Perspective Chapter: Epilepsy and Pregnancy

Abstract

Currently, there are approximately 15 million women of childbearing age worldwide. A total of 0.3–0.4% of newborns are born to mothers with epilepsy, with nearly half a percent of these women experiencing ongoing seizures. This chapter addresses issues related to pregnancy preparation, the prognostic influence of seizure frequency, epilepsy type, and course on pregnancy outcomes, as well as potential risks associated with the condition for both the mother and the fetus. Summary data on latest recommendations for therapy adjustments and data on the pharmacokinetic changes of antiepileptic drugs during pregnancy are provided. The classification of antiepileptic drugs based on their teratogenic potential and their impact on child development and behavior is presented. Various approaches to managing pregnancy are discussed. Scenarios for managing pregnancy in cases of poorly controlled epilepsy and status epilepticus, as well as therapy adjustments in the postpartum period and measures for the safe care of newborns, are also considered.

1. Introduction

The management of pregnancy in women with epilepsy (WWE) is a relevant issue, considering the estimated global population of around 15 million women of reproductive age [1]. Statistical reports indicate that approximately 0.3–0.4% of newborns are born to mothers with epilepsy. Furthermore, the improved effectiveness of epilepsy therapy in the past two decades, with the use of new antiseizure drugs (ASDs), has led to a fourfold increase in pregnancies in women with epilepsy (WWE) [2]. The prevalence of active epilepsy among pregnant women is reported to be 0.33% [3], but other studies indicate a slightly higher rate of 0.49% [4]. Epileptic seizures rarely occur exclusively during pregnancy, which is known as gestational epilepsy.

2. Epilepsy and pregnancy

2.1 Seizure control during pregnancy

Several studies have indicated that the frequency of seizures during pregnancy remains unchanged [5]. However, when seizures have been in remission for 9 months or longer before conception, there is hope for their absence during pregnancy [6].

In a prospective observational multicenter cohort study conducted by Pennell et al. [5], the frequency of seizures during pregnancy and the first 6 weeks after delivery (n = 299) (observation period I) was compared with the frequency in the postpartum period (the subsequent 7.5 months after pregnancy) (period II). A control group (n = 93) consisted of nonpregnant women of similar age who were observed over an 18-month period. Patient demographics did not significantly differ between the groups. The primary outcome assessed was the percentage of women who experienced a higher frequency of seizures with impaired consciousness during period I compared to period II. Changes in ASD dosage were also evaluated in both groups. The results indicated that the frequency of seizures with impaired consciousness remained unchanged, worsened, or improved to a similar extent in both pregnant and nonpregnant women: unchanged frequency was reported in 63% of pregnant women and 65% of nonpregnant women, improvement in 14% and 11%, respectively, and worsening in 23% and 25%. In the pregnant group, 74% of the cases required a change in drug dosage or additional ASD prescription, while in the control group, dosage adjustments were necessary in only 31% of the cases [5].

According to the largest EURAP study (n = 3806 pregnancies), absence of seizures during pregnancy was observed in 66.6% of the cases. The rate increased to 73.6% for idiopathic generalized epilepsy (IGE) and decreased to 59.5% for focal epilepsy (FE) [7]. The average increase in ASD dosage from the first to the third trimester was 26% for lamotrigine, 5% for carbamazepine, 11% for phenobarbital, and 6% for valproate. The study reported 21 cases of epileptic status, 10 of which were convulsive, with no maternal mortality and only one case of stillbirth. The authors emphasize the need for more active adjustment of ASD dosages during pregnancy, particularly in cases of seizures occurring in the first trimester [7].

In a single-center study (114 pregnancies), Voinescu et al. [8] observed a significantly milder course of IGE and nonfrontal focal epilepsy during pregnancy, particularly when achieving seizure control for a 9-month period prior to pregnancy. A more detailed analysis of the results revealed that patients with frontal epilepsy experienced an increase in seizures during pregnancy (75%) when seizure control was not achieved before pregnancy, compared to an increase of 33% when seizure control was established prior to pregnancy. A similar disparity was observed in cases of focal epilepsy with different localizations; however, the percentage of seizure exacerbation was significantly lower (26% and 5%, respectively) [8].

In an observational cohort study conducted in Nigeria, a higher likelihood of seizures during pregnancy was observed in cases of structural focal epilepsy with posttraumatic (P = .013) and infectious etiology (P = .041). The authors also noted that the absence of seizures for less than 6 months before pregnancy had an unfavorable impact on pregnancy outcomes (P = .043) [3].

