Epilepsy in pregnancy

Effect of pregnancy on epilepsy

A few prospective cohort studies have been conducted that show that there is no change in seizure frequency during pregnancy in the majority of WWE.8 However, the seizures may become more frequent in some (15-37% of epileptic women).10 Not much is known with certainty as to why some women experience increased seizure frequency during pregnancy. However, some factors that include sleep deprivation, altered anti-epileptic drug (AED) pharmacokinetics, or poor adherence to treatment may play a role. It was also found that women with focal onset epilepsy or those who were undergoing polytherapy experienced increased seizure frequency during pregnancy.10 During and immediately after labor, there is also a relatively increased risk of seizures (post-partum).11,12

Women who have catamenial epilepsy (CE) have been shown to have a better seizure control, during pregnancy as compared to those who do not have CE. Hence, information regarding CE should be considered while taking management decisions and counselling the pregnant women.13

Effect of epilepsy on pregnancy. Obstetrical complications:

Although most WWE have healthy pregnancies, they are still considered to be at an increased risk of suffering from pregnancy-related complications.8 This risk is higher when WWE are also on AED therapy.14 A pregnancy registry from India has shown that WWE are more likely to have spontaneous abortions as well as anemia, ovarian cysts, and fibroid uterus.15 Meta-analyses and population-based data from many other countries show a small but significant risk of caesarian sections, post-partum hemorrhage, and induction of labor with AED exposure.14,16,17 This risk should also be considered while counselling WWE.17 For WWE who do not take AED, there is a slight increase in the risk of cesarian delivery only.16

Fetal complications (without AED exposure)

Focal seizures including unilateral motor or non-motor seizures, or some generalized seizure types like absence, and myoclonic seizures do not have adverse effects on pregnancy or the fetus. However, they may have indirect but serious consequences if the patient sustains trauma because of them.8

Women with epilepsy who experience generalized tonic-clonic seizures may be at a relatively higher risk of harming the fetus during a seizure, even though the absolute risk remains very low and the level of risk may depend on seizure frequency.8 It should be noted that the risk of experiencing major congenital malformations (MCMs) in the general population varies between 1.6% and 3.2%, and WWE who do not receive AEDs show similar MCM rates.4 Hence, exposure to AED leads to teratogenic effects.

Fetal complications (with AED exposure). Anthropometric changes

Newborn infants of WWE who are exposed to AED in utero may have low birth weight and may also be small in size for their gestational age.16 Studies conducted in European and North American countries have shown that such infants have higher rates of low birth weight, preterm birth, intrauterine growth retardation, and smaller head circumference at birth.18,19 These infants also have lower APGAR score at birth.

Teratogenicity (Table 1).20-25

The AEDs are among those drugs that are used as long-term medications and, unfortunately, also have substantial teratogenic effects. Apparently, teratogenicity is variable among many different types of AEDs. We will consider the commonly used AEDs followed by some of the newer drugs separately for this purpose.

Carbamazepine (FDA pregnancy category D)

Animal studies have shown a consistent risk of teratogenicity, even though its risk level is the lowest among all AEDs. Human studies have mostly been observational and have not been conclusive, with some showing an increased risk while others find that it poses a minimal risk for the MCMs.26,27 Morrow et al28 in 2006 found that it exhibits the lowest risk of teratogenicity.However, this has not been shown consistently in later studies (Table 1).20-25 Carbamazepine is still considered as a safer option among the older anti-epileptics, especially when compared with Valproic acid. A very recent network meta-analysis showed an increased risk of overall MCMs with carbamazepine (OR, 1.37; 95% CrI, 1.10–1.71). Some studies have shown that the teratogenic effect of carbamazepine is rather dose-related.24,25

Phenytoin (FDA pregnancy category D)

The teratogenicity of phenytoin has been well established among clinicians for almost 40 years.20-22,29 “Fetal hydantoin syndrome”, is found in 11% of newborns who are exposed to phenytoin in utero.30 An additional 30% of such children express some (if not all) of its features.31 Infants with FHS suffer from intrauterine growth restriction and intellectual disability. They may also have facial dysmorphism, hypertelorism, depressed and broad nasal bridge with upturned nasal tip, prominent epicanthal folds, and wide prominent vermilion of the lips, digital hypoplasia, and irregular ossification of the distal phalanges.30,31

