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Use of topiramate in pregnancy and risk of oral clefts

      Objective

      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.

      Study Design

      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.

      Results

      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.

      Conclusion

      First-trimester use of topiramate may be associated with CL/P.

      Key words

      Approximately 0.5% of pregnant women in the United States have epilepsy.
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      • Hopp J.
      • Ting T.Y.
      • et al.
      Practice parameter update: management issues for women with epilepsy—focus on pregnancy (an evidence-based review): obstetrical complications and change in seizure frequency: report of the Quality Standards Subcommittee and Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and American Epilepsy Society.
      Unless the patient has been free of seizures for 2-5 years, the current recommendation is to continue antiepileptic therapy throughout pregnancy to avoid seizures that can cause hypoxic damage to the fetus and maternal morbidity and mortality.
      • Walker S.P.
      • Permezel M.
      • Berkovic S.F.
      The management of epilepsy in pregnancy.
      Older antiepileptics, such as phenytoin, phenobarbital, and valproic acid, carry an increased risk for various specific congenital malformations.
      • Holmes L.B.
      • Harvey E.A.
      • Coull B.A.
      • et al.
      The teratogenicity of anticonvulsant drugs.
      • Hernandez-Diaz S.
      • Werler M.M.
      • Walker A.M.
      • Mitchell A.A.
      Neural tube defects in relation to use of folic acid antagonists during pregnancy.
      • Werler M.M.
      • Ahrens K.A.
      • Bosco J.L.
      • et al.
      Use of antiepileptic medications in pregnancy in relation to risks of birth defects.
      However, little is known about the fetal safety of the increasingly used newer antiepileptics.
      • Vajda F.J.
      • Hollingworth S.
      • Graham J.
      • et al.
      Changing patterns of antiepileptic drug use in pregnant Australian women.
      • Molgaard-Nielsen D.
      • Hviid A.
      Newer-generation antiepileptic drugs and the risk of major birth defects.
      • Dugan K.
      • Margulis A.V.
      • Hernandez-Diaz S.
      Topiramate use in women of childbearing age from the U.S. National Health and Human Nutrition Examination Survey (NHANES) (abstract).
      See Journal Club, page 435
      Topiramate was approved in the United States for the treatment of generalized tonic-clonic and partial seizures in 1996 and for prevention of migraine in 2004 (the prevalence of migraine peaks at child-bearing age in women).
      • Kurth T.
      • Hernandez-Diaz S.
      Commentary: triptan use during pregnancy: a safe choice?.
      In 2006, a generic version was introduced in the US market. Off-label uses include conditions that are also prevalent among women of reproductive age: sleep
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      Treatment options for parasomnias.
      • Aurora R.N.
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      • et al.
      Best practice guide for the treatment of nightmare disorder in adults.
      and eating disorders,
      • Tata A.L.
      • Kockler D.R.
      Topiramate for binge-eating disorder associated with obesity.
      other psychiatric conditions,
      • Stoffers J.
      • Vollm B.A.
      • Rucker G.
      • Timmer A.
      • Huband N.
      • Lieb K.
      Pharmacological interventions for borderline personality disorder.
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      • Jenike M.A.
      • et al.
      Double-blind, placebo-controlled trial of topiramate augmentation in treatment-resistant obsessive-compulsive disorder.
      and weight loss.
      • Tata A.L.
      • Kockler D.R.
      Topiramate for binge-eating disorder associated with obesity.
      Animal studies reported an increased risk of craniofacial defects in litters exposed in utero to low doses of topiramate and other malformations and low birthweight at higher doses. Some postmarketing studies in pregnant women have suggested an increased risk in birth defects overall and, possibly, an increased risk in cleft lip with or without cleft palate (CL/P); however, evidence is inconclusive because neither the exposure nor oral clefts are frequent.
      • Molgaard-Nielsen D.
      • Hviid A.
      Newer-generation antiepileptic drugs and the risk of major birth defects.
      • Vajda F.J.
      • Hitchcock A.
      • Graham J.
      • O'Brien T.
      • Lander C.
      • Eadie M.
      The Australian Register of Antiepileptic Drugs in Pregnancy: the first 1002 pregnancies.
      • Ornoy A.
      • Zvi N.
      • Arnon J.
      • Wajnberg R.
      • Shechtman S.
      • Diav-Citrin O.
      The outcome of pregnancy following topiramate treatment: a study on 52 pregnancies.
      • Hunt S.
      • Russell A.
      • Smithson W.H.
      • et al.
      Topiramate in pregnancy: preliminary experience from the UK Epilepsy and Pregnancy Register.
      • Hernandez-Diaz S.
      • Mittendorf R.
      • Holmes L.B.
      Comparative safety of topiramate during pregnancy.
      The replication of these findings in large case-control studies, using methods suitable for small sample sizes is critical.
      We therefore conducted a matched case-control analysis to evaluate the risk of oral clefts in infants exposed to topiramate during the first trimester of pregnancy, using data from 2 large congenital malformations case-control studies in North America. We report both study-specific and pooled results.