The review by Eadie [9] focuses on the analysis of seizure dynamics during pregnancy over the past 50 years. In the majority of studies, there was a predominant, albeit insignificant, trend toward worsened control of epileptic seizures during pregnancy. A detailed analysis of this worsening seizure control during pregnancy identified several contributing factors, including the use of ASDs with lower teratogenic potential but less stable pharmacokinetics during pregnancy, noncompliance, the influence of steroid sex hormones on the estrogen/progesterone ratio, a more unfavorable course of focal epilepsy compared to generalized epilepsy, remission of seizures for less than 9–12 months before conception, and the use of monotherapy or polytherapy (polytherapy likely indicating pharmacoresistant disease) [9]. Additionally, negative influences on the course of epilepsy during pregnancy include nonadherence to a sleep-wake schedule (particularly in cases of generalized epilepsy), vomiting during pregnancy, anxiety, and depression [2].

As indicated in the Table 1, nearly all publications in the last 10 years report a predominance (sometimes minor) of increased seizure frequency during pregnancy compared to seizure reduction [9].

Author	Number of pregnant WWE (n)	Number of women (n)	Seizure reduction rate (%)	Seizure exacerbation rate (%)
Battino et al. 2013 [7]	3806	3451	12%	15.8%
Reisinger et al. 2013 [10]	115	95	17.4%	38.3%
Cagnetti et al. 2014 [11]		272	17.5%	23.4%
La Neve et al. 2015 [12]	56		8%	19%
Shahla et al. 2018 [13]		94	25.5%	28.7%
Pennell et al. 2020 [5]		351	14%	23%
Voinescu et al. 2022 [8]	114	99		21.1% for FE; 5.3% for IGE

Table 1.

Seizure dynamics during pregnancy according to Eadie (2021) [9] with supplemental data.

WWE—women with epilepsy; FE—focal epilepsy; IGE—idiopathic generalized epilepsy.

A limited number of studies have examined the dynamics of epilepsy during pregnancy in the absence of ASD therapy. The main conclusion drawn from observations of patients who refused to take ASDs during the first trimester or throughout their pregnancy is that their seizure frequency increased [14].

There are differing opinions regarding the influence of a previous pregnancy on the course of a current one. According to one viewpoint, an unfavorable course of a previous pregnancy increases the likelihood of decompensation in subsequent pregnancies. However, our experience suggests that such prediction is not possible [2].

To summarize the key points on Seizure control during pregnancy:

1. Achieving seizure control for 9 months before pregnancy is associated with a high likelihood of its maintaining during pregnancy [6].

2. The largest study (EURAP) reported a probability of seizure absence during pregnancy of 59.5% for focal epilepsy, 73.6% for IGE, and an average of 66.6% [7].

3. Frontal lobe epilepsy is more likely to worsen during pregnancy compared to other types of focal epilepsy [8].

4. Among focal epilepsies, there is a higher likelihood of increased seizures during pregnancy in cases of structural focal epilepsy (due to trauma or encephalitis) [3].

5. Status epilepsticus occurs during pregnancy in 0.55% of cases [7].

6. “Old” ASDs such as phenobarbital, valproate, and carbamazepine were found to be more effective in treating focal and generalized epilepsy during pregnancy [7]. However, valproate (and possibly phenobarbital according to some data) is not recommended for use during pregnancy due to its high teratogenic potential in terms of structural and cognitive effects [15].

7. Factors such as compliance, avoidance of smoking and alcohol and drug use, sufficient sleep (especially in the case of IGE), identification and timely therapy of anxiety/depression, and repeated administration of ASDs in case of vomiting during epilepsy shortly after ASD administration play an important role in maintaining stable seizure control during pregnancy [2].

2.2 Epileptic seizures: risk for mother and fetus

The main objective of using ASDs is to prevent seizure occurrence during pregnancy, as they have unfavorable effects on both the mother and the fetus/child. Generalized tonic-clonic seizures and focal seizures to bilateral tonic-clonic seizures have the most harmful impact on the mother, including the possibility of traumatic brain injury, limb injury, spinal cord injuries, blunt abdominal trauma, hypoxia, lactic acidosis, etc. [2]. Sudden unexpected death in epilepsy (SUDEP) is also a concern [16]. These seizures can also have adverse effects on the fetus, such as asphyxia, hypoxia, and trauma [15]. All other seizures have minimal impact unless they are associated with falls of pregnant WWE [2]. Focal seizures with impaired consciousness have been described to cause a short-term fetal distress syndrome characterized by a decrease in fetal heart rate to 3.5 min [17].

