Original Article
The Teratogenicity of Anticonvulsant Drugs
N Engl J Med 2001; 344:1132-1138April 12, 2001
- Abstract
Background
The frequency of major malformations, growth retardation, and hypoplasia of the midface and fingers, known as 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.
Media in This Article
Table 1
Physical Abnormalities Not Considered to Be Major Malformations.Table 2
Enrollment of Infants Born to Women Who Had Taken Anticonvulsant Drugs during Pregnancy, Infants Born to Women Who Had a History of Seizures but Had Not Taken Anticonvulsant Drugs, and Control Infants.Article Activity
- Article
Anticonvulsant drugs1 taken by pregnant women to prevent seizures are among the most common causes of potential harm to the fetus. In the 1970s and 1980s, the anticonvulsant drugs used most frequently to prevent seizures — phenobarbital, phenytoin, and carbamazepine — were found to cause major malformations, microcephaly, growth retardation, and distinctive minor abnormalities of the face and fingers in infants exposed to them during pregnancy.2-8
However, medical textbooks9-11 have suggested that these defects are caused by other factors, such as genetic abnormalities that cause the mother's epilepsy and are inherited by the fetus.12 To elucidate this issue, we conducted a cohort study of three groups of infants: those whose mothers took anticonvulsant drugs during the pregnancy, those whose mothers had epilepsy but took no anticonvulsant drugs during the pregnancy, and those whose mothers had no history of epilepsy and took no anticonvulsant drugs during the pregnancy (the control group).
Methods
Study Design
This study was conducted from 1986 to 1993 at five maternity hospitals in the Boston area: Brigham and Women's Hospital, Beth Israel Hospital, St. Margaret's Hospital, St. Elizabeth's Hospital, and Newton–Wellesley Hospital. Potential subjects were identified in the labor and delivery suites by nurses who asked the women if they had taken any medication for seizures during the pregnancy and if they had ever had a seizure.13 Women who answered yes to either question were then interviewed, with the approval of their obstetricians and nurses, to inform them about the study and to determine whether they qualified for inclusion. Women were excluded if they did not speak English, had a multiple-gestation pregnancy, or had another potentially teratogenic factor, such as type 1 diabetes mellitus. If the women qualified, they were asked to enroll and to give written informed consent. The study protocol was reviewed and approved annually by the institutional review board at each participating hospital. If a mother chose not to enroll, the results of the pediatrician's examination of her infant were reviewed to obtain birth weight, length, head circumference, and the presence or absence of any major malformations; these infants were not examined by a study physician.
The women enrolled in the study were asked to provide demographic data and to complete questionnaires administered by a research assistant to determine why they were taking anticonvulsant drugs (e.g., epilepsy or bipolar disorder); the dosage of each anticonvulsant drug; the characteristics of the seizures, their frequency during the pregnancy, and whether the women lost consciousness during seizures; and the family history with respect to epilepsy. With the written authorization of each woman, the results of all diagnostic tests (e.g., magnetic resonance images, electroencephalograms, and skull radiographs) and the dosages and serum concentrations of any anticonvulsant drugs were obtained. The responses to the questions and the results of the diagnostic evaluations of the women were reviewed by the study epileptologist to determine the type of epilepsy and its apparent cause with the use of an international classification of epilepsy.14
For each of the infants born to the enrolled women (i.e., either an infant exposed to anticonvulsant drugs or an infant not exposed to anticonvulsant drugs whose mother reported having had epilepsy), a control was recruited from the 10 infants born closest in time to him or her. Selecting randomly from this group of infants, we approached each mother until one was enrolled for each index infant. The same questionnaire was administered to the mothers of the control infants, with a separate consent form.
Examination of the Infants
The infants in all three groups were examined by a study physician; this physician was unaware of the exposure status of the infant during 93 percent of the examinations. The protocol for the physical examination listed 53 minor physical features to be recorded as present or absent. The dermal-ridge patterns (i.e., loops, whorls, and arches) on all fingers were recorded with magnification by otoscope, and 29 measurements were made, including the circumference and bitemporal width of the head, the inner canthal distance, and the length of the nose and upper lip (measured with a plastic ruler, a tape measure scored in millimeters, or sliding calipers; Seritex, Carlstadt, N.J.). The nose was measured from the lowest point in the depression of the bridge of the nose to the level of the alae nasi. The upper lip was measured from the base of the nasal septum to the upper edge of the vermilion border.
The outcomes of interest were major malformations, microcephaly, growth retardation, and hypoplasia of the midface and fingers. Major malformations were defined as structural abnormalities with surgical, medical, or cosmetic importance (identified during the first five days of life). Features that were not classified as major malformations are listed in Table 1Table 1
Physical Abnormalities Not Considered to Be Major Malformations..The analysis included only singleton infants, because multiple births are associated with an increased risk of malformations. Microcephaly and growth retardation were defined respectively as head circumference and length or weight more than 2 SD below the mean value for infants of the same race, sex, and gestational age.16 Normal values for black infants were adjusted to those of the previous week of gestation for white infants.17 Hypoplasia of the midface (in singleton infants born at 37 weeks of gestation or later) was defined as the presence of at least two of the following three features: a short nose, a long upper lip, and either telecanthus or a broad bridge of the nose. These features were considered to be present if the measurements were more than 1 SD above or below the mean values for the control infants. Hypoplasia of the fingers was defined as marked stiffness of the distal interphalangeal joint in 1 or more fingers or 6 or more arch patterns among the 10 dermal-ridge patterns. In a previous study,18 5 percent of the dermal-ridge patterns were arches among children who were not exposed to anticonvulsant drugs.
Statistical Analysis
Individual logistic-regression analyses were conducted for each of the main outcomes. The correlation between outcome and each category of exposure (no maternal history of seizure or exposure to drugs, maternal history of seizures without exposure to drugs, exposure to one drug, exposure to more than one drug, and exposure to all drugs) was adjusted for maternal cigarette smoking (half a pack or more per day); ingestion of alcohol (14.8 ml [0.5 oz] on two or more occasions per week); self-reported use of cocaine or other illicit drugs; loss of consciousness during a seizure, presence of a febrile illness with a temperature above 39°C (102°F) for 48 hours, or presence of an important medical illness (e.g., multiple sclerosis); maternal or paternal head size or height more than 2 SD below the mean; or the presence of a major malformation in a first-degree relative.
We used two logistic-regression techniques to evaluate the interrelated outcomes: collapsed logistic-regression analyses relating the probability of at least one of the outcomes to the category of exposure, and generalized estimating equations assessing a global effect of anticonvulsant drugs on each set of outcomes after adjustment for confounders and for correlation among outcomes measured in the same subject.19
Results
By screening 128,049 women in labor and delivery suites, we identified 509 who had taken one or more anticonvulsant drugs during pregnancy, 386 of whom had taken one drug and 123 of whom had taken two or more drugs (30 women who had switched from one drug to another were included in the latter group) (Table 2Table 2
Enrollment of Infants Born to Women Who Had Taken Anticonvulsant Drugs during Pregnancy, Infants Born to Women Who Had a History of Seizures but Had Not Taken Anticonvulsant Drugs, and Control Infants.). Among the 386 women who had taken only one anticonvulsant drug, 35 had taken the drug for medical conditions other than epilepsy. A total of 606 other women reported a history of seizures but had not taken an anticonvulsant drug during the pregnancy. We identified 1186 women who had not been exposed to anticonvulsant drugs during pregnancy and had no history of seizures.The number of subjects in each group was reduced by application of the exclusion criteria, refusals to participate, and missed examinations (Table 2). Fewer women who had taken an anticonvulsant drug declined to participate (17.0 percent [73 of 430]) than did the women with a history of seizures who had not taken an anticonvulsant drug (34.1 percent [119 of 349]) and the women in the control group (48.4 percent). The history of seizures in the 98 remaining women in the group who had a history of epilepsy but who had not taken an anticonvulsant drug during pregnancy was confirmed by a review of the medical records or electroencephalograms for 90 percent (records for 84 percent, electroencephalograms for 81 percent). Ninety-four percent of these women had taken an anticonvulsant drug at some time in their lives (73 percent for two or more years) before becoming pregnant with the infant in this study. The causes and types of seizures in the two groups are shown in Table 3Table 3
Apparent Cause and Type of Seizures in All Enrolled Women with Epilepsy Whose Singleton Infants Were Examined..Outcomes in Enrolled Infants
We examined singleton infants born to 223 of the 386 women who had taken one anticonvulsant drug, 93 of the 123 women who had taken two or more anticonvulsant drugs, 98 of the 98 women with a history of seizures who had not taken anticonvulsant drugs, and 508 of the 1186 women in the control group (Table 4Table 4
Frequency of Selected Outcomes in Examined Singleton Infants.). Among the women who had taken one anticonvulsant drug, 87 had taken phenytoin, 64 phenobarbital, 58 carbamazepine, 6 valproic acid, 6 clonazepam, 1 diazepam, and 1 lorazepam.There were no significant differences between the infants of mothers with a history of seizures who had not taken anticonvulsant drugs and the control infants, either in terms of individual outcomes or overall. The groups of infants exposed to either one anticonvulsant drug or two or more drugs had a higher frequency of all of the features of the embryopathy associated with exposure to anticonvulsants (i.e., major malformations, microcephaly, growth retardation, and hypoplasia of the midface and fingers) than did the other infants (20.6 percent of infants exposed to one drug and 28.0 percent of infants exposed to two or more anticonvulsant drugs had one or more of these abnormalities, as compared with 8.5 percent of control infants) (Table 4). The frequency of most outcomes was increased in the 87 infants exposed to phenytoin alone and the 64 infants exposed to phenobarbital alone, as compared with control infants. The frequency of major malformations, microcephaly, and growth retardation, but not hypoplasia of the midface and fingers, was higher in the 58 infants exposed to carbamazepine than in the 508 control infants.
