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Objective: To assess the safety of the newer antiepileptic drugs (AEDs) during pregnancy., Methods: The study population was pregnant women who enrolled in the North American AED Pregnancy Registry between 1997 and 2011. Data on AED use and maternal characteristics were collected through phone interviews at enrollment, at 7 months' gestation, and postpartum. Malformations were confirmed by medical records. The risk of major malformations was calculated among infants exposed to specific AEDs in monotherapy during the first trimester of pregnancy and among an unexposed group. Risk ratios (RRs) and 95% confidence intervals (CIs) were estimated with logistic regression., Results: The risk of major malformations was 9.3% (30 of 323) for valproate, 5.5% (11 of 199) for phenobarbital, 4.2% (15 of 359) for topiramate, 3.0% (31 of 1.033) for carbamazepine, 2.9% (12 of 416) for phenytoin, 2.4% (11 of 450) for levetiracetam, and 2.0% (31 of 1,562) for lamotrigine. Compared with lamotrigine, the RR was 5.1 (95% CI 3.0-8.5) for valproate, 2.9 (1.4-5.8) for phenobarbital, and 2.2 (1.2-4.0) for topiramate. The proportion of women with epilepsy who had seizures during pregnancy ranged from 23% for valproate to 31% for lamotrigine. Valproate was associated with a higher risk of neural tube defects, hypospadias, cardiac defects, and oral clefts and phenobarbital with a higher risk of cardiac defects and oral clefts; 5 infants exposed to topiramate (1.4%) had a cleft lip., Conclusions: AEDs such as valproate and phenobarbital were associated with a higher risk of major malformations than newer AEDs such as lamotrigine and levetiracetam. Topiramate was associated with an increased risk of cleft lip compared with that of a reference population.

Objective: To reassess the evidence for management issues related to the care of women with epilepsy (WWE) during pregnancy, including preconceptional folic acid use, prenatal vitamin K use, risk of hemorrhagic disease of the newborn, clinical implications of placental and breast milk transfer of antiepileptic drugs (AEDs), risks of breastfeeding, and change in AED levels during pregnancy., Methods: A 20-member committee evaluated the available evidence based on a structured literature review and classification of relevant articles published between 1985 and October 2007., Results: Preconceptional folic acid supplementation is possibly effective in preventing major congenital malformations in the newborns of WWE taking AEDs. There is inadequate evidence to determine if the newborns of WWE taking AEDs have a substantially increased risk of hemorrhagic complications. Primidone and levetiracetam probably transfer into breast milk in amounts that may be clinically important. Valproate, phenobarbital, phenytoin, and carbamazepine probably are not transferred into breast milk in clinically important amounts. Pregnancy probably causes an increase in the clearance and a decrease in the concentration of lamotrigine, phenytoin, and to a lesser extent carbamazepine, and possibly decreases the level of levetiracetam and the active oxcarbazepine metabolite, the monohydroxy derivative., Recommendations: Supplementing women with epilepsy with at least 0.4 mg of folic acid before they become pregnant may be considered (Level C). Monitoring of lamotrigine, carbamazepine, and phenytoin levels during pregnancy should be considered (Level B) and monitoring of levetiracetam and oxcarbazepine (as monohydroxy derivative) levels may be considered (Level C). A paucity of evidence limited the strength of many recommendations.

