Objective: To assess the safety of the newer antiepileptic drugs (AEDs) during pregnancy. Methods: The study population was pregnant women who enrolled in the North American AED Pregnancy Registry between 1997 and 2011. Data on AED use and maternal characteristics were collected through phone interviews at enrollment, at 7 months9 gestation, and postpartum. Malformations were confirmed by medical records. The risk of major malformations was calculated among infants exposed to specific AEDs in monotherapy during the first trimester of pregnancy and among an unexposed group. Risk ratios (RRs) and 95% confidence intervals (CIs) were estimated with logistic regression. Results: The risk of major malformations was 9.3% (30 of 323) for valproate, 5.5% (11 of 199) for phenobarbital, 4.2% (15 of 359) for topiramate, 3.0% (31 of 1.033) for carbamazepine, 2.9% (12 of 416) for phenytoin, 2.4% (11 of 450) for levetiracetam, and 2.0% (31 of 1,562) for lamotrigine. Compared with lamotrigine, the RR was 5.1 (95% CI 3.0–8.5) for valproate, 2.9 (1.4–5.8) for phenobarbital, and 2.2 (1.2–4.0) for topiramate. The proportion of women with epilepsy who had seizures during pregnancy ranged from 23% for valproate to 31% for lamotrigine. Valproate was associated with a higher risk of neural tube defects, hypospadias, cardiac defects, and oral clefts and phenobarbital with a higher risk of cardiac defects and oral clefts; 5 infants exposed to topiramate (1.4%) had a cleft lip. Conclusions: AEDs such as valproate and phenobarbital were associated with a higher risk of major malformations than newer AEDs such as lamotrigine and levetiracetam. Topiramate was associated with an increased risk of cleft lip compared with that of a reference population.

Comparative safety of antiepileptic drugs during pregnancy

OBJECTIVE: Bipolar disorder affects 0.5%–1.5% of individuals in the United States. The typical age at onset is late adolescence or early adulthood, placing women at risk for episodes throughout their reproductive years. General guidelines for the treatment of bipolar disorder are available from the American Psychiatric Association, but additional issues arise when these guidelines are applied in the treatment of peripartum women. The authors summarize knowledge regarding the management of bipolar disorder during pregnancy and the postpartum period, with a focus on managing mania, hypomania, and the psychotic components of the illness. METHOD: An expert panel reviewed articles that address the management of bipolar disorder and the consequences of the use of mood stabilizers during pregnancy, and a consensus document was generated. RESULTS: The treatment of bipolar disorder in pregnant women involves significant challenges. Some mood stabilizers, e.g., sodium valproate and carbamazepine, are human teratoge...

/pdf/management-of-bipolar-disorder-during-pregnancy-and-the-1ogafn7dh5.pdf

Management of Bipolar Disorder During Pregnancy and the Postpartum Period

Pregnancy outcomes in women with epilepsy: A systematic review and meta-analysis of published pregnancy registries and cohorts

Objective: To determine if exposure to benzodiazepines during the first trimester of pregnancy increases risk of major malformations or cleft lip or palate. Design Meta-analysis. Setting: Studies from 1966 to present. Subjects: Studies were located with Medline, Embase, Reprotox, and from references of textbooks, reviews, and included articles. Included studies were original, concurrently controlled studies in any language. Interventions:Data extraction and quality assessment were done independently and in duplicate. Main outcome measures: Maternal exposure to benzodiazepines in at least the first trimester; incidence of major malformations or oral cleft alone, measured as odds ratios and 95% confidence intervals with a random effects model. Results:Of over 1400 studies reviewed, 74 were retrieved and 23 included. In the analysis of cohort studies fetal exposure to benzodiazepine was not associated with major malformations (odds ratio 0.90; 95% confidence interval 0.61 to 1.35) or oral cleft (1.19; 0.34 to 4.15). Analysis of case-control studies showed an association between exposure to benzodiazepines and development of major malformations (3.01; 1.32 to 6.84) or oral cleft alone (1.79; 1.13 to 2.82). Conclusions:Pooled data from cohort studies showed no association between fetal exposure to benzodiazepines and the risk of major malformations or oral cleft. On the basis of pooled data from case-control studies, however, there was a significant increased risk for major malformations or oral cleft alone. Until more research is reported, level 2 ultrasonography should be used to rule out visible forms of cleft lip.

https://www.bmj.com/content/bmj/317/7162/839.full.pdf

Benzodiazepine use in pregnancy and major malformations or oral cleft: meta-analysis of cohort and case-control studies

