Developmental Malformations
X-linked hydrocephalus (L1 syndrome)
Dec. 12, 2024
Worddefinition
At vero eos et accusamus et iusto odio dignissimos ducimus qui blanditiis praesentium voluptatum deleniti atque corrupti quos dolores et quas.
Fetal anticonvulsant syndrome
- Updated 10.08.2024
- Released 11.15.1999
- Expires For CME 10.08.2027
Fetal anticonvulsant syndrome
Introduction
Overview
Fetal anticonvulsant syndrome includes a variety of congenital malformations in infants exposed to antiseizure drugs in utero. These include major congenital malformations, such as cardiac and neural tube defects, orofacial clefts, and hypospadias; minor malformations, such as craniofacial dysmorphisms (hypertelorism, flat nasal ridge, low-set ears, microcephaly, short neck); and digital anomalies (hypoplasia of the distal phalanges or nails), as well as cognitive and behavioral disturbances and intrauterine growth retardation. Many investigators have described a specific association between exposure to certain antiseizure drugs and dysmorphic features of the child, sometimes in combination with major congenital malformations and learning and behavioral problems. Such syndromes with specific patterns of fetal malformations attributed to single antiseizure drug exposure have been reported, and these are fetal trimethadione syndrome, fetal hydantoin syndrome, fetal barbiturate syndrome, fetal carbamazepine syndrome, and fetal valproate syndrome. However, though some of these congenital abnormalities may be more prominent in association with one antiseizure drug compared with another, it is now generally accepted that the separation of the various syndromes of embryofetal exposure to antiseizure drugs is not as clearcut as previously thought. Like other teratogens, antiseizure drugs produce a pattern of major congenital malformations with overlap among the individual antiseizure drugs (68); there is a considerable overlap in facial features in children exposed to different antiseizure drugs, and many of those features also frequently occur among unexposed children. Major congenital malformations seen more frequently with valproate, such as neural tube defects, can also occur following exposure to other antiseizure drugs, demonstrating that this is not an antiseizure drug–specific major congenital malformation. Studies on possible fetal anticonvulsant syndrome and major or minor malformations due to fetal exposure to the newest generation of antiseizure drugs are limited or lacking.
Key points
|
• Fetal anticonvulsant syndrome includes a variety of congenital malformations in infants exposed to antiseizure drugs in utero. | |
|
• Symptoms and signs of fetal anticonvulsant syndrome consist of major congenital malformations, minor malformations, cognitive and behavioral disturbances, and intrauterine growth retardation. | |
|
• A specific association between exposure to certain antiseizure drugs and dysmorphic features of the child, sometimes in combination with major congenital malformations and learning and behavioral problems, has been described particularly in relation to phenytoin, phenobarbital, and valproate. | |
|
• It is now generally accepted that the separation of the various syndromes of embryofetal exposure to antiseizure drugs is not as clearcut as previously thought. | |
|
• The highest risk of major congenital malformations and of adverse cognitive outcomes is with polytherapy mainly involving valproate or topiramate (combination of valproate and lamotrigine is of highest risk). | |
|
• With monotherapy the highest risk of major congenital malformations is found with valproate (approximately 10%), followed by phenobarbital (6% to 9%), phenytoin (5% to 7%), carbamazepine (4.0% to 4.7%), and topiramate (3.9% to 4.1%). | |
|
• Monotherapy with lamotrigine and levetiracetam has a low risk of major congenital malformations, near 2.5%. | |
|
• Folic acid taken at the time of conception decreases the risk of adverse outcomes. | |
|
• The preconception management is the cornerstone for care of people with epilepsy who wish to become pregnant. |
Historical note and terminology
In 1963, Müllers-Kuppers reported a child with cleft palate, microcephaly, malrotation of the intestine, speech problems, and intellectual disability after in utero exposure to mephenytoin (131). Janz and Fuchs retrospectively reviewed 426 pregnancies of epileptic mothers; although the mothers demonstrated an increased miscarriage and stillbirth rate, the incidence of malformations was not significantly different from that of the local healthy population (85). Subsequently in 1965, Centa and Rasore-Quartino reported a case in which congenital heart disease developed after in utero exposure to phenytoin and phenobarbital (21). Melchior and colleagues described orofacial clefts after in utero exposure to primidone and phenobarbital (124). Meadow reported six children who were exposed to anticonvulsant medication in utero showing orofacial clefts, which in four cases were accompanied by other dysmorphic facial features and congenital heart disease (123). He observed that many antiseizure drugs have folic acid-antagonist properties. He also noticed that the antiseizure drug-induced pattern of malformations was similar to the one seen after unsuccessful attempts to induce abortion with folic acid antagonists.
Subsequently, specific patterns of fetal malformations associated with single antiseizure drug exposures were reported. In 1970, German and colleagues reported the teratogenic effect of trimethadione (58), and later Zackai and colleagues coined the term “fetal trimethadione syndrome” (203). Several other reports of fetal anticonvulsant exposure syndromes have been reported, but one of the best known is probably the fetal hydantoin syndrome (109). The initial descriptions of phenytoin teratogenicity in humans were published in the 1960s and early 1970s (146; 123; 77; 109). In 1966, Massey reported the teratogenic effect of phenytoin in mice (113). Hanson and Smith coined the term “fetal hydantoin syndrome” (66). With time, it became evident that the separation of the various syndromes of embryo-fetal exposure to antiseizure drugs was not as clear-cut as previously thought (168; 91; 04).
Our knowledge concerning the risks of major congenital malformations in association with exposure to antiseizure drugs has increased substantially thanks to the establishment of epilepsy and pregnancy registers from the late 1990s. Reviews elaborate on the chronology of the reports and the progress made in our understanding of the teratogenic effects of antiseizure drugs (68; 174; 182; 149; 177). A Cochrane review of 49 studies, including more than 25,000 pregnancies, represents the latest evidence on the risk of malformations in pregnancies complicated by exposure to antiseizure medications (14).
Authors’ comments on nomenclature. The term “anticonvulsant drug” is traditionally used as synonymous with “antiepileptic medication (ASM)”, though not all antiepileptic drugs are anticonvulsant (see, for example, ethosuximide). Currently “antiseizure drug” is the preferred term instead of antiepileptic or anticonvulsant drug in order to emphasize that in humans these drugs affect the epileptic seizures (antiseizure action) and not the epilepsy itself (antiepileptic action).
The term “women with epilepsy” has historically been used to encapsulate the unique issues with epilepsy and its treatment associated with childbearing. There is a growing appreciation for the distinction between ability to bear children (presence of a uterus) and gender identity (woman, man, gender fluid, nonbinary, trans-man, etc.) and, therefore, the term suggested in the 2024 guidelines is “people with epilepsy of childbearing potential (PWECP)” to be as inclusive as possible. Throughout this article, the term “women” was kept when referring to historic studies that included women and updated to “people” when discussing conclusions based on prior studies.
Clinical manifestations
Presentation and course
Most people with active epilepsy need treatment with antiseizure drugs during pregnancy. Antiseizure drugs are also frequently used for other indications, such as migraine, pain syndromes, and psychiatric disorders, which are prevalent among people of childbearing age.
It is generally accepted that antiepileptic drug treatment during the first trimester of pregnancy is associated with a small, but significant, increase in the risk of major congenital malformations. This risk is:
• Probably no different or only slightly higher than the background (around 1% to 2%) in people with epilepsy who are not taking antiseizure drugs. | |
• Probably less than twice the background rate with commonly used antiseizure drugs (other than valproate and topiramate) as monotherapy, although the relative risk may vary with individual antiseizure drugs. | |
• Certainly increased with valproate monotherapy to three to five times the background rate. | |
• Certainly higher with polytherapy than monotherapy; valproate is a significant contributor to the high risk of major congenital malformations in polytherapy, particularly in combination with lamotrigine (10%). | |
• Likely to be dose dependent, at least for valproate and probably for lamotrigine (ie, the higher the plasma antiseizure drug concentration, the higher the relative risk of major congenital malformations) (175). |
New practice guidelines from The American Academy of Neurology (AAN), American Epilepsy Society (AES), and the Society for Maternal Fetal Medicine released in 2024 (144) are the first major updates since the guidelines were published in 2009 (67; 68; 69). Of note, these guidelines replace “women with epilepsy” with the more inclusive term “people with epilepsy of childbearing potential (PWECP).”
• Physicians and people with epilepsy of childbearing potential should engage in joint decision making about antiseizure medication choice and monitoring, preferably preconception, and recommend medications that optimize seizure control and fetal outcomes: at the outset of treatment, if possible. | |
• Reduce harm to the people with epilepsy of childbearing potential and fetus by reducing the risk of convulsive seizures during pregnancy by exercising caution in removing or replacing an effective antiseizure medication, and monitor levels of prescribed antiseizure medications and adjust the dose as needed. | |
• There are limited data on the pregnancy-related outcomes for acetazolamide, eslicarbazepine, ethosuximide, lacosamide, nitrazepam, perampanel, piracetam, pregabalin, rufinamide, stiripentol, tiagabine, and vigabatrin. | |
• Most desirable antiseizure medication in pregnancy: lamotrigine, levetiracetam, oxcarbazepine. | |
• Valproic acid must be avoided to reduce the risk of major congenital malformations, including neural tube defects (NTD), urogenital, and renal malformations, as well as risk of small for gestational age (SGA), reduction in full scale IQ at age 6, and autism spectrum disorder (ASD). | |
• Phenobarbital should be avoided to reduce the risk of cardiac malformations and oral clefts. | |
• Topiramate should be avoided to reduce the risk of oral clefts and small for gestational age. | |
• Folic acid should be prescribed 0.4 mg/day preconception and during pregnancy for any people with epilepsy of childbearing potential on any antiseizure medication to reducing the risk of neural tube defects and possibly lower the risk of autism spectrum disorder and lower IQ. |
In addition to the above, it is recommended that physicians counsel any people with epilepsy of childbearing potential initiating valproic acid of the elevated risks for major congenital malformation, small for gestational age, autism spectrum disorder, and IQ abnormalities.
The recommendations, based on these findings were: if possible, avoidance of valproate and antiseizure drug polytherapy during the first trimester of pregnancy should be considered to decrease the risk of major congenital malformations. If possible, avoidance of valproate and antiseizure drug polytherapy throughout pregnancy should be considered and avoidance of phenytoin and phenobarbital throughout pregnancy may be considered to prevent reduced cognitive outcomes.
An updated position statement by the AES in 2021 emphasized the importance of informing women of childbearing age of teratogenicity before initiating treatment with valproic acid.
The fetal anticonvulsant syndrome. Fetal anticonvulsant syndrome is a cluster of a variety of congenital malformations in infants exposed to antiseizure drugs in utero. These include major congenital malformations, minor malformations, cognitive and behavioral disturbances and intrauterine growth retardation. Many attempts have been made to characterize the different patterns of malformations that are typical or diagnostic for in utero antiseizure drug exposure. Nonetheless, now it is generally accepted that many of the conventional antiseizure drugs may produce a similar pattern of malformations (91; 04; 202; 68; 174; 182; 149; 177).
Major congenital malformations from in utero exposure to antiseizure drugs. Major congenital malformations are generally defined as abnormalities of an essential anatomical structure present at birth that interfere significantly with function and/or require major intervention. Such structural abnormalities are established during embryogenesis, up to 10 weeks of gestation, often before the woman is aware that she is pregnant. Malformations among offspring of people with epilepsy are not unique but generally follow a pattern similar to what is seen in the general population, with cardiac defects being the most common followed by facial clefts and hypospadias, but with some variation between different antiseizure drugs. Findings from several studies have confirmed greater risks of such malformations in children exposed to antiseizure drugs in utero; the risk was about three times that in the children of healthy people. A pooled analysis of data from 21 prospective studies looked at four different groups of major congenital malformations (cardiac, neural tube defects, orofacial clefts, and hypospadias) associated with monotherapy exposure to the five most commonly used antiseizure drugs in these studies (174). Cardiac malformations were the most frequent of the four major congenital malformations for carbamazepine, lamotrigine, barbiturates, and phenytoin, whereas neural tube defects were the most common for valproate. Cardiac malformations appeared more frequently with barbiturates than with any of the other antiseizure drugs, whereas neural tube defects and hypospadias were more prevalent with valproate than with the other antiseizure drugs. Phenytoin possibly contributes to the risk of cleft palate; carbamazepine possibly contributes to the risk of posterior cleft palate; valproate probably contributes to neural tube defects and facial clefts and possibly contributes to hypospadias; and phenobarbital exposure in utero possibly contributes to cardiac malformations (174).
Rates of major congenital malformations from the current major epilepsy and pregnancy registries associated with any specific antiseizure drug vary across the different registers, which can be explained by their methodological differences. However, some consistent patterns are seen within each register and have been synthesized in a 2023 Cochrane review of malformations in pregnancies complicated by antiseizure medication monotherapy (14). First, with few exceptions the major congenital malformation prevalence is highest in association with valproate exposure in all registers, ranging from 4.7% to 13.8%. Major congenital malformation rates with the two most frequently used antiseizure drugs, carbamazepine and lamotrigine, are lower than with valproate in all registers, and comparable between themselves in most studies. The major congenital malformation rate with phenobarbital is reported in three registers and appears to be in between rates reported for lamotrigine/carbamazepine and valproate. Major congenital malformation rates with phenytoin are highly variable, from 2.4% to 6.7%, and based on few exposures in most registers. The prevalence of major congenital malformations with levetiracetam appears to be low and so far in a similar range as lamotrigine/carbamazepine, although the number of exposures is still lower than for these older antiseizure drugs. Exposures to topiramate are too few to draw firm conclusions but the data from most registers indicate a higher prevalence than with lamotrigine/carbamazepine, although in general not as high as with valproate. It should be emphasized that the precision of the estimates with newer antiseizure drugs such as levetiracetam, oxcarbazepine, and topiramate is still unsatisfactory due to the limited number of exposed pregnancies. This is even more the case with other newer generation antiseizure drugs such as gabapentin, pregabalin, zonisamide, perampanel, and lacosamide (174; 177). See pregnancy and epilepsy.
Minor congenital malformations from in utero exposure to antiseizure drugs. Minor anomalies are defined as structural deviations from the norm that do not constitute a threat to health (149). They affect 6% to 20% of infants born to people with epilepsy, approximately 2.5-fold the rate of the general population (149), although there is little agreement about their frequency (166). The problem is complicated by the confounding influences of socioeconomic and genetic factors. Minor anomalies are usually subtle defects of appearance and structure evaluated subjectively or by measurement. Whereas malformations arise during blastogenesis and organogenesis, minor anomalies are defined as arising during phenogenesis (“attainment of final form,” between days 57 and 266 of development). Most of these features, though, have minor overlap with normal variations seen in children born to healthy mothers. Prospective and blinded studies have shown that only hypertelorism and digital hypoplasia occurred at any great frequency and even these associations are weak (166).
Minor congenital abnormalities include facial dysmorphisms, digital, skin, and genital anomalies, as well as digital anomalies (153; 55; 04; 193).