Phenobarbitone (FDA pregnancy category D)

The rate of MCM induced by PB monotherapy exposure during pregnancy varies between 2.9% and 6.5% in different studies. A recent network meta-analysis showed significantly higher rates of MCM with phenobarbitone with OR, 1.83; 95% CrI, 1.35-2.47, as compared with controls.32 A total of 60 to 65% of these malformations are of cardiac origin.

Valproate (FDA pregnancy category D)

Data from pregnancy registries and prospective studies have revealed a significantly increased risk of MCMs in the neonates born to pregnant women who consumed valproate during the first trimester of pregnancy (Table 1).20-25 The most common types of birth defects reported are as follows: neural tube defects, orofacial clefts, congenital heart defects, hypospadias, and skeletal abnormalities.33 In different prospective cohort studies from different populations, the prevalence rate of MCMs with valproate monotherapy ranges from 4.4% to 13.8%.20-25 The UK and Irish Pregnancy Registries recorded 3 times as many MCM cases from valproate exposure as from Lamotrigine (6.7 versus 2.3%).24 The Neurodevelopmental Effects of Antiepileptic Drugs (NEAD) Study Group showed that there is an increased risk of MCM or death with valproate (20.3% with valproate as opposed to 10.7% with phenytoin, 8.2% with carbamazepine, and 1% with lamotrigine).33 This study further elaborated that this effect is dose-dependent. A recent meta-analysis also revealed that valproate exposure in pregnancy was significantly associated with overall major congenital malformations with an OR of 2.93; (95% CrI, 2.36–3.69).32 Furthermore, polytherapy regimes that include valproate have shown a much increased MCM rate as compared with individual AED, which has also been shown with lamotrigine.32,33 The dose dependent risk of teratogenecity with valproate has been shown in many pregnancy registries. The risk usually increases when the daily dose exceeds 600 mg / day, but the highest risk is when the dose is 1000 mg / day or above.24,34 However, individual susceptibility is genetically determined, making some individuals highly susceptible even with very low daily dosages.34

Lamotrigine (FDA pregnancy category C)

Animal studies have shown that lamotrigine is developmentally toxic in doses that are less than those given to humans. Current data on humans suggest that lamotrigine is less teratogenic than most of other commonly used AEDs, including valproic acid or phenytoin.20-25 The International Lamotrigine Pregnancy Registry update reported a risk of 2.9% with 414 monotherapy exposures. The North American AED Pregnancy Registry found only an increased risk of orofacial clefts, with no significant risk of MCMs in 684 infants who were exposed in utero to lamotrigine. However, this increased risk of orofacial clefts was not found in the EUROCAT congenital anomaly registers for 40 children who were exposed to lamotrigine monotherapy. Perhaps, as suggested by some authors, there is a dose-dependent relationship between MCM and maternal lamotrigine use, with the risk of MCM being greater with higher lamotrigine doses.22 In many registries and meta- analyses carried out so far, Lamotrigine appears to be a safer option, and perhaps one of the least hazardous anticonvulsants than other commonly used AEDs, as far as teratogenecity is concerned (Table 1).20-25,32

Levetiracetam (FDA pregnancy category C)

Levetiracetam in animal studies caused developmental toxicity, and teratogenicity. In humans, the North American Epilepsy Registry reported 450 exposures during the first trimester and showed an MCM rate of 2.4%.21 However, the rate of MCM is much lower in other registries, e.g., in the UK and Ireland pregnancy registry, the rate of MCM was 0.7% (CI 0.19–2.51%). In the light of the most recent evidence, many authors consider levetiracetam as much safer and with no significant teratogenic effects on the human fetus (Table 1).20-25,32

Topiramate (FDA pregnancy category D)