      Materials and Methods

      Data sources and study populations

      The Boston University Slone Epidemiology Center Birth Defects Study (BDS) and the Centers for Disease Control and Prevention's (CDC) National Birth Defects Prevention Study (NBDPS) share several features related to study design, data collection, case classification, and analyses, which have been described in detail elsewhere.
      • Hernandez-Diaz S.
      • Werler M.M.
      • Walker A.M.
      • Mitchell A.A.
      Folic acid antagonists during pregnancy and the risk of birth defects.
      • Louik C.
      • Lin A.E.
      • Werler M.M.
      • Hernandez-Diaz S.
      • Mitchell A.A.
      First-trimester use of selective serotonin-reuptake inhibitors and the risk of birth defects.
      • Mitchell A.A.
      • Gilboa S.M.
      • Werler M.M.
      • Kelley K.E.
      • Louik C.
      • Hernandez-Diaz S.
      Medication use during pregnancy, with particular focus on prescription drugs: 1976-2008.
      • Yoon P.W.
      • Rasmussen S.A.
      • Lynberg M.C.
      • et al.
      The National Birth Defects Prevention Study.
      • Rasmussen S.A.
      • Olney R.S.
      • Holmes L.B.
      • Lin A.E.
      • Keppler-Noreuil K.M.
      • Moore C.A.
      Guidelines for case classification for the National Birth Defects Prevention Study.
      Both studies include infants with major congenital malformations as cases and infants with no malformations as controls. Prepregnancy and pregnancy exposure information is collected after delivery by means of a detailed computer-assisted telephone interview conducted in English or Spanish.
      Questions focus on maternal medical history and details of medication use and other exposures from 2 (BDS) or 3 (NBDPS) months prior to and through the end of pregnancy. Specifically, the questionnaires in both studies inquire about the presence of seizures or epilepsy and its treatment prior to and during pregnancy. To avoid duplication of participants, the BDS does not enroll women who are in the same catchments as NBDPS subjects. BDS subjects included women with conception dates from May 1997 to July 2009, and the NBDPS included women with expected due dates from October 1997 to December 2007.
      During the study period, the BDS recruited mothers of fetuses, stillborn and live-born infants with malformations, and infants without malformations in the greater metropolitan areas of Philadelphia, PA, San Diego, CA, and Toronto, Canada, and portions of Massachusetts and New York. Starting in 1998, subjects also included a random sample of all births without congenital malformations in Massachusetts as controls. To identify study subjects, BDS staff regularly review admissions and discharge records of birth centers, community hospitals, and pediatric clinics; subjects are also identified from the birth defects registries in Massachusetts and New York. Interviews are conducted within 6 months of delivery.
      • Hernandez-Diaz S.
      • Werler M.M.
      • Walker A.M.
      • Mitchell A.A.
      Folic acid antagonists during pregnancy and the risk of birth defects.
      • Louik C.
      • Lin A.E.
      • Werler M.M.
      • Hernandez-Diaz S.
      • Mitchell A.A.
      First-trimester use of selective serotonin-reuptake inhibitors and the risk of birth defects.
      • Mitchell A.A.
      • Gilboa S.M.
      • Werler M.M.
      • Kelley K.E.
      • Louik C.
      • Hernandez-Diaz S.
      Medication use during pregnancy, with particular focus on prescription drugs: 1976-2008.
      Infants with chromosomal abnormalities, single-gene conditions, and malformations associated with amniotic bands were excluded from the present study. The BDS is compliant with the Health Insurance Portability and Accountability Act of 1996 and is approved by the relevant institutional review boards.
      To ascertain cases, the NBDPS utilizes the birth defects surveillance systems of Arkansas, California, Georgia (Metropolitan Atlanta Congenital Defects Program operated by the CDC), Iowa, Massachusetts, North Carolina, New Jersey, New York, Texas, and Utah, covering an annual birth population of more than 482,000 (approximately 10% of births in the United States). Eligible subjects include liveborn infants with major congenital malformations and with no accompanying chromosomal abnormalities or single-gene conditions. Most states included stillborn infants and terminations with major congenital malformations, with the exception of New Jersey, which did not include either, and Massachusetts, which did not include terminations. Controls are liveborn infants with no major malformations randomly selected from birth certificates or hospital discharge data from the participating states. Interviews are conducted between 6 weeks and 24 months after the estimated date of delivery.
      • Mitchell A.A.
      • Gilboa S.M.
      • Werler M.M.
      • Kelley K.E.
      • Louik C.
      • Hernandez-Diaz S.
      Medication use during pregnancy, with particular focus on prescription drugs: 1976-2008.
      • Yoon P.W.
      • Rasmussen S.A.
      • Lynberg M.C.
      • et al.
      The National Birth Defects Prevention Study.
      • Rasmussen S.A.
      • Olney R.S.
      • Holmes L.B.
      • Lin A.E.
      • Keppler-Noreuil K.M.
      • Moore C.A.
      Guidelines for case classification for the National Birth Defects Prevention Study.
      The NBDPS is Health Insurance Portability and Accountability Act compliant and approved by the institutional review boards of the CDC and all participating study centers.