Characteristic dysmorphic features have been described with fetal exposure to phenytoin, valproate, and carbamazepine (127). The facial features of the fetal valproate syndrome include epicanthic folds, an infraorbital groove, medial deficiency of the eyebrows, flat nasal bridge, short nose with anteverted nares, smooth or shallow philtrum, a long thin upper lip, a thick lower lip, and a small, downturned mouth. Fetal phenytoin is said to be associated with hypertelorism, broad nasal bridge, short nose, and facial hirsutism. Fetal carbamazepine face includes epicanthic folds, short nose, long philtrum, and upward slanting palpebral fissures. However, these fetal anticonvulsant syndromes appear to have some features in common, such as a smooth or shallow philtrum and thin upper lip. Similar features give rise to the facial gestalt of fetal alcohol syndrome, of which the characteristic facial findings are short palpebral fissures, smooth philtrum, and a thin upper lip. It has also been reported that untreated maternal epilepsy is associated with minor dysmorphic features in the child, such as high forehead, frontal bossing, and epicanthus (127).
It has been suggested that there may be a “fetal teratogen face” arising from exposure to substances that affect the central nervous system and which includes epicanthic folds, short palpebral fissures, smooth philtrum, and thin upper lip (127). These features were seen with similar frequency in children exposed to any of the antiseizure drugs. Other facial features may be associated with specific teratogens, for example, a high, broad forehead, infraorbital grooves, broad nasal root with short nose, anteverted nares, and long philtrum were seen more commonly in valproate exposure. Telecanthus is more prominent with carbamazepine and phenytoin exposure (127).
The main anomaly of the fingers seen in this population is the hypoplasia of the distal phalanges or nails (55). The digital anomalies and transverse palmar creases may be more common with phenytoin exposure (55; 04).
Small for gestational age and antiseizure medications. A population-based cohort study from Nordic countries from 1966 to 2017 demonstrated that in 38,714 children born to mothers with epilepsy, prenatal monotherapy exposure to the following antiseizure medications was associated with an increased risk of being born small for gestational age: carbamazepine (aOR 1.25, 95% CI 1.12-1.4), pregabalin (aOR 1.16, 95% CI 1.02-1.31), oxcarbazepine (aOR 1.48, 95% CI 1.28-1.71), clonazepam (aOR 1.27, 95% CI 1.1-1.48), and topiramate (aOR 1.48, 95% CI 1.18-1.85). Carbamazepine was associated with microcephaly (aoR 1.43, 95% CI 1.11-1.47) (23).
Fetal hydantoin exposure and syndrome.
Current findings. In studies major congenital malformation rates with phenytoin are highly variable, from 2.4% to 6.7%, and based on few exposures in most registers (177). Cardiac malformations and cleft palate are the most common major congenital malformation attributed to phenytoin (174).
Previous findings. The initial descriptions of the phenytoin teratogenicity in the humans were published in the 1960s and early 1970s (146; 123; 77; 109). In 1966, Massey reported the teratogenic effect of phenytoin in mice (113). Many of those early reports (77; 109; 66) were clouded by the in utero exposure to other antiseizure drugs.
Hanson and Smith observed a combination of craniofacial and digital dysmorphic features associated with growth deficiency, microcephaly, and intellectual disability in phenytoin-exposed children of epileptic mothers and called it “fetal hydantoin syndrome.” Phenytoin was considered to be the most probable cause of these symptoms, and the risk of developing the full syndrome was estimated to be about 11% (65).
Nine craniofacial and digital features have been considered as typical of fetal hydantoin syndrome: epicanthus, hypertelorism, typical nose, long philtrum, abnormal ears, low hairline, nail hypoplasia, distal phalangeal hypoplasia, and three or more dermal arches (55). Epicanthus is considered present if there is a distinct vertical skin fold at the medial end of the palpebral fissure. Hypertelorism is scored by inspection to determine whether the eyes appear unusually wide set in relation to other facial structures. A typical nose is considered present if nares are anteverted and the nose is small or the nasal bridge is low. Philtrum length is assessed by clinical impression in relation to other structures. Ears are considered abnormal if the auricles are either dysmorphic, low, or posteriorly rotated. Low hairline is considered present if growth of hair on the neck extends lower than usual. Nails that are smaller or more brittle than normal and distal phalanges that are either unusually short or tapering are considered hypoplastic. Of the nine typical features investigated by Gaily and colleagues, only hypertelorism, nail hypoplasia, distal phalangeal hypoplasia, and dermal arches in the offspring were associated with maternal phenytoin treatment (55). Other cranio-facial anomalies include wide anterior fontanelle, ocular hypertelorism, flat nasal bridge, short nose, and bowed upper lip (88).
Though digital and nail hypoplasia is often described as being typical of the fetal hydantoin syndrome (77; 65; 55; 19), this pattern is also seen with exposure to phenobarbital (164), primidone (162), and carbamazepine (89). In a study of the offspring of 98 people who took phenytoin during the pregnancy, only 30% were found to have exclusively digital hypoplasia (92).
The hypoplastic nails may improve or resolve over time (77). Polydactyly without digital-nail hypoplasia has been reported in a patient exposed to phenytoin in utero (198). A case report of fetal hydantoin syndrome with unilateral atypical cleft hand was indicative for a vascular disruption sequence (39).
Cleft lip and palate have been linked with the gestational exposure to phenytoin since early on (77). In a Norwegian study, the incidence of cleft lip and palate in infants of mothers with epilepsy declined in direct proportion with the decrease of phenobarbital and phenytoin use (94).
Infants exposed to phenytoin in utero may have delayed psychomotor development or mental retardation (77). Mental retardation is often mild, or the intelligence may be borderline (88). The association between mental retardation and in utero phenytoin exposure has been questioned. In a study of 103 infants of mothers with epilepsy exposed to phenytoin during pregnancy, only 1.4% had this problem, a frequency similar to that reported in the general population (55). Learning disabilities may be present in children who are not frankly retarded (189).
On these aspects of phenytoin teratogenicity see more reports below in “cognitive effects of fetal exposure to antiseizure drugs”. Failure to thrive has also been noticed in infants exposed to phenytoin in utero (77). The growth problems in these patients are prenatal and postnatal (66; 19).
Other malformations occasionally seen after the gestational exposures to phenytoin include hypospadias, congenital heart disease (tetralogy of Fallot, septal defects, coarctation of aorta, etc.), dislocation of the hip, dural epidermal cyst, pyloric stenosis, diaphragmatic and inguinal hernias, hirsutism, short neck, and colobomata (77; 122; 88). A rare malignancy associated with in utero phenytoin exposure is lymphoblastic lymphoma (132).
Fetal carbamazepine exposure and syndrome.
Current findings. From studies, carbamazepine does not appear to be as teratogenic as previously believed. The overall rates of major congenital malformation found in current major epilepsy and pregnancy registries for monotherapy exposure to carbamazepine are: 0.8% to 1.57% for cardiovascular, 0.14% to 0.48% for orofacial clefts, 0.19% to 0.64% for hypospadias, and 0.2% to 0.36%for neural tube defects (177). These values are comparable to those with lamotrigine exposure (177; 150). In the latest report using data from The Health Improvement Network, the authors identified women who have given live birth and their offspring. Four subgroups were selected based on the antiseizure drug treatment in early pregnancy: valproate, carbamazepine, lamotrigine, and women not receiving antiseizure drug treatment. A total of 229 women were prescribed valproate in pregnancy, 357 were prescribed lamotrigine, 334 were prescribed carbamazepine, and 239,151 women were not prescribed antiseizure drugs. Fifteen out of 229 (6.6%) women prescribed valproate gave birth to a child with a major congenital malformation. The figures for lamotrigine, carbamazepine, and women not prescribed antiseizure drugs were 2.7%, 3.3%, and 2.2%, respectively. For women prescribed valproate in polytherapy, the prevalence was 4-fold higher (150).
According to an assessment, lamotrigine (2.31% in 4195 pregnancies) and levetiracetam (1.77% in 817 pregnancies) were associated with the lowest risk and valproate was associated with the highest risk (10.93% in 2565 pregnancies) compared with the offspring of women without epilepsy (2.51% in 2154 pregnancies) (16).
Previous findings. Maternal exposure to carbamazepine has been implicated in the genesis of spina bifida in infants of mothers with epilepsy. Spina bifida was mentioned in 8 of 20 published and unpublished studies of maternal carbamazepine exposures (157). The latter surveys found 11 cases of spina bifida in 1457 maternal exposures to carbamazepine (without valproate exposure), which implies an incidence of 1 in 132 cases. That is about 10 times the expected ratio in the general population. However, this was an overexaggeration because the estimation gave a rate of 0.2% to 0.36% for neural tube defects (177). The association between encephalocele and in utero carbamazepine exposure has been reported both alone and in combination with valproate exposure (157).
Jones and colleagues described a carbamazepine-related syndrome characterized by dysmorphic facial features, microcephaly, digital anomalies, and developmental delay (89). The facial dysmorphic features include up slanting palpebral fissures, epicanthal folds, short nose, and long philtrum. The study revealed that 20% of exposed children had developmental delay. These motor and cognitive deficits have been questioned (199; 202). In one of the newer reports the more commonly noted features with exposure to carbamazepine were full cheeks with a small chin and everted lower lip, giving a ‘‘doll-like’’ appearance (95).
Fetal barbiturate exposure and syndrome.
Current findings. From reports, the overall rates of major congenital malformation found in current major epilepsy and pregnancy registries for monotherapy exposure to phenobarbital exposure are: 2.5% to 2.76% for cardiovascular, 0.46% to 2.0% for orofacial clefts, 0.46% to 0.97% for hypospadias, and 0.0% to 0.46%for neural tube (177).
Previous findings. Although phenobarbital had the reputation of being safe for use during pregnancy, Seip described children with pre- and postnatal growth retardation, developmental delay, dysmorphic facies, and minor abnormalities in association with phenobarbital use during the pregnancy (164). The facial anomalies included short nose, broad nasal bridge, hypertelorism, epicanthal folds, ptosis, low-set ears, and wide mouth with protruding lips. He recommended that a new fetal barbiturate syndrome not be created due to the similarities among the effects of phenobarbital, phenytoin, or alcohol exposures in utero. Phenobarbital, phenytoin, and alcohol can cause folate deficiency and are common mechanisms for these malformations (164).
Data are controversial as far as the true extent of the teratogenic effects of phenobarbital in humans. In animal studies, an increased frequency of cleft lip and palate, congenital heart disease, and other minor congenital anomalies were found in the offspring of pregnant mice or rats treated with phenobarbital (51). The extent that these studies can be compared to human situations is unknown because the phenobarbital dose used in mice was several times higher (in relation to body weight) than the one normally used in humans (53; 137; 35).
The frequency of congenital anomalies including major and minor malformations was not shown to be higher in 1415 women treated with phenobarbital (not necessarily for seizures) in the first 4 months of pregnancy in the National Collaborative Perinatal Project (71). Other studies have shown an increased frequency of congenital anomalies in infants born to mothers taking phenobarbital during the pregnancy for seizure disorders (165). Similar findings were seen in other series that reported an increased incidence of cleft palate and congenital heart disease in the fetuses born to epileptic women taking phenobarbital when compared to controls (61; 161; 134). Fetuses chronically exposed to phenobarbital in utero have been shown to have a 10% to 20% incidence of malformations, including serious problems such as congenital heart disease (168; 05). The incidence of fetal malformation may be increased in patients taking phenobarbital in combination with other antiseizure drugs (157). The exception for that rule is the lowering of the risk of spina bifida in patients exposed to valproate in combination with phenobarbital. This effect is not unexpected because phenobarbital has an accelerating effect on the catabolism of valproate, and lower antiseizure drug levels have been associated with a lower risk of fetal malformation (34; 157). One report mentioned the association of aortic stenosis with in utero exposure to high dose barbiturate (secobarbital and amobarbital) (156).
In the National Collaborative Perinatal Project, the intelligence quotient of children exposed and unexposed to phenobarbital in utero was compared (165). No statistically significant differences could be demonstrated in that study.
Phenobarbital exposure in utero has been associated with transient neonatal sedation and withdrawal symptoms in infants (40; 97). The withdrawal symptoms are similar to the ones seen with other addictive drug exposures in utero such as cocaine and opiates. The newborns tend to be irritable, have altered sleeping patterns, are difficult to feed, have increased startle reflex, and have hyperreflexia. The timing of the withdrawal symptoms appears to be different, with the mean onset around the seventh day and an average of 3-month duration (40). A similar syndrome, but with early onset of irritability in the first hours of life, was described after mephobarbital exposure in utero (77). The irritability continued until the fourth month of life.
Hemorrhagic disease of the newborn due to vitamin K deficiency has been described after phenobarbital exposure during the pregnancy (36; 77). Vitamin K should be administrated to all newborns exposed to barbiturates in utero (129).
Primidone exposure and embryopathy. Knowledge about the effects of primidone exposure in utero is based mostly on case reports. Primidone exposure in utero has been implicated in the development of specific facial dysmorphology. The latter includes increased facial hair (especially on the forehead), abnormal noses with anteverted nostrils, long philtrums, and thick nasal roots (162; 62). Cleft lip and palate have also been reported (157). Some of these patients appear to have features similar to Goldenhar syndrome (62). Patients with the primidone embryopathy pattern may also have cognitive and motor delays, retardation, and congenital heart disease. They are often small for gestational age at birth (162; 62). These reports also mention finger and nail abnormalities similar to ones seen with phenytoin exposure. Congenital heart disease has also been reported in cases of primidone exposure, including aortic coarctation and dextrocardia (157). Other rare associations include anencephaly and oculo-auriculo-vertebral anomaly (157). Two cases of spina bifida have been reported, one after primidone monotherapy exposure and the other in polytherapy with valproate and carbamazepine (157). Hemorrhagic disease of the newborn due to vitamin K deficiency has been described after primidone exposure in utero. Vitamin K should be administrated to all newborns exposed to primidone in utero.
Fetal trimethadione syndrome (fetal dione syndrome). This syndrome is now rare due to the decreased use of oxazolidine derivatives such as trimethadione and paramethadione. German and collaborators reported a case of an epileptic woman treated with trimethadione who had four unsuccessful pregnancies followed by the delivery of two healthy infants after she stopped taking the drug (58). Zackai and colleagues described a clinical phenotype of the fetal trimethadione syndrome (203).
This syndrome consists of intrauterine growth retardation, microcephaly, facial malformations, congenital heart disease, and genitourinary anomalies. Facial malformations include v-shaped eyebrows, epicanthal folds, low-set ears, and irregular teeth. Central nervous system malformations may also be seen. Mental retardation is present in up to 29% of the patients, speech delay in 47%, and developmental delay in 53% (160).
Congenital heart diseases include hypoplastic left heart syndrome, tetralogy of Fallot, and transposition of the great vessels (160). Malformations can be seen in the kidneys, trachea, larynx, and esophagus. The high rate of malformations, many of them severe, has been associated with a high neonatal mortality rate that may go close to 40%. In a study of 53 pregnancies in which trimethadione was used, 46 cases of fetal loss or congenital anomalies were recorded (47).
One follow-up study of patients who were exposed to trimethadione in utero demonstrated a 29% rate of mental retardation, microcephaly in 50% of the cases, and short stature in 53% (160).
