topiramate and Abnormalities--Drug-Induced

This study was undertaken to examine the comparative safety of antiseizure medication (ASM) monotherapy in pregnancy with respect to risk of major congenital malformations (MCMs), overall and by MCM subtype.. We conducted a population-based cohort study using national health register data from Denmark, Finland, Iceland, Norway, and Sweden (1996-2020). We compared pregnancies with first trimester exposure to lamotrigine monotherapy to ASM-unexposed, carbamazepine, valproate, oxcarbazepine, levetiracetam, and topiramate to lamotrigine monotherapy, and stratified monotherapy groups by dose. The outcome was nongenetic MCM and specific subtypes. We estimated adjusted risk ratios (aRRs) and 95% confidence intervals (CIs) with log-binomial regression and propensity score weights.. There was a higher crude risk of any MCM in pregnancies exposed to lamotrigine monotherapy (n = 8,339) compared to ASM-unexposed pregnancies (n = 4,866,362), but not after confounder adjustment (aRR = 0.97, 95% CI = 0.87-1.08). Compared to lamotrigine, there was an increased risk of malformations associated with valproate (n = 2,031, aRR = 2.05, 95% CI = 1.70-2.46) and topiramate (n = 509, aRR = 1.81, 95% CI = 1.26-2.60), which increased in a dose-dependent manner. We found no differences in malformation risk for carbamazepine (n = 2,674, aRR = 0.91, 95% CI = 0.72-1.15), oxcarbazepine (n = 1,313, aRR = 1.09, 95% CI = 0.83-1.44), or levetiracetam (n = 1,040, aRR = 0.78, 95% CI = 0.53-1.13). Valproate was associated with several malformation subtypes, including nervous system, cardiac, oral clefts, clubfoot, and hypospadias, whereas lamotrigine and carbamazepine were not.. Topiramate is associated with an increased risk of MCM similar to that associated with valproate, but lower doses may mitigate the risks for both drugs. Conversely, we found no increased risks for lamotrigine, carbamazepine, oxcarbazepine, or levetiracetam, which is reassuring. ANN NEUROL 2023;93:551-562.

Topics: Abnormalities, Drug-Induced; Anticonvulsants; Benzodiazepines; Carbamazepine; Cohort Studies; Epilepsy; Female; Humans; Lamotrigine; Levetiracetam; Male; Oxcarbazepine; Pregnancy; Topiramate; Valproic Acid

To investigate in the Australian Pregnancy Register of Antiepileptic Drugs patterns of fetal malformation associated with intrauterine exposure to particular currently available antiseizure medications taken by women with epilepsy.. There was statistically significant evidence (P < 0.05) of an increased hazard of fetal malformation associated with exposure to valproate, carbamazepine, topiramate, zonisamide, and with conception after assisted fertilization, but a reduced hazard in the offspring of women who continued to smoke during pregnancy. Valproate exposure was associated with malformations in a wide range of organs and organ systems, carbamazepine and topiramate with hydronephrosis, topiramate also with hypospadias, zonisamide with spina bifida and assisted fertilization with heart and great vessel maldevelopment.. Prenatal valproate exposure appears to interfere with the development of many if not all, fetal tissues. It seems likely that prenatal exposure to carbamazepine and topiramate, and possibly exposure to zonisamide, but also some process related to in vitro fertilization, may more selectively affect the normal development of particular fetal tissues or organs.

Topics: Abnormalities, Drug-Induced; Anticonvulsants; Australia; Carbamazepine; Female; Humans; Male; Pregnancy; Pregnancy Complications; Topiramate; Valproic Acid; Zonisamide