      Exposure ascertainment

      First-trimester exposure was defined as the use of topiramate in the first 90 days after the conception date (first trimester). To avoid confounding by other antiepileptic drugs, the analysis was restricted to topiramate monotherapy, defined as no use of other antiepileptic drugs in the first trimester. Information on dose and indication was available in BDS data.

      Outcomes

      Both data sources define major congenital malformations as structural malformations with medical, surgical, or cosmetic relevance. In both studies, information on the presence of congenital malformations is obtained from hospital discharges and medical records, and experts review and classify each identified birth defect. Undescended testis, patent foramen ovale, or patent ductus arteriosus in newborns of less than 37 completed weeks of gestational age at birth are not included in analyses of either data set.
      The current study focused on cases diagnosed with CL/P because this was the specific malformation hypothesized to be associated with topiramate in previous postmarketing studies. Because some shared risk factors have been identified,
      • Mossey P.A.
      • Little J.
      • Munger R.G.
      • Dixon M.J.
      • Shaw W.C.
      Cleft lip and palate.
      we also planned to separately consider risks for cleft palate alone (CP). However, there were no infants with CP exposed to topiramate in either study, so no further analysis was conducted.

      Statistical analyses

      Main analysis

      We used conditional logistic regression to compare the use of topiramate monotherapy in the first trimester with no antiepileptic use in the 60 days prior to conception or in the first 90 days of pregnancy. All odds ratios (ORs) are reported with exact 95% confidence intervals (CIs). The analysis focused on major congenital malformations as a group (including oral clefts) and separately on CL/P with or without other major congenital malformations. In the study-specific primary analyses, matched sets were formed on the basis of year (2-year categories) and region (California, Massachusetts, New York, Pennsylvania, and Ontario for BDS and Arkansas, California, Georgia, Iowa, Massachusetts, New Jersey, New York, North Carolina, Texas, and Utah for NBDPS) of birth to account for potential differences in case selection that might have been introduced across regions and time. Matched sets contained as many cases and controls as were available per stratum. In analyses on pooled data, matched sets were formed on the basis of year and region of birth and study (BDS and NBDPS).