Fetal valproate syndrome. Valproate is the most teratogenic of all other antiseizure drugs. It is definitely associated with an elevated risk for major congenital malformation (Tables 1 and 2), including a 10fold increase in spina bifida aperta (1%-2% of infants exposed). The overall rates of major congenital malformations found in current major epilepsy and pregnancy registries for monotherapy exposure to valproate are: 1.1% to 2.18% for cardiovascular, 0.4% to 1.2% for orofacial clefts, 1.2% to 3.1% for hypospadias, and 1.09% to 1.2% for neural tube (177). The risk is doserelated, particularly at doses of more than 1000 mg/day. Polytherapy with valproate and any other antiseizure drug is highly teratogenic and appears to be even worse in combination with lamotrigine (1 of 10 infants exposed) (31; 130). In regard to minor congenital abnormalities, in one of the newer reports facial features often noted in children exposed to valproate were medial deficiency of eyebrows, infraorbital grooves, broad nasal bridge, anteverted nose, abnormal philtrum, and a thin upper lip. Trigonocephaly (triangular shaped skull) was not a common finding (95). Considering that valproate is possibly also associated with cognitive impairment of infants exposed to this drug during pregnancy (117; 26; 118), it should be avoided in people with epilepsy of childbearing age.
Table 1. Major Congenital Malformation Rates After Exposure to Antiseizure Drug Monotherapy
AED | Range (%) (14) | Battino (95% CI n=9840) |
Carbamazepine | 4.0%-4.7% | 5.4% (4.5-6.4%) |
Lamotrigine | 2.7%-3.5% | 3.1% (2.5-3.7%) |
Levetiracetam | 2.6%-2.8% | 2.5% (1.8-3.5%) |
Oxcarbazepine | 2.8%-4.8% | 2.9% (1.7-5.0%) |
Phenobarbital | 6.3%-8.8% | 6.2% (4.1-9.3%) |
Phenytoin | 5.4%-6.8% | 6.3% (3.4-11.6%) |
Topiramate | 3.9%-4.1% | 4.9% (2.7-8.8%) |
Valproate | 9.7%-9.8% | 9.9% (8.5-11.5%) |
Background risk for malformations: 2% to 3% | ||
| ||
Previous findings. The first reports of a teratogenic effect of valproic acid appeared in the early 1980s (32; 24; 60). Subsequently, Robert and Guiband described the association between valproate and neural tube defects (155). DiLiberti and colleagues consolidated the idea of the specific constellation of malformations of the fetal valproate syndrome (41). The malformations considered to be characteristic of this syndrome were the typical facial dysmorphism and neural tube defects (08; 88). These malformations appear to be dose related because mothers using more than 1000 mg of valproate per day were more likely to have malformed infants than the ones taking 600 mg or less per day (163). Pre-pregnancy dose reduction resulted in fewer infants with malformations, and cessation prior to pregnancy lowered malformation prevalence to population baseline in an Australian registry of 580 pregnancies (180). The frequency of facial and minor malformations after valproate exposure in utero has been estimated to be between 50% to 75% (08; 101).
The neural tube defects that are often referred to loosely as “spina bifida” are probably the most conspicuous malformation associated with valproate exposure in utero. Ardinger and colleagues found both lumbosacral meningomyelocele and talipes equinovarus (with intact spine) to be typical of the fetal valproate syndrome (07). Neural tube defects have also been reported in patients exposed to carbamazepine in utero (157), and two patients (patient 9 and patient 16) with lumbosacral meningomyeloceles were also exposed to carbamazepine (07). The prevalence of neural tube defects is 10 to 20 times higher in fetuses exposed to valproate in utero when compared with the general population (138). The risk of neural tube defect after in utero exposure to valproate has been estimated to be 1% to 5% (08).
The facial appearance of these patients is rather typical, with epicanthal folds forming a crease under the orbits, telecanthus, and broad and low nasal bridge with short nose and anteverted nostrils (41; 07; 08; 88). Long philtrum, thin vermilion border, mid-face hypoplasia, and small mouth (microstomia) are often also present in the syndrome (41; 07). Cleft lip and palate have also been reported (07; 88; 101) but are infrequent, occurring in 1 out of 19 patients (07). Ardinger and colleagues found the outer orbital ridge deficiency and bifrontal narrowing to be typical of the facial appearance of patients with fetal valproate syndrome.
The fingers and toes of fetal patients with valproate syndrome are thin and overlapping, and the nails are hyperconvex and may be also hypoplastic (41; 08). Postaxial polydactyly, triphalangeal thumbs, thumb aplasia, syndactyly, and radial aplasia may also be seen (88; 101).
Mental retardation is usually mild to moderate (101). Cognitive deficits with or without other neurologic abnormalities are present in 71% of the monotherapy in utero exposures and in 90% of the polytherapy exposures (07).
Ardinger and colleagues evaluated 19 children exposed to valproate in utero in an attempt to verify the phenotype of the fetal valproate syndrome (07). In spite of the total absence of prenatal or postnatal growth deficiency in the children exposed to valproate monotherapy in utero, two thirds of the children also exposed to other antiseizure drugs had postnatal growth deficiency and microcephaly.
Signs of newborn encephalopathy appear to be more frequent than expected in infants of mothers taking valproate for seizures (83). This problem has been described with low Apgar scores (28% of the cases) and perinatal distress that are often followed by postnatal growth problems and decreased head circumference. Jeavons reports that 19.8% of the deliveries were abnormal after valproate exposure in utero, but no evidence of a dose response effect exists (86). Jeavons and Jager-Roman and colleagues’ data should be interpreted with caution due to the difficulties in diagnosing perinatal depression distress or newborn encephalopathy after in utero exposure to valproate. These reports (86; 83) may in fact reflect, at least in part, the sedative and teratogenic effect of valproate in the fetus. This view is supported by the almost universal hyperammonemia and sedation seen when valproate is used in the treatment of neonatal seizures (56).
High-dose valproate in utero has been associated with drug withdrawal and hypotonia in the neonatal period and subsequent motor and language delay (83).
Cardiovascular defects include aortic coarctation or valvular stenosis, hypoplastic left heart, atrial or ventricular septal defect, patent ductus arteriosus, and tetralogy of Fallot (07; 08; 88).
Other less frequently associated malformations include growth failure, hypospadias, cryptorchidism, bifid rib, broad chest, inguinal and umbilical hernia, supernumerary nipples, and lung hypoplasia (88; 101; 84). Studies have reported associations with craniosynostosis, autism, and ophthalmologic findings including dry eyes, myopia, and newborn nuchal edema (102; 194; 59; 196). In addition, three families have been described in whom the occurrence of fetal valproate syndrome occurred in all the siblings, strongly suggesting hereditary susceptibility to valproate-induced outcome (110).
In a study from Italy, no significant differences were observed in the risk of congenital malformations between 526 cases exposed to antiseizure drugs and 3682 controls, except for valproic acid (odds ratio (OR): 2.29; 95% confidence interval (CI): 1.24-4.22), where cases were more likely to be small for gestational age (chi(2)=7.66; p=0.006) (152).
Cognitive effects of fetal exposure to antiseizure drugs. There is significant uncertainty about the effect of epilepsy and antiseizure drug therapy on cognition in children born to mothers with epilepsy (10; 11). Results from the Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) study of 351 women with epilepsy and 105 without epilepsy demonstrated no difference in neurodevelopmental outcomes at 3 years of age in children with fetal exposure to newer antiseizure medications (lamotrigine and levetiracetam) (119). In contrast, a Nordic registrar study of antiepileptic drugs in pregnancy (SCAN-AED) found an increased risk of neurodevelopmental disorders, such as autism and intellectual disability, in children exposed to topiramate, valproic, and several duotherapies in utero (13). This finding supports prior studies demonstrating the relative safety of newer antiseizure medications.
In the AAN/AES practice parameter, the outcome measure was an assessment of the child’s intelligence quotient (IQ) at age 2 years or older (144), as well as the development of autism spectrum disorder (ASD). In the previous practice parameter, studies were downgraded if they did not control for maternal IQ. It was also assumed that the cognitive risk was related to antiseizure drug exposure throughout pregnancy and was not confined to the first trimester. The main conclusions of this AAN/AES report are:
(1) In utero exposure to valproic acid is probably not associated with reduced full scale IQ at age 6 compared to gabapentin and lamotrigine in monotherapy, and possibility associated with a decrease compared to carbamazepine, levetiracetam, and topiramate; possibly no difference with phenytoin.
(2) In utero exposure to valproic acid is associated with increased risk of autism spectrum disorder or traits compared to other antiseizure medications.
A study from Norway compared executive function in 97 children born to women with epilepsy and found no difference in executive function between children with and without prenatal exposure to antiseizure medications. However, both children with and without antiseizure medication exposure born to mothers with epilepsy had reduced executive function compared to 50 typically developing controls (03). This is contrast to the Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic drugs (MONEAD) study, which found no differences in executive function between children of mothers with epilepsy and children of mothers without epilepsy (119). The MONEAD study prospectively observed 456 pregnant women (351 with epilepsy and 105 without) across 20 specialty centers in the USA, and blindly assessed the verbal index score, adjusting for maternal IQ, education, anxiety, gestational age, sex and ethnicity. They found no difference in the children of women with or without epilepsy. On secondary analysis, they found exposure-dependent effects of antiseizure medication as previously shown. The neurocognitive extension (NCEP) of the EURAP study (Battino) found an adverse effect of VPA on verbal development (170).
In prior reports, the association between valproate use and IQ was dose dependent (117; 118). Children’s IQs were significantly related to maternal IQs among children exposed to carbamazepine, lamotrigine, or phenytoin, but not among those exposed to valproate. A subsequent report of follow-up at age 6 years confirmed that children exposed to valproate did poorly on measures of verbal and memory abilities compared with those exposed to the other antiseizure drugs and on nonverbal and executive functions compared with lamotrigine (but not carbamazepine or phenytoin) (118). High doses of valproate were negatively associated with IQ, verbal ability, nonverbal ability, memory, and executive function, but other antiseizure drugs were not. Age 6 IQ correlated with IQs at younger ages, and IQ improved with age for infants exposed to any antiseizure drug. Mean IQs were higher in children exposed to periconceptional folate (108, 95% CI: 106-111) than they were in unexposed children (101, 98-104; p = 0.0009).
Reassuringly, a study of 277 children with antenatal antiseizure medication exposure to lamotrigine and levetiracetam found no evidence for worse cognition, adjusting for other maternal and child factors (14).
In a 20-year study of 8815 children exposed to antenatal antiseizure medications, the risk of autism was increased for those exposed to topiramate, valproate, and lamotrigine; however, after adjustment for indication and other confounders, only valproic acid was associated with a persistent increased risk (72).
Furthermore, children of mothers who took valproate during their pregnancy were at a significantly greater risk for a diagnosis of attention deficit hyperactivity disorder (ADHD), difficulty with adaptive functioning, and atypical behaviors than those in the lamotrigine and phenytoin groups (26).
A relevant Cochrane review on neurodevelopmental outcomes in the child of women with epilepsy has been published (15). The most important finding is the reduction in IQ in the valproate exposed group, which is sufficient to affect education and occupational outcomes in later life.
Velez-Ruiz and Meador present a comprehensive review on the neurodevelopmental effects of fetal antiseizure drug exposure (185).
A systematic review and network meta-analysis assessed cognitive development and autism or dyspraxia in children exposed to antiseizure drugs during pregnancy and breastfeeding (186). Among all antiseizure drugs, only valproate was statistically significantly associated with more children experiencing cognitive developmental delay compared with control (OR=7.40, 95% credible interval (CrI) 3.00 to 18.46). Furthermore, compared with control, only valproate (OR 17.29, 95% CrI 2.40 to 217.60), oxcarbazepine (OR 13.51, 95% CrI 1.28 to 221.40), lamotrigine (OR 8.88, 95% CrI 1.28 to 112.00), and lamotrigine combined with valproate (OR 132.70, 95% CrI 7.41 to 3851.00) were significantly associated with increased occurrence of autism or dyspraxia. For the cognitive developmental delay and psychomotor developmental delay outcomes, children exposed to the combination of carbamazepine, phenobarbital, and valproate were at greater odds of harm than those who were not exposed to antiseizure drugs (186).
Childhood- and adolescent-onset psychiatric disorders in children with prenatal exposure to antiseizure medications were explored in a large cohort study of more than 38,000 children born during 1996 to 2017 (43). The study demonstrated increased risk with valproic acid, mostly driven by neurodevelopmental disorders, and no increased risk with exposure to lamotrigine, carbamazepine, or oxcarbazepine. There was an increased risk of ADHD with topiramate exposure and of both anxiety and ADHD with levetiracetam exposure.
Table 2. Major Congenital Malformations in Two Large Pregnancy Registries
Number of women with epilepsy | MCM (%) | 95% CI | ||||
UK Epilepsy Pregnancy Register | North American Epilepsy Pregnancy Register | UK Epilepsy Pregnancy Register | North American Epilepsy Pregnancy Register | UK Epilepsy Pregnancy Register | North American Epilepsy Pregnancy Register | |
No exposure to AEDS | 445 | 442 | 2.2 | 1.1 | 1.2-4.1 | 0.37-2.6 |
Exposure to AEDS | 5475 | 3.9 | 3.4-7.2 | |||
Monotherapy | 4276 | 3.4 | 2.9-4.9 | |||
Monotherapy with valproate | 1290 | 323 | 6.7 | 9.3 | 5.5-8.3 | 6.4-13.0 |
Monotherapy with carbamazepine | 1718 | 1033 | 3 | 2.6 | 1.9-3.5 | 2.1-4.2 |
Monotherapy with lamotrigine | 2198 | 1562 | 2.3 | 2 | 1.8-3.1 | 1.4-2.8 |
Monotherapy with levetiracetam | 367 | 450 | 0.7 | 2.4 | 0.2-2.5 | 1.2-4.3 |
Monotherapy with topiramate | 359 | 197 | 4.8 | 4.2 | 1.9-7.6 | 2.4-6.8 |
Polytherapy (> 130 AED combinations) | 1199 | 5.8 | 4.6-7.2 | |||
Polytherapy with valproate | 451 | 8.6 | 6.4-11.6 | |||
Polytherapy with carbamazepine | 526 | 4.9 | 3.4-7.1 | |||
Polytherapy with lamotrigine | 644 | 5.3 | 3.8-7.3 | |||
Polytherapy with levetiracetam | 367 | 5.6 | 3.5-8.6 | |||
Polytherapy with topiramate | 162 | 8.6 | 5.2-14.0 | |||
| ||||||
Commonly used new generation of broad spectrum antiseizure drugs and major congenital malformations. Based on existing evidence, the risks for major congenital malformations associated with three of the more widely used broad spectrum antiseizure drugs – lamotrigine, levetiracetam, and topiramate (Table 2) – are as follows:
Lamotrigine. The overall rates of major congenital malformations found in current major epilepsy and pregnancy registries for monotherapy exposure to lamotrigine are: 0.19% to 0.63% for cardiovascular, 0.1% to 0.45% for orofacial clefts, 0.0% to 0.5% for hypospadias, and 0.0% to 0.17% for neural tube (177).