Most of the major malformations identified were types of abnormalities that also occur in infants whose mothers have not taken an anticonvulsant drug (Table 5Table 5
Major Malformations Identified in Singleton Infants Enrolled and Examined by Study Physicians.). However, two of the major malformations are known to be more common in infants exposed to anticonvulsant drugs: marked hypoplasia of the nails plus stiff joints, which is much more common in infants exposed to phenytoin with or without phenobarbital than in unexposed infants,21,22 and lumbosacral spina bifida, which is most common in infants exposed to either carbamazepine or valproic acid.23 Among the infants exposed to one drug, there was no difference in the frequency of the five outcomes between those whose mothers had cryptogenic or familial epilepsy and those whose mothers had epilepsy due to trauma, infection, a tumor, a vascular event, or a congenital anomaly. The frequency of the major outcomes among the 35 infants whose mothers had taken an anticonvulsant drug to treat other conditions, such as manic–depressive disease, was also increased (9.3 percent had major malformations and 25.3 percent had growth retardation or microcephaly). Fifty-three of the 316 women who had taken any anticonvulsant drug reported having had convulsive seizures with whole-body shaking during the pregnancy. Twenty-seven of the 53 women had the convulsive seizures in the first trimester. Two of the 27 infants whose mothers had convulsive seizures in the first trimester had a major malformation (7.4 percent), as compared with 22 of the 281 infants of women who reported other types of seizures (7.8 percent).
Outcomes in Unenrolled Infants
Since not all of the mothers who were approached about enrolling in this study chose to participate, the medical records (i.e., the results of the pediatricians' examinations) of the infants who were eligible but not enrolled were reviewed to determine whether they had a major malformation or growth retardation. This analysis showed that there were no significant differences between infants who were enrolled and examined by the study investigators and infants who were eligible but were not enrolled and examined by study personnel. The 114 eligible, unexamined infants who were exposed to anticonvulsant drugs were somewhat less likely to have a major malformation than the 316 examined infants who were exposed to anticonvulsant drugs (1.8 percent vs. 5.7 percent, P=0.10) and slightly but not significantly more likely to have microcephaly (6.1 percent vs. 3.6 percent, P=0.30) or growth retardation (5.3 percent vs. 4.8 percent, P=0.90). Among the eligible control infants, there were no significant differences between the 508 infants who were enrolled and examined as part of the study and 536 infants who were not enrolled in the frequency of major malformations (1.8 percent vs. 1.7 percent, P=0.90), microcephaly (1.6 percent vs. 2.6 percent, P=0.30), or growth retardation (1.2 percent vs. 1.7 percent, P=5.00). Data were not analyzed for unenrolled infants born to mothers with a history of epilepsy who had not taken an anticonvulsant drug during pregnancy, because we could not confirm the maternal history of epilepsy.
Discussion
We found that infants exposed to a single anticonvulsant drug taken by the mother during pregnancy had a significantly higher frequency of associated abnormalities than control infants, and that infants whose mothers had a history of epilepsy but took no anticonvulsant drugs during pregnancy did not have an increased rate of these abnormalities. This study had several strengths: the examiner, who was almost always unaware of the infants' status regarding exposure to drugs, looked systematically for all of the features of the embryopathy associated with exposure to anticonvulsant drugs in the three groups of infants; the findings were objective12,24-27; and explicit criteria for the inclusion and exclusion of major malformations were used. Since teratogens cause distinctive patterns of abnormalities, the statistical analysis took into account the interrelation of several outcomes.
This study addressed the conflicting interpretations of two previous analyses of the same 104 infants exposed to anticonvulsant drugs.5,28 In those studies, epidemiologists concluded that the mother's epilepsy, not the anticonvulsant drug, was the teratogen.28 By contrast, the clinicians concluded that these infants had the physical features of embryopathy associated with exposure to anticonvulsant drugs.5 The authors of both reports recommended that future studies enroll a group of infants whose mothers had previously had epilepsy but who had taken no anticonvulsant drugs during pregnancy and that these infants be examined for the features of this embryopathy.5,28,29
The identification and recruitment of mothers with a history of epilepsy who had taken no anticonvulsant drugs during the pregnancy was another strength of our study. Such women were recruited in two other recent studies,27,30 which also found no increase in the risk of embryopathy in infants whose mothers had epilepsy but took no anticonvulsant drugs during pregnancy. Other studies12,28,31,32 have reached different conclusions, but there was a risk of misclassification, because the process of classifying the mother's reported epilepsy did not include a personal interview or a review of her medical records.
There is also concern that the mother's seizures themselves could have a harmful effect on the fetus, as suggested in case reports.33 This issue was addressed to a limited extent in our study. The frequency of major malformations was the same in the infants of women taking anticonvulsant drugs who had loss of consciousness during seizures in the first trimester of pregnancy and in infants of women taking anticonvulsant drugs who had other types of seizures. We also found that infants of women who had taken anticonvulsant drugs as treatment for mood disorders, migraine, or pain had an increase in the frequency of embryopathy that was similar to that among infants of women with epilepsy. A limitation of our study is that we did not include pregnancies that were terminated electively after fetal abnormalities associated with anticonvulsant drugs were diagnosed by prenatal screening. We identified additional cases in which the fetus was exposed to anticonvulsant drugs among pregnancies terminated electively at the largest participating hospital, through a separate surveillance program for malformations,34 but we did not include these pregnancies because we could not enroll a comparison group of unexposed fetuses among the other elective terminations.
In previous studies,7,26,27 infants exposed to carbamazepine were considered by clinical inspection to have an increased frequency of hypoplasia of the face and fingers characteristic of the embryopathy associated with exposure to anticonvulsant drugs. This feature was not found in the infants exposed to carbamazepine whom we examined. The difference in the findings can be addressed with more objective methods, such as cephalometric radiography35,36 and dermatoglyphy and radiography of the hands.22 This difference is important, because the hypoplasia of the midface35,36 associated with hypoplasia of the facial bones could be a marker for cognitive dysfunction.37
One would predict that some infants exposed to anticonvulsant drugs have a greater risk of harmful effects than others because of an underlying genetic susceptibility. Such an interrelation between genetic factors and environmental exposure has been suggested in studies of the teratogenicity of maternal cigarette smoking38 and alcohol use.39 In the case of anticonvulsant drugs, a deficiency of the detoxifying enzyme epoxide hydrolase40,41 and an increase in free radicals formed by the anticonvulsant drug42 are two theories of the reason for increased susceptibility. We predict that the correlations identified in this study will be much stronger in the more susceptible subgroup of children exposed to anticonvulsant drugs. Phenytoin, phenobarbital, and carbamazepine are folic acid antagonists, and one postulated mechanism for their teratogenicity has been the induction of folic acid deficiency.43 However, Hernández-Díaz and her associates44 recently reported that when pregnant women taking these anticonvulsant drugs also took a multivitamin supplement that included folic acid, it did not reduce the incidence of cardiovascular or urinary tract abnormalities or oral clefts in their infants.
We conclude that exposure in utero to anticonvulsant drugs is associated with a distinctive pattern of physical abnormalities in infants that are best identified by objective examination. The physical features of infants exposed to various anticonvulsant drugs are not the same. We found no evidence that infants born to women with a history of epilepsy who took no anticonvulsant drugs during pregnancy have an increased risk of the pattern of physical abnormalities associated with exposure to anticonvulsant drugs. The occurrence of such embryopathy was correlated with exposure to anticonvulsant drugs, regardless of the underlying maternal illness being treated.
Supported by a grant (NS 24125) from the National Institutes of Health.