      Confounding factors

      Given the small number of exposed subjects involved in the analyses, it would be inappropriate to attempt to control confounding by traditional multivariable approaches. Instead, in our secondary analyses, to assess potential confounding by characteristics beyond year and region of birth, we repeated the conditional logistic regression analysis in the pooled data on new matched sets. To form these sets, we matched in this analysis case infants to control infants on year and region of birth, study and 1 more variable at a time from the following a priori defined list: maternal race/ethnicity; family history of oral clefts (first-degree relatives with CL/P or CP); maternal age at conception (age <25, 25 to <30, 30 to <35, ≥35 years); prepregnancy maternal body mass index (BMI; <18.5, 18.5 to <25, 25 to <30, ≥30 kg/m2); first-trimester cigarette smoking; first-trimester alcohol consumption; diagnosis of epilepsy; diagnosis of diabetes or gestational diabetes prior to or during the index pregnancy; and folic acid supplementation from single-ingredient or folic-acid containing multivitamin products (any use in the 2 months prior to the beginning of pregnancy or the first 2 months of pregnancy).

      Dose and indication

      We identified daily dose and indication among infants with CL/P and among controls from the BDS.
      Analyses were performed in SAS 9.1 (SAS Institute Inc, Cary, NC).

      Results

      Slone Birth Defects Study

      The study population consisted of 6983 controls and 10,618 infants with major congenital malformations (the latter excluded 2594 infants with chromosomal abnormalities, single-gene inherited diseases, malformations associated with amniotic bands, syndromic or metabolic disorders). Among the infants with malformations, 785 had CL/P. Maternal and offspring characteristics of CL/P cases and controls are presented in Table 1. Five infants with malformations were exposed to topiramate monotherapy, of which 3 had CL/P; 2 of the controls were exposed to topiramate. The OR comparing first-trimester exposure to topiramate monotherapy to no antiepileptic drug use for major congenital malformations was 1.22 (95% CI, 0.19–13.01) and for CL/P was 10.13 (95% CI, 1.09–129.21) (Table 2).
      TABLE 1Maternal and offspring characteristics of study participants
      CharacteristicsSlone Birth Defects StudyNational Birth Defects Prevention Study
      Infants without malformations (n = 6983)Infants with CL/P (n = 785)Infants without malformations (n = 8494)Infants with CL/P (n = 2283)
      Maternal age (y), mean (SD)29.3 (5.9)28.5 (6.1)27.3 (6.1)27.0 (6.1)
      Prepregnancy BMI (kg/m2), n (%)
       <18.5207 (3.0)38 (4.8)439 (5.2)150 (6.6)
       18.5 to <253964 (56.8)379 (48.3)4180 (49.2)1069 (46.8)
       25 to <301564 (22.4)173 (22.0)2033 (23.9)504 (22.1)
       30 to <35566 (8.1)75 (9.6)912 (10.7)255 (11.2)
       ≥35327 (4.7)52 (6.6)564 (6.6)182 (8.0)
      Maternal race/ethnicity, n (%)
       Non-Hispanic white4917 (70.4)507 (64.6)5004 (58.9)1376 (60.3)
       Non-Hispanic black538 (7.7)65 (8.3)959 (11.3)139 (6.1)
       Hispanic997 (14.3)124 (15.8)1975 (23.3)609 (26.7)
       Asian/Pacific Islander386 (5.5)71 (9.0)250 (2.9)59 (2.6)
       Native American/Alaskan NativeNANA43 (0.5)19 (0.8)
       Other139 (2.0)15 (1.9)260 (3.1)81 (3.5)
      Maternal education (y), n (%)
       ≤121936 (27.7)287 (36.6)3446 (40.6)1106 (48.4)
       13; 151635 (23.4)195 (24.8)2260 (26.6)583 (25.5)
       ≥163409 (48.8)303 (38.6)2637 (31.0)573 (25.1)
      First-degree relative with CL/P or CP31 (0.4)56 (7.1)29 (0.3)126 (5.5)
      Diabetes, n (%)365 (5.2)67 (8.5)559 (6.6)204 (8.9)
      Periconceptional folic acid supplementation, n (%)6087 (87.2)640 (81.5)6282 (74.0)1654 (72.4)
      Any smoking in first trimester, n (%)1150 (16.5)174 (22.2)1350 (15.9)494 (21.6)