The presence of seizures during pregnancy, regardless of classification, was reported to lead to decreased size and weight of the newborn as well as premature birth [18].

Currently, there is no evidence of a direct link between seizures and the occurrence of major congenital malformations (MCM) in the fetus [15]. However, certain conditions can increase the likelihood of MCM, such as prolonged generalized tonic-clonic seizures or status epilepticus, which can result in severe hypoxia and acidosis. Depending on the gestational age at which the seizure occurred, pregnancy outcomes vary. If there is a significant loss of germinal material miscarriage occurs. In case of complete regeneration of germinal material, structural defects do not develop. During the period of histogenesis and organogenesis, the development of MCM is possible, while in the second and third trimesters, the development of minor anomalies, developmental delays, and adverse cognitive and behavioral consequences may occur. Nevertheless, prospective studies have not yet confirmed the influence of generalized tonic-clonic seizures on the development of the nervous system [19, 20].

2.2.1 Pharmacokinetics of ASD during pregnancy

Significant changes in the pharmacokinetics of ASDs occur during pregnancy, starting from the early stages, including alterations in absorption, increased distribution volume, enhanced renal excretion, and induction of hepatic metabolism. Table 2 presents summarized data on predicting ASD concentrations during pregnancy with an unchanged daily dose.

ASD	Decrease in serum concentration	Decrease in serum free (unbound) concentration	Recommendations to perform therapeutic drug monitoring, if available
Phenobarbital	Up to 55%	Up to 50%	Yes
Phenytoin	60–70%	20–40%	Yes, free concentration
Carbamazepine	0–12%	None	Optional
Valproate	Up to 23%	None	Optional, free concentration if done
Oxcarbazepine monohydroxy-derivative (MHD)	36–62%	N/A	Yes
Lamotrigine	0.77 of population: 69% decrease 0.23 of population: 17% decrease	N/A	Yes
Topiramate	Up to 30%	N/A	Yes
Levetiracetam	40–60%, with maximal decrease reached in first trimester	N/A	Yes
Zonisamide	Up to 35%; data is limited	N/A	Yes

Table 2.

Summary data on prediction of individual ASD concentrations during pregnancy with unchanged daily dose of ASD (AED—antiepileptic drug) daily dose according to Tomson et al. [15] with modifications.

N/A: not applicable.

As indicated in Table 2, the most unstable pharmacokinetics during pregnancy are observed when using phenobarbital (PHB), phenytoin (PHT), oxcarbazepine (OXC), lamotrigine (LTG), levetiracetam (LEV), ZNS, gababentin (GBP). Therefore, during pregnancy, the concentration of these ASDs should be monitored. In several studies by Harden et al. [6], Reisinger et al. [10], and Voinescu et al. [21], a critical decrease in ASD concentration was identified, which constituted 65% of the concentration before pregnancy [6, 10, 21]. Accordingly, a decrease in the concentration by just 35% can lead to an increase in epileptic seizures. If monitoring concentration is not possible, it is necessary to increase the daily dose of ASDs with variable pharmacokinetics by 30–50% in advance, especially in cases of unstable disease progression, short-term medication remission, initial difficulty in selecting therapy, structural focal epilepsy, history of generalized tonic-clonic seizures or focal seizures with impaired awareness, and with a minimal daily dose of ASDs [22].

2.2.2 The impact of ASDs on fetal growth and development

The impact of ASDs on fetal growth and development has been extensively studied using data from national registries and population-based studies, including those conducted in Australia, Denmark, Finland, Norway, Russia [23], EURAP, NAAPR, NEAD, Sweden, and the UK and Ireland Epilepsy and Pregnancy Registers. The findings suggest that the use of polytherapy during pregnancy, as well as monotherapy with Primidone, Phenobarbital, carbamazepine (CBZ), valproic acid (VPA), and newer ASDs such as topiramate (TPM) and zonisamide (ZNS), may be associated with varying degrees of intrauterine growth restriction, with TPM having the greatest negative impact [15]. The prospective NEAD study revealed an increased incidence of microcephaly with the use of VPA and CBZ during pregnancy, although by the age of 2 years, the child’s head size was not significantly different from population norms (the measures were equalized) [24].