We are indebted to the many families, nurses, and physicians whose cooperation was essential to the success of this project; to Lynn Rosenberg, Sc.D., Barbara R. Pober, M.D., M.P.H., and Martha Werler, Sc.D., for their suggestions about study design; to the research assistants — Jennifer Greene, Catherine Rooks, Meredith Miller, Nancy Goodman, Susan Tan Torres, M.D., and Joan Drury — for their diligence and diplomacy in carrying out this study; and to Ellice Lieberman, M.D., Dr.P.H., for her comments and suggestions on the manuscript.
Source Information
From the Genetics and Teratology Unit, Pediatric Service, Massachusetts General Hospital (L.B.H., E.A.H., K.B.H., A.M.H.); the Department of Biostatistics, Harvard School of Public Health (B.A.C., L.M.R.); and the Department of Neurology, Brigham and Women's Hospital (S.K.) — all in Boston.
Address reprint requests to Dr. Holmes at the Genetics and Teratology Unit, Warren 801, Massachusetts General Hospital, 55 Fruit St., Boston, MA 02114-2696, or at holmes.lewis@mgh.harvard.edu.
- References
References
1
Woodbury DM, Penry JK, Pippenger CE. Antiepileptic drugs. 2nd ed. New York: Raven Press, 1982.
2
Speidel BD ,Meadow SR . Maternal epilepsy and abnormalities of the fetus and the newborn. Lancet 1972;2:839-843
CrossRef | Web of Science | Medline3
Hill RM ,Verniaud WM ,Horning MG ,McCulley LB ,Morgan NF . Infants exposed in utero to antiepileptic drugs: a prospective study. Am J Dis Child 1974;127:645-653
Web of Science | Medline4
Hanson JW ,Smith DW . The fetal hydantoin syndrome. J Pediatr 1975;87:285-290
CrossRef | Web of Science | Medline5
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;89:662-668
CrossRef | Web of Science | Medline6
Seip M . Growth retardation, dysmorphic facies and minor malformations following massive exposure to phenobarbitone in utero. Acta Paediatr Scand 1976;65:617-621
CrossRef | Web of Science | Medline7
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;320:1661-1666
Full Text | Web of Science | Medline8
Lindhout D ,Hoppener RJEA ,Meinardi H . Teratogenicity of antiepileptic drug combinations with special emphasis on epoxidation (of carbamazepine). Epilepsia 1984;25:77-83
CrossRef | Web of Science | Medline9
Bennett JC, Plum F, eds. Cecil textbook of medicine. 20th ed. Vol. 2. Philadelphia: W.B. Saunders, 1995:2123.
10
Barron WM, Lindheimer MD, eds. Medical disorders during pregnancy. 2nd ed. St. Louis: Mosby–Year Book, 1994:443.
11
Dalessio DJ . Seizure disorders and pregnancy. N Engl J Med 1985;312:559-563
Full Text | Web of Science | Medline12
Gaily E ,Granstrom M-L ,Hiilesmea V ,Brady A . Minor anomalies in offspring of epileptic mothers. J Pediatr 1988;112:520-529
CrossRef | Web of Science | Medline13
Holmes LB ,Harvey EA ,Brown KS ,Hayes AM ,Khoshbin S . Anticonvulsant teratogenesis. I. A study design for newborn infants. Teratology 1994;49:202-207
CrossRef | Medline14
Commission on Classification and Terminology of the International League Against Epilepsy
CrossRef | Web of Science | Medline15
Dunn PM . Congenital postural deformities. Br Med Bull 1976;32:71-76
Web of Science | Medline16
Wong KS ,Scott KE . Fetal growth at sea level. Biol Neonate 1972;20:175-188
CrossRef | Medline17
Yogman MW ,Kraemer HC ,Kindlon D ,Tyson JE ,Casey P ,Gross RT . Identification of intrauterine growth retardation among low birth weight preterm infants. J Pediatr 1989;115:799-807
CrossRef | Web of Science | Medline18
Preus M ,Fraser FC . Dermatoglyphics and syndromes. Am J Dis Child 1972;124:933-943
Web of Science | Medline19
Dunnett CW . A multiple comparison procedure for comparing several treatments with a control. J Am Stat Assoc 1955;50:1096-1121
CrossRef | Web of Science20
Lefkopoulou M ,Moore D ,Ryan L . The analysis of multiple correlated binary outcomes: application to rodent teratology experiments. J Am Stat Assoc 1989;84:810-815
CrossRef | Web of Science21
Sabry MA ,Farag TI . Hand anomalies in fetal-hydantoin syndrome: from nail/phalangeal hypoplasia to unilateral acheiria. Am J Med Genet 1996;62:410-412
CrossRef | Web of Science | Medline22
Lu MCK ,Sammel MD ,Cleveland RH ,Ryan LM ,Holmes LB . Digit effects produced by prenatal exposure to antiepileptic drugs. Teratology 2000;61:277-283
CrossRef | Medline23
Rosa FW . Spina bifida in infants of women treated with carbamazepine during pregnancy. N Engl J Med 1991;324:674-677
Full Text | Web of Science | Medline24
Dansky LV ,Finnell RH . Parental epilepsy, anticonvulsant drugs, and reproductive outcome: epidemiologic and experimental findings spanning three decades. 2. Human studies. Reprod Toxicol 1991;5:301-335
CrossRef | Web of Science | Medline25
Yerby MS ,Leavitt A ,Erickson DM , et al. Antiepileptics and the development of congenital anomalies. Neurology 1992;42:Suppl 5:132-140
Web of Science | Medline26
Ornoy A ,Cohen E . Outcome of children born to epileptic mothers treated with carbamazepine during pregnancy. Arch Dis Child 1996;75:517-520
CrossRef | Web of Science | Medline27
Nulman I ,Scolnik D ,Chitayat D ,Farkas LD ,Koren G . Findings in children exposed in utero to phenytoin and carbamazepine monotherapy: independent effects of epilepsy and medications. Am J Med Genet 1997;68:18-24
CrossRef | Web of Science | Medline28
Monson RR ,Rosenberg L ,Hartz SC ,Shapiro S ,Heinonen OP ,Slone D . Diphenylhydantoin and selected congenital malformations. N Engl J Med 1973;289:1049-1052
Full Text | Web of Science | Medline29
Are hydantoins (phenytoins) human teratogens? J Pediatr 1977;90:673-675
CrossRef | Web of Science | Medline30
Holmes LB ,Rosenberger PB ,Harvey EA ,Khoshbin S ,Ryan L . Intelligence and physical features of children of women with epilepsy. Teratology 2000;61:196-202
CrossRef | Medline31
Olafsson E ,Hallgrimsson JT ,Hauser WA ,Ludvigsson P ,Gudmundsson G . Pregnancies of women with epilepsy: a population-based study in Iceland. Epilepsia 1998;39:887-892
CrossRef | Web of Science | Medline32
Shapiro S ,Hartz SC ,Siskind V , et al. Anticonvulsants and parental epilepsy in the development of birth defects. Lancet 1976;1:272-275
CrossRef | Web of Science | Medline33
Minkoff H ,Schaffer RM ,Delke I ,Grunebaum AN . Diagnosis of intracranial hemorrhage in utero after a maternal seizure. Obstet Gynecol 1985;65:Suppl:22S-24S
Web of Science | Medline34
Nelson K ,Holmes LB . Malformations due to presumed spontaneous mutations in newborn infants. N Engl J Med 1989;320:19-23
Full Text | Web of Science | Medline35
Krauss CM ,Holmes LB ,VanLang Q ,Keith DA . Four siblings with similar malformations after exposure to phenytoin and primidone. J Pediatr 1984;105:750-755
CrossRef | Web of Science | Medline36
Orup HI Jr ,Holmes LB . Persistence of craniofacial effect of antiepileptic drug (AED) teratogenicity into adult years. Teratology 1997;55:34-34 abstract.37
Holmes LD ,Adams J ,Coull B ,Harvey EA . Anticonvulsant face: association with cognitive dysfunction. Pediatric Res 2000;47:Suppl:82A-82A abstract.
