure in utero possibly contributes to cardiac malformations (Figure 2).
(Enlarge Image)
Figure 2.
Specific major congenital malformations associated with different antiepileptic drug monotehrapies (combined data from 21 prospective studies).
Reproduced with permission from [44].
Since these practice parameter updates, major epilepsy pregnancy registries and several prospective studies looked at various monotherapy and polytherapy combinations. These studies consistently showed higher risk of MCMs with valproic acid (Figure 3). Wlodarczyk et al. provide a detailed review of animal and human studies, including historical and updated information, about each of the AEDs.
(Enlarge Image)
Figure 3.
Number (%) and 95% CIs of major congenital malformations identified among infants exposed to a specific AED in monotherapy during the first trimester and among the internal comparison group of unexposed infants: North American Antiepileptic Drug Pregnancy Registry 1997–2011.
Data taken from [45].
Lamotrigine has been the most widely studied with promising findings in various international registries for about 20 years. Among 1558 first-trimester monotherapy exposures, 35 infants were noted to have MCMs (2.2%; 95% CI: 1.6–3.1%). These rates appear similar to the estimates from general population-based cohorts. Though the MCM rates were significantly higher at 10.7% among lamotrigine/valproate polytherapy exposure group, it was 2.8% among infants exposed to lamotrigine polytherapy without valproate. There is no specific MCM pattern consistently observed so far, although the North American AED Pregnancy Registry has reported higher rates for oral clefts, and further monitoring is ongoing through various registries and surveillance networks.
Data regarding MCMs related to topiramate exposure during pregnancy are available through the UK Epilepsy and Pregnancy Registry that had 203 pregnancies with 178 live births. The reported incidence was 9.0%, and 4.8% on monotherapy. MCMs like oral clefts (2.2%) and hypospadias (5.1%) were reported. In spite of the sample size being small and wide confidence intervals, caution should be noted with usage of topiramate as this incidence is 11 times the background rate. This risk has been replicated even in other studies. Based on North American Pregnancy Registry data, Hernandez-Diaz et al. reported a higher MCM rate of 4.2% (15 of 359) related to topiramate use, compared with that of reference population.
The results from the UK and Ireland epilepsy and pregnancy registry provide reassuring findings on first trimester exposure of levetiracetam, which is especially helpful given that it is a commonly prescribed AED including in women of child-bearing age. As a monotherapy agent, the MCM rate was 0.70%; CI: 0.19–2.51%. Polytherapy use of levetiracetam with lamotrigine had MCM rate of 1.77%; which is considerably less than combinations with valproate (6.90%) or carbamazepine (9.38%).
Recent data from other pregnancy registries also noted that the malformation risk is dose-dependent. Investigators from the EURAP analyzed MCM rates by dose at the time of conception. Doses later in pregnancy were not accounted for in this analysis. The MCM rates were lowest with lamotrigine at less than 300 mg per day (2.0%; 95% CI: 1.19–3.24) and carbamazepine at less than 400 mg per day (3.4%; 95% CI: 1.11–7.71). Compared with lamotrigine monotherapy at doses less than 300 mg per day, risks of malformation were higher with carbamazepine at doses greater than 400 mg per day and significantly higher with valproic acid and phenobarbital at all doses (Table 4). Therefore, reduction of the dose prior to conception while maintaining seizure control can further reduce the risk of structural teratogenicity. Determining the women's individual target concentration preconception can also be a valuable tool for therapeutic drug monitoring during pregnancy.
A population-based cohort study from Denmark on newer generation AEDs showed that among 1532 infants exposed to lamotrigine (n = 1019), OXC (n = 393), topiramate (n = 108), gabapentin (n = 59) or levetiracetam (n = 58) during the first trimester, 49/3.2% were diagnosed with a major birth defect compared with 19,911/2.4% of the 836,263 who were not exposed to an AED (95% CI: 0.72–1.36). However, this study did not distinguish polytherapy from monotherapy. In a small prospective comparative cohort study involving gabapentin exposed pregnancies, the rates of major malformations appeared to be similar in both exposed and unexposed groups.
It is important to note that reproductive safety information is still lacking for many newer AEDs (often referred to as third-generation AEDs), and many of the second-generation AEDs do not yet have long-term neurodevelopmental data (see below), although prospective studies are underway. AEDs without reproductive safety information should be avoided when possible in women with epilepsy during pregnancy, unless they are the only medications that provided seizure control for that individual.
Surveillance for Birth Defects
A multidisciplinary approach is essential for women on AEDs during pregnancy, and if possible, during preconceptional planning. Many women with epilepsy on AEDs will be referred to a perinatologist/maternal fetal medicine specialist in addition to her general obstetrician, but this varies greatly by region of practice. The important principle is that she be offered prenatal testing including a detailed structural ultrasound. Many regions have genetic counselors that are part of this multidisciplinary team, either early in the process or if a malformation is suspected. It is important to rule out other potential contributing factors such as genetic. If a malformation is identified, this not only allows the woman and her family to make decisions about termination, but also to provide in utero and neonatal treatment options if the pregnancy will continue. Additionally serial surveillance may be considered for fetal growth under the guidance of an obstetrician.