In multiple animal species, topiramate demonstrated developmental toxicity, including teratogenicity, in the absence of maternal toxicity at clinically relevant doses. In humans, Topiramate exposure has been shown to be harmful for the fetus in pregnant women. The data from pregnancy registries indicate that infants exposed to topiramate in utero are at an increased risk for MCM, cleft lip and/or cleft palate (oral clefts), hypospadias, being small in size for gestational age, and increased combined fetal loss. Some studies have shown variable rates of MCM with topiramate that ranged between 2.4% to 4.2%.20-25 The North American AED pregnancy registry reported on 359 women with first-trimester exposure, with a prevalence of 4.2% versus 1.1% in the unexposed reference group (with 95% CI; 1.4–10.6).21

In a recently published systematic review by Veroniki et al,32 topiramate exposure in utero was associated with high incidence of MCM, having an odds ratio of 1.90 (95% CrI 1.17–2.97)

Clonazepam (FDA pregnancy category D)

Clonazepam is a medication that is widely used not only as an antiepileptic drug. Several studies have also revealed that it is not associated with an increased risk of MCMs if it is used as a monotherapy and that it presents no complications from the obstetric perspective.32 Some studies have shown that the risk will significantly increase to 6% if it is used as polytherapy.22

Clobazam (FDA pregnancy category C)

Although limited data are available in regard to exposure to clobazam during pregnancy, benzodiazepines, in general, can have sedative effects on newborns. In a recently published study by Thomson et al., the pregnancy registry of South India showed Clobazam use in 9 patients, and MCM occurred in 2 pregnancies (22%), RR, as compared to unexposed healthy pregnancies, was 6.44 (95% CI 1.67–24.94).20 This increased risk needs to be confirmed in larger cohorts.

Oxcarbazepine (FDA pregnancy category C)

Vajda et al22 reported the risk of MCM to be 5.9% if oxcarbazepine is used as monotherapy during pregnancy. However, the risk will increase to 11.1% if it used as a polytherapy.Veroniki et al32 in their network meta-analysis found insignificant association with MCMs, OR 1. (CrI 0.72,2.29)32

Zonisamide (FDA pregnancy category C)

Kondo et al35 investigated the impact of zonisamide exposure in pregnancy. They prospectively followed 26 pregnant women, of which 22 were on polytherapy and 4 were on monotherapy. No MCMs were detected in the 4 newborns who were exposed to monotherapy. Only 2 offsprings (7.7%) in the polytherapy group had MCMs, with 1 case of anencephaly and 1 with atrial septal defect. However, as the zonisamide blood levels were low in both cases below the therapeutic range, so the results were not conclusive. A Cochrane database systematic review in 2016 concluded that zonisamide was not associated with an increased risk of MCM, however, very few data for this drug is available.25

In 2014, Hernández-Díaz et al36 demonstrated the relationship between the exposure to zonisamide during pregnancy and low birth weight. A total of 98 exposed pregnancies were followed in their study and the prevalence for low birth weight was discovered to be 12.2%.

Lacosamide (FDA pregnancy category C)

Over the span of the past few years, limited information has become available on the safety of Lacosamide during pregnancy. In 2011, Hoeltzenbein et al37 studied 7 pregnant ladies on lacosamide, of which 1 pregnancy was terminated at the gestational age of 20 weeks due to multiple malformations. However, the mother was on 6 antiepileptic drugs, and lacosamide was started after week 15 of gestational age. They also reported 1 case of spontaneous abortion at the gestational age of 6 weeks. In that series, 5 infants were born, 3 of whom had congenital anomalies. Major anomalies were reported in 1 of the 3 newborns such as atrial septal defect/patent foramen ovale. In addition, the mother was on other 2 antiepileptic medications. Recently, a case series of 3 patients was studied by Lattanzi et al,38 in which the 3 pregnant mothers were exposed to lacosamide during pregnancy and breastfeeding with no teratogenicity, no major or minor congenital abnormalities. More studies have to be conducted to study the safety of the use of lacosamide during pregnancy.