Web of Science38
Hwang S-J ,Beaty TH ,Panny SR , et al. Association study of transforming growth factor alpha (TGFα) TaqI polymorphism and oral clefts: indication of gene-environment interaction in a population-based sample of infants with birth defects. Am J Epidemiol 1995;141:629-636
Web of Science | Medline39
McCarver DG ,Thomasson HR ,Martier SS ,Sokol RJ ,Li T-K . Alcohol dehydrogenase-2*3 allele protects against alcohol-related birth defects among African Americans. J Pharmacol Exp Ther 1997;283:1095-1101
Web of Science | Medline40
Buehler BA ,Delimont D ,van Waes M ,Finnell RH . Prenatal prediction of risk of the fetal hydantoin syndrome. N Engl J Med 1990;322:1567-1572
Full Text | Web of Science | Medline41
Strickler SM ,Dansky LV ,Miller MA ,Seni M-H ,Andermann E ,Spielberg SP . Genetic predisposition to phenytoin-induced birth defects. Lancet 1985;2:746-749
CrossRef | Web of Science | Medline42
Wells PG ,Winn LM . Biochemical toxicology of chemical teratogenesis. Clin Rev Biochem Mol Biol 1996;31:1-40
CrossRef | Web of Science | Medline43
Dansky LV ,Andermann E ,Rosenblatt D ,Sherwin AL ,Andermann F . Anticonvulsants, folate levels, and pregnancy outcome: a prospective study. Ann Neurol 1987;21:176-182
CrossRef | Web of Science | Medline44
Hernandez-Diaz S ,Werler MM ,Walker AM ,Mitchell AA . Folic acid antagonists during pregnancy and the risk of birth defects. N Engl J Med 2000;343:1608-1614
Full Text | Web of Science | Medline
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P.P. Saramma, P.S. Sarma, Sanjeev V. Thomas. (2011) Women with epilepsy have poorer knowledge and skills in child rearing than women without epilepsy. Seizure 20:7, 575-579
CrossRef11
David Banji, Otilia J.F. Banji, Saidulu Abbagoni, Md. Sikinder Hayath, Srilatha Kambam, Vijaya Lakshmi Chiluka. (2011) Amelioration of behavioral aberrations and oxidative markers by green tea extract in valproate induced autism in animals. Brain Research 1410, 141-151
CrossRef12
Suzanne M. Gilboa, Cheryl S. Broussard, Owen J. Devine, Kara N. Duwe, Audrey L. Flak, Sheree L. Boulet, Cynthia A. Moore, Martha M. Werler, Margaret A. Honein. (2011) Influencing clinical practice regarding the use of antiepileptic medications during pregnancy: Modeling the potential impact on the prevalences of spina bifida and cleft palate in the United States. American Journal of Medical Genetics Part C: Seminars in Medical Genetics 157:3, 234-246
CrossRef13
Bogdan J. Wlodarczyk, Ana M. Palacios, Claudia J. Chapa, Huiping Zhu, Timothy M. George, Richard H. Finnell. (2011) Genetic basis of susceptibility to teratogen induced birth defects. American Journal of Medical Genetics Part C: Seminars in Medical Genetics 157:3, 215-226
CrossRef14
Melissa M. Ahern, Michael Hendryx, Jamison Conley, Evan Fedorko, Alan Ducatman, Keith J. Zullig. (2011) The association between mountaintop mining and birth defects among live births in central Appalachia, 1996–2003. Environmental Research 111:6, 838-846
CrossRef15
Ercan Tureci, Ziya Asan, Mediha Eser, Taner Tanriverdi, Faruk Alkan, Pamir Erdincler. (2011) The effects of valproic acid and levetiracetam on chicken embryos. Journal of Clinical Neuroscience 18:6, 816-820
CrossRef16
Asher D. Schachter, Isaac S. Kohane. (2011) Drug target-gene signatures that predict teratogenicity are enriched for developmentally related genes. Reproductive Toxicology 31:4, 562-569
CrossRef17
Ferenc Bánhidy, Erzsébet H. Puhó, Andrew E. Czeizel. (2011) Efficacy of medical care of epileptic pregnant women based on the rate of congenital abnormalities in their offspring. Congenital Anomalies 51:1, 34-42
CrossRef18
Fernanda Pohl-Guimaraes, Thomas E. Krahe, Alexandre E. Medina. (2011) Early valproic acid exposure alters functional organization in the primary visual cortex. Experimental Neurology 228:1, 138-148
CrossRef19
Hilal Özkan, Merih Çetinkaya, Nilgün Köksal, Şenay Yapici. (2011) Severe fetal valproate syndrome: combination of complex cardiac defect, multicystic dysplastic kidney, and trigonocephaly. Journal of Maternal-Fetal and Neonatal Medicine 24:3, 521-524
CrossRef20
K. J. Meador, G. A. Baker, N. Browning, M. J. Cohen, J. Clayton-Smith, L. A. Kalayjian, A. Kanner, J. D. Liporace, P. B. Pennell, M. Privitera, D. W. Loring, . (2011) Foetal antiepileptic drug exposure and verbal versus non-verbal abilities at three years of age. Brain 134:2, 396-404
CrossRef21
Andrew E. Czeizel, Istvan Dudás, Ferenc Bánhidy. (2011) Interpretation of Controversial Teratogenic Findings of Drugs Such As Phenobarbital. ISRN Obstetrics and Gynecology 2011, 1-8
CrossRef22
Georgia Ramantani, Chrysanthy Ikonomidou, Beate Walter, Dietz Rating, Juergen Dinger. (2011) Levetiracetam: Safety and efficacy in neonatal seizures. European Journal of Paediatric Neurology 15:1, 1-7
CrossRef23
Leticia Tornes, Cynthia L Harden. (2010) Antiepileptic drug pregnancy registries: do the latest findings concur?. Therapy 7:5, 517-526
CrossRef24
Monika Witczak, Iwona Kociszewska, Jan Wilczyński, Dobrosława Łopaczyńska, Tomasz Ferenc. (2010) Evaluation of chromosome aberrations, sister chromatid exchange and micronuclei in cultured cord-blood lymphocytes of newborns of women treated for epilepsy during pregnancy. Mutation Research/Genetic Toxicology and Environmental Mutagenesis 701:2, 111-117
CrossRef25
Dominic C. Heaney, David J. Williams, Patrick O'Brien, Chris Elton. 2010. Neurologic Disorders in Obstetric Practice. , 371-403.
CrossRef26
Denise S Hill, Bogdan J Wlodarczyk, Ana M Palacios, Richard H Finnell. (2010) Teratogenic effects of antiepileptic drugs. Expert Review of Neurotherapeutics 10:6, 943-959
CrossRef27
James C. Johnston. (2010) Neurological Malpractice and Nonmalpractice Liability. Neurologic Clinics 28:2, 441-458
CrossRef28
Ingrid Borthen, Nils Erik Gilhus. (2010) Maternal epilepsy and adverse pregnancy outcomes. Expert Review of Obstetrics & Gynecology 5:3, 347-355
CrossRef29
Chrysanthy Ikonomidou. (2010) Prenatal Effects of Antiepileptic Drugs. Epilepsy Currents 10:2, 42-46
CrossRef30
Megan Galbally, Martien Snellen, Susan Walker, Michael Permezel. (2010) Management of antipsychotic and mood stabilizer medication in pregnancy: recommendations for antenatal care. Australian and New Zealand Journal of Psychiatry 44:2, 99-108
CrossRef31
Chrysanthy Ikonomidou, Lechoslaw Turski. (2010) Antiepileptic drugs and brain development. Epilepsy Research 88:1, 11-22
CrossRef32
Kai Eriksson, Reetta Kälviäinen. (2010) Long-term neurocognitive adverse effects of prenatal antiepileptic drug exposure. Expert Review of Clinical Pharmacology 3:1, 131-137
CrossRef33
Alberto Verrotti, Claudia D’Egidio, Giangennaro Coppola, Pasquale Parisi, Francesco Chiarelli. (2009) Epilepsy, sex hormones and antiepileptic drugs in female patients. Expert Review of Neurotherapeutics 9:12, 1803-1814
CrossRef34
Linda J. Stephen, Martin J. Brodie. (2009) Selection of Antiepileptic Drugs in Adults. Neurologic Clinics 27:4, 967-992
CrossRef35
Torbjörn Tomson, Dina Battino. (2009) Teratogenic Effects of Antiepileptic Medications. Neurologic Clinics 27:4, 993-1002
CrossRef36