Objective: To compare the risk for congenital malformations in offspring between women with epilepsy being treated with antiepileptic drugs (AEDs) during pregnancy and those who discontinued their antiepileptic medication before pregnancy in a population-based cohort of female patients with epilepsy. Methods: All patients with epilepsy (n = 20,101) eligible for AED reimbursement for the first time during 1985 to 1994 were identified from the Social Insurance Institution of Finland. Information on births during 1991 to 2000 was obtained from the National Medical Birth Registry. Information on AED use during pregnancy and on pregnancy outcomes was abstracted from medical records. Results: Congenital malformations were more common among offspring of women on antiepileptic medication (65/1,411; 4.6%) than among offspring of untreated patients (26/939; 2.8%) ( p = 0.02). The risk of malformations was substantially higher in the offspring of patients using valproate as monotherapy (OR = 4.18; 95% CI: 2.31, 7.57) or valproate as polytherapy (OR = 3.54; 95% CI: 1.42, 8.11) than of untreated patients. Polytherapy without valproate was not associated with increased risk of malformations. Conclusion: Excess risk was confined to patients using valproate during pregnancy. The risk for malformations was not elevated in offspring of mothers using carbamazepine, oxcarbazepine, or phenytoin (as monotherapy or polytherapy without valproate).

Antiepileptic drug use of women with epilepsy and congenital malformations in offspring.

Summary: A multi-institutional collaborative study was conducted concerning the course of pregnancy and delivery and the incidence of abnormal infants delivered of epileptic women. Of 657 women receiving antiepileptic drugs, 73% delivered live infants, 14% had miscarriage or stillbirth, and 13% underwent induced abortion. In contrast to the above findings, 80% of 162 patients not receiving antiepileptic drugs delivered live infants and 4% had miscarriage or stillbirth. The latter outcome was significantly increased in the medicated patients. In this series, 63 (9.9%) of 638 live births were malformed, 55 (11.5%) being from medicated mothers and 3 (2.3%) from nonmedicated mothers. The incidence of fetal malformation in medicated mothers was thus five times as high as that in nonmedicated mothers. Cleft lip and/or palate and malformations involving the cardiovascular system were found frequently in the infants from medicated mothers. General background factors that might exert teratogenic effects on pregnant patients with epilepsy were studied, and the potential toxicity of antiepileptic drugs to the fetus was also analyzed. In this regard, consideration should be given to whether the patient has partial epileptic seizures, whether the patient herself exhibits any malformation, or whether her previous pregnancy resulted in an abnormal outcome. The incidence of fetal malformation was the highest (12.7%) in the medicated patients who had epileptic seizures during the pregnancy. It is presumed on the basis of the results of analysis of the data that a combination of more than three drugs and a daily dose greater than a certain minimal level is likely to produce malformed infants.



ZUSAMMENFASSUNG

In vielen Institutionen wurde eine kollaborative Studie uber den Verlauf der Schwangerschaft, der Geburt und die Haufigkeit von Abnormitaten bei Kin-dern von Schwangeren mit Epilepsie durchgefuhrt. 73% der 657 Frauen unter antiepileptischer Therapie bekamen lebende Kinder, 14% hatte eine Fehl- oder Totgeburt und bei 13% wurde ein Abort eingeleitet ImGegensatz zu diesen Ergebnissen hatten 80% von 162 Patienten ohne Antiepileptica Lebendgeburten, 4% eine Fehloder Totgeburt. Die letztere war signifikant hoher bei den Patientinnen, die Antiepileptica erhielten. In dieser Serie waren 63 von 638 Lebendgeburten (9.9%) miRbildet, 55 (1 1.5%) stammten von therapier-ten Muttern, 3 (2,3)%) von nicht therapierten Muttern.



Die Haufigkeit fetaler Fehlbildungen bei therapierten war 5mal hoher als bei nicht therapierten Muttern. Lippen- und/oder Gaumenspalte und MiRbildungen im kardiovaskularen Bereich wurden haufig bei Kindern therapierter Mutter gefunden. Die allgemeinen Hintergrundsfaktoren, die einen teratogenen EinfluR auf Schwangere mit Epilepsie ausuben konnten, wurden untersucht und die mogliche Toxicitat der Antiepileptica auf den Fetus analysiert. In diesen Untersuchungen sollte berucksichtigt werden, ob der Patient fokale epileptische Anfalle hat, o b e r selbst eine MiDbildung hat oder ob fruhere Schwangerschaften abnorm endeten. Die Haufigkeit der fetalen Fehlbildungen war am groRten (12.7%) bei therapiertenPatienten, die epileptische Anfalle wahrend der Schwangerschaft bekamen. Aufgrund dieser Resultate wird angenommen, daR die Kombination von mehr als 3 Medikamenten und eine tagliche Dosierung oberhalb eines Grenzwertes wahrscheinlich zu fehlgebildeten Kindern fuhren.

