Topiramate During Pregnancy and Risk of Birth Defects
Objective.— To evaluate the risk of oral cleft and major congenital malformation occurrence in infants born to women exposed to topiramate in their first trimester of pregnancy compared with women who used other anti-epileptic drugs or those with disease states in which topiramate may have been used.
Methods.— Sourced from patients' pharmacy and medical claims from 2002 through 2010, this study identified infants born from mothers exposed to topiramate (n = 870) and other anti-epileptic drugs (n = 3615) in the first trimester of pregnancy. First trimester exposure was based on prescription dispensing dates and days supplied relative to infant birth date, accounting for premature delivery. Infants born to women with migraine without epilepsy (n = 26,865), women with epilepsy (n = 2607), and women with diabetes mellitus (n = 13,062), as well as randomly sampled women (n = 99,761), were used for comparison. Topiramate use was excluded from all groups with the exception of the topiramate and random sample cohorts. Non-anti-epileptic drug teratogens were excluded from each cohort (except random sample). Unadjusted relative risks and 95% confidence intervals for topiramate vs each comparator were calculated. Risks >1 indicate a higher risk with topiramate vs comparator, whereas risks <1 indicate a lower risk with topiramate vs comparator.
Results.— The frequency of oral clefts was 0.23% for topiramate use, 0.17% for other anti-epileptic drug use (topiramate vs comparator relative risk = 1.39 [95% confidence interval: 0.28–6.85]), 0.16% for migraineurs (1.47 [0.36–6.06]), 0.31% for epileptics (0.75 [0.16–3.52]), 0.26% for diabetics (0.88 [0.21–3.67]), and 0.16% for the random sample (1.44 [0.36–5.81]). The frequency of major congenital malformations was 4.33% for topiramate use, 3.21% for other anti-epileptic drugs (1.33 [0.92–1.90]), 3.79% for migraineurs (1.12 [0.81–1.55]), 4.33% for epileptics (0.98 [0.68–1.41]), 6.58% for diabetics (0.65 [0.47–0.89]), and 3.77% for the random sample (1.13 [0.82–1.55]).
Conclusions.— This retrospective study quantified the association between topiramate exposure during pregnancy and the risk of oral cleft or major congenital malformations, and suggested little or no increase in risk in comparison with exposure to other anti-epileptic drugs or to disease states, such as migraine, epilepsy, or diabetes. However, small numbers of events limit the strength of inferences.
Migraine, epilepsy, and diabetes mellitus are chronic conditions that may be associated with increased rates of major congenital malformations (MCMs) in infants born to women with these conditions.
Migraines affect approximately 30 million adults in the United States, with studies showing a 1-year prevalence of 18% in women and 6% in men. In women, the prevalence of migraines is highest (approximately 25.0–30.0%) during peak reproductive years from age 20–40 years. The few studies that have assessed pregnancy outcomes in women with migraine have found no evidence of increased incidence of poor outcomes, such as preterm labor, low birth weight, or congenital anomalies in infants born to untreated women.
Most women with epilepsy require continued treatment with anti-epileptic drugs (AEDs) during pregnancy, and several studies document an increased risk of birth defects with their use. Congenital malformations can increase by up to 3-fold with use of older generation AEDs. The frequency of MCMs in the literature range from 1.0–2.3% for infants born to non-epileptic women to approximately 3.0% in untreated women with epilepsy and from 4.0% to 9.0% for infants born to women exposed to AEDs.
Similarly, the frequency of MCMs can increase in infants born to women with diabetes ranging from 1.5% to 2.1% for infants born to women without diabetes to 6.1–7.2% for infants born to women with diabetes.
In contrast with conditions such as epilepsy and diabetes, there are few agents approved by the US Food and Drug Administration (FDA) for the prevention of migraine. Among those that are approved, most are classified as either pregnancy category C or D, notably propranolol (C), timolol (C), divalproex (D), and topiramate (D). In addition, amitriptyline, which has efficacy in treating migraine, is pregnancy category C, and onabotulinum toxin A has been approved for chronic migraine only.
Even fewer options exist for the acute treatment of migraine during pregnancy. Triptans are all classified as pregnancy category C, whereas opioid analgesics are not very effective in the acute treatment of migraines and are associated with an increased risk of dependency in the mother and developing fetus. Ergots (pregnancy category X) are contraindicated in pregnancy. Butalbital-containing combination agents, which are pregnancy category C, are not approved by the FDA for the treatment of migraine and have very few controlled studies supporting their use in the treatment of migraine.
Topiramate is indicated for use as monotherapy and adjunctive therapy for epilepsy and as a preventive treatment in migraine headache. In addition, topiramate is currently being investigated in combination with phentermine for the treatment of obesity. Preliminary registry data identified a potential for an increased risk of birth defects with the use of topiramate in pregnancy, specifically oral cleft (OC) malformations. Subsequently, the FDA classified topiramate as pregnancy category D.
Recent data from a large-scale, whole-population study in Denmark suggested that the use of newer AEDs, including topiramate, was not associated with an increased risk of major birth defects. In addition, in data from 2 large case-controlled data programs, there was no overall increased risk of MCMs following first trimester exposure to topiramate; however, according to data from the US National Health and Nutrition Examination Survey, topiramate use by women of child-bearing age increased steadily in the last decade.
In the present study, a retrospective analysis of medical and pharmacy claims and reported malformations from topiramate, we used pharmacy and medical claims data to evaluate the risk of birth defects in infants born to women exposed to topiramate in the first trimester of pregnancy as compared with those born to women exposed to other AEDs and those with disease states such as migraine, epilepsy, and diabetes in which topiramate was used.