Significant differences in the risk for major congenital malformations have been reported by the UK and the North American pregnancy registries, though the rate of major congenital malformations was similar (2.3%-2.4%). The UK Epilepsy and Pregnancy Registry noted a positive doseresponse relationship for major congenital malformations with lamotrigine (p = 0.006) with a major congenital malformation rate of 5.4% (95% CI 3.3%-8.7%) for total daily doses of more than 200 mg (130). However, in the report “A non-significant trend towards higher MCM rate with increasing dose was found with lamotrigine. MCM rate for high-dose lamotrigine (> 400 mg daily) was lower than the MCM rate for pregnancies exposed to less than 600 mg daily of valproate, but this was not significant (3.4% vs. 5.0%, p = 0.31)” (20).
The North American antiseizure drug pregnancy registry reported a 10.4fold increase (95% CI 4.3-24.9) in isolated cleft palate or cleft lip deformity (79), but this has not been confirmed in the UK (82) and the European Surveillance of Congenital Anomalies (EUROCAT) registries (42).
The initial report of the international lamotrigine pregnancy registry concluded that “the risk of all major birth defects after first trimester exposure to lamotrigine monotherapy (2.9%) was similar to that in the general population” (31), but this was considered to be an overestimate by other authorities, who suggested that a more accurate conclusion may be “the risk for major malformations associated with first trimester exposure to lamotrigine is only about twice that of the general population... when similar definitions, inclusions and case identification strategies are used” (70). Furthermore, it would be even more difficult to assess the risks of major congenital malformations with lamotrigine precisely without therapeutic drug monitoring if the finding of a doserelated effect is replicated because of the significant decrease in plasma levels of lamotrigine (nearly by 50%) in the first trimester of pregnancy.
In polytherapy with lamotrigine and other antiseizure drugs, the risk of major congenital malformations is 5.6% (Table 2), and this doubles to around 10.7% in combination with valproate.
Alarmingly, lamotrigine plus valproate is the most frequently used antiseizure drug combination in pregnancy according to a EURAP report (46), despite the fact that it may harm 1 in 10 exposed babies. This is twice the frequency seen with any other combination and indicates a lack of information reaching those prescribing antiseizure drugs for women; the messages either do not get through or are unclear.
Lamotrigine in combination with levetiracetam is associated with a 60% lower risk of major congenital malformations than valproate monotherapy, which may present safer dual-therapy option (27)
A systematic review and meta-analysis of 19 studies comparing lamotrigine with other antiseizures in pregnancy found that lamotrigine and levetiracetam appear to achieve the best combination of efficacy and safety in pregnancy (188). However, there is recent evidence for higher risk of spontaneous abortion in pregnancies with dural levetiracetam and lamotrigine, which requires further investigation (78).
The conclusions of the “Lamotrigine Pregnancy Registry Final Report, Issue Date: July 2010” are:
Lamotrigine monotherapy. There were 35 outcomes with major defects among 1558 outcomes (2.2%) involving a first trimester monotherapy exposure (95% CI: 1.6%-3.1%). There were four outcomes with a major defect among 95 outcomes following a second trimester monotherapy exposure and one outcome with a major defect among the 18 outcomes following a third trimester monotherapy exposure.
Polytherapy including valproate. There were 16 outcomes with major defects among 150 total outcomes (10.7%) involving first trimester exposure to lamotrigine and valproate, with or without one or more additional antiseizure drugs (95% CI: 6.4%-17.0%). There was one outcome with a major defect among the seven outcomes following a second trimester exposure to lamotrigine and valproate, with or without one or more additional antiseizure drugs. This exposure group had the highest proportion with major defects observed among first trimester exposures in the registry.
Polytherapy not including valproate. There were 12 outcomes with major birth defects among 430 total outcomes (2.8%) involving first trimester exposure to lamotrigine and at least one other antiseizure drug, excluding valproate (95% CI: 1.5%-5.0%). There was one outcome with a major birth defect among the three total outcomes involving third trimester exposure to lamotrigine and at least one other antiseizure drug, excluding valproate. There was no consistent pattern among the major birth defects reported prospectively to the registry.
Because Morrow and colleagues noted a positive dose-response effect for major congenital malformations with lamotrigine use, the Lamotrigine Pregnancy Registry Advisory Committee continuously examined the registry data related to dose and included the data in this report (130). The committee considered the data as reassuring, providing no evidence of a dose effect. The available data are insufficient to make a definitive conclusion, but they do suggest that any dose effect that might exist is likely to be small. The report can be accessed at: PregnancyRegistry.gsk.com.
The EURAP epilepsy and pregnancy registry found an increase in malformation rates with increasing dose at the time of conception for carbamazepine, lamotrigine, valproate, and phenobarbital (175).
Levetiracetam. The number of women treated with levetiracetam in pregnancy registries is still relatively small, but the data so far are encouraging (Table 2), with the major congenital malformations ranging from 0.7% to 2.4% for levetiracetam monotherapy (74; 114).
The overall rates of major congenital malformations found in current major epilepsy and pregnancy registries for monotherapy exposure to levetiracetam are: 0.0% to 0.22% for cardiovascular, 0.0% to 0.0% for orofacial clefts, 0.0% to 0.0% for hypospadias, and 0.0% to 0.22%for neural tube (177).
Topiramate. There is a growing body of evidence that this drug should not be given to women of childbearing age unless absolutely necessary (178). This is because topiramate (a) is teratogenic in animals, even at subtoxic doses (equivalent to 0.2 to 10 times the therapeutic doses recommended in humans) (145), (b) has serious adverse drug reactions that are likely to affect the fetus because of the extensive transplacental transfer of the drug, and (c) relevant results from pregnancy registries indicate that such precautions are justified (see Table 2) with an increased rate of major congenital malformations between 4.2% to 4.8%. In the UK Epilepsy and Pregnancy Register (Table 2), the major congenital malformations rate in 79 women receiving topiramate monotherapy was 3.8% (95% CI: 1.3-10.6) and in 162 women receiving polytherapy was 8.6% (95% CI: 5.2-14) (81). The rate of major congenital malformations was even higher (9.8%) in a report of 41 live births from 52 pregnancies during topiramate treatment (29 on monotherapy and 23 on polytherapy) (140); this finding has, however, been undermined by statistical deficiencies (49). Veiby and associates found that infants exposed to topiramate had a considerable risk of microcephaly and small for gestational age birth weight (184). Furthermore, topiramate malformation rates are higher in polytherapy pregnancies involving topiramate even when valproate is not used (181; 178).
Oxcarbazepine. There is practically no evidence of the teratogenic potential with oxcarbazepine, though preliminary results indicate that this may not be significant (30). However, oxcarbazepine is associated with an increase in seizure frequency during pregnancy, probably because of the significant 26% to 38% decrease in levels of its active monohydroxy derivative (151).
Teratogenesis of the newer antiseizure drugs. Data concerning the risk for congenital malformations associated with other newer antiseizure drugs (levetiracetam, gabapentin, felbamate, oxcarbazepine, tiagabine, topiramate, zonisamide, and vigabatrin) are still limited. In a review of the teratogenic effects of the newer antiseizure drugs in animal studies, felbamate, gabapentin, lamotrigine, oxcarbazepine, topiramate, tiagabine, and vigabatrin can cause intrauterine growth retardation (128). Felbamate, gabapentin, lamotrigine, and topiramate cause skeletal malformations, but only high doses of topiramate can cause limb agenesis. Vigabatrin can cause cleft lip and palate in animals. Teratogenic effects of vigabatrin were found in mouse fetuses; the exencephaly, mandibular and maxillary hypoplasia, arched palate, cleft palate, limb defects, omphalocele, and exomphalos were observed in the fetuses exposed to vigabatrin in utero (01). It is also possible that clobazam may be teratogenic, as indicated from very limited preliminary data on MCM rate for nine clobazam monotherapy women (22.2%; 95% CI 6.2-54.7) (172).
Gabapentin. A large postmarketing surveillance study of 3100 English patients receiving the drug identified only 11 pregnancies without any congenital anomalies (195). In another study of 39 women and 51 pregnancies receiving gabapentin, the rate of major malformations was 4.5%. Eighty-seven percent of the pregnancies resulted in live births, 11.3% in miscarriages, and 2% in therapeutic abortions (126).
Zonisamide. The largest reported cohort of pregnant women exposed to zonisamide was 112, with major congenital malformations in 3 of 26 (12%) on monotherapy and 5 of 86 (6%) with polytherapy exposure (115). A different registry of 98 live births exposed to prenatal zonisamide monotherapy found 0 out of 98 major congenital malformations (73).
Prognosis and complications
The true prognosis of fetal anticonvulsant syndrome depends greatly on the degree of involvement and the type of malformation seen (19; 157; 157). Major congenital malformations and particularly some neural tube and cardiac defects are the most serious. Patients with neural tube defects may develop hydrocephalus and tethered cord as complications; both require neurosurgical treatment.
Fetal trimethadione syndrome has a bad prognosis due to the high rate of serious malformations and neonatal death (160). The same is true for the fetal valproate syndrome due to its association with neural tube defects.
Individuals with fetal valproate exposure are now having their own families. A survey of 23 men and 85 women with complications due to fetal valproate exposure found that in their 187 cumulative children there were 43 (23%) with malformations and 82% (44%) with neurodevelopmental disorders, suggesting possible epigenetic inheritance (111). Further rigorous studies are required.
Clinical vignette
A neurologic consultation was requested for a 7-day-old infant who had neonatal seizures. The patient was born to a 34-year-old mother with a history of generalized tonic-clonic seizures since adolescence that had been treated with phenobarbital 90 mg per day. The treatment allowed the mother to be seizure-free, although she occasionally complained of feeling sad. The pregnancy was otherwise uncomplicated, and the mother was seizure-free through the gestation. A male baby was delivered without problems after a 39-week gestation; the birth weight was 2200 gm (small for gestational age), and the Apgar scores were 7 (1 minute) and 8 (5 minutes). Difficulty feeding and sedation were noticed from day 1. The feeding difficulties improved slowly, but formula and breast milk had to be given through gavage. A pediatric neurology consultation was requested on the seventh day of life due to poor feeding and spontaneous shaking movements involving the upper more than the lower extremities, lasting a few seconds, and occurring intermittently. The patient’s physical exam showed short nose, broad nasal bridge, hypertelorism, epicanthal folds, and wide mouth. A small palate cleft could be seen but no cleft lip was noted. The neurologic exam was remarkable for irritability alternating with sleepiness. The patient was almost never in the quiet alert state. Mild to moderate axial hypotonia was noticed. A few episodes of spontaneous fast (several cycles per second) shaking of the extremities were seen, which could be suppressed by restraining. Otherwise, the neurologic exam was normal for the patient’s chronological and gestational age.
A lumbar puncture was done, and the patient was started on ampicillin and gentamicin due to presumed sepsis. The cerebrospinal fluid was clear and had zero red cells and one white cell; protein and glucose were within the normal range for the patient’s age. An EEG was mildly abnormal due to dysmature features, but no electroencephalographic seizures were seen.
The hospital course was characterized by slow improvement of the patient irritability. The feeding improved with upright positioning and special nipple use for bottle-feeding. The patient was discharged on day 21 of life, feeding by mouth and gaining weight (10 to 20 g per day). The patient was referred to the cranio-facial clinic for management of the cleft palate. The patient was seen on follow-up (from 3 to 12 months old), and the neurologic exam was completely normal.
Biological basis
Etiology and pathogenesis
The reasons for the increased risks are multifactorial and may include genetic factors, maternal epilepsy and seizures during pregnancy, and socio-economic status, but accumulating data strongly suggest that antiseizure drugs are the main reason for the increased risk (68). Fetal anticonvulsant syndrome has been linked mainly to exposure to antiseizure drugs and effect independent of epilepsy (201). There are various proposed mechanisms of teratogenicity caused by antiseizure drugs. 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 antiseizure drugs in particular.
In general, the biological basis of the fetal anticonvulsant syndrome remains largely speculative, although some evidence points to epoxide and free-radical toxicity playing a role in the teratogenesis associated with these drugs. Many drugs are primarily metabolized into epoxides (87). Among the epoxides, the arene oxides have been associated with a carcinogenic and mutagenic effect due to their electrophilic properties and covalent binding to macromolecules (87; 135; 167). One of the pathways of epoxide detoxification (epoxide hydrolase enzyme) is much less active in fetuses when compared to adults (142). Another contributing factor may be the fact that at least one third of the fetal circulation bypasses the liver, which is one of the main sites of drug detoxification (143).
Animal models suggest that antiseizure drug-induced apoptosis, altered neurotransmitter environment, and impaired synaptogenesis are some of the mechanisms responsible for cognitive and behavioral teratogenesis (185).
A study from Finland showed that signs of adverse effects of prenatal antiseizure drug exposure on brain function could already be detected during the first 2 weeks of life (187). The authors studied prospectively 56 full-term newborns with prenatal exposure to antiseizure drugs and 67 unexposed newborns for the following characteristics: background information, antiseizure drugs exposure data, pregnancy outcome, neuropsychological evaluation of the mothers, clinical neurologic status with Hammersmith Neonatal Neurological Examination, and early cortical activity using EEG. For EEG assessment, the authors developed and provided automated quantitation algorithms of several earlier described features: oscillatory bouts at theta and alpha frequencies, frequency spectra, interhemispheric synchrony, and interburst intervals. It was found that the antiseizure drug-exposed newborns had lower limb and axial tone and were less irritable than the unexposed newborns. EEG assessment disclosed significant differences in alpha bouts, in the frequency spectra, as well as in the spatial distributions of interhemispheric synchrony and interburst intervals. The authors concluded their results indicate that fetal antiseizure drug exposure may affect early neonatal neurologic status and several features of early cortical activity, and the results suggest that interference of activity-dependent network development may be a possible mechanism to explain the link from fetal antiseizure drug exposure to later neurocognitive sequelae (187).
Phenytoin forms a transdihydrodiol metabolite that may be detected in the human newborn exposed to that drug in utero (80). Phenytoin binds irreversibly in vitro to rat liver, and this binding is increased by inhibition of the epoxide hydrolase but decreased by glutathione (112). Spielberg and colleagues demonstrated that phenytoin toxicity in vitro is increased by inhibition of epoxide hydrolase (169).
Few human studies have been done that explore the role of epoxides in the fetal anticonvulsant syndrome. Strickler and colleagues incubated human lymphocytes and phenytoin with the microsomal system of mice (171). An increased death rate in the cells of the system was noticed when the lymphocytes came from children with major malformations. The lymphocytes from family members of these children often yield a similar response. Strickler and colleagues suspected that a low arene oxide detoxification capability was responsible for the increased risk of malformations after phenytoin exposure (171). One element that was missing in the latter study was the lack of measurement of the epoxide hydrolase activity in these patients. In 1985, Buehler found that a higher epoxide hydrolase activity correlated with an increased number of features of fetal hydantoin syndrome in a pair of dizygotic twins (17). In another study, the activity of the epoxide hydrolase was measured by thin-layer chromatography in amniotic cells of 100 pregnant women to establish normal levels; a trimodal distribution was found, suggesting that the enzyme is regulated by a single gene with two allelic forms (18). Fetuses homozygous for the recessive allele have low epoxide hydrolase activity and, therefore, would be at high risk if exposed to phenytoin or other epoxide producing drugs during gestation. In 19 cases of pregnant mothers receiving phenytoin monotherapy, in which the pregnancies were monitored by amniocentesis, the 15 mothers at low risk for fetal hydantoin syndrome on the basis of normal epoxide hydrolase activity delivered infants lacking the phenotype of the fetal phenytoin syndrome, but four fetuses considered at high risk on this basis all showed features of the syndrome at birth (18). These findings allow for some prenatal prediction of the risk of fetal malformation in mothers taking phenytoin. Even though all the evidence for peroxide teratogenicity above is impressive, ethotoin, mephenytoin, and trimethadione have been shown to have teratogenic effects but do not have arene oxide metabolites (199). Genetically determined patterns of detoxification and metabolization of anticonvulsants have an impact on teratogenic risk (106). Wells and colleagues reviewed the role of oxidative damage in chemical teratogenesis (190). Studies in pregnant mice that demonstrated sensitivity to phenytoin-induced malformations and that involved chronic phenytoin exposure have shown significantly altered expression of several genes at different times of morphogenesis; in particular, retinoic acid receptors alpha, beta, and gamma were significantly increased (57).