Certain antiepileptic drugs are associated with an increased risk for major congenital malformations (MCM). However, little is known regarding recent patterns of antiepileptic drug (ASM) prescriptions to women of childbearing age with epilepsy (WCE) in the United States.. Data from the Medical Expenditure Panel Survey was analyzed between the years 2004-2015 to determine trends in national antiepileptic drug prescriptions for WCE. Analysis of associations between demographic covariates and prescription of ASMs with MCM rate > 5% (topiramate, valproate, or phenobarbital) was performed with logistic regression.. There was a weighted total of 395,292 WCE. 29.1% (23.2%-35.8%) of WCE were prescribed an AED with MCM rate > 5%. The odds of a LEV prescription significantly increased in the 2010-2012 (OR 2.91, 95% CI 1.09-7.79) and 2013-2015 (OR 5.06, 95% CI 2.02-12.67) intervals compared to 2004-2006. Conversely, the odds of PB prescriptions significantly decreased in 2010-2012 (OR 0.13, 95% CI 0.02-0.83) and 2013-2015 (OR 0.13, 95% CI 0.02-0.93) compared to 2004-2006. WCE between the ages of 25-34 (OR = 2.67, 95% CI = 1.32-5.41) and 35-44 years (OR = 2.59, 95% CI = 1.23-5.45), had lower odds of being prescribed ASMs with MCM rate > 5% compared to those between the ages of 15-24 years.. Between 2004 and 2015, the prescriptions of ASMs given to WCE has changed. Regardless, nearly one third were prescribed potentially teratogenic medications despite available and affordable safer alternatives. Identifying factors associated with the prescription of teratogenic drugs to WCE is critical so that it may be further limited in the future.

Topics: Abnormalities, Drug-Induced; Adult; Anticonvulsants; Epilepsy; Female; Humans; Pregnancy; Pregnancy Complications; Topiramate; United States; Valproic Acid

To assess the relative risk of oral clefts associated with maternal use of high and low doses of topiramate during the first trimester for epilepsy and nonepilepsy indications.. This population-based study nested in the US 2000-2010 Medicaid Analytic eXtract included a cohort of 1,360,101 pregnant women with a live-born infant enrolled in Medicaid from 3 months before conception through 1 month after delivery. Oral clefts were defined as the presence of a recorded diagnosis in claims during the first 90 days after birth. Women with a topiramate dispensing during the first trimester were compared with those without any dispensing and with an active reference group of women with a lamotrigine dispensing during the first trimester. Risk ratios (RRs) were estimated with generalized linear models with fine stratification on the propensity score of treatment to control for potential confounders. Stratified analyses by indication of use and dose were conducted.. The risk of oral clefts at birth was 4.1 per 1,000 in the 2,425 infants born to women exposed to topiramate compared with 1.1 per 1,000 in the unexposed group (RR 2.90, 95% confidence interval [CI] 1.56-5.40). The RR among women with epilepsy was 8.30 (95% CI 2.65-26.07); among women with other indications such as bipolar disorder, it was 1.45 (95% CI 0.54-3.86). The median daily dose for the first prescription filled during the first trimester was 200 mg for women with epilepsy and 100 mg for women without epilepsy. For topiramate monotherapy, the RR for oral clefts associated with doses ≤100 mg was 1.64 (95% CI 0.53-5.07) and for doses >100 mg it was 5.16 (95% CI 1.94-13.73). Results were similar when lamotrigine was used as a reference group.. The increased risk of oral clefts associated with use of topiramate early in pregnancy was more pronounced in women with epilepsy, who used higher doses.

Topics: Abnormalities, Drug-Induced; Adult; Anticonvulsants; Cleft Palate; Cohort Studies; Dose-Response Relationship, Drug; Epilepsy; Female; Humans; Lamotrigine; Pregnancy; Pregnancy Complications; Pregnancy Trimester, First; Risk; Topiramate; United States; Young Adult

