Final results from the 16-year sumatriptan, naratriptan, and treximet pregnancy registry.

OBJECTIVES: To monitor for a signal of major teratogenicity by determining the risk of all birth major defects following in utero exposure to sumatriptan, naratriptan, and the sumatriptan/naproxen sodium combination product (tablets marketed in the United States as Treximet [GlaxoSmithKline, Research Triangle Park, NC, USA]), and to monitor for unusual patterns of defects that might suggest teratogenicity. BACKGROUND: The prevalence of migraine is highest in women of childbearing age. Coupled with the recurrent nature of migraine attacks and the high proportion of unplanned pregnancies, intentional and inadvertent exposure to anti-migraine drugs in pregnancy is likely. The Sumatriptan, Naratriptan, and Treximet Pregnancy Registry captured data on women exposed to those drugs during pregnancy to monitor for evidence of major teratogenicity. METHODS: In this primarily prospective, observational study, health care professionals from anywhere in the world enrolled, on a voluntary basis, women exposed to sumatriptan, naratriptan, or the sumatriptan/naproxen sodium combination product during their pregnancies. Only pregnancies with unknown outcomes at the time of enrollment were included in the analysis. The proportion of infants or fetuses with major birth defects was calculated as the total number of infants/fetuses with major birth defects divided by the sum of the number of infants/fetuses with major birth defects + the number of live births without defects. The risk of major birth defects was further stratified by earliest trimester of pregnancy exposure. RESULTS: The registry enrolled 680 evaluable exposed pregnant women, which resulted in 689 infants and fetuses (outcomes). Of these outcomes, 626 were exposed to sumatriptan, 57 were exposed to naratriptan (seven were exposed to both sumatriptan and naratriptan), and six were exposed to the sumatriptan/naproxen sodium combination product. Twenty outcomes with major birth defects were reported among 528 outcomes exposed in the first trimester to sumatriptan. The estimated risk of major birth defects following first-trimester sumatriptan exposure is 4.2% (20/478 [95% confidence interval [CI] 2.6%-6.5%]). Among 52 first-trimester exposures to naratriptan, major birth defects were reported in one outcome, an infant with exposure to both sumatriptan and naratriptan [birth defect risk of 2.2% (1/46 [95% CI 0.1%-13.0%]). No major defects were reported among the five outcomes with first-trimester exposure to the sumatriptan/naproxen sodium combination products. CONCLUSIONS: The Sumatriptan, Naratriptan, and Treximet Pregnancy Registry detected no signal of teratogenicity associated with major birth defects for sumatriptan. This finding is consistent with results from other observational studies using a variety of control groups. Enrollment in the registry was insufficient to permit definitive conclusions of the risks associated with naratriptan or sumatriptan/naproxen sodium tablets, or to assess the risk of individual birth defects in any of the products studied. Low enrollment and high rates of loss to follow up within the registry over an extended period of time led the registry's scientific advisory committee to conclude that continuation of the registry beyond its 16 years would offer little additional power to rule out more moderate increases in the risk of birth defects. Data from the other ongoing surveillance sources constitute an important element of post-marketing surveillance of these medications. The lack of a signal of major teratogenicity with sumatriptan across these several sources of data is encouraging.

First trimester paroxetine use and the prevalence of congenital, specifically cardiac, defects: a meta-analysis of epidemiological studies.

BACKGROUND: Several studies have evaluated maternal first trimester paroxetine use and the prevalence of congenital defects, particularly cardiac defects. To synthesize current epidemiologic information, a meta-analysis was conducted. METHODS: A systematic literature search was conducted for original research published from January 1, 1992, through September 30, 2008. Results were extracted using predefined criteria, and authors were contacted for additional information when necessary. Compiled results were evaluated for funnel plot asymmetry, heterogeneity, and study characteristic associations. Where appropriate, fixed-effect summary estimates were calculated and sensitivity analyses performed. RESULTS: Twenty reports (11 including results for aggregated congenital and combined cardiac defects, six for aggregated congenital defects only, and three for combined cardiac defects only) met prespecified inclusion criteria. There was little evidence of funnel plot asymmetry or overall heterogeneity. Summary estimates were produced for combined cardiac defects (prevalence odds ratio [POR], 1.46; 95% confidence interval [CI], 1.17-1.82) and aggregated congenital defects (POR, 1.24; 95% CI, 1.08-1.43) and first trimester paroxetine use. Some study characteristics may be associated with differential POR estimates for paroxetine and either combined cardiac or aggregated congenital defects. CONCLUSIONS: This meta-analysis found little evidence of publication bias or overall statistical heterogeneity and only weak evidence of associations with some study characteristics. Although subject to limitations, the summary estimate indicates an increased prevalence of combined cardiac defects with first trimester paroxetine use. The summary estimate also indicates an increased prevalence of aggregated congenital defects with paroxetine; however, this association may be explained, in part, by the increased prevalence of combined cardiac defects.

Paroxetine in the first trimester and the prevalence of congenital malformations.

