Effects of Seizures and Their Treatment on Fetal Brain
Address correspondence and reprint requests to Dr. S. L. Moshé at Department of Neurology, K316, Albert Einstein College of Medicine, 1410 Pelham Parkway South, Bronx, NY 10461, U.S.A. E-mail: email@example.com
Summary: Purpose: To describe the effects of pregnancy on seizures, the effects of seizures during pregnancy on the fetus, and the effects of antiepileptic drugs (AEDs) on fetal brain and development.
Methods: The available literature was reviewed and summarized.
Results: There is a paucity of prospective studies. Retrospective studies indicate that, during pregnancy, alterations in seizure frequency can occur in an unpredictable fashion. Generalized tonic-clonic seizures may have adverse effects on the fetus. It is unclear whether complex partial seizures or absence seizures have negative consequences. AEDs may have potentially detrimental effects on the fetus and its subsequent development, but the full spectrum and clinical significance are under investigation. Monotherapy is strongly encouraged.
Conclusions: Dealing with the pregnant epileptic patient is a difficult and challenging task. Although there are several risks for the mother and the fetus, most epileptic women bear normal, healthy children.
Most women with epilepsy can become pregnant and have healthy children, although several potential difficulties may occur. Their pregnancies are prone to more complications with a high risk of adverse effects on the fetal brain. Pregnancy itself can influence epilepsy. In addition, seizures can affect the fetus and the fetal brain, and finally, the use of antiepileptic drugs (AEDs) to control seizures also may have affects on fetal brain and development. To date very few well-designed clinical prospective or animal studies address these issues. Most of the clinical information is derived from retrospective studies, with several concomitant factors that may influence the outcome. Although epilepsy and its treatment during pregnancy may have detrimental effects on the fetus, the spectrum of consequences is unknown, and additional studies are needed. The majority of women with epilepsy bear children who will develop normally.
Providing care to the pregnant epilepsy patient is quite challenging. The clinician is actually taking care of two patients; the expectant mother and the fetus. In most instances, women with epilepsy have healthy children, but the clinician must consider numerous differences from the practice of caring for nonpregnant women. Changes in the physiology, pharmacokinetics, and the effects of medications and seizures on the developing fetus and its brain are only few of the numerous aspects that must be considered. In this review, we discuss the effects of pregnancy on epilepsy, the effects of seizures on the fetus and fetal brain, and the effects of AEDs on fetal brain.
EFFECTS OF PREGNANCY ON EPILEPSY
During pregnancy, alterations in seizure frequency can occur in an unpredictable fashion. One third of patients will have an increase in seizure frequency, another one third will have a decrease in seizure frequency, and the last one third will not experience any change in seizure frequency. The changes in seizure frequency are unrelated to seizure type, duration of epilepsy, or seizure frequency in prior pregnancies. These changes are often presumed to be secondary to altered levels of circulating hormones (1). It has been suggested that estrogen increase and progesterones decrease seizure thresholds (1). Recent studies suggest that estrogens have no effects (2,3), whereas others indicate that estrogens may have anticonvulsant as well as neuroprotective effects (4–6). The effects of estrogen on seizures are probably multifactorial, depending on seizure type, duration, and treatment, and may occur at any time during the pregnancy (7–9). One study found that an increase in seizure frequency was seen more often with male fetuses (8), but this study has not been replicated. Other factors that may lead to increased seizures include stress, anxiety, sleep deprivation, as well as increased water and sodium retention. Low therapeutic AED levels may be seen in women with epilepsy during pregnancy (10). Increases in blood volume that occur during pregnancy contribute to this, but they are not the sole cause (10). Alterations in pharmacokinetics including malabsorption, an increased volume of distribution, increased drug metabolism, and changes in protein binding also lead to changes in serum AED levels (10). Mothers may become less compliant during pregnancy because of to their valid concerns regarding the anticonvulsant effects on the developing fetus. This decrease in compliance may lead to increasing seizures (11).