      Any alcohol use in first trimester, n (%)2754 (39.4)257 (32.7)3087 (36.3)850 (37.2)
      Missing data among nonmalformed infants and infants with CL/P: Slone Birth Defects Study: 423 subjects did not report their BMI, 9 subjects did not report race/ethnicity, 3 did not report years of education, 262 did not report on smoking status, and 37 did not report on alcohol intake; National Birth Defects Prevention Study: 489 subjects did not report their BMI, 3 subjects did not report race/ethnicity, 172 did not report years of education, 144 did not report on smoking status.
      BMI, body mass index; CL/P, cleft lip with or without cleft palate; CP, cleft palate; NA, category not available.
      Margulis. Topiramate use in pregnancy and oral clefts. Am J Obstet Gynecol 2012.
      TABLE 2Use of topiramate in monotherapy in the first trimester of pregnancy and risk of major congenital malformations and CL/P
      Use of antiepileptic drugsInfants without malformationsInfants with major congenital malformations
      The major congenital malformations found in topiramate-exposed infants were left cleft lip, right cleft lip, and cleft palate, unilateral cleft lip and palate (unspecified side), cleft lip (not otherwise specified), bilateral cleft lip, bilateral cleft lip and palate, left Bochdalek diaphragmatic hernia, patent ductus arteriosus, patent foramen ovale, atrial septal defect (ostium secundum type), unspecified atrial septal defect, unspecified ventricular septal defect, coarctation of the aorta, pulmonary valve stenosis, unspecified brain anomalies, spina bifida, and anal atresia with fistula;
      Infants with CL/P
      nnOR (95% CI)nOR (95% CI)
      Slone Birth Defects Study
      Analyses conditional on year and region of birth;
       No use of antiepileptic drugs
      No antiepileptic drug use refers to no use of antiepileptic drugs in the 2 months prior to pregnancy or in the first trimester of pregnancy;
      693310,503Reference778Reference
       Topiramate monotherapy in first trimester251.22 (0.19-13.01)310.13 (1.09-129.21)
      National Birth Defects Prevention Study
      Analyses conditional on year and region of birth;
       No use of antiepileptic drugs843423,102Reference2256Reference
       Topiramate monotherapy in first trimester4100.92 (0.26-4.06)43.63 (0.66-20.00)
      Pooled data
      Analyses conditional on year and region of birth and study.
       No use of antiepileptic drugs15,36733,605Reference3034Reference
       Topiramate monotherapy in first trimester6151.01 (0.37-3.22)75.36 (1.49-20.07)
      CI, confidence interval; CL/P, cleft lip with or without cleft palate; OR, odds ratio.
      Margulis. Topiramate use in pregnancy and oral clefts. Am J Obstet Gynecol 2012.
      a The major congenital malformations found in topiramate-exposed infants were left cleft lip, right cleft lip, and cleft palate, unilateral cleft lip and palate (unspecified side), cleft lip (not otherwise specified), bilateral cleft lip, bilateral cleft lip and palate, left Bochdalek diaphragmatic hernia, patent ductus arteriosus, patent foramen ovale, atrial septal defect (ostium secundum type), unspecified atrial septal defect, unspecified ventricular septal defect, coarctation of the aorta, pulmonary valve stenosis, unspecified brain anomalies, spina bifida, and anal atresia with fistula;
      b Analyses conditional on year and region of birth;
      c No antiepileptic drug use refers to no use of antiepileptic drugs in the 2 months prior to pregnancy or in the first trimester of pregnancy;
      d Analyses conditional on year and region of birth and study.
      The daily dose and indication of topiramate among cases of CL/P were 25 mg (migraine) and 100 mg (epilepsy); the third case mother, who took the drug for depression, did not report the dose. The 2 control infants were both exposed to a daily dose of 100 mg for migraine prophylaxis.