Objective: To reassess the evidence for management issues related to the care of women with epilepsy (WWE) during pregnancy., Methods: Systematic review of relevant articles published between January 1985 and June 2007., Results: It is highly probable that intrauterine first-trimester valproate (VPA) exposure has higher risk of major congenital malformations (MCMs) compared to carbamazepine and possible compared to phenytoin or lamotrigine. Compared to untreated WWE, it is probable that VPA as part of polytherapy and possible that VPA as monotherapy contribute to the development of MCMs. It is probable that antiepileptic drug (AED) polytherapy as compared to monotherapy regimens contributes to the development of MCMs and to reduced cognitive outcomes. For monotherapy, intrauterine exposure to VPA probably reduces cognitive outcomes. Further, monotherapy exposure to phenytoin or phenobarbital possibly reduces cognitive outcomes. Neonates of WWE taking AEDs probably have an increased risk of being small for gestational age and possibly have an increased risk of a 1-minute Apgar score of <7., Recommendations: If possible, avoidance of valproate (VPA) and antiepileptic drug (AED) polytherapy during the first trimester of pregnancy should be considered to decrease the risk of major congenital malformations (Level B). If possible, avoidance of VPA and AED polytherapy throughout pregnancy should be considered to prevent reduced cognitive outcomes (Level B). If possible, avoidance of phenytoin and phenobarbital during pregnancy may be considered to prevent reduced cognitive outcomes (Level C). Pregnancy risk stratification should reflect that the offspring of women with epilepsy taking AEDs are probably at increased risk for being small for gestational age (Level B) and possibly at increased risk of 1-minute Apgar scores of <7 (Level C).

A committee assembled by the American Academy of Neurology (AAN) reassessed the evidence related to the care of women with epilepsy (WWE) during pregnancy, including preconceptional folic acid and prenatal vitamin K use and the clinical implications of placental and breast-milk transfer of antiepileptic drugs (AEDs). The committee evaluated the available evidence based on a structured literature review and classification of relevant articles. Preconceptional folic acid supplementation is possibly effective in preventing major congenital malformations in the newborns of WWE taking AEDs. There is inadequate evidence to determine if the newborns of WWE taking AEDs have a substantially increased risk of hemorrhagic complications. Primidone and levetiracetam probably transfer into breast milk in clinically important amounts. Valproate, phenobarbital, phenytoin, and carbamazepine probably are not transferred into breast milk in clinically important amounts. Pregnancy probably causes an increase in the clearance and a decrease in the concentrations of lamotrigine, phenytoin, and, to a lesser extent carbamazepine, and possibly decreases the level of levetiracetam and the active oxcarbazepine metabolite, the monohydroxy derivative (MHD). Supplementing WWE with at least 0.4 mg of folic acid before pregnancy may be considered. Monitoring of lamotrigine, carbamazepine, and phenytoin levels during pregnancy should be considered, and monitoring of levetiracetam and oxcarbazepine (as MHD) levels may be considered. A paucity of evidence limited the strength of many recommendations.

A committee assembled by the American Academy of Neurology (AAN) reassessed the evidence related to the care of women with epilepsy (WWE) during pregnancy, including antiepileptic drug (AED) teratogenicity and adverse perinatal outcomes. It is highly probable that intrauterine first-trimester valproate (VPA) exposure has higher risk of major congenital malformations (MCMs) compared to carbamazepine (CBZ), and possibly compared to phenytoin (PHT) or lamotrigine (LTG). It is probable that VPA as part of polytherapy and possible that VPA as monotherapy contribute to the development of MCMs. AED polytherapy probably contributes to the development of MCMs and reduced cognitive outcomes compared to monotherapy. Intrauterine exposure to VPA monotherapy probably reduces cognitive outcomes and monotherapy exposure to PHT or phenobarbital (PB) possibly reduces cognitive outcomes. Neonates of WWE taking AEDs probably have an increased risk of being small for gestational age and possibly have an increased risk of a 1-minute Apgar score of <7. If possible, avoidance of VPA and AED polytherapy during the first trimester of pregnancy should be considered to decrease the risk of MCMs. If possible, avoidance of VPA and AED polytherapy throughout pregnancy should be considered and avoidance of PHT and PB throughout pregnancy may be considered to prevent reduced cognitive outcomes.