2.2.3 Teratogenesis

ASDs have been classified into categories based on their teratogenic potential, with LTG and LEV having minimal potential, pregabalin and TPM having moderate potential, and VPA having the highest potential (Table 3) [15]. However, the results of a nationwide cohort study conducted in France over a period of more than 4 years, involving all pregnancies ≥20 weeks (n = 1,886,825), did not show significant associations with major congenital malformations (MCM) for LTG, LEV, OXC, and CBZ [29]. For drugs with high and moderate risks of congenital malformations, there is a direct correlation between the increase in daily dosage and the frequency of MCM, particularly for VPA [15]. Furthermore, a specific organ-specificity of congenital malformation development has been demonstrated: for VPA, eight associations were identified, including spina bifida, four cardiovascular variants, facial anomalies, anorectal anomalies, and hypospadias. In the case of TPM, cleft palate and cleft lip were observed, while cardiac malformations were associated with the use of barbiturates (Table 4).

ASD	The rate of congenital malformations development
	EURAP [25]	NAAPR [26]	UK and Ireland [27]	Australian [28]
Carbamazepine	5.5%	3.0%	2.6%	5.5%
Valproic acid	10.3%	9.3%	6.7%	13.8%
Phenobarbital	6.5%	5.5%
Topiramate	3.9%	4.2%	4.3%	2.4%
Lamotrigine	2.9%	2.0%	2.3%	4.6%
Levetiracetam	2.8%	2.4%	0.7%	2.4%
Phenytoin	6.4%	2.9%	3.7%
Oxcarbazepine	3.0%	2.2%

Table 3.

Prevalence of major congenital malformations with monotherapy based on data from 4 prospective registries according to Tomson et al. [15] with supplemental information.

ASD	Malformation type	Odds Ratio [95% confidence interval]
Topiramate	Cleft lip or cleft palate	6.8 [1.4–20.0]
Barbiturates	Congenital Heart Defects	10.5 [1.3–39.3]
Valproate	Spina bifida	19.4 [8.6–43.5]
	Ventricular septal defect	4.0 [2.1–7.8]
	Patent foramen ovale	9.0 [5.4–15.0]
	Pulmonary atresia	27.8 [3.3–102.5]
	Hypoplastic left heart syndrome	19.6 [2.4–71.7]
	Cleft palate	5.4 [1.1–15.8]
	Anorectal atresia	11.7 [2.4–34.4]
	Hypospadias	4.8 [2.4–9.8]

Table 4.

ASDs and the associated MCMs according to Blotière et al. [29].

In recent years, the perspective on the use of bi- or polytherapy has shifted, focusing on the specific drugs involved rather than the fact of polytherapy itself. Data from the Australian registry indicate that any combination of ASDs with VPA and TPM is not recommended, whereas combining ASDs with LTG and LEV does not significantly increase the risk [28]. However, if the use of VPA and TPM during pregnancy cannot be avoided, it is advised to administer them at the minimum effective doses necessary to control generalized tonic-clonic seizures and focal to bilateral tonic-clonic seizures.

2.2.4 Fetal anticonvulsant syndrome

Fetal anticonvulsant syndrome, also known as fetal embryopathy or fetal anticonvulsant (primidone, hydantoin, phenobarbital, valproate, carbamazepine) syndrome, is a condition that occurs with the use of ASDs during pregnancy. It is characterized by minor structural abnormalities in the fetus that do not typically require treatment. Although this aspect of ASD use has received limited attention in recent scientific literature, information on this issue can be obtained from the Genetic and Rare Disease (GARD) website (https://rarediseases.info.nih.gov/diseases/6435/fetal-hydantoin-syndrome).

2.2.5 The impact of ASDs on child development and behavior

In addition to structural teratogenesis, there is also a phenomenon known as “cognitive teratogenesis.”

VPA takes precedence in terms of cognitive, as well as structural teratogenesis. The use of valproate during pregnancy in WWE is associated with a significant dose-dependent risk of cognitive impairments and developmental disorders of the nervous system in the child, as well as an increased occurrence of autistic spectrum disorders. In utero exposure to VPA has been correlated with developmental problems in infancy [30], decreased IQ and cognitive function impairments during childhood [31], and adolescence [32]. Prenatal exposure to VPA is also linked to a higher risk of developing autistic spectrum disorders, attention deficit hyperactivity disorder, and other behavioral problems [33]. There is a clear dose-dependent relationship, with even low doses of VPA (less than 400 mg/day) associated with decreased verbal IQ and increased need for educational assistance [19, 20, 34].