      National Birth Defects Prevention Study

      The study population consisted of 8494 controls and 23,333 case infants. Of these, 2283 had CL/P. Maternal and offspring characteristics of CL/P cases and controls are presented in Table 1. Ten case infants, including 4 infants with CL/P, and 4 control infants received first-trimester monotherapy exposure to topiramate. The OR comparing first-trimester exposure to topiramate and no antiepileptic drug use for major congenital malformations was 0.92 (95% CI, 0.26–4.06) and for CL/P was 3.63 (95% CI, 0.66–20.00). The mothers of 2 infants with major congenital malformations (1 of them with CL/P) and 1 control infant reported having been diagnosed with epilepsy.

      Pooled data

      Among the pooled study population, first-trimester monotherapy exposure to topiramate was not associated with an increase in the risk of major congenital malformations overall (OR, 1.01; 95% CI, 0.37–3.22), but it was associated with an elevated risk of CL/P (OR, 5.36; 95% CI, 1.49–20.07). Point estimates and CIs were not substantially modified by matching on any additional characteristic in the analyses of either major congenital malformation (OR point estimates varied between 0.91 and 1.03) or CL/P (OR point estimates varied between 4.01 and 5.92) (data not shown).

      Comment

      Monotherapy topiramate use during the first trimester of pregnancy was associated with an increased risk of CL/P as compared with no use of antiepileptics in pooled data from the BDS and NBDPS.
      Topiramate has effects on multiple physiological pathways. It affects cell polarization through effects on various ion channels; it also inhibits the carbonic anhydrase
      • Tata A.L.
      • Kockler D.R.
      Topiramate for binge-eating disorder associated with obesity.
      and histone deacetylases; histone deacetylases are also inhibited by valproic acid.
      • Martinez-Frias M.L.
      Topiramate in pregnancy: preliminary experience from the UK Epilepsy and Pregnancy Register (letter to the editor).
      Litters born to pregnant rodents exposed to doses equivalent to 50% of the recommended human dose for epilepsy, or below, had an increased incidence of craniofacial defects (mice), low birthweight (mice and rats), or other structural variations (rats). Rabbits were affected only at high doses.
      In humans, a number of results, each based on a small number of exposed subjects, collectively suggest that the risk of major malformations is not increased or not largely so but that the risk of CL/P may be elevated. Our findings support these results. In 2008, Hunt et al
      • Hunt S.
      • Russell A.
      • Smithson W.H.
      • et al.
      Topiramate in pregnancy: preliminary experience from the UK Epilepsy and Pregnancy Register.
      reported an incidence of CL/P 11 times the background rate for topiramate-exposed infants in monotherapy, based on 2 cases among 70 exposures from the UK Epilepsy and Pregnancy Register; there were 3 infants with major congenital malformations in total. In the same year, Ornoy et al
      • Ornoy A.
      • Zvi N.
      • Arnon J.
      • Wajnberg R.
      • Shechtman S.
      • Diav-Citrin O.
      The outcome of pregnancy following topiramate treatment: a study on 52 pregnancies.
      reported 1 infant with a major congenital malformation (not an oral cleft) among 29 women exposed to topiramate monotherapy using the Israeli Teratology Service data. In 2010, Hernandez-Diaz et al
      • Hernandez-Diaz S.
      • Mittendorf R.
      • Holmes L.B.
      Comparative safety of topiramate during pregnancy.
      reported in an abstract 4 cases of cleft lip in 289 infants exposed in monotherapy in the first trimester in the North American Antiepileptic Drug Pregnancy Registry, which represented an elevated risk compared with an external reference population.
      These results were used by the US Food and Drug Administration in March 2011 to reclassify topiramate from pregnancy category C to pregnancy category D.
      Topamax (topiramate): label change—risk for development of cleft lip and/or cleft palate in newborns.
      Further information has been presented subsequent to these reports. In a population-based Danish cohort focused on newer antiepileptic medications, Molgaard-Nielsen and Hviid
      • Molgaard-Nielsen D.
      • Hviid A.
      Newer-generation antiepileptic drugs and the risk of major birth defects.
      identified 108 first-trimester topiramate-exposed pregnancies, among which there were 5 born with malformations; although they reported no significant increase in overall risk (OR, 1.44), it is of interest that one of the malformed infants had a CL/P (an absolute risk of 1% with wide confidence intervals).