Evidence for the comparative teratogenic risk of antiepileptic drugs is insufficient, particularly in relation to the dosage used. Therefore, we aimed to compare the occurrence of major congenital malformations following prenatal exposure to the eight most commonly used antiepileptic drugs in monotherapy.. We did a longitudinal, prospective cohort study based on the EURAP international registry. We included data from pregnancies in women who were exposed to antiepileptic drug monotherapy at conception, prospectively identified from 42 countries contributing to EURAP. Follow-up data were obtained after each trimester, at birth, and 1 year after birth. The primary objective was to compare the risk of major congenital malformations assessed at 1 year after birth in offspring exposed prenatally to one of eight commonly used antiepileptic drugs (carbamazepine, lamotrigine, levetiracetam, oxcarbazepine, phenobarbital, phenytoin, topiramate, and valproate) and, whenever a dose dependency was identified, to compare the risks at different dose ranges. Logistic regression was used to make direct comparisons between treatments after adjustment for potential confounders and prognostic factors.. Between June 20, 1999, and May 20, 2016, 7555 prospective pregnancies met the eligibility criteria. Of those eligible, 7355 pregnancies were exposed to one of the eight antiepileptic drugs for which the prevalence of major congenital malformations was 142 (10·3%) of 1381 pregnancies for valproate, 19 (6·5%) of 294 for phenobarbital, eight (6·4%) of 125 for phenytoin, 107 (5·5%) of 1957 for carbamazepine, six (3·9%) of 152 for topiramate, ten (3·0%) of 333 for oxcarbazepine, 74 (2·9%) of 2514 for lamotrigine, and 17 (2·8%) of 599 for levetiracetam. The prevalence of major congenital malformations increased with the dose at time of conception for carbamazepine (p=0·0140), lamotrigine (p=0·0145), phenobarbital (p=0·0390), and valproate (p<0·0001). After adjustment, multivariable analysis showed that the prevalence of major congenital malformations was significantly higher for all doses of carbamazepine and valproate as well as for phenobarbital at doses of more than 80 mg/day than for lamotrigine at doses of 325 mg/day or less. Valproate at doses of 650 mg/day or less was also associated with increased risk of major congenital malformations compared with levetiracetam at doses of 250-4000 mg/day (odds ratio [OR] 2·43, 95% CI 1·30-4·55; p=0·0069). Carbamazepine at doses of more than 700 mg/day was associated with increased risk of major congenital malformations compared with levetiracetam at doses of 250-4000 mg/day (OR 2·41, 95% CI 1·33-4·38; p=0·0055) and oxcarbazepine at doses of 75-4500 mg/day (2·37, 1·17-4·80; p=0·0169).. Different antiepileptic drugs and dosages have different teratogenic risks. Risks of major congenital malformation associated with lamotrigine, levetiracetam, and oxcarbazepine were within the range reported in the literature for offspring unexposed to antiepileptic drugs. These findings facilitate rational selection of these drugs, taking into account comparative risks associated with treatment alternatives. Data for topiramate and phenytoin should be interpreted cautiously because of the small number of exposures in this study.. Bial, Eisai, GlaxoSmithKline, Janssen-Cilag, Novartis, Pfizer, Sanofi-Aventis, UCB, the Netherlands Epilepsy Foundation, and Stockholm County Council.

Topics: Abnormalities, Drug-Induced; Adult; Anticonvulsants; Carbamazepine; Dose-Response Relationship, Drug; Epilepsy; Female; Humans; Lamotrigine; Levetiracetam; Logistic Models; Male; Oxcarbazepine; Phenobarbital; Phenytoin; Pregnancy; Pregnancy Complications; Topiramate; Valproic Acid; Young Adult

To investigate the relationship between antiepileptic drug (AED) polytherapy in pregnant women and the risk of fetal malformations as prescribing practice changed, with valproate being used less often and at lower doses. Specifically, the risks associated with two of the most common AEDs included in polytherapy over recent years, levetiracetam and topiramate, were examined.. An observational cohort study in which malformation rates were analyzed in 1,461 pregnancies exposed to AED monotherapy, and in 484 exposed to antiepileptic drug combinations, from the Australian Register of Antiepileptic Drugs in Pregnancy over a 15-year period (1999-2014).. Fetal malformation rates had fallen over time in monotherapy pregnancies, but increased in polytherapy pregnancies, despite decreasing use and lower dosages of valproate. The rise in polytherapy malformation rates began around 2005 when levetiracetam and topiramate use began to increase. Excluding pregnancies involving valproate exposure, malformation rates were higher in the remaining polytherapy pregnancies as compared with the monotherapy ones (6.90% vs. 3.64%; odds ratio [OR] 1.96, 95% confidence interval [CI] 1.14-3.39). Malformation rates were similar in polytherapy pregnancies whether or not levetiracetam was included (7.14% vs. 8.38%), but were higher in polytherapy pregnancies involving topiramate (14.94% vs. 6.55%: OR 2.507, 95% CI 1.23-5.10). Logistic regression showed that topiramate in polytherapy had a positive dose relationship with teratogenicity risk (p = 0.025).. The malformation risk associated with AED polytherapy depends on the specific drugs involved. Topiramate, when used as part of AED polytherapy that did not include valproate, was associated with a dose-related increased risk of fetal malformations.