Abstract and Introduction
Abstract
Objective.— To evaluate the risk of oral cleft and major congenital malformation occurrence in infants born to women exposed to topiramate in their first trimester of pregnancy compared with women who used other anti-epileptic drugs or those with disease states in which topiramate may have been used.
Methods.— Sourced from patients' pharmacy and medical claims from 2002 through 2010, this study identified infants born from mothers exposed to topiramate (n = 870) and other anti-epileptic drugs (n = 3615) in the first trimester of pregnancy. First trimester exposure was based on prescription dispensing dates and days supplied relative to infant birth date, accounting for premature delivery. Infants born to women with migraine without epilepsy (n = 26,865), women with epilepsy (n = 2607), and women with diabetes mellitus (n = 13,062), as well as randomly sampled women (n = 99,761), were used for comparison. Topiramate use was excluded from all groups with the exception of the topiramate and random sample cohorts. Non-anti-epileptic drug teratogens were excluded from each cohort (except random sample). Unadjusted relative risks and 95% confidence intervals for topiramate vs each comparator were calculated. Risks >1 indicate a higher risk with topiramate vs comparator, whereas risks <1 indicate a lower risk with topiramate vs comparator.
Results.— The frequency of oral clefts was 0.23% for topiramate use, 0.17% for other anti-epileptic drug use (topiramate vs comparator relative risk = 1.39 [95% confidence interval: 0.28–6.85]), 0.16% for migraineurs (1.47 [0.36–6.06]), 0.31% for epileptics (0.75 [0.16–3.52]), 0.26% for diabetics (0.88 [0.21–3.67]), and 0.16% for the random sample (1.44 [0.36–5.81]). The frequency of major congenital malformations was 4.33% for topiramate use, 3.21% for other anti-epileptic drugs (1.33 [0.92–1.90]), 3.79% for migraineurs (1.12 [0.81–1.55]), 4.33% for epileptics (0.98 [0.68–1.41]), 6.58% for diabetics (0.65 [0.47–0.89]), and 3.77% for the random sample (1.13 [0.82–1.55]).
Conclusions.— This retrospective study quantified the association between topiramate exposure during pregnancy and the risk of oral cleft or major congenital malformations, and suggested little or no increase in risk in comparison with exposure to other anti-epileptic drugs or to disease states, such as migraine, epilepsy, or diabetes. However, small numbers of events limit the strength of inferences.
Introduction
Migraine, epilepsy, and diabetes mellitus are chronic conditions that may be associated with increased rates of major congenital malformations (MCMs) in infants born to women with these conditions.
Migraines affect approximately 30 million adults in the United States, with studies showing a 1-year prevalence of 18% in women and 6% in men. In women, the prevalence of migraines is highest (approximately 25.0–30.0%) during peak reproductive years from age 20–40 years. The few studies that have assessed pregnancy outcomes in women with migraine have found no evidence of increased incidence of poor outcomes, such as preterm labor, low birth weight, or congenital anomalies in infants born to untreated women.
Most women with epilepsy require continued treatment with anti-epileptic drugs (AEDs) during pregnancy, and several studies document an increased risk of birth defects with their use. Congenital malformations can increase by up to 3-fold with use of older generation AEDs. The frequency of MCMs in the literature range from 1.0–2.3% for infants born to non-epileptic women to approximately 3.0% in untreated women with epilepsy and from 4.0% to 9.0% for infants born to women exposed to AEDs.
Similarly, the frequency of MCMs can increase in infants born to women with diabetes ranging from 1.5% to 2.1% for infants born to women without diabetes to 6.1–7.2% for infants born to women with diabetes.
In contrast with conditions such as epilepsy and diabetes, there are few agents approved by the US Food and Drug Administration (FDA) for the prevention of migraine. Among those that are approved, most are classified as either pregnancy category C or D, notably propranolol (C), timolol (C), divalproex (D), and topiramate (D). In addition, amitriptyline, which has efficacy in treating migraine, is pregnancy category C, and onabotulinum toxin A has been approved for chronic migraine only.
Even fewer options exist for the acute treatment of migraine during pregnancy. Triptans are all classified as pregnancy category C, whereas opioid analgesics are not very effective in the acute treatment of migraines and are associated with an increased risk of dependency in the mother and developing fetus. Ergots (pregnancy category X) are contraindicated in pregnancy. Butalbital-containing combination agents, which are pregnancy category C, are not approved by the FDA for the treatment of migraine and have very few controlled studies supporting their use in the treatment of migraine.
Topiramate is indicated for use as monotherapy and adjunctive therapy for epilepsy and as a preventive treatment in migraine headache. In addition, topiramate is currently being investigated in combination with phentermine for the treatment of obesity. Preliminary registry data identified a potential for an increased risk of birth defects with the use of topiramate in pregnancy, specifically oral cleft (OC) malformations. Subsequently, the FDA classified topiramate as pregnancy category D.
Recent data from a large-scale, whole-population study in Denmark suggested that the use of newer AEDs, including topiramate, was not associated with an increased risk of major birth defects. In addition, in data from 2 large case-controlled data programs, there was no overall increased risk of MCMs following first trimester exposure to topiramate; however, according to data from the US National Health and Nutrition Examination Survey, topiramate use by women of child-bearing age increased steadily in the last decade.
In the present study, a retrospective analysis of medical and pharmacy claims and reported malformations from topiramate, we used pharmacy and medical claims data to evaluate the risk of birth defects in infants born to women exposed to topiramate in the first trimester of pregnancy as compared with those born to women exposed to other AEDs and those with disease states such as migraine, epilepsy, and diabetes in which topiramate was used.
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