Background: Pregnancy registries for women taking anticonvulsant drugs have been developed to determine more efficiently the fetal risks of each drug. A total of 722 drug-exposed pregnancies are needed to identify a sevenfold increase in the rate of occurrence of a specific abnormality, such as spina bifida, with a frequency of 1 in 1,000., Methods: The infants with major malformations born to the 791 women who had taken lamotrigine as monotherapy and had enrolled in the North American AED Pregnancy Registry were identified. Medical records were obtained from the affected infants' doctors. A total of 107 of the 791 infants or pregnancies were excluded., Results: A total of 16 (2.3%) of 684 infants exposed to lamotrigine had major malformations that were identified at birth. Five infants (7.3/1,000) had oral clefts: isolated cleft palate (3), isolated cleft lip (1), and cleft lip and palate (1). The rate among the lamotrigine-exposed infants showed a 10.4-fold increase (95% CI: 4.3-24.9) in comparison to 206,224 unexposed infants surveyed at birth at Brigham and Women's Hospital in Boston, where the prevalence of isolated oral clefts was 0.7/1,000. A comparison was made also to 1,623 infants exposed to lamotrigine, as monotherapy, who had enrolled in five other registries. There were four infants with oral clefts: prevalence 2.5/1,000 (RR: 3.8, 95% CI: 1.4-10.0)., Conclusions: The infant exposed in the first trimester of pregnancy to the anticonvulsant drug lamotrigine has an increased risk to have an isolated cleft palate or cleft lip deformity.

The use of antiepileptic drugs (AEDs) in pregnancy is associated with an increased risk of fetal malformations. Although it is known that AEDs may differ with respect to the type of malformations they can induce, earlier studies have generally lacked the power to demonstrate differences between AEDs in their overall teratogenic potential. Furthermore, there is an urgent need to assess the clinical teratogenic potential of the newer-generation AEDs. Epilepsy and pregnancy registries have been established to provide such information, which is essential for the rational management of women with epilepsy with childbearing potential. The registries also provide opportunities for additional studies of seizures observed during pregnancy and labor and, with the enrolled woman's consent, for separate studies on cognitive outcomes and pharmacogenetics. Although most are prospective, the existing registries vary somewhat in design, which needs to be considered when their results are compared. Some registries are driven by pharmaceutical companies (often compelled by national or international drug licensing agencies) and provide data on pregnancy outcome related to the sponsor's own product. Others are organized by independent research groups and are potentially more useful in that they publish comparative data. This review provides a critical discussion and comparison of important methodological aspects of AED and pregnancy registries along with a summary of results published so far.

Objective: To determine the rate of occurrence of major malformations in infants whose mothers had taken the drug valproic acid (VPA) as monotherapy during the first trimester of pregnancy and had enrolled in the North American Antiepileptic Drug Pregnancy Registry., Methods: Data were collected from pregnant women throughout the United States and Canada through telephone-based interviews. Each woman was interviewed at enrollment, at 7 months' gestation, and postpartum. With her written permission, the medical records of each mother and her infant were obtained. The major malformations tabulated were those identified at or before 5 days of age. The prevalence of congenital malformations among offspring of monotherapy VPA-exposed women was compared with that among infants of women exposed to all other antiepileptic drugs (internal comparison group) and with that among newborns in the Active Malformations Surveillance Program at Brigham and Women's Hospital (external comparison group)., Results: Sixteen affected cases were identified among 149 VPA-exposed women (proportion: 10.7%; 95% CI: 6.3 to 16.9%). The prevalence in the internal comparison group was 2.9% (95% CI: 2.0 to 4.1%; odds ratio: 4.0, 95% CI: 2.1 to 7.4; p < 0.001). Assuming a 1.62% prevalence in the external comparison group, the relative risk of having an affected offspring for VPA-exposed women was 7.3 (95% CI: 4.4 to 12.2; p < 0.001)., Conclusion: Maternal exposure to valproic acid during the first trimester of pregnancy significantly increased the risk of major malformations.