Topics: Abnormalities, Drug-Induced; Anticonvulsants; Cohort Studies; Dose-Response Relationship, Drug; Drug Therapy, Combination; Epilepsy; Female; Fructose; Humans; Male; Pregnancy; Prenatal Exposure Delayed Effects; Regression Analysis; Risk Factors; Topiramate; Valproic Acid

We measured birth prevalence of major congenital malformations (MCMs) after topiramate use during pregnancy to screen for a possible signal of increased risk.. Using four healthcare databases, we identified three cohorts of pregnant women: cohort 1, used topiramate during the first trimester; cohort 2, used topiramate or another antiepileptic drug previously but not during pregnancy; and cohort 3, were pregnant and did not use topiramate but had indications for use individually matched to those of users. Cohort 1 was compared with cohorts 2 and 3. MCMs were a code for any major congenital malformation dated within 30 days of the delivery date on the mother's claims or within 365 days after infant birth date, excluding a genetic or syndromic basis, and with procedure or healthcare usage consistent with the MCM diagnosis code in the 365 days after infant birth.. Of the 10 specific common MCMs evaluated, 1 (conotruncal heart defects) had a prevalence ratio greater than 1.5 for both primary comparisons, and 4 (ventricular septal defect, atrial septal defect, hypospadias, coarctation of the aorta) had a prevalence ratio greater than 1.5 for one of the two comparisons. Following screening of organ systems with elevated MCMs, the prevalence ratio was greater than 1.5 for patent ductus arteriosus in both comparisons and for obstructive genitourinary defects in one comparison.. To evaluate a large number of MCMs across many pregnancies, we used crude methods for detecting potential signals. Therefore, these results should be seen as potential signals, not causal.

Topics: Abnormalities, Drug-Induced; Cohort Studies; Female; Fructose; Humans; Pregnancy; Prevalence; Risk Assessment; Topiramate; United States

The primary aim of this study was to assess the risks of fetal growth restriction and birth defects in children exposed prenatally to newer and older antiepileptic drugs, using an unselected epilepsy cohort. Deliveries recorded in the compulsory Medical Birth Registry of Norway 1999-2011 formed the study population. All 2,600 children exposed to antiepileptic drugs during pregnancy were compared to all 771,412 unexposed children born to women without epilepsy. Children of untreated mothers with epilepsy served as an internal control group. The main outcomes were small for gestational age birth weight and head circumference, and major congenital malformations. Children exposed to antiepileptic drugs had a moderate risk of growth restriction. Infants exposed to topiramate had a considerable risk of microcephaly (11.4 vs. 2.4 %; OR 4.8; CI 2.5-9.3) and small for gestational age birth weight (24.4 vs. 8.9 %; OR 3.1; 95 % CI 1.9-5.3). Carbamazepine, lamotrigine, levetiracetam, oxcarbazepine, gabapentin, and pregabalin had low malformation rates, whereas topiramate tended to have an elevated malformation rate. Valproate monotherapy was associated with a significant risk of birth defects (6.3 vs. 2.9 %; OR 2.5; CI 1.6-3.8), and specifically with septal heart defects and hypospadias. For mothers using valproate, the presence of major birth defect in one child was associated with a markedly increased risk for the siblings (42.9 vs. 6.7 %; OR 10.4; CI 2.3-46.7). Children of untreated mothers with epilepsy had malformation risk similar to the reference group. In conclusion, topiramate was associated with a substantial risk of fetal growth restriction, and possibly an increased malformation rate. Other newer-generation antiepileptic drugs had a low malformation rate. Valproate monotherapy had a significant malformation risk, especially in repeated pregnancies.

Topics: Abnormalities, Drug-Induced; Adult; Anticonvulsants; Birth Weight; Cohort Studies; Epilepsy; Female; Fetal Growth Retardation; Fructose; Humans; Infant, Newborn; Infant, Small for Gestational Age; Norway; Pregnancy; Pregnancy Complications; Registries; Risk; Topiramate; Valproic Acid