Brivaracetam (FDA pregnancy category C)

A new anti epileptic for add – on therapy in refractory focal onset epilepsy. There are very limited teratogencity data available in humans. In animal models teratogenecity was observed in maternal toxic doses of BRV.39,40 In humans it should therefore be used during pregnancy if the potential benefits outweigh possible risks.

Perampanel (FDA pregnancy category, not assigned)

The data available in human studies is not sufficient. A review of clinical studies identified 25 pregnancies in 22 women. Only 5 of these resulted in normal healthy infants, there were 12 induced abortions, 5 spontaneous abortions, one neonatal death, while 2 subjects were lost to follow. Perampanel also caused prolonged and irregular estrous cycle in rats, thus may affect fertility in humans. Therefore, currently Perampanel is not recommended for young women in child bearing age without contraception.41

Eslicarbazepine (FDA pregnancy category, Not assigned)

Animal studies have not shown a significantly increased risk of teratogencity. In humans the data available is not sufficient to draw any conclusions. According to a systematic review by Costa et al, total 91 pregnancies have been notified so far, congenital anomalies were found in 5 cases, and 18 cases resulted in abortion, however, the review concluded that the available data is insufficient, and such pregnancies should be monitored and evaluated further.42

In summary, valproic acid has consistently shown a significantly higher risk of teratogenicity, whereas phenytoin, phenobarbitone, and topiramate pose an intermediate risk. Carbamazepine and lamotrigine present relatively lower risks of congenital malformations. The use of levetiracetam appears promising. However, bigger studies are required.

Long-term cognitive outcomes in newborns

Data from registries in different populations have shown that many infants born to WWE and exposed to AEDs may have impaired mental and motor abilities. A prospective study from India showed that almost one-third of the infants who were exposed in utero to different AEDs experienced similar problems at 15 months of age. At the age of 6 years, they were re-examined and found to have a significantly lower IQ score as compared with children without prenatal AED exposure or maternal epilepsy that served as age-matched control.43 Similar observations were found in other registries. In general, monotherapy with valproate is clearly associated with impairment of cognitive development, as well as autism and autism spectrum disorders. In comparison to valproate, monotherapy with carbamazepine, Levetiracetam, lamotrigine or phenytoin seem to have better cognitive and behavioral outcomes. However, these AEDs may have a subtle effect on cognition and behavior, therefore more data is required to label these AEDs as completely safe in this respect.43 The AED polytherapy can also produce such long-term effects.

Managing epilepsy in pregnant ladies (Table 2)

There are many misconceptions regarding epilepsy in countries such as Saudi Arabia, which results not only in a late diagnosis of epilepsy but also missed or irregular follow-ups in epilepsy clinics. In the light of these observations, the following are the recommended treatment strategies when dealing with WWE:

Folic acid supplementation

It is recommended that all epileptic women and girls (with or without treatment with AEDs) should receive a daily supplementation of folic acid in a dose of 4–5mg/day before any possibility of pregnancy.8 Folic acid supplementation is believed to reduce the risk of MCMs in the offspring of pregnant, epileptic ladies. Although the evidence to support this hypothesis is not strong enough (class III studies), the studies that have been conducted so far do not show any evidence of harm and, apparently, there is no reason to suspect that it is not effective. Therefore, this recommendation is still valid.44

Pre-marriage steps

The aim of managing epilepsy in pregnant ladies should be the same as in any other epileptic patient, that is, the achievement of complete freedom from seizures. However, the management should start before conception or even before marriage. All women who are in their reproductive years, even if they are not yet married, should be put on the safest possible AEDs with monotherapy and the least possible dose. It is advisable to inform all such patients of childbearing age who are on any AED about the teratogenicity of these drugs.