      Additional reports, available only as abstracts, include a study by Day et al
      • Day W.
      • Yee S.
      • Peterson C.
      • Koren G.
      Assessment of the teratogenic risk in fetuses exposed to topiramate in utero.
      that reported almost identical risks of major congenital malformations in infants with topiramate monotherapy exposure in utero and infants born from untreated epileptic women, using pooled data from a variety of international sources, overlapping with some of the above-mentioned data (relative risk, 1.03). Pack et al
      • Pack A.
      • Meador K.
      • Bhattachuria A.
      Retrospective analysis of major congenital malformations (MCMs) and oral clefts (OC) associated with in utero topiramate exposure.
      reported no association between topiramate use in the 10 months prior to delivery and either major congenital malformations or oral clefts, relative to users of other antiepileptic drugs (relative risk for major congenital malformations, 1.18; for oral clefts, 1.26) and women with epilepsy who were not receiving topiramate (relative risk for major congenital malformations, 0.87; for oral clefts, 0.85), using commercial claims data from the United States.
      To our knowledge, no other specific malformations have been associated with topiramate. Although our findings do not suggest that topiramate increases the risk of malformations overall, we considered only one hypothesis related to specific malformations: CL/P. Although we observed no increased risk for other major malformations as a group, we cannot exclude the possibility that topiramate may be related to a modest increase in 1 or more specific defects.
      Although we were unable to perform a full dose-response analysis, our limited results do not suggest a threshold effect on infants born with CL/P because one case was exposed to the low dose of 25 mg/d for migraine prevention.
      Several antiepileptic drugs (eg, valproic acid, carbamazepine, phenytoin, phenobarbital, lamotrigine) have been associated with an increased risk of specific congenital malformations (eg, oral clefts, neural tube defects, heart defects, hypospadias, craniosynostosis, polydactyly).
      • Hernandez-Diaz S.
      • Werler M.M.
      • Walker A.M.
      • Mitchell A.A.
      Neural tube defects in relation to use of folic acid antagonists during pregnancy.
      • Werler M.M.
      • Ahrens K.A.
      • Bosco J.L.
      • et al.
      Use of antiepileptic medications in pregnancy in relation to risks of birth defects.
      • Jentink J.
      • Loane M.A.
      • Dolk H.
      • et al.
      Valproic acid monotherapy in pregnancy and major congenital malformations.
      • Jentink J.
      • Dolk H.
      • Loane M.A.
      • et al.
      Intrauterine exposure to carbamazepine and specific congenital malformations: systematic review and case-control study.
      • Holmes L.B.
      • Baldwin E.J.
      • Smith C.R.
      • et al.
      Increased frequency of isolated cleft palate in infants exposed to lamotrigine during pregnancy.
      A dose-related risk for major congenital malformations overall has been reported for valproic acid, phenobarbital, lamotrigine, and carbamazepine,
      • Morrow J.
      • Russell A.
      • Guthrie E.
      • et al.
      Malformation risks of antiepileptic drugs in pregnancy: a prospective study from the UK Epilepsy and Pregnancy Register.
      • Tomson T.
      • Battino D.
      • Bonizzoni E.
      • et al.
      Dose-dependent risk of malformations with antiepileptic drugs: an analysis of data from the EURAP epilepsy and pregnancy registry.
      although it was consistently replicated only for valproic acid.
      • Perucca E.
      Birth defects after prenatal exposure to antiepileptic drugs.
      • Cunnington M.
      • Ferber S.
      • Quartey G.
      Effect of dose on the frequency of major birth defects following fetal exposure to lamotrigine monotherapy in an international observational study.
      There is disagreement on whether antiepileptic drugs or epilepsy itself are responsible for the congenital malformations found in the infants born to epileptic women who are on antiepileptic treatment. Studies reported that epileptic women who do not use antiepileptic drugs during pregnancy are not at a higher risk of delivering affected infants than nonepileptic women who were not exposed to antiepileptic medications.
      • Holmes L.B.
      • Harvey E.A.
      • Coull B.A.
      • et al.
      The teratogenicity of anticonvulsant drugs.
      • Werler M.M.
      • Ahrens K.A.
      • Bosco J.L.
      • et al.
      Use of antiepileptic medications in pregnancy in relation to risks of birth defects.
      • Fried S.
      • Kozer E.
      • Nulman I.