To evaluate fetal or neonatal outcomes (with a focus on major congenital anomalies) with use of topiramate monotherapy and to examine whether differences occurred in the reporting and patterns of these outcomes for pregnant women with and without epilepsy.. Spontaneous, postmarketing reports involving women who used topiramate monotherapy during pregnancy from 18 July 1995 (International Birth Date of topiramate) through 30 April 2011 were retrieved from the sponsor's (Janssen Research & Development, LLC) Global Medical Safety database. All formulations for topiramate, used as monotherapy, were selected for the analysis. Monotherapy was defined as any situation where no other AED was listed in the pregnancy case report, either as a suspect or concomitant medication, regardless of indication. Results were summarized descriptively.. A total of 1163 cases of women who used topiramate monotherapy during pregnancy (for any indication) were retrieved from the Global Medical Safety database. Since some women used topiramate for more than one indication, there were a total of 1199 reported indications for topiramate monotherapy, which were primarily for treatment of epilepsy (n=599), accounting for half of the indications, and migraine prophylaxis (n=240, 20.0%). Out of 1163 cases, pregnancy outcome was reported in 50.6% (n=589). Live birth was the most frequently reported outcome, regardless of indication (epilepsy, 78.8% [312/396]; prophylaxis of migraine, 59. 3% [48/81]; other indication, 64.4% [85/132]). Cleft lip or palate anomalies (epilepsy, n=15; migraine, n=2; other indication, n=4; and indication not reported, n=2), limb, hand, or other skeletal anomalies (epilepsy, n=13; migraine, n=2; other indication, n=0; and indication not reported, n=1), and respiratory or cardiovascular anomalies (epilepsy, n=12; migraine, n=1; other indication, n=1; and indication not reported, n=2) were the most often reported major fetal or neonatal anomalies. More reported major fetal or neonatal anomalies occurred in patients being treated for epilepsy (53/79 anomaly-indication pairs) compared with patients being treated for migraine prophylaxis (10/79 anomaly-indication pairs).. Although incidence rates cannot be calculated based on spontaneous adverse event reporting, this summary of reported pregnancy and neonatal outcomes with use of topiramate monotherapy suggests that the risk for major fetal or neonatal anomalies may differ based on the indication for topiramate.

Topics: Abnormalities, Drug-Induced; Adult; Adverse Drug Reaction Reporting Systems; Anticonvulsants; Epilepsy; Female; Fructose; Humans; Infant, Newborn; Migraine Disorders; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Topiramate

To assess the risk of teratogenicity from maternal intake of the more widely used newer antiepileptic drugs, especially lamotrigine, levetiracetam and topiramate.. Use of confidence interval and regression methods to compare risks of foetal malformation in pregnancies in women exposed (n = 1572) and in women with epilepsy not exposed (n = 153) to antiepileptic drugs in the first trimester.. Compared with the foetal malformation rate in women with epilepsy who were untreated in the first trimester (3.3%), the malformation rates for lamotrigine (4.6%), levetiracetam (2.4%) and topiramate (2.4%), all in monotherapy, were not statistically significantly different. However, the malformation rates for topiramate as part of polytherapy (14.1%) and for valproate in both monotherapy (13.8%) and polytherapy (10.2%) were statistically significantly higher. Regression analysis of combined monotherapy and polytherapy data showed no statistically significant increased risk of teratogenesis associated with lamotrigine or levetiracetam, but a statistically significant and dose-related risk for first trimester topiramate (P = 0.01) and valproate (P < 0.0001) exposure.. Evidence from this and other studies suggests that lamotrigine and levetiracetam have low risk for teratogenesis, but that topiramate exposure early in pregnancy may be associated with dose-related anatomical teratogenesis, as valproate is already known to be.

Topics: Abnormalities, Drug-Induced; Adult; Anticonvulsants; Epilepsy; Female; Fetus; Fructose; Humans; Lamotrigine; Levetiracetam; Piracetam; Pregnancy; Registries; Risk; Topiramate; Triazines; Valproic Acid

To study associations between patterns of fetal malformation and individual antiepileptic drugs taken during pregnancy.. Multiple variable logistic regression and other statistical analyses of data relating to 1733 fetuses from 1703 pregnancies (147 of which were not exposed to antiepileptic drugs during pregnancy).. There were statistically significant (P < 0.05) associations between (i) valproate exposure and spina bifida, malformations of the heart and great vessels, digits, skull bones, and brain, but not hypospadias, cleft palate/lip and mouth abnormalities, (ii) topiramate exposure and hypospadias and brain maldevelopments, and (iii) carbamazepine (CBZ) exposure and renal tract abnormalities.. The valproate findings are mostly in keeping with the published literature, but the topiramate finding regarding hypospadias and the association between CBZ exposure and various renal tract abnormalities raise questions of organ specific teratogenesis. More extensive data are desirable, particularly in relation to topiramate, which is being used increasingly as a migraine prophylactic in women of childbearing potential.