J. Braeken, F. Tuerlinckx. (2009) A mixed model framework for teratology studies. Biostatistics 10:4, 744-755
CrossRef37
Sarah A. Collier, Marilyn L. Browne, Sonja A. Rasmussen, Margaret A. Honein, . (2009) Maternal caffeine intake during pregnancy and orofacial clefts. Birth Defects Research Part A: Clinical and Molecular Teratology 85:10, 842-849
CrossRef38
Frank J. E. Vajda, Alison A. Hitchcock, Janet Graham, Terence J. O’Brien, Cecilie M. Lander, Mervyn J. Eadie. (2009) The teratogenic risk of antiepileptic drug polytherapy. Epilepsia
CrossRef39
Gábor Timmermann, Nándor Ács, Ferenc Bánhidy, Andrew E. Czeizel. (2009) Congenital abnormalities of 88 children born to mothers who attempted suicide with phenobarbital during pregnany: the use of a disaster epidemiological model for the evaluation of drug teratogenicity. Pharmacoepidemiology and Drug Safety 18:9, 815-825
CrossRef40
Gyri Veiby, Anne K. Daltveit, Bernt A. Engelsen, Nils E. Gilhus. (2009) Pregnancy, delivery, and outcome for the child in maternal epilepsy. Epilepsia 50:9, 2130-2139
CrossRef41
Luigi Maccotta, Joseph E. Sullivan. (2009) Epilepsy: Should valproate be avoided during childbearing years?. Nature Reviews Neurology 5:8, 414-415
CrossRef42
Christina Fotopoulou, Rebekka Kretz, Steffen Bauer, J.C. Schefold, Bettina Schmitz, Joachim W. Dudenhausen, Wolfgang Henrich. (2009) Prospectively assessed changes in lamotrigine-concentration in women with epilepsy during pregnancy, lactation and the neonatal period. Epilepsy Research 85:1, 60-64
CrossRef43
Paige Jackson, Lisa Paquette, Valerie Watiker, Linda Randolph, Rangasamy Ramanathan, Istvan Seri. (2009) Intrauterine exposure to mycophenolate mofetil and multiple congenital anomalies in a newborn: Possible teratogenic effect. American Journal of Medical Genetics Part A 149A:6, 1231-1236
CrossRef44
Cynthia L. Harden, Kimford J. Meador, Page B. Pennell, W. Allen Hauser, Gary S. Gronseth, Jacqueline A. French, Samuel Wiebe, David Thurman, Barbara S. Koppel, Peter W. Kaplan, Julian N. Robinson, Jennifer Hopp, Tricia Y. Ting, Barry Gidal, Collin A. Hovinga, Andrew N. Wilner, Blanca Vazquez, Lewis Holmes, Allan Krumholz, Richard Finnell, Deborah Hirtz, Claire Le Guen. (2009) Management issues for women with epilepsy-Focus on pregnancy (an evidence-based review): II. Teratogenesis and perinatal outcomes. Epilepsia 50:5, 1237-1246
CrossRef45
Cynthia L. Harden, Page B. Pennell, Barbara S. Koppel, Collin A. Hovinga, Barry Gidal, Kimford J. Meador, Jennifer Hopp, Tricia Y. Ting, W. A. Hauser, David Thurman, Peter W. Kaplan, Julian N. Robinson, Jacqueline A. French, Samuel Wiebe, Andrew N. Wilner, Blanca Vazquez, Lewis Holmes, Allan Krumholz, Richard Finnell, Patricia O. Shafer, Claire L. Le Guen. (2009) Management issues for women with epilepsy-Focus on pregnancy (an evidence-based review): III. Vitamin K, folic acid, blood levels, and breast-feeding. Epilepsia 50:5, 1247-1255
CrossRef46
SP Walker, M Permezel, SF Berkovic. (2009) The management of epilepsy in pregnancy. BJOG: An International Journal of Obstetrics & Gynaecology 116:6, 758-767
CrossRef47
Meador, Kimford J., Baker, Gus A., Browning, Nancy, Clayton-Smith, Jill, Combs-Cantrell, Deborah T., Cohen, Morris, Kalayjian, Laura A., Kanner, Andres, Liporace, Joyce D., Pennell, Page B., Privitera, Michael, Loring, David W., . (2009) Cognitive Function at 3 Years of Age after Fetal Exposure to Antiepileptic Drugs. New England Journal of Medicine 360:16, 1597-1605
Full Text48
Ha T. T. Nguyen, Verinder Sharma, Roger S. McIntyre. (2009) Teratogenesis associated with antibipolar agents. Advances in Therapy 26:3, 281-294
CrossRef49
(2009) A Pregnant Pause to Consider Teratogenicity of Topiramate. Epilepsy Currents 9:2, 36-38
CrossRef50
Leyla H. Alparslan, Barbara N. Weissman. 2009. Imaging Findings of Drug-Related Musculoskeletal Disorders. , 264-279.
CrossRef51
Pamela M. Crawford. (2009) Managing Epilepsy in Women of Childbearing Age. Drug Safety 32:4, 293-307
CrossRef52
Umberto Aguglia, Giancarlo Barboni, Dina Battino, Giovan Battista Cavazzuti, Angela Citernesi, Roberto Corosu, Francesco Maria Guzzetta, Paola Iannetti, Daniela Mamoli, Alfredo Patella, Lorenzo Pavone, Emilio Perucca, Francesco Primiero, Dario Pruna, Salvatore Savasta, Luigi Maria Specchio, Alberto Verrotti. (2009) Italian Consensus Conference on Epilepsy and Pregnancy, Labor and Puerperium. Epilepsia 50, 7-23
CrossRef53
Joan Marilyn Stoler. (2009) A tribute to Lewis B. Holmes: Mentor and scholar. Birth Defects Research Part A: Clinical and Molecular Teratology 85:1, 1-5
CrossRef54
John Craig. 2008. The patient with epilepsy. , 107-120.
CrossRef55
Page B. Pennell. (2008) Antiepileptic drugs during pregnancy: What is known and which AEDs seem to be safest?. Epilepsia 49, 43-55
CrossRef56
Edward B. Bromfield, Barbara A. Dworetzky, Diego F. Wyszynski, Caitlin R. Smith, Elizabeth J. Baldwin, Lewis B. Holmes. (2008) Valproate teratogenicity and epilepsy syndrome. Epilepsia 49:12, 2122-2124
CrossRef57
Joshua J. Gagne, Vittorio Maio, Vincenzo Berghella, Daniel Z. Louis, Joseph S. Gonnella. (2008) Prescription drug use during pregnancy: a population-based study in Regione Emilia-Romagna, Italy. European Journal of Clinical Pharmacology 64:11, 1125-1132
CrossRef58
Kimford J. Meador. (2008) Effects of In Utero Antiepileptic Drug Exposure. Epilepsy Currents 8:6, 143-147
CrossRef59
Nobuko Taguchi, Evelyn T. Rubin, Akiko Hosokawa, Jacquelyn Choi, Angela Yating Ying, Myla E. Moretti, Gideon Koren, Shinya Ito. (2008) Prenatal exposure to HMG-CoA reductase inhibitors: Effects on fetal and neonatal outcomes. Reproductive Toxicology 26:2, 175-177
CrossRef60
Kimford Meador, Matthew W. Reynolds, Sheila Crean, Kyle Fahrbach, Corey Probst. (2008) Pregnancy outcomes in women with epilepsy: A systematic review and meta-analysis of published pregnancy registries and cohorts. Epilepsy Research 81:1, 1-13
CrossRef61
Meytal Avgil, Orna Diav-Citrin, Svetlana Shechtman, Judy Arnon, Rebecka Wajnberg, Asher Ornoy. (2008) Epstein–Barr virus infection in pregnancy—A prospective controlled study. Reproductive Toxicology 25:4, 468-471
CrossRef62
Joost Nicolai, Johan S.H. Vles, Albert P. Aldenkamp. (2008) Neurodevelopmental delay in children exposed to antiepileptic drugs in utero: A critical review directed at structural study-bias. Journal of the Neurological Sciences 271:1-2, 1-14
CrossRef63
FJE Vajda. (2008) Treatment options for pregnant women with epilepsy. Expert Opinion on Pharmacotherapy 9:11, 1859-1868
CrossRef64
Elizabeth Gerard, Alison M. Pack. (2008) Pregnancy registries: What do they mean to clinical practice?. Current Neurology and Neuroscience Reports 8:4, 325-332
CrossRef65
Torbjörn Tomson, Dina Battino. (2008) Teratogenic effects of antiepileptic drugs. Seizure 17:2, 166-171
CrossRef66
Mervyn J Eadie. (2008) Antiepileptic drugs as human teratogens. Expert Opinion on Drug Safety 7:2, 195-209
CrossRef67
Frank J.E. Vajda, Terrence O’Brien, Alison Hitchcock, Janet Graham, Cecilie Lander, Mervyn Eadie. (2008) The internal control group in a register of antiepileptic drug use in pregnancy. Journal of Clinical Neuroscience 15:1, 29-35