Objective: To identify and quantify the craniofacial effects from prenatal exposure to phenytoin monotherapy and polytherapy using cephalometric, hand-wrist, and panoramic radiographs and to determine if such deviations persist with age., Design: Craniofacial structures of 28 anticonvulsant-exposed individuals were evaluated using 20 landmarks in lateral cephalometric radiographs and 19 landmarks in frontal cephalometric radiographs. Skeletal maturity was assessed using hand-wrist radiographs. Dental maturity and the presence of dental anomalies were evaluated using panoramic radiographs. Eleven individuals were re-evaluated 7 years later, on average, to determine the persistence of any measured deviations., Setting and Sample Population: Department of Growth and Development, Harvard School of Dental Medicine and Massachusetts General Hospital. Patients were recruited from several sources., Outcome Measure: The evaluated dimensions included linear, angular, and proportional measures., Results: The most common deviations were decreased height and length of the maxilla, decreased length of the posterior cranial base, length of the mandible, cranial width and level of the cribriform plate, and a decrease in the Wits Appraisal assessment. The deviations were more significant in the polytherapy-exposed individuals than in the monotherapyexposed individuals. These deviations, especially in the maxilla, persisted with age as revealed in a re-evaluation of 11 individuals., Conclusion: The craniofacial skeletal findings among individuals exposed in utero to phenytoin monotherapy or phenytoin polytherapy, when considered in aggregate, suggest a mild pattern of maxillary hypoplasia that becomes more pronounced with age.

Background: The frequency of major malformations, growth retardation, and hypoplasia of the midface and fingers, known as the anticonvulsant embryopathy, is increased in infants exposed to anticonvulsant drugs in utero. However, whether the abnormalities are caused by the maternal epilepsy itself or by exposure to anticonvulsant drugs is not known., Methods: We screened 128,049 pregnant women at delivery to identify three groups of infants: those exposed to anticonvulsant drugs, those unexposed to anticonvulsant drugs but with a maternal history of seizures, and those unexposed to anticonvulsant drugs with no maternal history of seizures (control group). The infants were examined systematically for the presence of major malformations, signs of hypoplasia of the midface and fingers, microcephaly, and small body size., Results: The combined frequency of anticonvulsant embryopathy was higher in 223 infants exposed to one anticonvulsant drug than in 508 control infants (20.6 percent vs. 8.5 percent; odds ratio, 2.8; 95 percent confidence interval, 1.1 to 9.7). The frequency was also higher in 93 infants exposed to two or more anticonvulsant drugs than in the controls (28.0 percent vs. 8.5 percent; odds ratio, 4.2; 95 percent confidence interval, 1.1 to 5.1). The 98 infants whose mothers had a history of epilepsy but took no anticonvulsant drugs during the pregnancy did not have a higher frequency of those abnormalities than the control infants., Conclusions: A distinctive pattern of physical abnormalities in infants of mothers with epilepsy is associated with the use of anticonvulsant drugs during pregnancy, rather than with epilepsy itself.

Background: We report on inter-rater agreement in the assessment of newborn infants with respect to a range of minor physical features in a cohort study of the fetal effects of maternal anticonvulsant use during pregnancy., Methods: Infants from three groups (exposed to anticonvulsants, seizure history but no medication exposure, and unexposed controls) were examined by both a pediatrician/teratologist, who was blinded with respect to the mother's exposure status, and an unblinded research assistant. Agreement on assessments for selected anomalies associated with anticonvulsant therapy was measured by kappa-statistics, as well as by more sensitive log-linear modeling techniques, which allow examination of possible covariate effects on the strength of agreement. Although the physician and research assistant agreed on a high proportion of cases (80-90%), kappa values were modest (0.2-0. 5), partly because of the low prevalence of the anomalies considered. To explore how agreement varies within subgroups, we used recently developed methods for studying agreement based on log-linear models., Results: Log-linear modeling indicated that there was substantial variation in pattern of agreement between different individual research assistants but that other factors (e.g., exposure category, sex, and birthweight) did not appear to be related to agreement. Our results suggest that research assistants with more experience showed the highest degree of agreement with the physicians., Conclusions: Our results have implications for both clinical practice and epidemiologic research and underline the importance of thorough training of staff in the definitions to be used and also the need for multiple independent assessments of these subtle anomalies., (Copyright 2000 Wiley-Liss, Inc.)