Many antiseizure drugs have folic acid antagonistic properties, and similar patterns of malformations can be seen after in utero exposure to folic acid antagonists (unsuccessful attempts to induce abortion) (123). Hill and colleagues noticed that some mothers taking phenytoin who delivered malformed fetuses had borderline or low folate levels (77). Although the utility of folic acid supplementation for the general female reproductive population is clearly established, whether or not it reduces teratogenic risk for women with epilepsy taking antiseizure drugs is unclear. There have been three case reports of women who took good doses (3.5 to 5 mg) of folic acid supplementation months before conception and throughout pregnancy who were also on valproate with resultant neural tube defects (one with other malformations also) (29; 45). These cases are not that surprising as there has been demonstrated failure of folate to reduce valproate-induced neural tube defects and embryotoxicity both in vitro and in vivo rodent models (63; 64).
Other factors have been implicated in the genesis of fetal anticonvulsant syndrome, especially in association with phenytoin exposure. Acetylsalicylic acid inhibits prostaglandin synthase that oxidates phenytoin (100). The former reaction produces free radicals that may bind to proteins (100). Pretreatment of pregnant mice taking phenytoin with acetylsalicylic acid reduces the risk of cleft lip and palate in their offspring (191). The same authors found a similar effect with pretreatment with caffeic acid, an antioxidant agent.
A Swedish study in rats showed good correlation between pharmacokinetic data and pregnancy outcome data, ie, the degree of developmental toxicity was related to free maternal plasma phenytoin levels. The results suggest that the development of toxicity of phenytoin is caused by concentration-dependent induction of embryonic dysrhythmia and hypoxia-related damage during a restricted sensitive period (33).
Valproic acid can be used to induce an antiseizure drug-like behavior after a single injection in early postnatal mice, which may imply an epigenetic mechanism related to the well-known inhibitory effects of valproic acid on histone deacetylase (139).
Epidemiology
The reported incidence of major congenital malformations varies significantly by around 20fold, mainly because of methodological differences and deficiencies. Earlier studies usually rely on small numbers of recruited patients and lack statistical power. To understand the extent of the difficulties, a total of 722 drugexposed pregnancies is needed to identify a 7fold increase in the rate of occurrence of a specific abnormality, such as spina bifida, with a frequency of 1 in 1000 (79), or if drug A has a 3% risk for major congenital malformations and drug B doubles the risk to 6%, then 750 patients on monotherapy are needed in each group to reach p < 0.05 at 80% power. Several large prospective pregnancy registries throughout the world are collecting data on antiseizure drugrelated major congenital malformations and other pregnancy related outcomes in women with epilepsy (176). However, even these registries have important methodological differences in recruitment, ascertainment, inclusion/ exclusion criteria, malformation classification, and followup that may influence the results and prevent meaningful pooling of data (121).
Background rate of major congenital malformations is generally considered to be 1% to 2%, but reports vary. The Active Malformation Surveillance Program at Brigham and Women’s Hospital in Boston, United States, estimates the background rate to be 1.6% after exclusion of genetic and chromosomal anomalies (136). Some use the higher rate of 3.2% determined by the Metropolitan Atlanta Congenital Defects Program (28), but this populationbased registry uses active case identification from multiple sources, undertakes direct chart review of potential cases, and includes all malformations identified up to the age of 5 years (70).
A pooled analysis of data from 26 studies reported a major congenital malformation rate of 6.1% in offspring that had been exposed to antiseizure drugs compared to 2.8% in children of untreated women with epilepsy, and 2.2% in offspring of mothers without epilepsy (11). Similar results were reported in a formal meta-analysis of 10 studies. The offspring of women with epilepsy who received antiseizure drugs had higher prevalence of major congenital malformation than controls (odds ratio (OR) 3.26; 95% CI 2.15-4.93), whereas the risk for major congenital malformations in the offspring of women with untreated epilepsy was not significantly higher than among nonepilepsy controls (OR 1.92; 95% CI 0.92-4.00) (50).
There does not appear to be an association between antenatal antiseizure medication choice and risk of epilepsy in the child (43).
Previous studies. The rates of malformation in infants of mothers with epilepsy ranges from 2.3% (85) to 18.6% (125). The rate of malformations of the general population in various reports ranges from as low as 1.4% to as high as 50%. The most commonly accepted values are 1.5% to 3% (90; 91; 202). This wide range is caused by differences in the threshold for diagnosing minor facial or forefinger anomalies and the variability in methodology. In a review, 39 studies of malformation rates in the offspring of epileptic and control mothers were analyzed (202). The analysis demonstrated a combined estimate of malformation of 4% to 6% for an individual epileptic pregnancy. The same authors point out that most studies show that infants of mothers with epilepsy have about 2.5 to 10.5 times more malformations than the general control populations. A group studied the relative risks of particular major malformations with fetal exposure to antiseizure drugs. They found the relative risk for cardiovascular defects was 2.2, oral clefts 2.5, and urinary tract defects 2.5 (76). Fetal mortality is another risk for women with epilepsy. Reported rates of stillbirth (defined as greater than 20 weeks’ gestational age) vary between 1.3% and 14% compared with rates of 1.2% to 7.8% for women without epilepsy. Perinatal death rates are also up to two times higher for women with epilepsy (1.3% to 7.8%) compared to controls (1.0% to 3.9%) (200). Spontaneous abortions (less than 20 weeks’ gestation) may also occur more frequently although the figures vary considerably between different studies (148).
Several factors remain difficult to explain: women with epilepsy often will have a lower social economic status and decreased ability to hold high profile jobs, and they are more prone to accidents, falls, and serious injuries related to seizures. Epileptic patients are also less likely to be driving and may have more difficulty having access to prenatal care in areas where public transportation is not efficient. These factors may contribute in part to intrinsic differences in these populations, which are difficult to control. Genetic influences probably also play a role in the genesis of malformations in infants of mothers with epilepsy. The rate of malformations in the relatives of the affected children is higher than in the relatives of the ones without anomalies (35). Malformation rates appear to be higher in infants of untreated women with epilepsy than in those born of mothers without epilepsy (165; 98). A family history of spina bifida was present in 25% of the children who developed neural tube defects after antiseizure drug exposure in utero (107; 108). Spina bifida occulta is more common in the genetic epilepsies than in the symptomatic ones (96). Epilepsy is also more common among the first and second-degree relatives of patients with cleft lip and palate (44). Nonetheless, the authors still believe that malformations in infants of mothers with epilepsy are caused mostly by teratogenic effects of the antiseizure drugs (85; 168; 06; 133). When a child has fetal hydantoin syndrome, a 90% risk exists that the next sibling will be affected, in contrast to a 2% of risk if the first child is normal (183).
The rate of some specific malformations is especially increased in infants of mothers with epilepsy. For example, the rate of cleft lip and palate is 4.7 times higher when compared with the general population (52). The frequency of neural tube defects is 10 to 20 times higher in children exposed to valproate in utero (138) and about 10 times higher with carbamazepine exposure (157).
Most studies of cognitive outcomes of infants exposed to antiseizure drugs in utero report an increased risk of mental deficiency, affecting between 1.4% and 6% of children of women with epilepsy compared with 1% of controls (103; 99). Two studies from the United Kingdom involving a total of 350 children have shown that prenatal antiseizure drug exposure in the setting of maternal epilepsy is associated with developmental delay, particularly speech delay, and later childhood morbidity, in addition to congenital malformation (127; 37).
For more studies see above “cognitive effects of fetal exposure to antiseizure drugs”. The plasma concentrations of antiseizure drugs appear to be higher in the mothers of infants with epilepsy when compared to epileptic mothers who gave birth to normal children (34). A mother using more than 1000 mg of valproate per day is more likely to have malformed offspring than a mother taking 600 mg or less per day (163). The epileptic mother treated with antiseizure drug polytherapy is more likely to give birth to an infant with malformations when compared to the one treated with monotherapy (133).
The effect of maternal seizures in the incidence of malformation is unclear at this point. Annegers and colleagues and Nakane and associates found no impact of seizures in the risk of fetal malformations (06; 134). Lindhout and collaborators found a 3-fold increase in malformations in the fetuses exposed to seizures during the first trimester (107; 108).
Prevention
In many cases, the exposure to antiseizure drug medication is unavoidable during pregnancy. The current AES/AAN guidelines build on previous consensus articles (38; 129; 144), a practice parameter summary statement from the American Academy of Neurology (141; 69), and a review by Whelehan and Delanty (192) were published that outlined some guidelines for antiseizure drug use during pregnancy. The preconception management is the cornerstone for care of women with epilepsy who wish to become pregnant. Prepregnancy consultation provides an opportunity to review the clinical status of the woman, assess the risk of seizure recurrence during pregnancy and of fetal malformations and, thus, optimize therapy without undue risk to the mother or baby. The aim is, if possible, to treat with the least epileptogenic of the appropriate antiseizure drug, reduce the dosage, and switch some patients from polytherapy to monotherapy. Start with folic acid, provide detailed screening for fetal malformations in the third or fourth month of pregnancy, and monitor antiseizure drug blood levels for drug dosage corrections, particularly in the latter half of pregnancy and postpartum (173). Impact of planning of pregnancy in women with epilepsy is associated with good seizure control during pregnancy and less fetal exposure to antiseizure drugs (02).
It is important to note the potential for harm in switching or withdrawing medications that have been effective in controlling convulsive seizures. As noted in the new AES/AAN guidelines (144), care must be exercised in medication changes made during pregnancy, acknowledging the increased pregnancy mortality of people with epilepsy, mostly related to sudden unexpected death in epilepsy (SUDEP) (154). This is supported by a small study of 695 pregnancies in China that demonstrated a lack of benefit and potential harm in switching antiseizure medication in the first trimester (54).
Despite advances in the past decade, our knowledge of the teratogenic risks for most antiseizure drugs and the underlying mechanisms remain inadequate. Further, the long-term effects of antiseizure drugs in neonates and older children remain uncertain. The pace of progress is slow given the lifelong consequences of diminished developmental outcomes, exposing children unnecessarily to potential adverse effects. It is imperative that new approaches be employed to determine risks more expediently (120). Recommendations include a national reporting system for congenital malformations, federal funding of the North American AED Pregnancy Registry, routine meta-analyses of cohort studies to detect teratogenic signals, monitoring of antiseizure drugs prescription practices for women, routine preclinical testing of all new antiseizure drugs for neurodevelopmental effects, more specific Food and Drug Administration requirements to establish differential antiseizure drugs cognitive effects in children, and improved funding of basic and clinical research to fully delineate risks and underlying mechanisms for antiseizure drug-induced anatomical and behavioral teratogenesis (120).
Antiseizure drug-treated women with either a malformed fetus or a spontaneous abortion in their previous pregnancy had a statistically significant 2-fold to 3-fold increased risk of fetal malformation in their next pregnancy, compared with similarly treated women with normal offspring in their previous pregnancy (179). Thus, in assessing the hazard of an antiseizure drug-treated woman having a malformed fetus, it is important to know both the antiseizure drugs being taken and, if there had been a previous pregnancy, whether a fetal malformation or a spontaneous abortion occurred in it (179).
Although there is growing evidence for the risks of antenatal valproic acid exposure, there is variable uptake of these guidelines worldwide (09; 197), and gaps in knowledge for people with epilepsy of childbearing age (105). Furthermore, the risks of antiseizure medication use in pregnancy may disproportionately affect people of lower socioeconomic status, with more discontinuation, late initiation, and later switching observed in a population-based study from Nordic universal healthcare systems (104).
Differential diagnosis
Both the facial appearance and the history of antiseizure drug exposure during early pregnancy help make the diagnosis of fetal anticonvulsant syndrome. Some of the facial features are similar to the ones seen in fetal alcohol syndrome. Among the former are microcephaly, growth retardation, upturned nostrils, hypoplastic philtrum, and irritability (22). Micro- or retrognathia and hypoplastic maxilla are not common after fetal anticonvulsant exposure but are common in fetal alcohol syndrome (22). One of the features that tends to be helpful in supporting the diagnosis of fetal anticonvulsant syndrome is the hypoplasia of the nails and distal phalanges. Accurate physical diagnosis may be important because mothers who suffer from chemical dependency may not always volunteer the information about the drugs and alcohol during early pregnancy. On the other hand, phenytoin and other antiseizure drugs are commonly prescribed for patients with alcohol withdrawal seizures.
Diagnostic workup
The diagnosis of the fetal anticonvulsant syndromes, effects, and exposures is done by physical examination and observation of the patients.
Patients with suspected malformations of specific organs may require specialized radiological studies. When the neurologic examination of the lower extremities is abnormal, a spinal MRI is required to delineate neural tube defects. Patients exposed to antiseizure drugs in utero presenting with a heart murmur, cyanosis, and heart failure need thorough cardiological assessment including an echocardiogram.
Diagnostic criteria to establish a diagnosis of fetal valproate spectrum disorder were published by the European Reference Network for Congenital Malformations and Intellectual Disability in 2019 (25). The essential criteria include confirmed exposure, no other diagnosis to explain the phenotype, normal microarray-CGH, and fragile X studies, and other overlapping teratogenic disorders excluded. The specific malformations are listed as suggestive supporting features, such as classic facial dysmorphism.
Management
Counseling for women with epilepsy of childbearing potential surrounding pregnancy issues is of the utmost importance and should be done when antiseizure medications are prescribed and reviewed regularly. Physicians must be familiar with risks associated with antiseizure medication and should endeavor to minimize risks to a fetus while selecting best medications for epilepsy type (192).
No specific treatments exist for many of the antiseizure drug-specific effects other than the symptomatic effects. Obviously, detailed neurologic assessment is required. Physical, occupational, and speech therapy are indicated for patients with motor, cognitive, and language deficits. Patients with cleft lip and palate and head dysmorphisms (trigonocephaly) should undergo multidisciplinary evaluation and surgical treatment in centers familiarized with craniofacial pathology. Cardiac and other affected systems need to be evaluated and repaired accordingly. Uncommonly, newborns may have withdrawal symptoms, particularly if the mother was on large doses of barbiturates. This can be treated with phenobarbital, morphine, or other opiates.
There is evidence that delivery experiences are broadly similar in people with epilepsy of childbearing age, except that those with epilepsy are more likely to have unlabored caesarean sections, perhaps reflecting a perception of increased risk for vaginal delivery (147; 116).