Topics: Abnormalities, Drug-Induced; Anticonvulsants; Australia; Epilepsy; Female; Fetal Diseases; Fructose; Humans; Male; Pregnancy; Pregnancy Complications; Prenatal Exposure Delayed Effects; Regression Analysis; Risk Factors; Topiramate; Valproic Acid

In the United States, an estimate of 1.3 million women suffering from epilepsy are in their childbearing age. Potential teratogenicity of antiepileptic drugs (AEDs) is of concern to these women considering pregnancy because discontinuing pharmacotherapy during pregnancy may not be advised due to the risk of seizures that may be dangerous to the mother as well as the fetus. Using a Relational Online Analytical Processing (ROLAP) software licensed by Simultek, we searched for medications reported for congenital jaw and oral cavity malformation on the FDA Adverse Event Reporting System (AERS), a voluntary adverse event reporting program that contains over 55 million adverse event reports of medical products in the United.States. Our results indicate that various forms of valproic acid, and more importantly, newer generation antiepileptic agents including lamotrigine, topiramate, and gabapentin show signals for either congenital jaw or oral malformation. Although teratogenic potential of valproic acid has long been confirmed, information on teratogenicity of the newer generation antiepileptic drugs is relatively scarce and inconclusive. Early safety signals on the teratogenic potential of AEDs detected in this study are crude statistics that do not establish causation nor exclude confounding. The results require validation and further investigation via properly controlled epidemiological studies.

Topics: Abnormalities, Drug-Induced; Adverse Drug Reaction Reporting Systems; Amines; Anticonvulsants; Cyclohexanecarboxylic Acids; Data Mining; Datasets as Topic; Female; Fructose; Gabapentin; gamma-Aminobutyric Acid; Humans; Jaw Abnormalities; Lamotrigine; Mouth Abnormalities; Pregnancy; Risk Factors; Topiramate; Triazines; Valproic Acid

Data on the use in pregnancy of the new antiepileptic drugs (AED) are limited. We analysed data collected by the Australian Pregnancy Register to provide information on their relative teratogenicity. The database containing pregnancy outcomes from 1317 women with epilepsy (WWE) was examined for three widely used new AED in monotherapy in the first trimester--lamotrigine, levetiracetam and topiramate. This was compared with outcomes of pregnant WWE on monotherapy with three traditional AED, and with untreated women. The incidence of malformations associated with lamotrigine monotherapy was 12/231 (5.2%), with topiramate 1/31 (3.2%) and with levetiracetam 0/22 (0%). This compares with rates of 1/35 (2.9%) for phenytoin, 35/215 (16.3%) for valproate (VPA), 19/301 (6.3%) for carbamazepine and 6/116 (5.2%) for untreated women. There was no evidence of dose-dependent risks of foetal malformation, except with VPA monotherapy. We conclude that the new AED appear no more teratogenic than traditional drugs in monotherapy.

Topics: Abnormalities, Drug-Induced; Anticonvulsants; Australia; Drug Administration Schedule; Female; Fructose; Humans; Lamotrigine; Levetiracetam; Piracetam; Pregnancy; Registries; Topiramate; Triazines

BACKGROUND The second generation antiepileptic drugs (AEDs), which include lamotrigine, topiramate, and gabapentin, have been introduced during the past 20 years. Because the newer AEDs differ in their pharmacokinetics from the first generation AEDs, it is hoped that the second generation AEDs will be less teratogenic. METHODS The findings in pregnancy cohorts and case-control studies concerning lamotrigine, topiramate and gabapentin-exposed pregnancies have been analyzed. RESULTS The rate of all malformations in lamotrigine monotherapy-exposed pregnancies has been between 2.0 and 5.6%, in comparison to baseline rates of 1.1 to 3.6% in two unexposed comparison groups. Compared to reference populations, a higher risk (0.4%) of isolated oral clefts has been observed in one cohort of 1562 lamotrigine-exposed pregnancies, but the risk was lower (0.1%) in other studies. In topiramate-exposed pregnancies, the rate of all malformations has been 4.2 to 4.9%, with an increase in oral clefts with and without other anomalies. The limited information available now for gabapentin has shown no evidence of teratogenicity. Concerning other developmental effects of these drugs, young children exposed to lamotrigine in utero have shown no deficits in cognitive function. Prenatal exposure to topiramate has been associated with an elevated frequency of small size for gestational age newborns. CONCLUSIONS The information available suggests an increased risk of oral clefts in infants exposed to topiramate, and perhaps lamotrigine, early in pregnancy, and of growth retardation for topiramate-exposed infants. Larger sample sizes are needed to clarify the questions that have been raised.