Multi‐institutional Study on the Teratogenicity and Fetal Toxicity of Antiepileptic Drugs: A Report of a Collaborative Study Group in Japan

RESUME

Dans des experiences utilisant des rates gravides, les faits suivants ont ete remarques: 1/ chez les rates soumises a l'effet d'embrasement amygdalien, le seuil d'obtention des crises generalisees etait significativement plus eleve dans le groupe de rates gravides que dans le groupe non gravide; 2/ chez les rates prenant 4 mg/kg per os de phenobarbital une fois par jour, il n'y avait pas de difference significative des taux sanguins entre les groupes gravide et non gravide; 3/ chez les rates soumises a l'embrasement amygdalien et prenant 4 mg/kg de phenobarbital par voie orale une fois/jour, le seuil d'obtention de la crise generalisee etait significativement plus eleve dans le groupe gravide que dans le groupe non gravide. L'on peut suggerer que l'elevation du seuil due aux modifications physiologiques en relation avec la gravidite antagonise la chute du seuil qui devrait etre produite par la baisse des taux sanguins des anticonvulsivants, elle-meme due a l'augmentation du volume de distribution en relation avec la prise de poids pendant la gravidite, si la dose de medicaments est la meme.



RESUMEN

En un experimento utilizando ratas embarazadas se observaron los siguientes resultados. (1). De las ratas sometidas a un condicionamiento amigdalino (kindled), el umbral para ataques generalizados del grupo de ratas embarazadas fue significativamente mas alto que el de las ratas no embarazadas. (2). No se encontraron diferencias significativas entre el grupo de embarazadas y el de no embarazadas de los niveles sericos de fenobarbital administrado oralmente en dosis de 4 mg/kg en una dosis diaria. (3). De las ratas sometidas a un condicionamiento amigdalino (kindled) que tomaban una dosis unica al dia de fenobarbital de 4 mg/kg, el umbral para ataques generalizados en el grupo de ratas embarazadas fue significativamente mas elevado que el del grupo de no embarazadas. Se puede sugerir que el incremento del umbral debido a cambios fisiologicos durante la gestacion antagoniza la caida del umbral producido por una reduccion de los niveles sericos de los anticonvulsivantes al producirse un incremento del volumen de distribucion por aumentar el peso corporal durante el embarazo cuando la dosis de la medicacion permanece constante.



ZUSAMMENFASSUNG

In einem Rattenexperiment wurden folgende Ergebnisse erzielt: 1. Bei Ratten nach Amygdalon Kindling war die Schwelle fur das Triggern generalisierter Anfalle in der trachtigen Gruppe signifikant hoher als in der nicht-trachtigen Gruppe. 2. Bei Ratten, die oral 4 mg/kg Phenobarbital einmal taglich bekommen, existieren keine signifikanten Unterschiede in den Serum-Spiegeln zwischen der trachtigen und der nichttrachtigen Gruppe. 3. Bei Ratten mit Amygdalon Kindling, die einmal taglich 4 mg/kg Phenobarbital bekommen, ist die Schwelle fur das Triggern generalisierter Anfalle in der trachtigen Gruppe signifikant hoher als in der nicht-trachtigen Gruppe. Es kann daraus geschlossen werden, das die Erhohung der Krampfschwelle durch physiologische Gestationsveranderungen der Verminderung der Schwelle durch niedrige Serum-Spiegel von Antikonvulsiva entgegenwirkt, denn das vergroserte Verteilungs-volumen aufgrund des erhohten Korpergewichts wahrend der Schwangerschaft andert sich bei Dosiserhohung nicht.



Summary: In experiments using pregnant rats, the following results were noted: (a) Of the amygdaloid kindled rats, the generalized seizure triggering threshold of the pregnant group was significantly higher than that of the nonpregnant group. (b) Of the rats taking oral phenobarbital, 4 mg/kg once a day, there was no significant difference of serum levels between the pregnant group and the nonpregnant group. (c) Of the amygdaloid kindled rats taking oral phenobarbital, 4 mg/kg once a day, the generalized seizure triggering threshold of the pregnant group was significantly higher than that of the nonpregnant group. It may be suggested that, when the drug dose remains the same, the rise in threshold by gestational physiological changes antagonizes the fall in threshold by decreased serum levels of anticonvulsants because of increasing distribution volume due to increasing body weight during pregnancy.