CrossRef68
D Kjaer, E Horvath-Puhó, J Christensen, M Vestergaard, AE Czeizel, HT Sørensen, J Olsen. (2008) Antiepileptic drug use, folic acid supplementation, and congenital abnormalities: a population-based case-control study. BJOG: An International Journal of Obstetrics & Gynaecology 115:1, 98-103
CrossRef69
Usha Kini, Rebecca Lee, Alison Jones, Sarah Smith, Simon Ramsden, Alan Fryer, Jill Clayton-Smith. (2007) Influence of the MTHFR genotype on the rate of malformations following exposure to antiepileptic drugs in utero. European Journal of Medical Genetics 50:6, 411-420
CrossRef70
Zia I Carrim, Lorna McKay, Sikander S Sidiki, Timothy E Lavy. (2007) Early intervention for the ocular and neurodevelopmental sequelae of Fetal Valproate Syndrome. Journal of Paediatrics and Child Health 43:9, 643-645
CrossRef71
Joyce A. Cramer, Jacki Gordon, Steven Schachter, Orrin Devinsky. (2007) Women with epilepsy: Hormonal issues from menarche through menopause. Epilepsy & Behavior 11:2, 160-178
CrossRef72
Christian Danielsson, Faranak Azarbayjani, Anna-Carin Sköld, Niklas Sjögren, Bengt R. Danielsson. (2007) Polytherapy withhERG-blocking antiepileptic drugs: Increased risk for embryonic cardiac arrhythmia and teratogenicity. Birth Defects Research Part A: Clinical and Molecular Teratology 79:8, 595-603
CrossRef73
DIANE E. ATKINSON, SOPHIE BRICE-BENNETT, STEPHEN W. D???SOUZA. (2007) Antiepileptic Medication During Pregnancy: Does Fetal Genotype Affect Outcome?. Pediatric Research 62:2, 120-127
CrossRef74
R. Sankar. (2007) Teratogenicity of antiepileptic drugs: role of drug metabolism and pharmacogenomics. Acta Neurologica Scandinavica 116:1, 65-71
CrossRef75
Marianne Cunnington, Sandy Ferber, George Quartey, . (2007) Effect of Dose on the Frequency of Major Birth Defects Following Fetal Exposure to Lamotrigine Monotherapy in an International Observational Study. Epilepsia 48:6, 1207-1210
CrossRef76
Maurizio Carta, Marcello Cimador, Mario Giuffrè, Maria Sergio, Maria Rita Pace, Enrico Grazia, Giovanni Corsello. (2007) Unilateral multicystic dysplastic kidney in infants exposed to antiepileptic drugs during pregnancy. Pediatric Nephrology 22:7, 1054-1057
CrossRef77
Sanjeev V Kothare, Joseph Kaleyias. (2007) The adverse effects of antiepileptic drugs in children. Expert Opinion on Drug Safety 6:3, 251-265
CrossRef78
Cesario Bellantuono, Giovanni Migliarese, Salvatore Gentile. (2007) Serotonin reuptake inhibitors in pregnancy and the risk of major malformations: a systematic review. Human Psychopharmacology: Clinical and Experimental 22:3, 121-128
CrossRef79
Tarannum Musvee Lateef, Karin B. Nelson. (2007) In utero exposure to antiepileptic drugs: Teratogenicity and neonatal morbidity. Current Neurology and Neuroscience Reports 7:2, 133-138
CrossRef80
Dorte Kjær, Erzsébet Horvath-Puhó, Jakob Christensen, Mogens Vestergaard, Andrew E. Czeizel, Henrik Toft Sørensen, Jørn Olsen. (2007) Use of phenytoin, phenobarbital, or diazepam during pregnancy and risk of congenital abnormalities: a case-time-control study. Pharmacoepidemiology and Drug Safety 16:2, 181-188
CrossRef81
Peter Kovacic, Ratnasamy Somanathan. (2006) Mechanism of teratogenesis: Electron transfer, reactive oxygen species, and antioxidants. Birth Defects Research Part C: Embryo Today: Reviews 78:4, 308-325
CrossRef82
Eric D. Marsh, Amy R. Brooks-Kayal, Brenda E. Porter. (2006) Seizures and Antiepileptic Drugs: Does Exposure Alter Normal Brain Development?. Epilepsia 47:12, 1999-2010
CrossRef83
Roy G. Beran. (2006) The ethics of excluding women who become pregnant while participating in clinical trials of anti-epileptic medications. Seizure 15:8, 563-570
CrossRef84
William O Tatum. (2006) In utero antiepileptic drug exposure. Expert Review of Neurotherapeutics 6:12, 1785-1787
CrossRef85
Andrew J. Copp. 2006. Neural Tube Defects, Molecular Biology of. .
CrossRef86
Janet D. Cragan, J. M. Friedman, Lewis B. Holmes, Kathleen Uhl, Nancy S. Green, Laura Riley. (2006) Ensuring the Safe and Effective Use of Medications During Pregnancy: Planning and Prevention Through Preconception Care. Maternal and Child Health Journal 10:S1, 129-135
CrossRef87
Christopher J Stodgell, Jennifer L. Ingram, Melanie O'Bara, Barbara K. Tisdale, Heinz Nau, Patricia M. Rodier. (2006) Induction of the homeotic gene Hoxa1 through valproic acid's teratogenic mechanism of action. Neurotoxicology and Teratology 28:5, 617-624
CrossRef88
Asher Ornoy. (2006) Neuroteratogens in man: An overview with special emphasis on the teratogenicity of antiepileptic drugs in pregnancy. Reproductive Toxicology 22:2, 214-226
CrossRef89
A. Aldenkamp, F. Vigevano, A. Arzimanoglou, A. Covanis. (2006) Role of valproate across the ages. Treatment of epilepsy in children. Acta Neurologica Scandinavica 114:s184, 1-13
CrossRef90
E. Ben-Menachem, B. Schmitz, T. Tomson, F. Vajda. (2006) Role of valproate across the ages. Treatment of epilepsy in adults. Acta Neurologica Scandinavica 114:s184, 14-27
CrossRef91
Gholam K. Motamedi, Kimford J. Meador. (2006) Antiepileptic drugs and neurodevelopment. Current Neurology and Neuroscience Reports 6:4, 341-346
CrossRef92
William O Tatum. (2006) Use of antiepileptic drugs in pregnancy. Expert Review of Neurotherapeutics 6:7, 1077-1086
CrossRef93
Naghme Adab. (2006) Birth defects and epilepsy medication. Expert Review of Neurotherapeutics 6:6, 833-845
CrossRef94
Jillian Anger, Elizabeth Loder, Dawn Buse, Joan Golub. (2006) Treatment options for migraine during pregnancy. Future Neurology 1:3, 311-322
CrossRef95
Cynthia L Harden, Lakshmi Nadiminti. (2006) Treatment considerations during pregnancy for women with epilepsy. Women's Health 2:3, 415-423
CrossRef96
Pascale P. Quilichini, Catherine Chiron, Yehezkel Ben-Ari, Henri Gozlan. (2006) Stiripentol, a Putative Antiepileptic Drug, Enhances the Duration of Opening of GABAA-Receptor Channels. Epilepsia 47:4, 704-716
CrossRef97
Alison M Pack. (2006) Therapy Insight: clinical management of pregnant women with epilepsy. Nature Clinical Practice Neurology 2:4, 190-200
CrossRef98
Naghme Adab, David W Chadwick. (2006) Management of women with epilepsy during pregnancy. The Obstetrician & Gynaecologist 8:1, 20-25
CrossRef99
Katriina Viinikainen, Seppo Heinonen, Kai Eriksson, Reetta Kalviainen. (2006) Community-based, Prospective, Controlled Study of Obstetric and Neonatal Outcome of 179 Pregnancies in Women with Epilepsy. Epilepsia 47:1, 186-192
CrossRef100
Li-Xing Man, Benjamin Chang. (2006) Maternal Cigarette Smoking during Pregnancy Increases the Risk of Having a Child with a Congenital Digital Anomaly. Plastic and Reconstructive Surgery 117:1, 301-308
CrossRef101
Barbara Tettenborn. (2006) Management of Epilepsy in Women of Childbearing Age. CNS Drugs 20:5, 373-387
CrossRef102
Meli˙h Atahan Guven, Cem Batukan, Serdar Ceylaner, Gülay Ceylaner, Murat Uzel. (2006) A case of fetal anticonvulsant syndrome with severe bilateral upper limb defect. Journal of Maternal-Fetal and Neonatal Medicine 19:2, 115-117
CrossRef103
Pierre Genton, Franck Semah, Eugen Trinka. (2006) Valproic Acid in Epilepsy. Drug Safety 29:1, 1-21