Research on the intrauterine effects of CBZ suggests that this drug does not cause serious neurobehavioral disorders. However, there are risks associated with reduced verbal reasoning skills [20, 35], as well as slightly poorer performance in mathematics compared to the control group, although the difference was not significant [36]. Previous data on the development of autism spectrum disorders were not confirmed in subsequent national cohort studies, large observational studies, or studies based on parents’ assessments of autistic behavior symptoms in children [33].

Limited information is available regarding the effects of phenytoin monotherapy on cognitive and behavioral functions and socialization due to small sample sizes. However, some studies have shown that children exposed to phenytoin have higher IQs compared to children exposed to VPA, and their IQs are comparable to those on CBZ and LTG monotherapy [19, 34].

The best outcomes have been observed in children born to mothers who received LTG during pregnancy, with their IQs being comparable to those of children in the control group [20]. Children exposed to intrauterine LTG exposure have shown better results in early development and school periods compared to children whose mothers received VPA [19]. Furthermore, no higher risk of autism spectrum disorders has been found in this group [37].

Limited information is available regarding the effects of LEV, TPM, and other ASDs on cognitive performance and behavior in later childhood [15]. In conclusion, regarding the intrauterine effects of ASDs on children of WWE, it is important to note the lack of reliable data for most currently prescribed ASDs. Further studies on this issue are required, and the absence of evidence of harm should not be interpreted as evidence of the safety of any given ASD. When preparing for pregnancy, patients should discuss the known risk and benefit information for individual ASDs that is available at the time.

To summarize the key points on epilepsy and pregnancy:

1. Achieving seizure control for 9 months prior to pregnancy increases the likelihood of maintaining this control during pregnancy. Generalized tonic-clonic and focal to bilateral tonic-clonic seizures have the most unfavorable impact on both the mother and fetus.

2. IGE has a 10% higher rate of remission maintenance during pregnancy compared to FE. Structural FE and, in particular, frontal lobe epilepsy have a higher likelihood of seizure aggravation during pregnancy. Status epilepticus occurs in 0.5% of pregnant WWE.

3. “Old” ASDs such as phenobarbital, valproate, and carbamazepine have shown higher effectiveness in focal and generalized epilepsy during pregnancy. However, valproate is not recommended due to its high teratogenic potential.

4. Different ASDs have varying levels of teratogenic potential. Lamotrigine, levetiracetam, oxcarbazepine, and carbamazepine are considered to have minimal teratogenic potential, while topiramate and valproate have moderate to maximum teratogenic potential.

5. Changes in pharmacokinetics of ASDs during pregnancy necessitate monitoring and adjustment of daily dosage. Monitoring ASD serum concentrations is important, as some drugs (lamotrigine, levetiracetam, oxcarbazepine, phenobarbital, phenytoin, topiramate, and zonisamide) may exhibit significant increases or decreases of ASD elimination during pregnancy, affecting seizure control. A decrease in serum concentrations greater than 35% of optimal pre-pregnancy concentrations is associated with an increased risk of impaired seizure control.

6. The impact on pregnancy is attributed to the ASDs included in the dual therapy regimen, rather than the dual therapy itself. If the use of valproate and topiramate is necessary during pregnancy, minimal doses that control generalized tonic-clonic and focal to bilateral tonic-clonic seizures should be administered.

7. Factors such as compliance, avoidance of smoking, alcohol and drug use, sufficient sleep (especially for IGE), identification and timely treatment of anxiety/depression, and repeated intake of ASDs in case of vomiting shortly after administration all contribute to maintaining a stable condition during pregnancy.

3. Management of pregnancy in epilepsy

3.1 Therapy

The protocols for treatment of pregnant WWE are based on expert opinions and consensuses and incorporate evidence-based practices. Nowadays, epilepsy treatment utilizes a variety of ASDs. The treatment approach emphasizes adherence to lifestyle recommendations, such as the avoidance of sleep deprivation, alcohol consumption, and reflex stimuli in reflex epilepsy. Additionally, it involves strict adherence to the prescribed medication regimen and use of the appropriate dosages prescribed by an epileptologist. Monotherapy with a single ASD at the minimum effective daily dose is the preferred approach. Combination therapy with two or, in rare cases, three ASDs that exhibit synergistic pharmacodynamics and pharmacokinetics may be considered if monotherapy proves ineffective [22].

3.1.1 Drug therapy

The latest recommendations from the working group on providing assistance to pregnant WWE suggest that LTG, LEV, OXC, and, to a lesser extent, CBZ are not significantly associated with the development of congenital malformations in fetus [15]. While, the use of VPA and phenobarbital in women of childbearing age is generally discouraged [38]. If discontinuation of these drugs is not possible during preparation for pregnancy, it is recommended to use two ASDs at a minimal dose of VPA, with LTG, LEV, OXC, or CBZ serving as potential additional options.