Generalized Seizure Triggering Threshold and Serum Phenobarbital Levels During Pregnancy in Rats

It is known that the clinical ictal symptoms of frontal lobe epilepsy include those characterized by a unique motor manifestation that is differentiated from convulsion or gesturai automatism. A wide variety of ictal symptoms has been reported,la most of which are not clearly differentiated from gestural automatism and are symptomatologically defined obscurely. Those reports express different opinions about the correlation between seizure symptomatology and the localization EEG foci. We define brief, complicated motor seizure as a clinical symptom which is a motor manifestation mainly in the trunk and limbs, is complicated, violent, very mechanical, repetitive and short-lasting. This seizure is different from convulsion or gestural automatism. In this report, we describe the clinicoelectrographic correlation based on findings of ictal and interictal EEGs recorded with scalp electrodes.

Brief, complicated motor seizure.

Summary: : To determine the primary factors responsible for the increased incidence of malformation in the offspring of antiepileptic drug (AED)-treated epileptic mothers, special attention was paid to drug combinations in a prospective study of 172 deliveries. Variables used for analysis were eight antiepileptic drugs (AEDs) and total daily dosages (drug score), and seven background factors consisting of maternal age at delivery, gravida, outcome of previous pregnancy, etiology and type of epilepsy, occurrence of seizures in the first trimester of pregnancy, and seizure frequency during pregnancy. The overall rate of malformation was 14.0%. Thirty-one patients were administered a single drug, and the rate of malformation was 6.5%. The remaining 141 patients were treated with multiple AEDs, and the rate of malformation was 15.6%. The drug score of the latter group was significantly higher than the former (p = 0.01). There was no definite dose- dependent increase in the incidence of malformations associated with any individual AEDs. There was no relationship between the type of defect and individual AEDs. Wilcoxon rank-sum test revealed significant association between the drug score, valproate (VPA), and congenital malformation. Carbamazepine (CBZ) also reached an almost significant level. Furthermore, VPA polypharmacy produced the highest incidence of malformation, higher than that produced by any other AED or drug combination. There was no significant association between the presence of malformations and the other putative risk factors. These results suggest that high dose of AEDs reflecting polypharmacy, VPA polypharmacy in particular, are primary factors responsible for the increased incidence of congenital malformation in the offspring of treated epileptic mothers.



RESUME

Afin de determiner les facteurs primares de ľaccroissement do risque de malformation chez les enfants issus de meres egpileotiques traitees, une attention particuliee reaete portge aux associations de medicaments antigpeleptiques dans une euide prospective de 172 accouchements. Les variables suivantes ont ete analysees: 8 antiepileptiques et leur dose quotidienne totale, ainsi que 7 facteurs de contexte (age de la mere au moment de ľaccouchement, parite, resultats des grossesses anterieures, etiologie et type de ľepilepsie, survenue de crise pendant le premier trimestre de la grossesse, et frequence des crises pendant la grossesse). Le taux global de malformations a ete de 14.0%. 31 patientes recevaient une monotherapie, avec un taux de malformations de 6.5%. Les autres 141 patientes etaient traitees avec plusieurs medicaments antiepileptiques, et le taux de malformations a ete de 15.6%. Ce dernier taux est significativement plus eleve que le precedent (p = 0.01J. II n'y avait pas de dose-dependance evidente dans ľincidence des malformations en fonction des differents antiepileptiques. Il n'y avait pas de correlation entre le type de malformation et le type ďantiepileptique. Le test de Wilcoxon a revele une association significative entre le valproate (VPA) et les malformations con-genitales. La carbamazepine (CBZ) presentait une relation presque significative avec les malformations. De plus, une polymedication avec VPA a produit la plus importante incidence de malformations, supenieure a tout autreantiepileptique ou association. Il n'y a pas eu ďassociation significative entre la presence de malformations et les autres facteurs de risque possibles. Ces resultats suggerent que le traitement a doses elevees par medicaments antiepileptiques, en particulier la polytherapie au VPA, est un facteur primaire de ľaugmentation ďincidence des malformations congenitales chez les enfants issus de meres epileptiques.