The hypothesis tested was that digit anomalies among individuals exposed in utero to antiepileptic drugs (AED) are best identified by a systematic search, including radiographs and dermatoglyphics, rather than relying only on visual inspection. A systematic search was made for five types of digit abnormalities in 46 AED-exposed individuals ages 5-29 years in comparison with controls: visible anomalies, size of fingernails, dermal ridge patterns, length of metacarpals and phalanges, and qualitative changes in the distal phalanges. Among the AED-exposed, nail size was not decreased. However, there was a 10.8% frequency of digit anomalies, a 12% frequency of three or more arch patterns, and significant shortening and qualitative changes in the distal phalanges, all of which are consistent with the fetal effects of AED. Among the 42 individuals who underwent all evaluations, 14.3% had two or more of these abnormalities, most of which would not be identified by clinical inspection. This frequency is much higher in these AED-exposed individuals than in the general population. Radiographs in 13 individuals over a period of several years showed that the changes in the phalanges and metacarpals persisted., (Copyright 2000 Wiley-Liss, Inc.)

Prenatal exposure to anticonvulsant medication has been shown to cause craniofacial dysmorphology, prenatal growth retardation, hypoplastic nails and phalanges, and visceral abnormalities. In this study we examined maxillary and mandibular stone dental casts (45) and panoramic radiographs (39) from 45 individuals with ages 4.5 to 22.0 years for changes in mesiodistal crown size of deciduous and permanent teeth, and the presence of dental anomalies. These individuals had been exposed prenatally to antiepileptic drugs (AEDs). Mesiodistal crown diameters were measured from the dental casts and converted into standard scores (Z), using published normative data from the University of Michigan Longitudinal Craniofacial Growth Series. A significant increase in mesiodistal crown dimensions of the posterior maxillary teeth was observed, specifically in primary molars and their permanent premolar successors, as well as permanent molars. Changes in tooth size were more common in females than in males. Dental maturity, assessed using the panoramic radiographs, was equal to chronologic age. An increased frequency of hypodontia was the only notable dental anomaly.

Previous animal research has suggested that the phenytoin arene oxide metabolite is teratogenic in acute studies and that the fetal effects were increased after injecting an inhibitor of microsomal epoxide hydrolase (mEH) (Martz et al., Pharmacol Exp Ther 203:231-239, 1977, Barcellona et al., Teratog Carcinog Mutagen 7:159-168, 1987). We have studied the effects of chronic oral phenytoin exposure in utero and the mEH inhibitor trichloropropene oxide (TCPO) on the prenatal growth and development of an inbred mouse strain with a low incidence of spontaneous oral clefting (C57BL/6J). Chronic daily gastric gavage of phenytoin produced a plasma level (mean 10.7 micrograms/ml on gestation Day 8) within the range recommended to prevent epilepsy in humans; this did not produce an increase in oral clefting or ventricular septal defects in the exposed C57BL/6J pups. It did produce a significant delay in prenatal growth and development, including phalangeal ossification. However, except for percentage resorptions/implantation, there was no synergism between phenytoin and TCPO in contrast to the finding reported by Martz et al. in Swiss mice. This issue was also assessed in a test of the fetal effect of phenytoin injected with TCPO, as had been done by Martz et al. There were no oral clefts or ventricular septal defects or a difference (P > 0.05) in prenatal growth and development in these C57BL/6J pups compared to the chronic gastric phenytoin plus TCPO group. This suggests either that differences in the genotypes of Swiss and C57BL/6J mice may be a contributing factor or that other teratogenic mechanisms were involved.

The purpose of this paper is to demonstrate the application of generalized estimating equations to assess an exposure effect using multiple birth outcomes. This multivariate approach provides the flexibility of regression modeling and improved power, as compared to series of univariate analyses or collapsing the multiple end-points to a single indicator of affectedness. Motivating the discussion will be a large cohort study designed to assess the effects of anticonvulsant medications on a variety of birth outcomes, including major malformations, and growth and weight parameters, as well as a broad spectrum of minor physical anomalies. Because the study is still in progress, the aim here is not to present a definitive analysis, but to present and describe the application of these recently developed statistical methods to analyze studies with multiple outcomes. For simplicity, we will focus on the control and drug-exposed groups only from that study (ignoring the seizure history group), and we will concentrate on an analysis of minor physical anomalies.