EFFECTS OF SEIZURES ON THE FETUS AND THE FETAL BRAIN
One goal of treating pregnant women is to prevent seizures. Generalized tonic–clonic seizures may have adverse effects on the fetus. These seizures may cause hypoxia, which can lead to irreversible damage not only to the central nervous system but also to other organ systems. If hypoxia is sustained, the fetus may die. Whether seizures alone in the absence of hypoxia can induce damage is unclear. This is best documented by the study of Hallak et al. (12). In this article, the author reported that seizures in pregnant rats produced neuronal damage in the hippocampus and tegmentum. However, the authors did not mention the induced seizure type, seizure duration, or whether the seizure induced hypoxia. Trauma sustained by the mother and the fetus during a generalized tonic–clonic seizure also can lead to devastating consequences such as uterine hemorrhage and fetal intracranial hemorrhage (13). It is unclear whether complex partial seizures have similar negative consequences, but it is thought that in a patient with frequent complex partial seizures with a history of generalized seizures, it is prudent to attempt to abolish all seizures. Limited information is available regarding the effects of absence seizures on the fetus.
Children born to mothers with epilepsy are at higher risks for adverse outcomes. Perinatal complications are more common in newborns born to these mothers. The complications include stillbirths, prematurity, and low birth weight (14). Stillbirths can occur even after one seizure, but fortunately, reports of this event are rare (15). In addition, status epilepticus, although rare, does carry a high mortality rate for the mother and child (16). These newborns have a 4–11% risk of being born prematurely and a 10% chance of being of low birth weight (14,17). Studies have shown that fetal death and perinatal mortality rates were slightly elevated for infants of mothers with epilepsy. Interestingly, infant mortality rates also are higher throughout the first year in comparison with those in infants born to women without epilepsy (18). This increased risk cannot be accounted for by differences in socioeconomic status (19).
A form of neonatal hemorrhagic seen in babies born to mothers taking AEDs is due to a deficiency of vitamin K–dependent clotting factors (20). This has been linked to exposure to phenobarbital (PB), phenytoin (PHT), carbamazepine (CBZ), diazepam (DZP), ethosuximide (ESM), and usually when used in combination (10). To avoid this condition, oral vitamin K should be provided to the mother during the last month of pregnancy. If the condition should occur, treatment is with fresh frozen plasma (10).
Most women with epilepsy will inquire whether their child will also be afflicted with epilepsy. Studies have shown that children born to women with epilepsy are three times more likely to have seizures than is the general population (21). Maternal seizures during pregnancy also are associated with a higher risk of epilepsy in children (21). One study suggests that absence seizures in mothers are linked to an increased frequency of seizures in children born to these mothers, more so than generalized tonic–clonic seizures. In this study, some children were affected with the same type of epilepsy syndrome as their mothers, therefore implying genetic mechanisms (22). Paternal epilepsy is not associated with an increase risk of epilepsy in newborns (21). This finding may imply mitochondrial transmission of seizure disorders. The possibility also exists that during a seizure, the fetus may have a brain injury that is potentially epileptogenic. In this case, the infant may have a different epileptic syndrome than the mother. The use of AED therapy is not linked with epilepsy in children (23).
EFFECTS OF ANTIEPILEPTIC DRUGS (AEDS) ON FETAL BRAIN
A major consideration of effects of AEDs is congenital malformations, which are the most commonly reported adverse outcome (10). Malformations are serious medical or surgical defects in which anomalies are less well-defined minor physical defects (10). Both malformations and anomalies have been associated with maternal AED use. Speidel and Meadow (14) were the first to report in a retrospective study that congenital malformations were twice as common in infants born to mothers taking AEDs. The risks of these malformations are further increased by polytherapy (24). An increased risk of congenital malformations has been found in offspring of mothers with first-trimester seizures versus those with seizures in the second or third trimester (25).
Six clinical syndromes of congenital malformations are attributed to PHT, CBZ, PB, primidone (PRM), trimethadione (TMO), and valproic acid (VPA). All of these syndromes involve mostly midline facial abnormalities and the distal digits. The fetal hydantoin syndrome was recognized in 1973 (26). Children exposed to PHT were found to have craniofacial anomalies such as a broad nasal bridge, short upturned nose, hypertelorism, distal digital hypoplasia, intrauterine growth retardation, and metal deficiency. CBZ produces a syndrome characterized by craniofacial anomalies such as upslanting palpebral fissures, epicanthal folds, short nose, and a long philtrum, along with hypoplastic nails, and smaller head sizes (in comparison to controls), and developmental impairments (27). The fetal PB syndrome involves a short nose, low nasal bridge, hypertelorism, epicanthal folds, low-set ears, prognathism, distal digital hypoplasia, and developmental impairments (28). PRM causes a hirsute forehead, long philtrum, anteverted nostrils, hypoplastic nails, developmental impairments, and cardiac defects. VPA-exposed children exhibit epicanthal folds, flat nasal bridge, upturned nose, long upper lip, downturned mouth, and abnormalities of the distal digits. Kaneko (29) revealed that use of VPA in pregnancy leads to the highest malformation rate of all the AEDs (29). TMO is the only AED that produces its syndrome when used in monotherapy. Its use in pregnancy results in children with microcephaly, epicanthal folds, low-set ears, irregular teeth, and mental retardation (30). In addition, inguinal hernias and short stature occur. Concerning newer AEDs, as more experience is gained with their use, data will become available as to their safety in pregnancy.