After marriage and before conception, WWE along with their spouses should consult a neurologist. If a couple plans to start a family in the near future, they should be evaluated and properly counseled regarding the possibility of experiencing a change in frequency of seizures during pregnancy. They should also be informed about the possibility of their offspring having abnormalities that include anthropometric anomalies as well as teratogenicity, and its likelihood should be re-endorsed. If an adjustment is required in medications, then the clinician should discuss the relative benefits and risks of adjusting medication with the patient to enable her to make an informed decision.8

It is recommended that before conceiving, WWE should have an adequate seizure-free period of at least 9 months with a single anti-epileptic drug in the least possible dose.16 It is prudent to start folic acid supplementation after marriage or after the first pre-marriage visit, in case it has not been started before. It is better to maintain a preconception drug level with which the patient is seizure-free and aim to maintain this level during pregnancy.44 This is especially true with lamotrigine, which has shown to have decreased drug levels during pregnancy, which, in turn, is associated with the loss of seizure control.6 Similarly, monitoring carbamazepine and phenytoin levels should also be considered.44 There is a level C recommendation for monitoring levetiracetam and oxcarbazepine according to AAN guidelines.44 The rest of the AEDs, even though there is no conclusive evidence, may also be monitored, if feasible.44

Delivery

Taking vitamin K supplementation during the last month of pregnancy before delivery is advisable for pregnant WWE on enzyme-inducing AEDs who face the risk of intracerebral hemorrhage in the newborns.44 The delivery should be supervised by an expert obstetrician and a neonatologist. In addition, a neurologist should also be involved as a member of the team providing care to the patient. There is an increased risk of seizures during delivery, which can be caused due to multiple reasons such as physical stress, sleep deprivation, hypoglycemia, inappropriate AED dosage, missing doses, and co-medications. The routine AEDs that the woman was taking should also be administered in the labor room. It is better to obtain the AED levels beforehand to ensure that the drugs are in their therapeutic range. Parenteral lorazepam should be made available in the labor room and can be administered intravenously if the patient has a seizure during labor. The selected patients may require caesarian section if they are unable to participate in labor, for example, due to heavy sedation.

The respiratory efforts of the newborn can be sluggish if the mother takes phenobarbital or another sedative AEDs during pregnancy. A neonatologist or pediatrician should be available to resuscitate the infant. Many authorities recommend administering Vitamin K1 injections intramuscularly to the infant if the mother had received enzyme-inducing AEDs during pregnancy to reduce the risk of hemorrhagic complications in the newborn, even though the evidence supporting its usefulness is very limited.8,44

Breastfeeding

It has been shown that traces of maternal AEDs can be secreted in breast milk.15 Therefore, there is a potential risk that breastfeeding might negatively impact children’s development. However, a recent prospective study showed no such effect.33 On the contrary, few pregnancy registries have shown a positive effect, for example, a better cognitive profile of infants who were breastfed versus those who were not while the mothers were on AEDs (that included carbamazepine, lamotrigine, phenytoin, and valproic acid).33 However, more prospective studies are required to be conducted to evaluate AED exposure in infants who are breastfed.

The expression of AEDs in breast milk decreases if the protein-binding capacity of the drug is more and vice versa. WWE in their post-partum period should be encouraged to breastfeed their newborns before taking their dosage of AEDs to minimize the flow of AEDs into the breast milk.

It is important to get adequate sleep, which might be difficult during the early post-partum period as it is usually frequently disturbed at this time. This can lead to breakthrough seizures. Such mothers can be advised to use expressed milk to feed their babies during the night. Moreover, WWE are advised to be careful and avoid positions that can be harmful to the baby if a seizure occurs while they nurse their babies so that they do not suffocate or drop the baby or fall over.

In conclusions, gender and age should be important considerations when choosing AEDs for epileptic patients. Patients’ and spouses’ counselling is very important for managing WWE. As most of the women are already diagnosed with epilepsy before they become pregnant, it is prudent to give the safest medications along with folic acid supplementation from the beginning, even before they get married. Monotherapy is preferred with least possible doses. All AEDs are potentially teratogenic, but some of them such as includes carbamazepine, lamotrigine, and levetiracetam seem to have a better teratogenic profile. However, the decision regarding AED choice should be individualized. Normal vaginal delivery is safe with appropriate pain and adequate seizure control. The patients should also be supervised during the postpartum period as they may need titration of AED doses then.