topiramate and Cleft-Palate

Topiramate (TPM) is an increasingly used drug during childbearing ages for treatment of epilepsy, migraine, and appetite suppression as well as for off-label indications such as sleep and psychiatric disorders. Presently, while some reports suggested an increased risk of oral cleft (OC), these reports are balanced by studies that could not confirm such association. We conducted a meta-analysis of all studies reporting on women exposed to TPM during pregnancy. Of the 2327 publications reviewed, 6 articles met the inclusion criteria including 3420 patients and 1,204,981 controls. The odd ratio (OR) of OC after the first trimester exposure to TPM exposure was 6.26 (95% confidence interval: 3.13-12.51; P = 0.00001). This study provides strong evidence that TPM is associated with an increased risk of OC in infants exposed to TPM during embryogenesis and should lead to a careful review of TPM use in women of reproductive ages.

Topics: Anti-Obesity Agents; Anticonvulsants; Cleft Palate; Female; Fructose; Humans; Pregnancy; Pregnancy Trimester, First; Prenatal Exposure Delayed Effects; Risk; 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

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

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

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

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

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