Neural tube defects are usually disorders of secondary neurulation that occur early in fetal development (31). Because they occur within the first month of gestation, the injury may have happened before the mother realizes that she is pregnant. This condition has been linked to exposure of the fetus to VPA and CBZ (32). Multiple mechanisms have been proposed, the leading of which is a disruption of folate utilization.
In women with juvenile myoclonic epilepsy, for which VPA is often a first-line agent, the clinician may choose to discontinue or change the AED before conception and restart the medications at 6–8 weeks' gestation, provided that the pregnancy is planned.
AEDs can have adverse effects on the cognitive status of the child, based on early studies showing that the use of AEDs is associated with a higher risk of mental retardation in children (33). However, when controlled for parental intelligence and social economic status, no association was found between AED use and mental retardation (34). Maternal intelligence is the single most important indicator of cognitive function of offspring. This suggests that intelligence as well as seizure propensity for genetic epileptic syndromes may be mitochondrially inherited. Few studies suggest that children of mothers with epilepsy may show impairments of language acquisition (35). Further studies are needed to confirm this observation, as well as follow-up studies to determine whether this is a persistent deficit. In humans, it is unclear whether AEDs cause a decrease of the average head circumference in newborns exposed to these drugs. Several prospective studies have supported this concept, but conversely, other prospective studies do not reveal a relation between head growth and AED use (36–43).
In animal studies, AEDs may have deleterious effects on the fetal brain. PB has been shown to reduce brain weight as well as hippocampal cell density (44). Some reports indicate that it does so by inducing apoptosis. PB also has been shown to alter levels of catecholamines in mice (45). In rats, PB impairs the coordination and learning. These effects do not appear to be reversible, even after the discontinuation of medication (45). Similar neurobehavioral effects can be seen with other AEDs such as VPA, TMO, and PHT (46–49).
Several mechanisms by which AEDs may produce deleterious effects have been proposed, including genetic predisposition. Many AEDs are metabolized through arene oxide intermediates, which are highly reactive compounds thought to be teratogenic (50). A genetic predisposition may result in a lack of detoxifying enzymes, or AEDs may interfere with the metabolism of toxic substances. Epoxide hydrolase is the enzyme responsible for detoxifiying arene oxides (51). It has been found that deficiencies of this enzyme in mothers receiving PHT and their infants increase the risk of teratogenicity (51). Free radical–scavenging enzymes eliminate free radicals formed by metabolism of drugs. Deficiencies of these scavenging enzymes allow free radicals to produce cytotoxic effects that also are thought to play a role in teratogenesis (51). In other medications, such as TMO, the mechanism of teratogenicity is unknown. Folic acid is necessary for proper DNA and RNA synthesis, and many AEDs decrease the amount of available folate. Folate treatment during pregnancy has been shown to decrease the malformations rate in fetal mice exposed to PHT (52). In humans, Biale and Lewenthal (53) found lower rates of congenital malformations in those infants born to mothers with epilepsy receiving folate. It is current practice to give 1–4 mg of folic acid daily to women of childbearing age to prevent neural tube defects. Because many AEDs inhibit neuronal excitability, a reduction of neuronal excitation in utero may perhaps affect synaptic growth and may be responsible for changes in cognition and behavior (54).
Dealing with the pregnant epileptic patient is a difficult and challenging task. Alterations in physiology lead to multiple changes in drug absorption, metabolism, and AED levels. Seizures as well as AEDs can have serious consequences in the fetus, including congenital malformations, changes in brain weight, developmental impairments, and, in some instances, death. These effects are the result of a multitude of factors including genetic susceptibility as well as alterations in cellular processes. In most instances with proper prenatal care, judicious use of AEDs, preferably monotherapy, and an open and direct relationship with the patient, women with epilepsy are able to have normal and healthy children.
Acknowledgment: This study was supported in part by grant NS20253. Solomon L. Moshé is a Martin A and Emily L. Fisher Fellow in Neurology and Neurosciences.