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.
Approximately 0.5% of pregnant women in the United States have epilepsy. 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. Older antiepileptics, such as phenytoin, phenobarbital, and valproic acid, carry an increased risk for various specific congenital malformations. However, little is known about the fetal safety of the increasingly used newer antiepileptics.
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). 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 and eating disorders, other psychiatric conditions, and weight loss.
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. 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. 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. 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. 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, 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/m 2 ); 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 ).
| Characteristics | Slone Birth Defects Study | National 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/m 2 ), n (%) | ||||
| <18.5 | 207 (3.0) | 38 (4.8) | 439 (5.2) | 150 (6.6) |
| 18.5 to <25 | 3964 (56.8) | 379 (48.3) | 4180 (49.2) | 1069 (46.8) |
| 25 to <30 | 1564 (22.4) | 173 (22.0) | 2033 (23.9) | 504 (22.1) |
| 30 to <35 | 566 (8.1) | 75 (9.6) | 912 (10.7) | 255 (11.2) |
| ≥35 | 327 (4.7) | 52 (6.6) | 564 (6.6) | 182 (8.0) |
| Maternal race/ethnicity, n (%) | ||||
| Non-Hispanic white | 4917 (70.4) | 507 (64.6) | 5004 (58.9) | 1376 (60.3) |
| Non-Hispanic black | 538 (7.7) | 65 (8.3) | 959 (11.3) | 139 (6.1) |
| Hispanic | 997 (14.3) | 124 (15.8) | 1975 (23.3) | 609 (26.7) |
| Asian/Pacific Islander | 386 (5.5) | 71 (9.0) | 250 (2.9) | 59 (2.6) |
| Native American/Alaskan Native | NA | NA | 43 (0.5) | 19 (0.8) |
| Other | 139 (2.0) | 15 (1.9) | 260 (3.1) | 81 (3.5) |
| Maternal education (y), n (%) | ||||
| ≤12 | 1936 (27.7) | 287 (36.6) | 3446 (40.6) | 1106 (48.4) |
| 13; 15 | 1635 (23.4) | 195 (24.8) | 2260 (26.6) | 583 (25.5) |
| ≥16 | 3409 (48.8) | 303 (38.6) | 2637 (31.0) | 573 (25.1) |
| First-degree relative with CL/P or CP | 31 (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) |
| Use of antiepileptic drugs | Infants without malformations | Infants with major congenital malformations a | Infants with CL/P | ||
|---|---|---|---|---|---|
| n | n | OR (95% CI) | n | OR (95% CI) | |
| Slone Birth Defects Study b | |||||
| No use of antiepileptic drugs c | 6933 | 10,503 | Reference | 778 | Reference |
| Topiramate monotherapy in first trimester | 2 | 5 | 1.22 (0.19-13.01) | 3 | 10.13 (1.09-129.21) |
| National Birth Defects Prevention Study b | |||||
| No use of antiepileptic drugs | 8434 | 23,102 | Reference | 2256 | Reference |
| Topiramate monotherapy in first trimester | 4 | 10 | 0.92 (0.26-4.06) | 4 | 3.63 (0.66-20.00) |
| Pooled data d | |||||
| No use of antiepileptic drugs | 15,367 | 33,605 | Reference | 3034 | Reference |
| Topiramate monotherapy in first trimester | 6 | 15 | 1.01 (0.37-3.22) | 7 | 5.36 (1.49-20.07) |
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