3.1.2 Role of folic acid

For several decades, the administration of folic acid to patients with epilepsy before conception and during pregnancy has been considered essential. Studies have shown that folate supplementation reduces the incidence of congenital heart defects [39], lowers the risk of autistic spectrum disorders [40], and contributes to increased IQ in children born to mothers with epilepsy who take ASDs [19]. Population studies have also indicated a positive effect of folic acid on the development of the nervous system, behavior, verbal abilities [41], although further research is needed to gain additional evidence.

The recommended daily dose of folic acid varies significantly, ranging from 0.4 mg/day [42] to 5 mg/day [15]. Higher doses of folate, exceeding 0.4 mg/day, are recommended in cases where a family history of malformations is identified. However, it is important to note that the administration of increased doses of folic acid has been associated with an increased risk of oncological diseases, cognitive disorders, and cleft palate [43]. Therefore, ongoing research in this area is necessary. In our work, we recommend regular intake of folic acid at a dose of 3 mg for 1–2 months before conception and during the first 12 weeks of pregnancy [22]. However, obstetricians often recommend folate intake of at least 0.4 mg daily for women of childbearing age due to the high risk of unplanned pregnancies.

3.2 Preparation for pregnancy

Preparation for pregnancy begins during the puberty, when discussions about pregnancy and contraception are initiated with the patient and her relatives, including her mother and grandmother. Since epilepsy requires constant use of ASDs, the primary goal for a neurologist or an epileptologist is to achieve a seizure remission for at least 9 months prior to planned pregnancy using monotherapy with the minimum effective dosage of ASDs. Studies suggest that a period without seizures for 6 months is generally sufficient, but further research is needed to gather more data [2]. The need for continuous use of ASDs is justified by the fact that the risks associated with generalized seizures are greater for the patient and her child than the potential risks of continuous ASD usage [2, 15, 22, 23]. In preparation for pregnancy, in addition to selecting appropriate ASDs, a general physical examination is mandatory to exclude nonneurological diseases, particularly anemia, and assess the functional state of parenchymal organs involved in ASDs metabolism and elimination, namely the liver and kidneys.

The algorithm for preparing for pregnancy and managing pregnant WWE is presented in Figure 1. For ASDs such as LEV, LTG, OXC, ZNS, PHB, PHT, and benzodiazepines, it is important to consider the decrease in drug concentration due to increased renal blood flow starting from the end of the first trimester. Thus, physicians should be aware of the baseline concentration of ASD with variable pharmacokinetics before pregnancy and strive to maintain that baseline level throughout pregnancy. LTG exhibits the most significant changes in pharmacokinetics, with potential for threefold decrease in serum concentration, necessitating an increase in the daily dosage of the drug. The International League Against Epilepsy recommends monitoring these ASDs every 4 weeks, considering a clinically significant decrease in concentration by at least one-third of the original level. Therefore, if it is not possible to measure the ASD concentration during pregnancy, a 30–50% increase in the daily dosage is recommended at the end of the first trimester for patients on a minimal dose of ASDs with variable pharmacokinetics (LTG, LEV, OXC, ZNS, PHB, PHT), if these patients experience generalized tonic-clonic seizures or other seizure types associated with falls. The question of increasing the daily dosage should also be considered in cases of short-term, unstable remission in pregnant WWE with significant structural brain changes and in cases of polytherapy involving ASDs with variable pharmacokinetics [15].

Figure 1.

Algorithm for preparing for pregnancy, management of pregnancy and delivery in patients with epilepsy [22].

3.3 Assisted reproductive technologies

During in vitro fertilization with high doses of estrogens, it is important to consider the possible recurrence of epileptic seizures, as estrogens have pro-epileptic effects unlike progesterone. Furthermore, the use of female steroid sex hormones can significantly affect the pharmacokinetics of LTG, a commonly used antiepileptic drug, leading to a reduction in its blood levels by 2 or more times. Therefore, in cases of long-lasting, persistent drug-induced clinical remission, it is recommended to continue regular use of antiepileptic drugs and maintain a consistent sleep-wake cycle. Before performing ovarian stimulation procedures in patients with insufficiently compensated primary disease state, it is desirable to assess the blood levels of antiepileptic drugs both initially and during sex hormone administration [22]. If the concentration of antiepileptic drugs is reduced by one-third, it is recommended to increase the daily dose by 30–50%. If it is not possible to determine the concentration of LTG, its dosage should be increased by 50% before undergoing in vitro fertilization.

