topiramate and Cleft-Lip

Migraine is a very common medical disorder characterized by attacks of moderate-severe headache, nausea and disability. Topiramate is an effective, popular prophylactic migraine treatment, which is approved for use in adults and adolescents. Due to its multiple mechanisms of action, topiramate has multiple potential safety issues, including systemic and CNS adverse events, which may complicate therapy.. This review evaluates common adverse events as seen in the pivotal trials of topiramate for migraine as well as those observed in postmarketing studies. These include weight loss, metabolic acidosis, renal calculi, acute angle closure glaucoma, visual distortions and cognitive slowing. Topiramate use during pregnancy is associated with an increased risk of cleft lip. This review highlights both common and unusual safety issues associated with topiramate use, including important drug interactions and a comparison with other migraine prophylactic agents.. Topiramate is highly effective in migraine prophylaxis but clinicians using the drug need to be aware of the potential for bothersome or serious adverse events. When treating with topiramate, use a slow titration to the goal dose of 100 mg or the lowest dose, which helps prevent migraine.

Topics: Adolescent; Adult; Animals; Anticonvulsants; Cleft Lip; Dose-Response Relationship, Drug; Drug Interactions; Female; Fructose; Humans; Infant, Newborn; Migraine Disorders; Pregnancy; Topiramate

Topiramate is an anti-epileptic drug that is commonly prescribed not just to prevent seizures but also migraine headaches, with over 8 million prescriptions dispensed annually. Topiramate use during pregnancy has been linked to significantly increased risk of babies born with orofacial clefts (OFCs). However, the exact molecular mechanism of topiramate teratogenicity is unknown. In this study, we first used an unbiased antibody array analysis to test the effect of topiramate on human embryonic palatal mesenchyme (HEPM) cells. This analysis identified 40 differentially expressed proteins, showing strong connectivity to known genes associated with orofacial clefts. However, among known OFC genes, only TGFβ1 was significantly upregulated in the antibody array analysis. Next, we validated that topiramate could increase expression of TGFβ1 and of downstream target phospho-SMAD2 in primary mouse embryonic palatal mesenchyme (MEPM) cells. Furthermore, we showed that topiramate treatment of primary MEPM cells increased expression of SOX9. SOX9 overexpression in chondrocytes is known to cause cleft palate in mouse. We propose that topiramate mediates upregulation of TGFβ1 signaling through activation of γ-aminobutyric acid (GABA) receptors in the palate. TGFβ1 and SOX9 play critical roles in orofacial morphogenesis, and their abnormal overexpression provides a plausible etiologic molecular mechanism for the teratogenic effects of topiramate.

Topics: Animals; Anticonvulsants; Cell Line; Cells, Cultured; Cleft Lip; Cleft Palate; Gene Expression Regulation, Developmental; Humans; Mice; Palate; SOX9 Transcription Factor; Teratogens; Topiramate; Transforming Growth Factor beta1; Up-Regulation

First marketed in the USA in 1996, topiramate (TPM) is an antiepileptic drug later approved for migraine prophylaxis, and in 2012 for weight loss in combination with phentermine. Some studies indicate an elevated prevalence of oral cleft (OC) in infants exposed to TPM in utero. We evaluated the association between TPM use in early pregnancy and the risk of OC.. This retrospective cohort study used 1997-2011 automated data from four sources: HealthCore and OptumInsight (commercial insurance claims), Truven Health (Medicaid claims), and Kaiser Permanente Northern California Region (electronic medical records). We compared the prevalence of OCs in infants of women exposed to TPM in the first trimester (TPM cohort) with the prevalence in infants of women formerly exposed to TPM or other antiepileptic drugs (formerly exposed [FE] cohort) and infants of women with similar medical profiles (SMPs) to the TPM cohort that were not exposed to TPM (SMP cohort). To control for confounding, we used stratification and standardization for individual variables and propensity score deciles.. The birth prevalence of OCs was 0.36% (7/1945) in the TPM cohort, 0.14% (20/13 512) in the FE cohort, and 0.07% (9/13 614) in the SMP cohort. Standardized by site, the prevalence ratio (PR) for TPM versus FE was 2.5 (95% CI: 1.0-6.0) and for TPM versus SMP was 5.4 (95% CI: 2.0-14.6). Adjustment for covariates one at a time or by propensity score yielded similar results.. Consistent with other recent epidemiologic research, first-trimester TPM exposure was associated with an elevated birth prevalence of OC.

Topics: California; Cleft Lip; Cleft Palate; Cohort Studies; Databases, Factual; Electronic Health Records; Female; Fructose; Humans; Infant, Newborn; Pregnancy; Prenatal Exposure Delayed Effects; Prevalence; Retrospective Studies; Topiramate

The objective of this study was to evaluate the association between the use of monotherapy topiramate in pregnancy and cleft lip with or without cleft palate (CL/P) in the offspring.. Data from the Slone Epidemiology Center Birth Defects Study (BDS) from 1997 to 2009 and the National Birth Defects Prevention Study (NBDPS) from 1997 to 2007 were analyzed. Conditional logistic regression was used to compare the first-trimester use of topiramate monotherapy to no antiepileptic drug use during the periconceptional period between the mothers of infants with CL/P and the mothers of controls for each study separately and in pooled data.. The BDS contained 785 CL/P cases and 6986 controls; the NBDPS contained 2283 CL/P cases and 8494 controls. The odds ratios (exact 95% confidence intervals) for the association between topiramate use and CL/P were 10.1 (1.1-129.2) in the BDS, 3.6 (0.7-20.0) in the NBDPS, and 5.4 (1.5-20.1) in the pooled data.. First-trimester use of topiramate may be associated with CL/P.

Topics: Adult; Anticonvulsants; Case-Control Studies; Cleft Lip; Cleft Palate; Epilepsy; Female; Fructose; Humans; Incidence; Pregnancy; Pregnancy Trimester, First; Prenatal Exposure Delayed Effects; Prevalence; Risk; Topiramate; Young Adult

In the roundtable that follows, clinicians discuss a study published in this issue of the Journal in light of its methodology, relevance to practice, and implications for future research. Article discussed: Margulis AV, Mitchell AA, Gilboa SM, et al; National Birth Defects Prevention Study. Use of topiramate in pregnancy and risk of oral clefts. Am J Obstet Gynecol 2012;207:405.e1-7.

Topics: Anticonvulsants; Cleft Lip; Cleft Palate; Female; Fructose; Humans; Pregnancy; Prenatal Exposure Delayed Effects; Topiramate