      • Einarson T.R.
      • Koren G.
      Malformation rates in children of women with untreated epilepsy: a meta-analysis.
      However, residual confounding by epilepsy severity is generally difficult to rule out because severe, active epilepsy rarely remains untreated. In this study, epilepsy was reported by less than half of topiramate users. Epilepsy was a weak confounder; we could not assess the impact of seizures in pregnancy on congenital malformations.
      To our knowledge, no reports have suggested an association between migraine and congenital malformations. The vasoactive drug ergotamine, used to treat migraine crises, is contraindicated in pregnancy because of its risk of fetopathy,
      Ergomar sublingual tablets, 2 mg (ergotamine tartrate tablets, USP), prescribing information.
      but none of the women exposed to topiramate in our study reported exposure to ergotamine.
      Despite our use of data from 2 large birth defects case-control studies, the main limitation of this analysis is its low number of exposed cases and exposed controls. For this reason, even though we applied methods that are appropriate for small cell counts, our ability to control for confounding is limited. We matched on data collection–related factors in all analyses and assessed other potential confounders individually, but we could not assess confounding by combinations of these or conduct stratified analyses because of the paucity of data. The differences in effect size for topiramate and CL/P between the BDS and the NBDPS may be due to the sampling variability, the different amounts of residual confounding, or varying underlying risk.
      Our results must be interpreted in light of several additional limitations: recall bias is a potential limitation of this study because exposure information is collected after the pregnancy outcome is known. To diminish the potential for bias, the computer-assisted interview is scripted, ensuring identical questions are asked to mothers of case and control infants. Recall is enhanced by presenting the interviewees with a list of medications and illnesses in the script. Some studies have attempted to diminish the risk of recall bias by comparing infants with the malformation of interest with infants with malformations unrelated to the exposure. In this study, we did not use such a comparison group because the safety pattern of topiramate is not yet well characterized. However, the fact that we found an association with only the a priori hypothesized malformation (ie, CL/P) and not with overall malformations argues against recall bias.
      Pregnancies terminated because of congenital malformations in the fetus are eligible for inclusion in the BDS and in most of the participating states in the NBDPS. Neither data source identifies the presence of congenital malformations in spontaneous abortions less than 20 gestational weeks. This potential underascertainment of major congenital malformations would bias risk estimates toward the null. However, CL/P is not lethal and we do not expect substantial underascertainment of CL/P in the absence of associated syndromes or chromosomal abnormalities.
      In conclusion, the results of our pooled analysis are consistent with recent reports of an increased risk of CL/P associated with the use of topiramate in the first trimester of pregnancy. However, the absolute risk should be kept in perspective. Approximately 1 in 1000 infants is born with CL/P
      • Parker S.E.
      • Mai C.T.
      • Canfield M.A.
      • et al.
      Updated National Birth Prevalence estimates for selected birth defects in the United States, 2004-2006.
      Prevalence at birth of cleft lip with or without cleft palate: data from the International Perinatal Database of Typical Oral Clefts (IPDTOC).
      ; assuming our results are valid and accurate, our observed pooled OR of approximately 5 would translate into a risk in the order of 5 per 1000 for any individual topiramate-exposed pregnancy. Clinical decision makers should weigh the risks of treatment with topiramate against the risks of alternative therapeutic choices as well as the comparative effectiveness of topiramate and alternative treatments.

      Acknowledgments

      Coding of drug information in the NBDPS used the Slone Drug Dictionary under license from the Slone Epidemiology Center at Boston University. The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention. We thank the health care providers, project coordinators, medical records reviewers, interviewers, research assistants, programmers in all study centers and participating institutions, and the mothers who were interviewed for the studies.

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