3.4 Management of pregnancy in epilepsy

There are formal contraindications to pregnancy, which include difficult-to-control epilepsy with frequent epileptic seizures accompanied by falls, generalized tonic-clonic or focal to bilateral tonic-clonic seizures, status epilepticus, and marked personality changes posing a threat to the health and life of both the mother and the fetus [2, 22]. These contraindications are considered formal because if a woman decides to become pregnant, neurologists and obstetricians are obligated to use all possible means to preserve the pregnancy.

Given the certain risk of developing MCM, consultation with a geneticist is mandatory. Invasive methods of genetic testing may be performed based on specific indications.

In cases of compensated epilepsy with seizure remission, regular visits to the neurologist are required every 2 months, while visits to the obstetrician-gynecologist should follow standard guidelines. For patients experiencing focal seizures, more frequent visits to the neurologist every month are recommended, with visits to the obstetrician-gynecologist occurring every 2–3 weeks. Patients and their relatives should be strongly advised to consult an epileptologist if seizures occur more frequently. Increased or exacerbated seizures may be caused by sleep deprivation, concurrent diseases, medication regimen violations, and others. Epilepsy itself is not an indication for pregnant women to receive inpatient treatment in a specialized neurological department.

The determination of ASD concentrations is performed every 2 months or less frequently during compensated epilepsy, and in cases of observed seizures, once a month or at every visit to the neurologist during pregnancy. During the first trimester of pregnancy, it is necessary to investigate the concentrations of ASDs with variable pharmacokinetics, including LTG, LEV, OXC, TPM, felbamate, and ZNS. It is known that clearance increases at the end of the first trimester due to increased renal blood flow, which can subsequently lead to decreased ASD concentrations. In the case of LTG, increase in clearance, glucuronidation and conjugation, can collectively reduce its concentration by up to three times [44, 45].

The concentrations of hormones of the fetoplacental complex (placental lactogen, progesterone, estriol, cortisol) and alpha-fetoprotein should be studied starting from the end of the first trimester of pregnancy and subsequently no less than once a month. Dynamic ultrasound examination of the fetus should be performed when the pregnant woman is registered, at 19–21 weeks (to exclude fetal developmental anomalies), and at 30–31 weeks. Starting from the 20th week of pregnancy, it is advisable to perform Doppler assessment of blood flow in the umbilical artery, aorta, and middle cerebral artery of the fetus during ultrasound examination, considering the high risk of developing placental insufficiency. When performing ultrasound associations of different congenital malformations, anomalies with certain ASDs should be taken into account.

From the 26th week of pregnancy, the use of cardiotocography is recommended to provide an objective assessment of uterine motility and fetal condition.

Diagnosis and treatment of fetal growth restriction and placental dysfunction should follow standard protocols. In patients with controlled epilepsy, i.e. in a state of medical (and non-medical) remission, there are no peculiarities in prenatal preparation [22].

3.5 Status epilepticus

The treatment of generalized tonic-clonic seizures and focal to bilateral tonic-clonic seizures should follow the latest recommendations of 2020 [46]. Indications for Cesarean section include status epilepticus in the prepartum period. Status epilepticus of focal seizures without or with impaired consciousness and absence of status epilepticus does not serve as indications for pregnancy termination or C-section. All decisions regarding the treatment strategy and the prolongation of pregnancy during the status epilepticus should be made by a multidisciplinary team consisting of an obstetrician, neurologist, and anesthesiologist (perinatologist). Therefore, C-section is performed in all cases based on obstetric indications, except for status epilepticus in the prepartum period.

3.6 Delivery, pain relief, and pregnancy outcomes

Epilepsy is not a contraindication for vaginal delivery. Along with generally accepted obstetric indications, status epilepticus and uncontrolled increase in frequency of epileptic seizures in the prepartum period are grounds for performing a cesarean section [22].

Pharmacological intervention in labor and delivery and pain relief in epilepsy do not differ from the usual approach. Contraindications for epidural anesthesia are very rare, particularly in cases of impaired cerebrospinal fluid circulation due to acute cerebral and/or spinal pathology in the past.

Currently, there is insufficient data confirming or refuting the necessity of prescribing Vitamin K to a newborn during the early postpartum period when using ASDs with the aim to stimulate the cytochrome C450 enzymes [42]. Previous studies indicate a balance in the hemostasis system of newborns regardless of the ASDs used [47].