Topics: Abnormalities, Drug-Induced; Adult; Amines; Anticonvulsants; Case-Control Studies; Child; Child, Preschool; Cleft Palate; Cognition; Cohort Studies; Cyclohexanecarboxylic Acids; Female; Fructose; Gabapentin; gamma-Aminobutyric Acid; Gestational Age; Humans; Infant; Infant, Newborn; Lamotrigine; Learning; Maternal Exposure; Pregnancy; Registries; Risk; Topiramate; Triazines

Topics: Abnormalities, Drug-Induced; Anti-Obesity Agents; Benzazepines; Delayed-Action Preparations; Drug Approval; Drug Combinations; Female; Fructose; Humans; Obesity; Phentermine; Pregnancy; Serotonin Receptor Agonists; Topiramate; United States; United States Food and Drug Administration; Weight Loss

Recent information suggests that use of the antiepileptic drug topiramate in pregnancy may raise some concerns, especially if used in polytherapy. Moreover, data on the safety of this antiepileptic drug for the breastfed infant are very limited. However, use of topiramate may be unavoidable in women who wish to become pregnant but who have already experienced severe adverse reactions to antiepileptic medications considered relatively safe in this female condition. Hence, we describe the healthy outcome of a male infant exposed to topiramate through the placenta and maternal milk and who was conceived while the mother was undergoing folic acid supplementation.

Topics: Abnormalities, Drug-Induced; Anticonvulsants; Breast Feeding; Dietary Supplements; Epilepsy; Female; Folic Acid; Fructose; Humans; Infant, Newborn; Maternal-Fetal Exchange; Milk, Human; Pregnancy; Risk Assessment; Topiramate; Vitamins; Young Adult

To study the impact of pregnancy on the serum concentration/dose ratio (C/D-ratio) of topiramate (TPM).. Twelve women with epilepsy using TPM during pregnancy, and 15 pregnancies were studied. The main target variable was the C/D-ratio at baseline and during pregnancy. Additional variables were changes in TPM dose, concomitant use of other antiepileptic drugs, seizure frequency, and pregnancy outcome. Clinical and pharmacological data were obtained from the women's medical records.. The average C/D-ratios in the second and third trimester were 30% (p = 0.002, n = 11) and 34% (p = 0.001, n = 8) lower than the baseline values, respectively. The interindividual variability was pronounced. Increased seizure frequency was common in pregnant women using TPM, but a correlation to the decline in TPM C/D-ratio could not be established from our data.. Dose-corrected serum concentrations of TPM appear to decline gradually throughout pregnancy. The underlying mechanisms are not known. Increased glomerular filtration may play a major role. During pregnancy, therapeutic drug monitoring of TPM may be useful.

Topics: Abnormalities, Drug-Induced; Anticonvulsants; Dose-Response Relationship, Drug; Drug Therapy, Combination; Epilepsies, Myoclonic; Epilepsies, Partial; Epilepsy; Epilepsy, Absence; Epilepsy, Tonic-Clonic; Female; Fructose; Humans; Infant, Newborn; Metabolic Clearance Rate; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Pregnancy Trimester, First; Pregnancy Trimester, Second; Pregnancy Trimester, Third; Topiramate; Treatment Outcome

Topics: Abnormalities, Drug-Induced; Anticonvulsants; DNA Damage; Female; Fructose; Histone Deacetylase Inhibitors; Histone Deacetylases; Humans; Infant, Low Birth Weight; Infant, Newborn; Mutagenicity Tests; Neural Tube Defects; Patient Education as Topic; Pregnancy; Prenatal Exposure Delayed Effects; Risk Assessment; Topiramate; Ultrasonography, Prenatal; Valproic Acid

(1) Numerous follow-up studies of pregnancies in women with epilepsy show that valproic acid is more teratogenic than other antiepileptics. The risk of malformations increases with doses above 1000 mg/day; (2) Malformations associated with valproic acid include neural tube defects in 1-2% of exposed children, as well as urogenital, craniofacial and digital abnormalities. Cardiac disorders and limb defects have also been reported; (3) Convergent results of several cohort studies show that exposure to valproic acid in utero has detrimental effects on intelligence, language and behavior, which appear in school-age children; (4) In practice, the use of valproic acid should be avoided throughout pregnancy, as well as by women of childbearing age not using effective contraception. If a woman is planning pregnancy, the choice of valproic acid should be reassessed with the patient. If valproic acid therapy is maintained, the minimum effective daily dose should be determined and folic acid supplementation initiated.