Children exposed to antenatal antiseizure medications should have a comprehensive neurodevelopment screening for intellectual disability, learning disorders, and autism spectrum disorders when they are school-aged, if possible (144).
There is evidence that young adults with fetal valproate spectrum disorder have limited access to specialized resources to address the lifelong physical, cognitive, emotional, social, and behavioral challenges associated with the disorder (93).
References
- 01
- Abdulrazzaq YM, Bastaki SM, Padmanabhan R. Teratogenic effects of vigabatrin in TO mouse fetuses. Teratology 1997;55(3):165-76. PMID 9181670
- 02
- Abe K, Hamada H, Yamada T, Obata-Yasuoka M, Minakami H, Yoshikawa H. Impact of planning of pregnancy in women with epilepsy on seizure control during pregnancy and on maternal and neonatal outcomes. Seizure 2014;23(2):112-6. PMID 24183922
- 03
- Adriaenssen DJ, Farmen AH, Oie MG, Skogli EW. Impaired executive functioning in children of women with epilepsy. Epilepsy Behav 2024;156:109864. PMID 38795457
- 04
- Aicardi J. The effects of antiepileptic drugs. In: Aicardi J, editor. Disease of the central nervous system in childhood. London: Mac Keith Press, 1992:29-46.
- 05
- Annegers JF, Elveback LR, Hauser WA, et al. Do anticonvulsants have a teratogenic effect. Arch Neurol 1974;31:364-73. PMID 4441320
- 06
- Annegers JF, Hauser WA, Elveback LR, Anderson VE, Kurland LI. Congenital malformations and seizure disorders in the offspring of parents with epilepsy. Int J Epidemiol 1978;7:241-7. PMID 721359
- 07
- Ardinger HH, Atkin JF, Blackston RD, et al. Verification of fetal valproate syndrome phenotype. Am J Med Genet 1988;29:171-85. PMID 3125743
- 08
- Ayme S. Fetal valproate syndrome. In: Buyse ML, editor. Birth defects encyclopedia. Cambridge: Blackwell Scientific Publications, 1990:730.
- 09
- Baloyi MG, Khalema R, Adam S. What do women with epilepsy know about pregnancy? S Afr Fam Pr 2024;66(1):e1-9. PMID 39221728
- 10
- Battino D, Tomson T. Seizure control in pregnancy. In: Panayiotopoulos CP, Crawford P, Tomson T, editors. Volume 4. Epilepsies in girls and women. Oxford: Medicinae, 2008:138-42.
- 11
- Battino D, Tomson T. The management of epilepsy in pregnancy. In: Shorvon S, Pedley TA, editors. The epilepsies 3. Philadelphia: Saunders, Elsevier, 2009:241-64.
- 12
- Battino D, Tomson T, Bonizzoni E, et al. Risk of major congenital malformations and exposure to antiseizure medication monotherapy. JAMA Neurol 2024;81(5):481-9. PMID 38497990
- 13
- Bjork MH, Zoega H, Leinonen MK, et al. Association of prenatal exposure to antiseizure medication with risk of autism and intellectual disability. JAMA Neurol 2022;79(7):672-81. PMID 35639399
- 14
- Bromley R, Adab N, Bluett-Duncan M, et al. Monotherapy treatment of epilepsy in pregnancy: congenital malformation outcomes in the child. Cochrane Database Syst Rev 2023;8(8):CD010224. PMID 37647086
- 15
- Bromley R, Weston J, Adab N, et al. Treatment for epilepsy in pregnancy: neurodevelopmental outcomes in the child. Cochrane Database Syst Rev 2014;10:CD010236. PMID 25354543
- 16
- Bromley RL, Weston J, Marson AG. Maternal use of antiepileptic agents during pregnancy and major congenital malformations in children. JAMA 2017;318(17):1700-1. PMID 29114815
- 17
- Buehler BA. Epoxide hydrolase activity and the “fetal hydantoin syndrome”. Clin Res 1985;33:129.
- 18
- Buehler BA, Delimont D, van Waes M, Finnell RH. Prenatal prediction of risk of the fetal hydantoin syndrome. N Engl J Med 1990;322:1567-72. PMID 2336087
- 19
- Buehler BA, Hanson JW. Fetal hydantoin syndrome. In: Buyse ML, editor. Birth defects encyclopedia. Cambridge: Blackwell Scientific Publications, 1990:714-5.
- 20
- Campbell E, Kennedy F, Russell A, et al. Malformation risks of antiepileptic drug monotherapies in pregnancy: updated results from the UK and Ireland Epilepsy and Pregnancy Registers. J Neurol Neurosurg Psychiatry 2014;85(9):1029-34. PMID 24444855
- 21
- Centa E, Rasore-Quartino A. La sindrome malformatine 'digitocardiaca' forme genetsche e fenocopie. Probabile Azione Tertogena dei Farmaci Antiepileptici Pathologica 1965;57:227-32.
- 22
- Chiriboga CA, Ferriero DM. Neurological complications of maternal drug abuse. In: Berg BO, editor. Principles of child neurology. New York: McGraw-Hill, 1996:1363-74.
- 23
- Christensen J, Zoega H, Leinonen MK, et al. Prenatal exposure to antiseizure medications and fetal growth: a population-based cohort study from the Nordic countries. Lancet Reg Heal Eur 2024;38:100849. PMID 38476755
- 24
- Clay SA, McVie R, Chen H. Possible teratogenic effect of valproic acid. J Pediatr 1981;99:828. PMID 6795327
- 25
- Clayton-Smith J, Bromley R, Dean J, et al. Diagnosis and management of individuals with fetal valproate spectrum disorder; a consensus statement from the European Reference Network for Congenital Malformations and Intellectual Disability. Orphanet J Rare Dis 2019;14(1):180. PMID 31324220
- 26
- Cohen MJ, Meador KJ, Browning N, et al. Fetal antiepileptic drug exposure: adaptive and emotional/behavioral functioning at age 6 years. Epilepsy Behav 2013;29(2):308-15. PMID 24012508
- 27
- Cohen JM, Alvestad S, Suarez EA, et al. Comparative risk of major congenital malformations with antiseizure medication combinations vs valproate monotherapy in pregnancy. Neurology 2024;102(2):e207996. PMID 38165339
- 28
- Cragan JD, Friedman JM, Holmes LB, Uhl K, Green NS, Riley L. Ensuring the safe and effective use of medications during pregnancy: planning and prevention through preconception care. Matern Child Health J 2006;10(5 Suppl):129-35. PMID 16850277
- 29
- Craig J, Morrison P, Morrow J, Patterson V. Failure of periconceptual folic acid to prevent a neural tube defect in the offspring of a mother taking sodium valproate. Seizure 1999;8:253-4. PMID 10452927
- 30
- Crawford PM. Managing epilepsy in women of childbearing age. Drug Saf 2009;32(4):293-307. PMID 19388721
- 31
- Cunnington M, Tennis P; International Lamotrigine Pregnancy Registry Scientific Advisory Committee. Lamotrigine and the risk of malformations in pregnancy. Neurology 2005;64:955-60. PMID 15781807
- 32
- Dalens B, Raynaud EJ, Gaulme J. Teratogenicity of valproic acid. J Pediatr 1980;97:332-3. PMID 6772753
- 33
- Danielsson B, Skold AC, Azarbayjani F, Ohman I, Webster W. Pharmacokinetic data support pharmacologically induced embryonic dysrhythmia as explanation to fetal hydantoin syndrome in rats. Toxic Appl Pharmacol 2000;163:164-75. PMID 10698674
- 34
- Dansky LV, Andermann E, Sherwin AL, Andermann F, Kinch RA. Maternal epilepsy and congenital malformations: a prospective study with monitoring of plasma anticonvulsant levels during pregnancy. Neurology 1980;3:15.
- 35
- Dansky LV, Finnell RH. Parental epilepsy, anticonvulsant drugs, and reproductive outcome: epidemiologic and experimental findings spanning three decades; 2: Human studies. Reprod Toxicol 1991;5:301-35. PMID 1806139
- 36
- Davies PP. Coagulation defect due to anticonvulsant drug treatment in pregnancy. Lancet 1970;1:413. PMID 4189710
- 37
- Dean JC, Hailey H, Moore SJ, Lloyd DJ, Turnpenny PD, Little J. Long term health and neurodevelopment in children exposed to antiepileptic drugs before birth. J Med Genet 2002;39:251-9. PMID 11950853
- 38
- Delgado-Escueta AV, Janz D. Consensus guidelines: preconception counseling, management and care of the pregnant woman with epilepsy. Neurology 1992;42:149-60. PMID 1574171
- 39
- De Smet L, Debeer P. Fetal hydantoin syndrome with unilateral atypical cleft hand: additional evidence for vascular disruption. Genet Couns 2002;13:157-61. PMID 12150216
- 40
- Desmond MM, Schwanecke RP, Wilson GS, Yasunaga S, Burgdorff I. Maternal barbiturate utilization and neonatal withdrawal symptomatology. J Pediatr 1972;80:190-7. PMID 5008817
- 41
- DiLiberti JH, Farndon PA, Dennis NR, Curry CJ. The fetal valproate syndrome. Am J Med Genet 1984;19:473-81. PMID 6439041
- 42
- Dolk H, Jentink J, Loane M, Morris J, de Jong-van den Berg LT, EUROCAT Antiepileptic Drug Working Group. Does lamotrigine use in pregnancy increase orofacial cleft risk relative to other malformations? Neurology 2008;71(10):714-22. PMID 18650491
- 43
- Dreier JW, Bjork MH, Alvestad S, et al. Prenatal exposure to antiseizure medication and incidence of childhood- and adolescence-onset psychiatric disorders. JAMA Neurol 2023;80:568-77. PMID 37067807
- 44
- Dronamraju KR. Epilepsy and cleft lip and palate. Lancet 1970;2:876-7. PMID 4097781
- 45
- Duncan S, Mercho S, Lopes-Cendes I, et al. Repeated neural tube defects and valproate monotherapy suggest a pharmacogenetic abnormality. Epilepsia 2001;42:750-3. PMID 11422330
- 46
- EURAP study group. Utilization of antiepileptic drugs during pregnancy: comparative patterns in 38 countries based on data from the EURAP registry. Epilepsia 2009;50(10):2305-9. PMID 19453723
- 47
- Feldman GL, Weaver DD, Lovrien EW. The fetal trimethadione syndrome: report of an additional family and further delineation of this syndrome. Am J Dis Child 1977;131:89-92. PMID 412416
- 48
- Finnell RH, Dansky LV. Parental epilepsy, anticonvulsant drugs, and reproductive outcome: epidemiologic and experimental findings spanning three decades; 1: Animal studies. Reprod Toxicol 1991;5:281-99. PMID 1806138
- 49
- Fountain NB. A pregnant pause to consider teratogenicity of topiramate. Epilepsy Curr 2009;9(2):36-8. PMID 19421375
- 50
- Fried S, Kozer E, Nulman I, Einarson TR, Koren G. Malformation rates in children of women with untreated epilepsy: a meta-analysis. Drug Saf 2004;27(3):197-202. PMID 14756581
- 51
- Friedman JM, Polifka JE. Phenobarbital. In: Friedman JM, Polifka JE, editors. Teratogenic effects of drugs: a resource for clinicians. Baltimore: Johns Hopkins University Press, 1994:490-4.
- 52
- Friis ML. Facial clefts and congenital heart disease in children of parents with epilepsy: genetic and environmental etiologic factors. Acta Neurol Scand 1989;79:433-59. PMID 2675529
- 53
- Fritz H, Muller D, Hess R. Comparative study of the teratogenicity of phenobarbitone, diphenylhydantoin and carbamazepine in mice. Toxicology 1976;6:323-30. PMID 996878
- 54
- Fu Y, Shi F, Sha L, et al. Effects of antiseizure medication withdrawal during the first trimester of pregnancy on seizure control and offspring outcomes. Epilepsia 2024;65(11):3186-98. PMID 39287982
- 55
- Gaily E, Granstrom ML, Hiilesmaa V, Bardy A. Minor anomalies in offspring of epileptic mothers. J Pediatr 1988;112:520-9. PMID 3351676
- 56
- Gal P, Oles KS, Gilman JT, Weaver R. Valproic acid efficacy, toxicity, and pharmacokinetics in neonates with intractable seizures. Neurology 1988;38:467-71. PMID 3126410
- 57
- Gelineau-Van Waes J, Bennett GD, Finnell RH. Phenytoin-induced alterations in craniofacial gene expression. Teratology 1999;59:23-34. PMID 9988880
- 58
- German J, Kowal A, Ehlers KH. Trimethadione and human teratogenesis. Teratology 1970;3:349-62. PMID 5006237
- 59
- Glover SJ, Quinn AG, Barter P, et al. Ophthalmic findings in fetal anticonvulsant syndrome(s). Ophthalmology 2002;109:942-7. PMID 11986102
- 60
- Gomez MR. Possible teratogenicity of valproic acid. J Pediatr 1981;98:508-9. PMID 6782218
- 61
- Greenberg G, Inman WH, Weatherall JA, et al. Maternal drug histories and congenital abnormalities. Br Med J 1977;2:853-6. PMID 922327
- 62
- Gustavson EE, Chen H. Goldenhar syndrome, anterior encephalocele, and aqueductal stenosis following fetal primidone exposure. Teratology 1985;32:13-7. PMID 4035586
- 63
- Hansen DK, Grafton TF. Lack of attenuation of valproic acid-induced effects by folinic acid in rat embryos in vitro. Teratology 1991;43(6):575-82. PMID 1882348
- 64
- Hansen DK, Grafton TF, Dial SL, Gehring TA, Siitonen PH. Effect of supplemental folic acid on valproic acid-induced embryotoxicity and tissue zinc levels in vivo. Teratology 1995;52(5):277-85. PMID 8838251
- 65
- Hanson JW, Myrianthopoulos NC, Harvey MA, Smith DW. Risks to the offspring of women treated with hydantoin anticonvulsants, with emphasis on the fetal hydantoin syndrome. J Pediatr 1976;89:662-8. PMID 957016
- 66
- Hanson JW, Smith DW. The fetal hydantoin syndrome. J Pediatr 1975;87:285-90. PMID 50428
- 67
- Harden CL, Hopp J, Ting TY, et al. Practice parameter update: management issues for women with epilepsy--focus on pregnancy (an evidence-based review): obstetrical complications and change in seizure frequency: report of the Quality Standards Subcommittee and Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and American Epilepsy Society. Neurology 2009a;73(2):126-32. PMID 19398682
- 68
- Harden CL, Meador KJ, Pennell PB, et al. Practice parameter update: management issues for women with epilepsy--focus on pregnancy (an evidence-based review): teratogenesis and perinatal outcomes: report of the Quality Standards Subcommittee and Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and American Epilepsy Society. Neurology 2009b;73(2):133-41. PMID 19398681
- 69
- Harden CL, Pennell PB, Koppel BS, et al. Practice parameter update: management issues for women with epilepsy--focus on pregnancy (an evidence-based review): vitamin K, folic acid, blood levels, and breastfeeding: report of the Quality Standards Subcommittee and Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and American Epilepsy Society. Neurology 2009c;73(2):142-9. PMID 19398680
- 70
- Hauser WA, Tomson T. Lamotrigine and the risk of malformations in pregnancy. Neurology 2006;66(1):153-4. PMID 16401876
- 71
- Heinonen OP, Slone D, Shapiro S. Birth defects and drugs in pregnancy. Littleton: John Wright-PSG, 1977:343.