CrossRef104
2006. Antiepileptic drugs. , 274-301.
CrossRef105
Mizuho Maekawa, Ken-ichi Ohta, Ryu-ichi Katagiri, Etsuko Ueta, Ichiro Naruse. (2005) Exencephaly induction by valproic acid in the genetic polydactyly/arhinencephaly mouse, Pdn/Pdn. Congenital Anomalies 45:4, 132-136
CrossRef106
E. Ben-Menachem. (2005) Data from regulatory studies: what do they tell? What don't they tell?. Acta Neurologica Scandinavica 112:s181, 21-25
CrossRef107
Claudia M. Klier, Mario Horst Lanczik. (2005) Die Behandlung von schwangeren und gebärfähigen Frauen mit Psychopharmaka. Psychiatrie und Psychotherapie 1:1, 17-24
CrossRef108
Emilio Perucca. (2005) Birth defects after prenatal exposure to antiepileptic drugs. The Lancet Neurology 4:11, 781-786
CrossRef109
Arnaud Biraben, Anne Beauplet. (2005) Treatment options for epilepsy during pregnancy. Therapy 2:6, 937-944
CrossRef110
Júlia Métneki, Erzsébet Puhó, Andrew E. Czeizel. (2005) Maternal diseases and isolated orofacial clefts in Hungary. Birth Defects Research Part A: Clinical and Molecular Teratology 73:9, 617-623
CrossRef111
Torbjörn Tomson, Dina Battino. (2005) Teratogenicity of antiepileptic drugs: state of the art. Current Opinion in Internal Medicine 4:4, 353-358
CrossRef112
Kai Eriksson, Katriina Viinikainen, Anne Mönkkönen, Marja Äikiä, Pirkko Nieminen, Seppo Heinonen, Reetta Kälviäinen. (2005) Children exposed to valproate in utero—Population based evaluation of risks and confounding factors for long-term neurocognitive development. Epilepsy Research 65:3, 189-200
CrossRef113
Willemijn M. Meijer, Hermien E.K. de Walle, Wilhelmina S. Kerstjens-Frederikse, Lolkje T.W. de Jong-van den Berg. (2005) Folic acid sensitive birth defects in association with intrauterine exposure to folic acid antagonists. Reproductive Toxicology 20:2, 203-207
CrossRef114
F. Petitjean. (2005) La prescription de psychotropes chez une patiente traitée pour trouble bipolaire. Annales Médico-psychologiques, revue psychiatrique 163:5, 440-442
CrossRef115
Daniela Manthey, Stella Asimiadou, Vanya Stefovska, Angela M. Kaindl, Jessica Fassbender, Chrysanthy Ikonomidou, Petra Bittigau. (2005) Sulthiame but not levetiracetam exerts neurotoxic effect in the developing rat brain. Experimental Neurology 193:2, 497-503
CrossRef116
Georgia Montouris. (2005) Safety of the newer antiepileptic drug oxcarbazepine during pregnancy. Current Medical Research and Opinion 21:5, 693-701
CrossRef117
Eric R. Detrait, Timothy M. George, Heather C. Etchevers, John R. Gilbert, Michel Vekemans, Marcy C. Speer. (2005) Human neural tube defects: Developmental biology, epidemiology, and genetics. Neurotoxicology and Teratology 27:3, 515-524
CrossRef118
AUDREY E. JAIN, TIMOTHY LACY. (2005) Psychotropic Drugs in Pregnancy and Lactation. Journal of Psychiatric Practice 11:3, 177-191
CrossRef119
Torbjörn Tomson, Dina Battino. (2005) Teratogenicity of antiepileptic drugs: state of the art: review. Current Opinion in Neurology 18:2, 135-140
CrossRef120
Noriko Ejiri, Kei-ichi Katayama, Kunio Doi. (2005) Induction of cytochrome P450 isozymes by phenobarbital in pregnant rat and fetal livers and placenta. Experimental and Molecular Pathology 78:2, 150-155
CrossRef121
Elizabeth W. Loder, Dawn C. Buse, Joan R. Golub. (2005) Headache and Combination Estrogen-Progestin Oral Contraceptives: Integrating Evidence, Guidelines, and Clinical Practice. Headache: The Journal of Head and Face Pain 45:3, 224-231
CrossRef122
Bengt R. Danielsson, Alf Johansson, Christian Danielsson, Faranak Azarbayjani, Bo Blomgren, Anna-Carin Sk
ld. (2005) Phenytoin teratogenicity: Hypoxia marker and effects on embryonic heart rhythm suggest an hERG-related mechanism. Birth Defects Research Part A: Clinical and Molecular Teratology 73:3, 146-153
CrossRef123
N ADAB. (2005) Neurological problems in pregnancy. Women's Health Medicine 2:2, 32-37
CrossRef124
Margaret J Jackson. (2005) Choice of antiepileptic drug, which one to try first and what to do if it fails .... Practical Neurology 5:1, 6-17
CrossRef125
Renata C. Gallagher, Kerry Kingham, H. Eugene Hoyme. 2005. Fetal Anticonvulsant Syndrome. .
CrossRef126
Albert E. Chudley, Sally E. Longstaffe. 2005. Fetal Alcohol Syndrome and Fetal Alcohol Spectrum Disorder. .
CrossRef127
C. Schaefer. (2005) St
CrossRef128
Jeanette Wiltse. (2005) Mode of Action: Inhibition of Histone Deacetylase, Altering WNT-Dependent Gene Expression, and Regulation of Beta-Catenin—Developmental Effects of Valproic Acid. Critical Reviews in Toxicology 35:8-9, 727-738
CrossRef129
Page B. Pennell. (2005) Using Current Evidence in Selecting Antiepileptic Drugs for Use During Pregnancy. Epilepsy Currents 5:2, 45-51
CrossRef130
Anthony W Fox, Merle L Diamond, Egilius L H Spierings. (2005) Migraine During Pregnancy. CNS Drugs 19:6, 465-481
CrossRef131
Seiji Endo, Hiroshi Hagimoto, Hiroshi Yamazawa, Satoshi Kajihara, Shinji Kubota, Atsushi Kamijo, Kaori Nakajima, Ryo Furusho, Toshiro Miyauchi, Masaya Endo. (2004) Statistics on Deliveries of Mothers with Epilepsy at Yokohama City University Hospital. Epilepsia 45:s8, 42-47
CrossRef132
Page B. Pennell. (2004) Pregnancy in women who have epilepsy. Neurologic Clinics 22:4, 799-820
CrossRef133
Marianne C. Cunnington. (2004) The International Lamotrigine Pregnancy Registry Update for the Epilepsy Foundation. Epilepsia 45:11, 1468-1468
CrossRef134
BN Chodirker, AE Chudley. (2004) Genetic landmarks through philately - epilepsy and clinical genetic issues. Clinical Genetics 66:4, 290-292
CrossRef135
Torbjörn Tomson, Emilio Perucca, Dina Battino. (2004) Navigating toward Fetal and Maternal Health: The Challenge of Treating Epilepsy in Pregnancy. Epilepsia 45:10, 1171-1175
CrossRef136
Matitiahu Berkovitch, Orna Diav-Citrin, Revital Greenberg, Michal Cohen, Mordechai Bulkowstein, Svetlana Shechtman, Oxana Bortnik, Judy Arnon, Asher Ornoy. (2004) First-trimester exposure to amoxycillin/clavulanic acid: a prospective, controlled study. British Journal of Clinical Pharmacology 58:3, 298-302
CrossRef137
Angela E. Lin, Allyson J. Peller, Marie-Noel Westgate, Kara Houde, Aleda Franz, Lewis B. Holmes. (2004) Clonazepam use in pregnancy and the risk of malformations. Birth Defects Research Part A: Clinical and Molecular Teratology 70:8, 534-536
CrossRef138
Sophie Choulika, Eric Grabowski, Lewis B Holmes. (2004) Is antenatal vitamin K prophylaxis needed for pregnant women taking anticonvulsants?. American Journal of Obstetrics and Gynecology 190:4, 882-883
CrossRef139
Lucio G. Costa, Michael Aschner, Annabella Vitalone, Tore Syversen, Offie Porat Soldin. (2004) D
EVELOPMENTAL NEUROPATHOLOGY OF ENVIRONMENTAL AGENTS . Annual Review of Pharmacology and Toxicology 44:1, 87-110
CrossRef140
CM O'Leary. (2004) Fetal alcohol syndrome: Diagnosis, epidemiology, and developmental outcomes. Journal of Paediatrics and Child Health 40:1-2, 2-7
CrossRef141
H.Dix Christensen, William F Rayburn, K.Michael Parker, Christina L Gonzalez, Karen P Gold. (2004) Chronic prenatal exposure to carbamazepine and perinatal outcomes of C3H/He mice. American Journal of Obstetrics and Gynecology 190:1, 259-263
CrossRef142
A. Sabers, M. Dam, B. a-Rogvi-Hansen, J. Boas, P. Sidenius, M. Laue Friis, J. Alving, M. Dahl, J. Ankerhus, A. Mouritzen Dam. (2004) Epilepsy and pregnancy: lamotrigine as main drug used. Acta Neurologica Scandinavica 109:1, 9-13
CrossRef143