3.7 Postpartum management

Due to the risk of epileptic seizures during the postpartum period, the regular intake of prescribed ASD and sufficient rest are strongly recommended [2, 15].

The decrease in concentration of ASD required for seizure control after delivery can lead to the overdose, especially in cases of increased daily doses during pregnancy, potentially resulting in intoxication. There are reported cases of ASD overdose in the early postpartum period, with symptoms such as drowsiness, nystagmus, and ataxia in women, requiring a reduction in daily dosage and immediate monitoring of drug concentrations. The overdose of ASDs is attributed to a relative increase in concentration due to a mother weight decrease, blood loss during delivery, changes in ASD absorption, and other factors. Generally, returning to the daily dosage used before pregnancy is sufficient in the postpartum period, especially in cases when the daily dose of ASD was increased during pregnancy. According to the recommendations of Tomson et al. [1, 15], the normalization of lamotrigine pharmacokinetics occurs over the course of 3 weeks in the postpartum period [15]. However, there have been no observed signs of ASD overdose in the postpartum period in our practice [22].

If seizures persist or there is a risk of their occurrence or recurrence, it is recommended to have a relative constantly present with the mother. Seizures that can result in falls and harm the baby include generalized tonic-clonic, focal to bilateral tonic-clonic, atonic, myoclonic, and myoclonic-tonic-clonic seizures. Any epileptic seizure with impairment of consciousness also poses a danger to the baby. In all these situations, the newborn care, including bathing, diapering, and carrying, should be done with constant assistance from relatives [22].

There is no justification for discontinuing breastfeeding of a newborn since, during pregnancy the fetus is usually exposed to higher concentrations of ASDs than a newborn receiving ASD through a breast milk [15]. Breastfeeding should be done in a lying position to prevent injury in case a seizure occurs.

To summarize the key points on Management of Pregnancy in Epilepsy:

1. For women with epilepsy, treatment with ASD during pregnancy is usually necessary.

2. The primary treatment goal during preparation for pregnancy and management of pregnant WWE is to prevent generalized tonic-clonic seizures and focal to bilateral tonic-clonic seizures. Focal and generalized nonconvulsive seizures are generally considered harmless in terms of their impact on pregnancy and fetal development.

3. Patients should prepare for pregnancy. The main objective of such preparation is to achieve a drug-induced remission of generalized seizures, preferably using the lowest effective daily dose of a single medication.

4. The choice of antiseizure drug depends on achieving drug-induced remission. No antiepileptic drug is completely safe in terms of teratogenic effects. Lamotrigine, levetiracetam, oxcarbazepine, and to a lesser extent, carbamazepine, are currently believed to have the lowest teratogenic potential. If the patient’s condition allows, it is preferable to avoid antiepileptic medication during pregnancy.

5. The management of pregnancy in women with epilepsy requires a comprehensive multidisciplinary approach involving a neurologist-epileptologist, obstetrician, and geneticist.

6. Indications for cesarean section are uncontrolled epilepsy in the prenatal period and status epilepticus.

7. In the prenatal period, adherence to general lifestyle recommendations and treatment regimens is crucial. In most cases, natural breastfeeding is practiced if the infant’s condition allows it.

4. Conclusion

Research on the topic of “Epilepsy and Pregnancy” is an ongoing process, but many aspects still need to be studied. The analysis of publications is challenging due to multiple limitations such as small sample sizes, insufficient study quality, ethical constraints on conducting placebo-controlled studies, and other factors. Therefore, the main recommendations for managing epilepsy in pregnancy are based on expert opinions rather than strictly high-level evidence-based research. Nevertheless, significant progress has been made in recent years. Notably, the publication of “Management of epilepsy in pregnancy: a report from the International League Against Epilepsy Task Force on Women and Pregnancy” [15] provides valuable insights into the main issues, directions for further research, and recommendations for preparing and managing pregnancy in patients with epilepsy. A condensed version of the article with key positions was also published [1]. In 2020, the same group of researchers conducted a global survey of International League Against Epilepsy (ILAE) national chapters to assess the current state of the problem worldwide. The survey revealed that many countries still rely on outdated or overly general guidelines, while information on the topic is continuously evolving. The working group plans to collaborate with the ILAE Wikipedia team to create a series of pages containing updated recommendations for pregnancy in women with epilepsy and their care, ensuring that the latest information becomes available [48].

Conflict of interest

The authors declare no conflict of interest.