The basis for the apparent teratogenicity of maternal epilepsy is controversial. Is the critical factor the anticonvulsant drugs taken by the pregnant woman, or the genes which cause the mother's epilepsy? We describe a study design developed to assess these competing theories in a cohort study of newborn infants. We show the feasibility of ascertaining exposed and unexposed infants at several birthing hospitals in one urban area. Between 1986 and 1988, we identified 180 drug-exposed and 218 epilepsy-history infants among 49,403 infants. The rate of exposure to seizure medication was 0.36% and of maternal history of epilepsy was 0.44%. A significant number of infants could not be evaluated because they were missed, ineligible, or either the doctor, nurse or parent refused to participate. Overall, there was a significant increase in major malformations, microcephaly or growth retardation among the drug-exposed infants in comparison to both the epilepsy-history and the unexposed infants. The types of epilepsy and the apparent etiology were the same among women who took anticonvulsants and women with a history of epilepsy but no anti-convulsants during pregnancy. This study must be extended to include a sufficient number of infants exposed to each commonly used drug as monotherapy to allow for a comparison of the effect of each drug on pregnancy outcomes; to provide a comparison of infants whose mothers had a strong family history of epilepsy with infants whose mothers had trauma-induced epilepsy; and to assess the possible impact of the severity of the mothers' disease on the infants.

At least two maternal conditions have been shown to be associated with an increased risk for the occurrence of anencephaly, spina bifida and encephalocele: insulin-dependent diabetes mellitus in the mother and maternal epilepsy for which anticonvulsant treatment is being used. Of 147 infants born at the Brigham and Women's Hospital with anencephaly, spina bifida and encephalocele among 123,489 live-born, still-born and elective terminations surveyed, 7.5% were infants of insulin-dependent diabetics and 0.7% had been exposed to anticonvulsants in utero. In addition to these proven causal associations neural tube defects have been postulated by some, but not all, studies as being more common among infants exposed to hyperthermia in utero and to drugs used to induce ovulation.

Twenty phenytoin exposed children between 48 and 99 months of age had an evaluation of behavior and intelligence by a single examiner who was unaware of exposure status. The controls were 98 children identified at birth as having three or more minor anomalies. None of the children evaluated were mentally retarded. In both, a case-by-case comparison and a comparison of the two entire groups, the phenytoin-exposed children had significantly lower scores for both Performance IQ (PIQ), Full Scale IQ (FSIQ), and Visual Motor Integration Test (VMIT). Similar abnormalities have been found in studies of animals exposed to phenytoin in utero. These results suggest that the teratogenic effects of phenytoin may include an effect on cognitive function.

It has been widely reported that some children exposed to anticonvulsants in utero have a characteristic pattern of craniofacial anomalies including a broad, low nasal bridge with a short upturned nose, wide mouth, low set ears, epicanthal folds, and ocular hypertelorism, while others show no evidence of craniofacial abnormalities. The purpose of this paper is to define the craniofacial features in nine exposed children using anthropometric measurements and frontal and lateral cephalometric radiographs. These children were identified at birth as part of a prospective study of infants exposed to anticonvulsants at the Boston Hospital for Women (now part of the Brigham and Women's Hospital). At birth, none of these infants had any major malformations; at 4 to 10 years of age, none demonstrated any growth deficiency or mental deficiency, and all external craniofacial measurements were within the normal range. However, cephalometric analyses demonstrated a pattern of reduced bony interorbital distance, maxillary size, mandibular length, cranial base and skull size, and a reduction in nose dimensions when compared to data of normal populations. This study demonstrates the inadequacy of external measurements in determining the details of underlying craniofacial architecture. The data also suggest that a subtle craniofacial change occurs in exposed children which is characterized by a decrease in bony interorbital distance and the size of the cranial base and maxilla with concomitant decreases in nose and mandibular dimensions.