RESUMEN

En un estudio prospectivo de 172 partos, se ha prestado atencien especial a la utilizacion de combinacion de medicamentos para determinar los factores primarios que pudieran ser respon-sables de un incremento de la incidencia de malformaciones en los recien nacidos de madres epileapticas tratadas con medicacion antiepileptica. Se han utilizado 8 medicaciones antiepilepticas como variables para determinar en este analisis (AEDs) asi como el total de las dosis utilizadas diariamente (“score” de medica-mento) y 7 factores de los antecedentes: edad de la madre en el momento del parto, numero de embarazos, resultado de los embarazos previos, etio logia y tipo de la epilepsyia, presencia de ataques en el primer trimestre del embarazo y frecuencia de los ataques durante el embarazo. El numero total de malformaciones fue de 14.0%. Treinta y un casos habian tornado solo una medicacion y el numero de malformaciones fue de 6.5%. Los restantes 141 casos habian sido tratados con multiples AEDs y el numero de malformaciones fue del 15.6%. La “score” de medi-camento de este ultimo grupo fue significativamente mas elevado que en el previo (p = 0.01). No se encontrf un incremento definitivo, dosis-dependiente, en la incidencia de las malformaciones en relacion con ningen AEDs individual. No se observo‘ ningen tipo de relation entre la clase de defecto y los AEDs individuales. El test del nivel de la suma de Wilcoxon mostro una relacion significativa entre la “score” de la medicacioan, Valproate (VPA), y la malformacion congenita. La Carbamacepina (CBZ) tambien alcanzo un nivel casi significativo. Ademas, la polifarmacia VPA produjo los mas altos niveles de incidencia de malformaciones, mas elevados que ninguna otra malformacion antiepileptica o combinacion de drogas. No se encontro asociacion significativa entre la presencia de malformaciones y la de otros factores de riesgo putativos. Estos resultados sugieren que dosis altas de medicaciones antiepilepticas que reflejan polifarmacia, en particular la polifarmacia de VPA, son los factores mas importantes responsables para el aumento de la incidencia de malformaciones congenitas en los hijos de las madres epilepticas tratadas.



ZUSAMMENFASSUNG

Um die primar verantwortlichen Faktoren fur das erhohte Vorkommen von Fehlbildungen bei Kindern von mit Antiepilep-tika behandelten Muttern zu ermitteln, wurde in einer prospektiven Studie bei 172 Geburten der Kombination von Antiepileptika besondere Aufmerksamkeit gewidmet. Als Variable gal ten 8 Antiepileptika (AEDs), sowie tagliche Gesamtdosis (drug-score) und 7 Hintergrundfaktoren, wie Alter der Mutter, Schwangerschaft, vorherige Schwangerschaften, Atiologie und Typ der Epilepsie, Auftreten von Anfallen im ersten Trimester der Schwangerschaft und Anfallshafigkeit wahrend der Schwanger-schaft. Die Gesamtrate der Fehlbildungen lag bei 14.0%. Bei Patienten mit Monotherapie lagen die Fehlbildungen bei 6.5%. Die verbliebenen 141 Falle erhielten eine Kombinationstherapie und boten in 15.6% Fehlbildungen. Bei dieser Gruppe lag der drug-score wesentlich hoher als bei der ersten Gruppe (p = 0.01). Ein eindeutiger dosis-abhangiger Anstieg von Malformationen mit irgendeinem Antiepileptikum konnte nicht gefunden werden. Ferner bestand keine Beziehung zwischen Typ des Defekts und Antiepileptika. Der Wilcoxon-Test zeigte signifikante Assoziationen zwischen dem drug-score von Valproat und con-genitalen Fehlbildungen. Auch Carbamazepin erreichte eine fast signifikante Ḧone. Weiterhin bewirkte die Valproat-Kombination die hochste Malformationsrate–hoher als irgendeine andere Kombination oder ein einzelnes Antiepileptikum. Es bestand keine signifikante Korrelation zwischen Auftreten von Fehlbildungen und den anderen Risikofaktoren. Die Ergenisse lassen vermuten, daβ hohe Dosen von Antiepileptika im Sinne der Polypharmazie, besonders Valproat, fur das erhote Auftreten von Fehlbildungen verantwortlich sind bei Kindern von antiepileptisch behandelten Muttern.

Teratogenicity of antiepileptic drugs: analysis of possible risk factors.

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Papers

Multi‐institutional Study on the Teratogenicity and Fetal Toxicity of Antiepileptic Drugs: A Report of a Collaborative Study Group in Japan

Generalized Seizure Triggering Threshold and Serum Phenobarbital Levels During Pregnancy in Rats

Brief, complicated motor seizure.

Teratogenicity of antiepileptic drugs: analysis of possible risk factors.