- 72
- Hernandez-Diaz S, Straub L, Bateman BT, et al. Risk of autism after prenatal topiramate, valproate, or lamotrigine exposure. N Engl J Med 2024;390:1069-79. PMID 38507750
- 73
- Hernandez-Diaz S, Mittendorf R, Smith C, et al. Association between topiramate and zonisamide use during pregnancy and low birth weight. Obstet Gynecol 2014;123(1):21-8. PMID 24463659
- 74
- Hernandez-Diaz S, Smith CR, Shen A, et al. Comparative safety of antiepileptic drugs during pregnancy. Neurology 2012;78(21):1692-9. PMID 22551726
- 75
- Hernandez-Diaz S, Straub L, Bateman BT, et al. Risk of autism after prenatal topiramate, valproate, or lamotrigine exposure. N Engl J Med 2024;390:1069-79. PMID 38507750
- 76
- Hernandez-Diaz S, Werler M, Walker A. Folic acid antagonists during pregnancy and the risk of birth defects. N Engl J Med 2000;343:1608-14. PMID 11096168
- 77
- Hill RM, Horning MG, Horning EC. Antiepileptic drugs and fetal well-being. In: Boreus LO, editor. Fetal pharmacology. New York: Raven Press, 1973:375-80.
- 78
- Hoeltzenbein M, Bartz I, Fietz AK, et al. Antiepileptic treatment with levetiracetam during the first trimester and pregnancy outcome: an observational study. Epilepsia 2024;65(1):26-36. PMID 37857460
- 79
- Holmes LB, Baldwin EJ, Smith CR, et al. Increased frequency of isolated cleft palate in infants exposed to lamotrigine during pregnancy. Neurology 2008;70(22 Pt 2):2152-8. PMID 18448870
- 80
- Horning MG, Stratton C, Wilson A, Horning EC, Hill RM. Detection of 5-(3,4-diphenylhydantoin) in the newborn human. Res Commun Chem Pathol Pharmacol 1974;4:537-82.
- 81
- Hunt S, Russell A, Smithson WH, et al. Topiramate in pregnancy: preliminary experience from the UK Epilepsy and Pregnancy Register. Neurology 2008;71(4):272-6. PMID 18645165
- 82
- Hunt SJ, Craig JJ, Morrow JI. Increased frequency of isolated cleft palate in infants exposed to lamotrigine during pregnancy. Neurology 2009;72(12):1108-9. PMID 19307550
- 83
- Jager-Roman E, Deichl A, Jakob S, et al. Fetal growth, major malformations, and minor anomalies in infants born to women receiving valproic acid. J Pediatr 1986;108:997-1004. PMID 3086531
- 84
- Janas MS, Arroe M, Hansen SH, Graem N. Lung hypoplasia--a possible teratogenic effect of valproate. Case report. APMIS 1998;106:300-4. PMID 9531963
- 85
- Janz D, Fuchs U. Are antiepileptic drugs harmful when given during pregnancy. Ger Med Mon 1964;9:20-2. PMID 14158990
- 86
- Jeavons PM. Non-dose related side-effects of valproate. Epilepsia 1984;25:S50-5. PMID 6425047
- 87
- Jerina DM, Daly JW. Arene oxides: a new aspect of drug metabolism. Science 1974;185:573-82. PMID 4841570
- 88
- Jones KL. Fetal hydantoin syndrome, fetal trimethadione syndrome and fetal valproate syndrome. In: Jones KL, editor. Recognizable patterns of human malformation. 5th ed. Philadelphia: WB Saunders, 1997:559-67.
- 89
- Jones KL, Lacro RV, Johnson KA, Adams J. Pattern of malformations in the children of women treated with carbamazepine during pregnancy. N Engl J Med 1989;320:1661-6. PMID 2725616
- 90
- Kalter H, Warkany J. Congenital malformations. N Engl J Med 1983;308:491-7. PMID 6337336
- 91
- Kelly TE. Teratogenicity of anticonvulsant drugs I: review of literature. Am J Med Genet 1984a;19:413-34. PMID 6391167
- 92
- Kelly TE. Teratogenicity of anticonvulsant drugs III: radiographic hand analysis of children exposed in utero to diphenylhydantoin. Am J Med Genet 1984b,19:445-50. PMID 6507490
- 93
- Khanom S, Astill D, Astill N, et al. The lived experience of young adults with fetal valproate spectrum disorder, and the perspective of their parents: a qualitative study. Epilepsy Behav 2024;152:109680. PMID 38335859
- 94
- King PB, Lie RT, Irgens LM. Spina bifida and cleft lip among newborns of Norwegian women with epilepsy: changes related to the use of anticonvulsants. Am J Public Health 1996;86:1454-6. PMID 8876519
- 95
- Kini U, Adab N, Vinten J, et al. Dysmorphic features: an important clue to the diagnosis and severity of fetal anticonvulsant syndromes. Arch Dis Child Fetal Neonatal Ed 2006;91(2):F90-5. PMID 16239295
- 96
- Klepel H, Freitag G. Spina bifida occulta in epilepsy syndromes. Neurology 1992;42:126-7. PMID 1574167
- 97
- Koch S, Goepfert-Geyer I, Haeuser I, et al. Neonatal behaviour disturbances in infants of epileptic women treated during pregnancy. Prog Clin Biol Res 1985;163B:453-61. PMID 3983173
- 98
- Koch S, Losche G, Jager-Roman E, et al. Major and minor birth malformations and antiepileptic drugs. Neurology 1992;42:83-8. PMID 1574183
- 99
- Koch S, Titze K, Zimmermann RB, Schroder M, Lehmkuhl U, Rauh H. Long-term neuropsychological consequences of maternal epilepsy and anticonvulsant treatment during pregnancy for school age children and adolescents. Epilepsia 1999;40:1237-43. PMID 10487186
- 100
- Kuenssberg EV, Knox JD. Teratogenic effects of anticonvulsants. Lancet 1973;1:198. PMID 4118804
- 101
- Kunze J, Wiedemann HR. Hydantoin-barbiturate-carbamazepine embryofoetopathy and embryofoetal valproic acid syndrome. In: Wiedemann HR, Kunze J, editors. Clinical syndromes. 4th German and 3rd English ed. London: Times Mirror International Publishers Limited, 1997:524-7.
- 102
- Lajeunie E, Barcik U, Thorne JA, Ghouzzi VE, Bourgeois M, Renier D. Craniosynostosis and fetal exposure to sodium valproate. J Neurosurg 2001;95:778-82. PMID 11702867
- 103
- Leavitt AM, Yerby MS, Robinson N, Sells CJ, Erickson DM. Epilepsy in pregnancy: developmental outcome of offspring at 12 months. Neurology 1992;42(Suppl 5):141-3. PMID 1574170
- 104
- Leinonen MK, Igland J, Dreier JW, et al. Socioeconomic differences in use of antiseizure medication in pregnancies with maternal epilepsy: A population‐based study from Nordic universal health care systems. Epilepsia 2024;65(8):2397-411. PMID 38804650
- 105
- Li Q, Cao Y, Zhang J, et al. Pregnancy‐related knowledge in women with epilepsy in childbearing age: A pilot questionnaire survey from China. Brain Behav 2024;14(2):e3400. PMID 38340294
- 106
- Lindhout D. Pharmacogenetics and drug interactions: role in antiepileptic-drug-induced teratogenesis. Neurology 1992;42:43-7. PMID 1574175
- 107
- Lindhout D, Meinardi H, Meijer JW, Nau H. Antiepileptic drugs and teratogenesis in two consecutive cohorts: changes in prescription policy paralleled by changes in pattern of malformations. Neurology 1992a;42:94-110. PMID 1574185
- 108
- Lindhout D, Omtzigt JG, Cornel MC. Spectrum of neural-tube defects in 34 infants prenatally exposed to antiepileptic drugs. Neurology 1992b;42:111-8. PMID 1574164
- 109
- Loughnan PM, Gold H, Vance JC. Phenytoin teratogenicity in man. Lancet 1973;1:70-2. PMID 4118650
- 110
- Malm H, Kajantie E, Kivirikko S, Kaariainen H, Peippo M, Somer M. Valproate embryopathy in three sets of siblings: further proof of hereditary susceptibility. Neurology 2002;59:630-3. PMID 12196666
- 111
- Martin M, Hill C, Bewley S, MacLennan AH, Braillon A. Transgenerational adverse effects of valproate? A patient report from 90 affected families. Birth Defects Res 2022;114(1):13-6. PMID 34866359
- 112
- Martz F, Failinger C, Blake DA. Phenytoin teratogenesis: correlation between embryopathic effect and covalent binding of putative arene oxide metabolite to gestational tissue. J Pharmacol Exp Ther 1977;203:231-9. PMID 909055
- 113
- Massey KM. Teratogenic effects of diphenylhydantoin sodium. J Oral Ther Pharmacol 1966;2:380-5. PMID 5949015
- 114
- Mawhinney E, Craig J, Morrow J, et al. Levetiracetam in pregnancy: results from the UK and Ireland epilepsy and pregnancy registers. Neurology 2013;80(4):400-5. PMID 23303847
- 115
- McCluskey G, Kinney MO, Russell A, et al. Zonisamide safety in pregnancy: Data from the UK and Ireland epilepsy and pregnancy register. Seizure 2021;91:311-5. PMID 34273670
- 116
- McElrath TF, Druzin M, Van Marter LJ, et al. The obstetrical care and delivery experience of women with epilepsy in the MONEAD study. Am J Perinatol 2024;41(7):935-43. PMID 35253116
- 117
- Meador KJ, Baker GA, Browning N, et al. Cognitive function at 3 years of age after fetal exposure to antiepileptic drugs. N Engl J Med 2009;360(16):1597-605. PMID 19369666
- 118
- Meador KJ, Baker GA, Browning N, et al. Fetal antiepileptic drug exposure and cognitive outcomes at age 6 years (NEAD study): a prospective observational study. Lancet Neurol 2013;12(3):244-52. PMID 23352199
- 119
- Meador KJ, Cohen MJ, Loring DW, et al. Cognitive outcomes at age 3 years in children with fetal exposure to antiseizure medications (MONEAD study) in the USA: a prospective, observational cohort study. Lancet Neurol 2023;22:712-22. PMID 37479375
- 120
- Meador KJ, Loring DW. Developmental effects of antiepileptic drugs and the need for improved regulations. Neurology 2016;86(3):297-306. PMID 26519545
- 121
- Meador KJ, Pennell PB, Harden CL, et al. Pregnancy registries in epilepsy: a consensus statement on health outcomes. Neurology 2008;71(14):1109-17. PMID 18703463
- 122
- Meadow R. Anticonvulsants in pregnancy. Arch Dis Child 1991;66:62-5. PMID 1996897
- 123
- Meadow SR. Anticonvulsant drugs and congenital abnormalities. Lancet 1968;2:1296. PMID 4177489
- 124
- Melchior IC, Svenswark O, Trolle D. Placental transfer to phenobarbitone in women and elimination in newborns. Lancet 1967;2:860-1. PMID 12387244
- 125
- Meyer JG. The teratological effects of anticonvulsants and the effects of pregnancy and birth. Eur Neurol 1973;10:179-80. PMID 4761600
- 126
- Montouris G. Safety of gabapentin treatment during pregnancy [Abstract]. Epilepsia 2002;43(Suppl 7):234.
- 127
- Moore SJ, Turnpenny P, Quinn A, et al. A clinical study of 57 children with fetal anticonvulsant syndromes. J Med Genet 2000;37:489-97. PMID 10882750
- 128
- Morrell MJ. The new antiepileptic drugs and women: efficacy, reproductive health, pregnancy, and fetal outcome. Epilepsia 1996;37:S34-44. PMID 8941040
- 129
- Morrell MJ. Guidelines for the care of women with epilepsy. Neurology 1998;51:S21-7. PMID 9818920
- 130
- Morrow J, Russell A, Guthrie E, et al. Malformation risks of antiepileptic drugs in pregnancy: a prospective study from the UK Epilepsy and Pregnancy Register. J Neurol Neurosurg Psychiatry 2006;77:193-8. PMID 16157661
- 131
- Mullers-Kuppers von M. Embryopathy during pregnancy caused by taking anticonvulsants. Acta Paedopsychiatr 1963;30:401-5.
- 132
- Murray JC, Hill RM, Hegemier S, Hurwitz RL. Lymphoblastic lymphoma following prenatal exposure to phenytoin. J Pediatr Hematol Oncol 1996;18:241-3. PMID 8846150
- 133
- Nakane Y. Congenital malformations among infants of epileptic mothers treated during pregnancy. Folia Psychiatr Neurol Jpn 1979;33:363-9. PMID 520954
- 134
- Nakane Y, Okuma T, Takahashi R, et al. Multi-institutional study on the teratogenicity and fetal toxicity of antiepileptic drugs: a report of a collaborative study group in Japan. Epilepsia 1980;21:663-80. PMID 7439133
- 135
- Nebert DW, Jensen NM. The Ah locus: genetic regulation of the metabolism of carcinogens, drugs, and other environmental chemicals by cytochrome P-450 mediated mono-oxygenases. CRC Crit Rev Biochem 1979;6:401-37. PMID 378536
- 136
- Nelson K, Holmes LB. Malformations due to presumed spontaneous mutations in newborn infants. N Engl J Med 1989;320(1):19-23. PMID 2909875
- 137
- Nishimura KY, Terada Y, Mukumoto K, et al. Teratogenic effects of phenobarbital in fetal rats. Teratology 1979;20:156-7.
- 138
- Omtzigt JG, Los FJ, Grobee DE, et al. The risk of spina bifida aperta after first-trimester exposure to valproate in a prenatal cohort. Neurology 1992;42:119-25. PMID 1574165
- 139
- Ornoy A, Echefu B, Becker M. Valproic acid in pregnancy revisited: neurobehavioral, biochemical and molecular changes affecting the embryo and fetus in humans and in animals: a narrative review. Int J Mol Sci 2023;25(1):390. PMID 38203562
- 140
- Ornoy A, Zvi N, Arnon J, Wajnberg R, Shechtman S, Diav-Citrin O. The outcome of pregnancy following topiramate treatment: a study on 52 pregnancies. Reprod Toxicol 2008;25(3):388-9. PMID 18424066
- 141
- Quality Standards Subcommittee of the American Academy of Neurology. Practice parameter: management issues for women with epilepsy (summary statement). Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 1998;51(4):944-8. PMID 9781510
- 142
- Pacifici GM, Colizzi C, Giuliani L, Rane A. Cytosolic epoxide hydrolase in fetal and adult human liver. Arch Toxicol 1983;54:331-41. PMID 6667124
- 143
- Pacifici GM, Rane A. Metabolism of styrene oxide in different human fetal tissues. Drug Metab Dispos 1982;10:302-5. PMID 6126324
- 144
- Pack AM, Oskoui M, Roberson SW, et al. Teratogenesis, perinatal, and neurodevelopmental outcomes after In utero exposure to antiseizure medication: practice guideline from the AAN, AES, and SMFM. Neurology 2024;102(11):e209279. PMID 38748979
- 145
- Palmieri C, Canger R. Teratogenic potential of the newer antiepileptic drugs: what is known and how should this influence prescribing? CNS Drugs 2002;16(11):755-64. PMID 12383031
- 146
- Pantarotto MF. A case of bone marrow aplasia in a newborn attributable to anticonvulsant drugs used by the mother during pregnancy. Quad Clin Ostet Ginecol 1965;67:343-8.