Topics: Abnormalities, Drug-Induced; Anticonvulsants; Carbamazepine; Cohort Studies; Contraindications; Dose-Response Relationship, Drug; Epilepsy; Female; Fructose; Humans; Intelligence; Lamotrigine; Language Development Disorders; Phenytoin; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Prenatal Exposure Delayed Effects; Psychomotor Disorders; Topiramate; Triazines; Valproic Acid

Topiramate (Topamax) is licensed to be used, either in monotherapy or as adjunctive treatment, for generalized tonic clonic seizures or partial seizures with or without secondary generalization and for prevention of migraine. The safety of topiramate in human pregnancy is largely unknown. Here we report on our experience of pregnancies exposed to topiramate.. This study is part of a prospective, observational, registration and follow-up study. Suitable cases are women with epilepsy who become pregnant while taking topiramate either singly or along with other antiepileptic drugs (AEDs), and who are referred before outcome of the pregnancy is known. The main outcome measure is the major congenital malformation (MCM) rate. Secondary outcomes include risk of specific MCM, minor malformation rate, birthweight, and gestational age at delivery.. Full outcome data are available on 203 pregnancies. Of these, 178 resulted in live birth; 16 had an MCM (9.0%; 95% CI 5.6% to 14.1%). Three MCMs were observed in 70 monotherapy exposures (4.8%; 95% CI 1.7% to 13.3%) and 13 in cases exposed to topiramate as part of a polytherapy regimen (11.2%; 95% CI 6.7% to 18.2%). Four of the MCMs were oral clefts (2.2%; 95% CI 0.9% to 5.6%). Four cases of hypospadias were reported (5.1%; 95% CI 0.2% to 10.1%) among 78 known live male births of which two were classified as major malformations.. The number of outcomes of human pregnancies exposed to topiramate is low, but the major congenital malformation rate for topiramate polytherapy raises some concerns. Overall, the rate of oral clefts observed was 11 times the background rate. Although the present data provide new information, they should be interpreted with caution due to the sample size and wide confidence intervals.

Topics: Abnormalities, Drug-Induced; Adult; Anticonvulsants; Cleft Palate; Confidence Intervals; Drug Therapy, Combination; Epilepsy; Female; Follow-Up Studies; Fructose; Gestational Age; Humans; Hypospadias; Incidence; Infant, Newborn; Male; Pregnancy; Prospective Studies; Registries; Sample Size; Topiramate; United Kingdom

In spite of a substantial increase in the use of topiramate at child bearing age, very little is known regarding its use in pregnancy. We describe the outcome of 52 pregnancies with 41 liveborn infants from which it seems that topiramate reduces birth weight without decreasing gestational age at delivery, but does not seem to increase the risk for structural defects. There was an increased rate of spontaneous abortions not related to the drug effects.

Topics: Abnormalities, Drug-Induced; Abortion, Spontaneous; Anticonvulsants; Birth Weight; Female; Fructose; Humans; Infant, Newborn; Pregnancy; Topiramate

Topiramate is a new generation, antiepileptic drug used for the treatment of persistent partial crises. To date no specific teratogenic effects have been reported in humans, but they have appeared in experimental animals. We present the case of a neonate whose mother suffered from partial epilepsy, which was treated with topiramate throughout pregnancy at doses of 300 mg per day. When the child was born agenesis of the right thumb, hypoplasia of the left thumb, and syndactylia of the second and third toes of the foot with agnesis of some phalanges, and hypoplasia of the right orbicular muscle in the mouth were observed. No etiologic cause was found. We discuss whether there could have been a causal relationship with topiramate monotherapy.

Topics: Abnormalities, Drug-Induced; Abnormalities, Multiple; Anticonvulsants; Bone and Bones; Female; Fructose; Humans; Infant, Newborn; Male; Maternal-Fetal Exchange; Pregnancy; Topiramate

Topics: Abnormalities, Drug-Induced; Acetates; Adult; Amines; Anti-Anxiety Agents; Anticonvulsants; Bipolar Disorder; Carbamazepine; Cognition Disorders; Cyclohexanecarboxylic Acids; Dizziness; Dose-Response Relationship, Drug; Drug Therapy, Combination; Fructose; Gabapentin; gamma-Aminobutyric Acid; Heart Defects, Congenital; Humans; Lamotrigine; Nausea; Obesity; Stevens-Johnson Syndrome; Topiramate; Triazines; Valproic Acid