Shawn Fried, Eran Kozer, Irena Nulman, Thomas R Einarson, Gideon Koren. (2004) Malformation Rates in Children of Women with Untreated Epilepsy. Drug Safety 27:3, 197-202
CrossRef144
Margaret A Honein, Cynthia A Moore, J David Erickson. (2004) Can We Ensure the Safe Use of Known Human Teratogens?. Drug Safety 27:14, 1069-1080
CrossRef145
Helen M. Lyon, Lewis B. Holmes, Taosheng Huang. (2003) Multiple congenital anomalies associated with in utero exposure of phenytoin: Possible hypoxic ischemic mechanism?. Birth Defects Research Part A: Clinical and Molecular Teratology 67:12, 993-996
CrossRef146
Pierre Thomas, W. Emanuel Severus. (2003) Managing bipolar disorder during pregnancy and lactation: is there a safe and effective option?. European Psychiatry 18, 3s-8s
CrossRef147
Pasquale Parisi, Ada Francia, Nicola Vanacore, Stefania Fiore, Anna Teresa Giallonardo, Mario Manfredi. (2003) Psychomotor development and general movements in offspring of women with epilepsy and anticonvulsant therapy. Early Human Development 74:2, 97-108
CrossRef148
Lawrence C. Tsen. (2003) Neurologic Complications of Labor Analgesia and Anesthesia. International Anesthesiology Clinics 40:4, 67-88
CrossRef149
Jürgen Bauer, Markus Reuber. (2003) Medical treatment of epilepsy. Expert Opinion on Emerging Drugs 8:2, 457-467
CrossRef150
R. Padmanabhan, Y.M. Abdulrazzaq, S.M.A. Bastaki, M. Shafiullah, S.I. Chandranath. (2003) Experimental studies on reproductive toxicologic effects of lamotrigine in mice. Birth Defects Research Part B: Developmental and Reproductive Toxicology 68:5, 428-438
CrossRef151
Elizabeth A. Harvey, Brent A. Coull, Lewis B. Holmes. (2003) Anticonvulsant teratogenesis 5: Observer bias in a cohort study. Birth Defects Research Part A: Clinical and Molecular Teratology 67:6, 452-456
CrossRef152
Martha J. Morrell. (2003) Reproductive and Metabolic Disorders in Women with Epilepsy. Epilepsia 44, 11-20
CrossRef153
William S Webster, Jane AD Freeman. (2003) Prescription drugs and pregnancy. Expert Opinion on Pharmacotherapy 4:6, 949-961
CrossRef154
Blanaid E. Gavin, Brendan D. Kelly, Thomas Brennan. (2003) Anorexia nervosa and anticonvulsant exposure during gestation. European Psychiatry 18:3, 144
CrossRef155
PETRA BITTIGAU, MARCO SIFRINGER, CHRYSANTHY IKONOMIDOU. (2003) Antiepileptic Drugs and Apoptosis in the Developing Brain. Annals of the New York Academy of Sciences 993:1, 103-114
CrossRef156
Dieter Schmidt, Steven C. Schachter. (2003) Comment. Epilepsy & Behavior 4:2, 15-16
CrossRef157
James I Morrow, John J Craig. (2003) Anti-epileptic drugs in pregnancy: current safety and other issues. Expert Opinion on Pharmacotherapy 4:4, 445-456
CrossRef158
Reetta Kälviäinen. (2003) A woman with seven monotherapies. Epilepsy & Behavior 4:2, 8-11
CrossRef159
Carlo Bellini, Amedeo Citana, Carmen La Rosa, Eugenio Bonioli. (2003) Phenobarbital Enhances Sister Chromatid Exchanges In Vivo. Epilepsia 44:4, 621-622
CrossRef160
J. Liporace, A. D'Abreu. (2003) Epilepsy and Women's Health: Family Planning, Bone Health, Menopause, and Menstrual-Related Seizures. Mayo Clinic Proceedings 78:4, 497-506
CrossRef161
L. de Jong-Potjer. (2003) Women's interest in GP-initiated pre-conception counselling in The Netherlands. Family Practice 20:2, 142-146
CrossRef162
R. Padmanabhan, M. Mohamed Shafiullah. (2003) Amelioration of sodium valproate-induced neural tube defects in mouse fetuses by maternal folic acid supplementation during gestation. Congenital Anomalies 43:1, 29-40
CrossRef163
R. Padmanabhan, M. Mohamed Shafiullah. (2003) Amelioration of sodium valproate-induced neural tube defects in mouse fetuses by maternal folic acid supplementation during gestation. Clinical Genetics 43:1, 29-40
CrossRef164
Harold Kalter. (2003) Teratology in the 20th century. Neurotoxicology and Teratology 25:2, 131-282
CrossRef165
Camilla Barrett, Alan Richens. (2003) Epilepsy and pregnancy: Report of an Epilepsy Research Foundation Workshop. Epilepsy Research 52:3, 147-187
CrossRef166
J. W. Britton. (2002) Antiepileptic Drug Withdrawal: Literature Review. Mayo Clinic Proceedings 77:12, 1378-1388
CrossRef167
Dieter Schmidt, Christian Elger, Gregory L Holmes. (2002) Pharmacological overtreatment in epilepsy. Epilepsy Research 52:1, 3-14
CrossRef168
Lewis B. Holmes. (2002) Teratogen-induced limb defects. American Journal of Medical Genetics 112:3, 297-303
CrossRef169
Amy I. Whitsel, Casey B. Johnson, Cynthia J. Forehand. (2002) An in ovo chicken model to study the systemic and localized teratogenic effects of valproic acid. Teratology 66:4, 153-163
CrossRef170
Patricia Tennis, R. R. Eldridge, . (2002) Preliminary Results on Pregnancy Outcomes in Women Using Lamotrigine. Epilepsia 43:10, 1161-1167
CrossRef171
D.L.W Davidson. (2002) Letter to the Editor: Discordant twins for neural tube defect on treatment with sodium valproate. Seizure 11:7, 445
CrossRef172
Aqiba Bokhari, Brent A. Coull, Lewis B. Holmes. (2002) Effect of prenatal exposure to anticonvulsant drugs on dermal ridge patterns of fingers. Teratology 66:1, 19-23
CrossRef173
Kimford J. Meador. (2002) Neurodevelopmental effects of antiepileptic drugs. Current Neurology and Neuroscience Reports 2:4, 373-378
CrossRef174
Philip N. Patsalos, Walter Fröscher, Francesco Pisani, Clementina M. Van Rijn. (2002) The Importance of Drug Interactions in Epilepsy Therapy. Epilepsia 43:4, 365-385
CrossRef175
WENDY F. HANSEN, JEROME YANKOWITZ. (2002) Pharmacologic Therapy for Medical Disorders During Pregnancy. Clinical Obstetrics and Gynecology 45:1, 136-152
CrossRef176
Michiko Kimura Bruno, Cynthia L. Harden. (2002) Epilepsy in pregnant women. Current Treatment Options in Neurology 4:1, 31-40
CrossRef177
James W. McAuley, Gail D. Anderson. (2002) Treatment of Epilepsy in Women of Reproductive Age. Clinical Pharmacokinetics 41:8, 559-579
CrossRef178
Emilio Perucca. (2002) Pharmacological and Therapeutic Properties of Valproate. CNS Drugs 16:10, 695-714
CrossRef179
Carmela Palmieri, Raffaele Canger. (2002) Teratogenic Potential of the Newer Antiepileptic Drugs. CNS Drugs 16:11, 755-764
CrossRef180
S Matalon, S Schechtman, G Goldzweig, A Ornoy. (2002) The teratogenic effect of carbamazepine: a meta-analysis of 1255 exposures. Reproductive Toxicology 16:1, 9-17
CrossRef181
Joan Marilyn Stoler. (2001) Maternal antiepileptic drug use and effects on fetal development. Current Opinion in Pediatrics 13:6, 566-571
CrossRef182
Ettore Beghi, John F. Annegers, . (2001) Pregnancy Registries in Epilepsy. Epilepsia 42:11, 1422-1425
CrossRef183
Torbjörn Tomson. (2001) Teratogenesis with antiepileptic drugs: practical management of young women with epilepsy. Expert Review of Neurotherapeutics 1:2, 192-198
CrossRef184
Lewis B. Holmes. (2001) Looking for long-term effects from prenatal exposures to anticonvulsants. Teratology 64:4, 175-176
CrossRef185
L James Willmore. (2001) Lamotrigine. Expert Review of Neurotherapeutics 1:1, 33-42
CrossRef186
(2001) Current Awareness. Pharmacoepidemiology and Drug Safety 10:5, 467-482
CrossRef187
&NA;. (2001) Anticonvulsants, not maternal epilepsy, are teratogenic. Reactions Weekly &NA;:848, 4
CrossRef188
R. Padmanabhan, M. Mohamed Shafiullah. (1993) Amelioration of sodium valproate-induced neural tube defects in mouse fetuses by maternal folic acid supplementation during gestation. Clinical Genetics 43:1, 29-40
CrossRef