- 147
- Pekoz MT, Aslan-Kara K, Tekin B, et al. Birth outcomes in pregnant women with epilepsy: A Nationwide multicenter study from Türkiye. Epilepsia 2023;64(9):2310-21. PMID 37357418
- 148
- Pennell PB. The importance of monotherapy in pregnancy. Neurology 2003;60(Suppl 4):S31-8. PMID 12796519
- 149
- Pennell PB. Treatment of epilepsy during pregnancy. In: Wyllie E, Gidal BE, Goodkin HP, Loddenkemper T, Sirven JI, editors. Wyllie's treatment of epilepsy. Principle and practice. 6th edition. Philadelphia: Walters Kluwer, 2015:559-67.
- 150
- Petersen I, Collings SL, McCrea RL, et al. Antiepileptic drugs prescribed in pregnancy and prevalence of major congenital malformations: comparative prevalence studies. Clin Epidemiol 2017;9:95-103. PMID 28243149
- 151
- Petrenaite V, Sabers A, Hansen-Schwartz J. Seizure deterioration in women treated with oxcarbazepine during pregnancy. Epilepsy Res 2009;84(2-3):245-9. PMID 19231139
- 152
- Putignano D, Clavenna A, Campi R, et al. Perinatal outcome and healthcare resource utilization in the first year of life after antiepileptic exposure during pregnancy. Epilepsy Behav 2019;92:14-7. PMID 30599457
- 153
- Rating D, Koch S, Jager-Roman E, Jacob S, Helge H. The influence of antiepileptic drugs on minor anomalies in the offspring of epileptic parents. Prog Clin Biol Res 1985;163C:57-60. PMID 3991655
- 154
- Razaz N, Igland J, Bjork MH, et al. Risk of perinatal and maternal morbidity and mortality among pregnant women with epilepsy. JAMA Neurol 2024;81:985-95. PMID 39102246
- 155
- Robert E, Guiband E. Maternal valproic acid and congenital neural tube defects. Lancet 1982;2:934. PMID 6126782
- 156
- Rosa FW. Human barbiturate teratology. Teratology 1986;33:27A.
- 157
- Rosa FW. Primidone embryopathy. In: Buyse ML, editor. Birth defects encyclopedia. Cambridge: Blackwell Scientific Publications, 1990:690-1.
- 158
- Rosa FW, Fryns JP. Fetal barbiturate effects. In: Buyse ML, editor. Birth defects encyclopedia. Cambridge: Blackwell Scientific Publications, 1990:687-8.
- 159
- Rosa FW, Lindhout D. Fetal carbamazepine exposure. In: Buyse ML, editor. Birth defects encyclopedia. Cambridge: Blackwell Scientific Publications, 1990:690-1.
- 160
- Rosen RC, Lightner EW. Phenotypic malformations in association with maternal trimethadione therapy. J Pediatr 1978;92:240. PMID 413897
- 161
- Rothman KJ, Fyler DC, Goldblatt A, Kredberg MB. Exogenous hormones and other drug exposures of children with congenital heart disease. Am J Epidemiol 1979;109:433-9. PMID 443241
- 162
- Rudd NL, Freedom RM. A possible primidone embryopathy. J Pediatr 1979;94:835-7. PMID 448502
- 163
- Samren EB, van Duijn CM, Koch S, et al. Maternal use of antiepileptic drugs and the risk of major congenital malformations: a joint European prospective study of human teratogenesis associated with maternal epilepsy. Epilepsia 1997;38:981-90. PMID 9579936
- 164
- Seip M. Growth retardation, dysmorphic facies and minor malformations following massive exposure to phenobarbital in utero. Acta Paediatr Scand 1976;65:617-21. PMID 822687
- 165
- Shapiro S, Hartz SC, Siskind V, et al. Anticonvulsants and parental epilepsy in the development of birth defects. Lancet 1976;1:272-5. PMID 55587
- 166
- Shorvon SD. Management of chronic epilepsy in adults. In: Shorvon S, Perucca E, Engel J Jr, editors. The treatment of epilepsy (3rd edition). Oxford: Willey-Blackwell, 2009:153-62.
- 167
- Shum S, Jensen NM, Nebert DW. The murine Ah locus: in utero toxicity and teratogenesis associated with genetic differences in benzo(a)pyrene metabolism. Teratology 1979;20:365-76. PMID 542892
- 168
- Speidel BD, Meadow SR. Maternal epilepsy and abnormalities of the fetus and newborn. Lancet 1972;2:839-43. PMID 4116552
- 169
- Spielberg SP, Gordon GB, Blade DA, Mellits ED, Bross DS. Anticonvulsant toxicity in vitro: possible role of arene oxides. J Pharmacol Exp Ther 1981;217:386-9. PMID 7229980
- 170
- Stjerna S, Huber-Mollema Y, Tomson T, et al. Cognitive outcomes after fetal exposure to carbamazepine, lamotrigine, valproate or levetiracetam monotherapy: Data from the EURAP neurocognitive extension protocol. Epilepsy Behav 2024;159:110024. PMID 39217754
- 171
- Strickler SM, Dansky LV, Miller MA, Seni MH, Andermann E, Spielberg SP. Genetic predisposition to phenytoin induced birth defects. Lancet 1985;1:746-9. PMID 2864485
- 172
- Thomas SV, Jose M, Divakaran S, Sankara Sarma SP. Malformation risk of antiepileptic drug exposure during pregnancy in women with epilepsy: results from a pregnancy registry in South India. Epilepsia 2017;58(2):274-81. PMID 28084641
- 173
- Thomas SV, Tomson T, Harden CL. Management of epilepsy and pregnancy. In: Harden CL, Thomas SV, Tomson T, editors. Epilepsy in Women. Oxford: John Wiley & Sons, 2013.
- 174
- Tomson T, Battino D. Teratogenic effects of antiepileptic drugs. Lancet Neurol 2012;11(9):803-13. PMID 22805351
- 175
- Tomson T, Battino D, Bonizzoni E, et al. Dose-dependent risk of malformations with antiepileptic drugs: an analysis of data from the EURAP epilepsy and pregnancy registry. Lancet Neurol 2011;10(7): 609-17. PMID 21652013
- 176
- Tomson T, Battino D, French J, et al. Antiepileptic drug exposure and major congenital malformations: the role of pregnancy registries. Epilepsy Behav 2007;11(3):277-82. PMID 17996635
- 177
- Tomson T, Xue H, Battino D. Major congenital malformations in children of women with epilepsy. Seizure 2015;28:46-50. PMID 25777785
- 178
- Vajda FJ, Graham JE, Hitchcock AA, Lander CM, O'Brien TJ, Eadie MJ. Antiepileptic drugs and foetal malformation: analysis of 20 years of data in a pregnancy register. Seizure 2019;65:6-11. PMID 30593875
- 179
- Vajda FJ, O'Brien TJ, Graham JE, Hitchcock AA, Lander CM, Eadie MJ. Antiepileptic drugs, foetal malformations and spontaneous abortions. Acta Neurol Scand 2017;135(3):360-5. PMID 27573510
- 180
- Vajda FJ, O’Brien T, Graham JE, Hitchcock AA, Lander CM, Eadie MJ. Pregnancy after valproate withdrawal—fetal malformations and seizure control. Epilepsia 2020;61(5):944-50. PMID 32314363
- 181
- Vajda FJ, O'Brien TJ, Lander CM, Graham J, Eadie MJ. Antiepileptic drug combinations not involving valproate and the risk of fetal malformations. Epilepsia 2016;57(7):1048-52. PMID 27265509
- 182
- Vajda FJ, O'Brien TJ, Lander CM, Graham J, Eadie MJ. The teratogenicity of the newer antiepileptic drugs - an update. Acta Neurol Scand 2014;130(4):234-8. PMID 25040242
- 183
- Van Dyke DC, Hodge SE, Heide F, Hill LR. Family studies in fetal phenytoin exposure. J Pediatr 1988;113:301-6. PMID 3397793
- 184
- Veiby G, Daltveit AK, Engelsen BA, Gilhus NE. Fetal growth restriction and birth defects with newer and older antiepileptic drugs during pregnancy. J Neurol 2014;261:579-88. PMID 24449062
- 185
- Velez-Ruiz NJ, Meador KJ. Neurodevelopmental effects of fetal antiepileptic drug exposure. Drug Saf 2015;38(3):271-8. PMID 25693658
- 186
- Veroniki AA, Rios P, Cogo E, et al. Comparative safety of antiepileptic drugs for neurological development in children exposed during pregnancy and breast feeding: a systematic review and network meta-analysis. BMJ Open 2017;7(7):e017248. PMID 28729328
- 187
- Videman M, Tokariev A, Stjerna S, Roivainen R, Gaily E, Vanhatalo S. Effects of prenatal antiepileptic drug exposure on newborn brain activity. Epilepsia 2016;57(2):252-62. PMID 26705760
- 188
- Wan X, Wu Y, Zou Q, Yuan B, Huang L, Hu M. Seizure control and adverse outcomes of lamotrigine use during pregnancy: A systematic review and meta-analysis. Epilepsy Behav 2024;157:109924. PMID 38945077
- 189
- Weiner TS, Romanczyk RG, Donovick PJ. Specificity of treatment effects for learning disabilities in a boy prenatally exposed to Dilantin. Pediatr Rehabil 1998;2:41-5. PMID 9661711
- 190
- Wells PG, Kim PM, Laposa RR, Nicol CJ, Parman T, Winn LM. Oxidative damage in chemical teratogenesis. Mutat Res 1997;396:65-78. PMID 9434860
- 191
- Wells PG, Zubovits JT, Wong ST, Malinaro LM, Ali S. Modulation of Phenytoin teratogenicity and embryonic covalent binding by acetylsalicylic acid, caffeic acid and alpha-phenyl-N-E-butylnitrone: implications for bioactivation of prostaglandin synthase. Toxicol Appl Pharmacol 1989;97:192-202. PMID 2493687
- 192
- Whelehan A, Delanty N. Therapeutic strategies for treating epilepsy during pregnancy. Expert Opin Pharmacother 2019;20(3):323-32. PMID 30526135
- 193
- Wide K, Winbladh B, Tomson T, Sars-Zimmer K, Berggren E. Psychomotor development and minor anomalies in children exposed to antiepileptic drugs in utero: a prospective population-based study. Dev Med Child Neurol 2000;42(2):87-92. PMID 10698324
- 194
- Williams G, King J, Cunningham M, Stephan M, Kerr B, Hersh JH. Fetal valproate syndrome and autism: additional evidence of an association. Dev Med Child Neurol 2001;43:202-6. PMID 11263692
- 195
- Wilton LV, Shakir S. A postmarketing surveillance study of gabapentin as add-on therapy for 3,100 patients in England. Epilepsia 2002;43:983-92. PMID 12199723
- 196
- Witters I, Van Assche F, Fryns JP. Nuchal edema as the first sign of fetal valproate syndrome. Prenat Diagn 2002;22:834-5. PMID 12224082
- 197
- Wojcik K, Kruk M, Koń B, Słowik A, Bosak M. Treatment patterns in women of childbearing age and pregnant women with epilepsy in Poland between the years 2019 and 2022—A nationwide population-based cohort study. Seizure 2024;115:75-80. PMID 38232647
- 198
- Yalcinkaya C, Tuysuz B, Somay G, Cenani A. Polydactyly and fetal hydantoin syndrome: an additional component of the syndrome. Clin Genet 1997;51:343-5. PMID 9212184
- 199
- Yerby MS. The treatment of epilepsy during pregnancy. In: Wyllie E, editor. The treatment of epilepsy: principles and practice. Baltimore: Williams and Wilkins, 1996:785-98.
- 200
- Yerby MS. Quality of life, epilepsy advances, and the evolving role of anticonvulsants in women with epilepsy. Neurology 2000;55:S21-31. PMID 11001359
- 201
- Yerby MS. Teratogenicity of anticonvulsant medication. In: Pellock JM, Dodson WE, Bourgeois BF, editors. Pediatric Epilepsy: Diagnosis and Therapy. 2nd ed. New York: Demos Medical Publishing Co, 2001:357-72.
- 202
- Yerby MS, Collins SD. Teratogenicity of antiepileptic drugs. In: Wyllie E, editor. The treatment of epilepsy: principles and practice. Baltimore: Williams and Wilkins, 1997:785-98.
- 203
- Zackai EH, Mellman WJ, Neiderer B, Hanson JW. The fetal trimethadione syndrome. J Pediatr 1975;87:280-4. PMID 50427
Contributors
All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.
Author
-
Mary Dunbar MD MSc FRCPC
Dr. Dunbar of University of Calgary has no relevant relationships to disclose.
See Profile
Editor
-
Harvey B Sarnat MS MD FRCPC
Dr. Sarnat of the University of Calgary has no relevant financial relationships to disclose.
See Profile
Former Authors
- Marcio A Sotero de Menezes MD
- John B Bodensteiner MD
- Laura Flores-Sarnat MD
- Yu-tze Ng MD
- C P Panayiotopoulos MD PhD
Patient Profile
- Age range of presentation
-
- 0 to 23 months
- Sex preponderance
-
- male=female
- Heredity
-
- heredity may be a factor
- Population groups selectively affected
-
- none selectively affected
- Occupation groups selectively affected
-
- none selectively affected
ICD & OMIM codes
- ICD-10
-
- Congenital malformations, deformations and chromosomal abnormalities: Q00-Q99
- Fetal hydantoin syndrome: Q86.1
- Pregnancy-related condition, unspecified: O26.9
- ICD-11
-
- Fetal hydantoin syndrome: LD2F.01
- Other specified multiple developmental anomalies or syndromes: LD2Y
This is an article preview.
Start a Free Account
to access the full version.
-
Nearly 3,000 illustrations, including video clips of neurologic disorders.
-
Every article is reviewed by our esteemed Editorial Board for accuracy and currency.
-
Full spectrum of neurology in 1,200 comprehensive articles.
-
Listen to MedLink on the go with Audio versions of each article.
Questions or Comment?
MedLink®, LLC
3525 Del Mar Heights Rd, Ste 304
San Diego, CA 92130-2122
Toll Free (U.S. + Canada): 800-452-2400
US Number: +1-619-640-4660
Support: service@medlink.com
Editor: editor@medlink.com
ISSN: 2831-9125
Also in This Category
-
-
Developmental Malformations
Cerebro-oculo-facio-skeletal syndrome
Nov. 22, 2024
-
Developmental Malformations
Schizencephaly
Oct. 13, 2024
-
Developmental Malformations
Rhombencephalosynapsis
Oct. 06, 2024
-
Developmental Malformations
Malformations of the brain
Sep. 28, 2024
-
Developmental Malformations
Von Hippel-Lindau disease
Sep. 28, 2024
-
Developmental Malformations
Vein of Galen malformations
Sep. 22, 2024
-
Developmental Malformations
Mobius syndrome
Sep. 20, 2024