PURPOSE: To refine a preliminary analysis identifying a possibly increased prevalence of malformations among infants born to women exposed to paroxetine in the first trimester. METHODS: This study used data from UnitedHealthcare, a large U.S. insurer, using datasets originally for a study of bupropion in pregnancy. We identified women with a live-born delivery between January 1995 and September 2004. We classified women according to their first trimester mono- or mono/polytherapy exposure to paroxetine and other antidepressants. We confirmed malformation cases by medical record abstraction. We calculated the adjusted odds ratios (AORs) through logistic regression. RESULTS: For paroxetine, there were 815 infants among 791 women exposed as monotherapy, and 1020 infants among 989 women exposed as mono- or polytherapy. For other antidepressants, there were 4198 infants among 4072 women exposed as monotherapy, and 4936 infants among 4767 women exposed as mono- or polytherapy. AORs for all congenital malformations associated with paroxetine were 1.89 (95%CI 1.20-2.98) for monotherapy, and 1.76 (95%CI 1.18-2.64) for mono- or polytherapy. AORs for cardiovascular malformations associated with paroxetine were 1.46 (95%CI 0.74-2.88) for monotherapy, and 1.68 (95%CI 0.95-2.97) for mono- or polytherapy. CONCLUSIONS: These more detailed paroxetine findings confirm previous findings of analyses of these data among women exposed to all types of antidepressants. The present findings are consistent with other recent results suggesting the possibility of a modestly increased occurrence of congenital malformations following first trimester exposure to paroxetine compared to other antidepressants.

Evaluation of the General Practice Research Database congenital heart defects prevalence: comparison to United Kingdom national systems.

BACKGROUND: As part of an effort to validate the General Practice Research Database (GPRD) for future studies of medication use in pregnancy, this study examined whether the rates of all, and specific types of, congenital heart defects obtained from the GPRD are similar to those obtained from UK national systems. METHODS: The prevalence rates of heart defects for 2001-2003 were determined from the GPRD and compared with both the National Congenital Anomaly System (NCAS) and the European Concerted Action of Congenital Anomalies and Twins (EUROCAT). Rate ratios (RRs) and 95% CIs were calculated comparing the prevalence of all congenital heart defects as well as specific types of heart defects in the three data sources. In addition, the effect of the child's age on the frequency of heart defects in the GPRD was determined. RESULTS: The prevalence of heart defects in the GPRD was more than twice as high as in the NCAS and slightly higher than in the EUROCAT. All differences were statistically significant. The prevalence of specific heart defects varied across the GPRD, NCAS, and EUROCAT. The measured prevalence of congenital heart defects in the GPRD was higher if calculated including children up to age 6. CONCLUSIONS: The comparisons of the GPRD prevalence rates to national prevalence estimates demonstrate that the GPRD can serve as a more complete source of background prevalence for the most commonly occurring congenital heart defects, which is essential to properly assess possible associations between maternal exposures and congenital heart defects.

The incidence of congestive heart failure associated with antidiabetic therapies.

BACKGROUND: Increased risk for CHF in persons with type 2 diabetes is well established. Our objectives were to estimate the CHF risk associated with specific therapies for diabetes and to determine the differences in incidence rates of CHF associated with adding various antidiabetic agents. METHODS: Subjects were members of the Kaiser Permanente Northwest (KPNW) diabetes registry as of 1 January 1998, with no prior history of CHF (n = 8063). We identified their therapy as of that date and then defined the start of the subject study period as the date when their drug regimen changed, either by switching to or by adding another antidiabetic drug. We defined the new therapy as the index therapy and the date of initiating the new therapy as the index date. Follow-up on the patients was done until the index therapy was discontinued or changed, or until 31 December 2002, whichever came earlier. We calculated the incidence rate of CHF in patients on various therapeutic regimens adjusting for age, gender, diabetes duration, existing ischemic heart disease, hypertension, renal insufficiency and glycemic control (HbA(1c)). RESULTS: CHF incidence rates were highest in index therapy categories that included insulin and lowest in regimens that included metformin. When insulin was added to an initial therapy, CHF incidence was increased 2.33 times (p < 0.0001) and 2.66 times (p < 0.0001) compared to the addition of sulphonylurea or metformin respectively. CONCLUSIONS: Our findings support the theory that elevated serum insulin levels promote the development of cardiac disease. Consistent with the UKPDS, metformin may offer some protection from incident CHF relative to sulphonylurea or insulin.

The incidence of congestive heart failure in type 2 diabetes: an update.

OBJECTIVE: The aims of this study were to update previous estimates of the congestive heart failure (CHF) incidence rate in patients with type 2 diabetes, compare it with an age- and sex-matched nondiabetic group, and describe risk factors for developing CHF in diabetic patients over 6 years of follow-up. RESEARCH DESIGN AND METHODS: We performed a retrospective cohort study of 8,231 patients with type 2 diabetes and 8,845 nondiabetic patients of similar age and sex who did not have CHF as of 1 January 1997, following them for up to 72 months to estimate the CHF incidence rate. In the diabetic cohort, we constructed a Cox regression model to identify risk factors for CHF development. RESULTS: Patients with diabetes were much more likely to develop CHF than patients without diabetes (incidence rate 30.9 vs. 12.4 cases per 1,000 person-years, rate ratio 2.5, 95% CI 2.3-2.7). The difference in CHF development rates between persons with and without diabetes was much greater in younger age-groups. In addition to age and ischemic heart disease, poorer glycemic control (hazard ratio 1.32 per percentage point of HbA(1c)) and greater BMI (1.12 per 2.5 units of BMI) were important predictors of CHF development. CONCLUSIONS: The CHF incidence rate in type 2 diabetes may be much greater than previously believed. Our multivariate results emphasize the importance of controlling modifiable risk factors for CHF, namely hyperglycemia, elevated blood pressure, and obesity. Younger patients may benefit most from risk factor modification.

Lifetime prevalence of migraine and other headaches lasting 4 or more hours: the Atherosclerosis Risk in Communities (ARIC) study.

OBJECTIVES: To evaluate the lifetime prevalence of migraine and other headaches lasting 4 or more hours in a population-based study of older adults. BACKGROUND: Migraine and other headaches not fulfilling migraine criteria are common afflictions. Yet the health and social effects of these conditions have not been fully appreciated, particularly among older adults. METHODS: The study included 12 750 participants in the Atherosclerosis Risk in Communities (ARIC) Study from 4 US communities. Prevalence estimates of a lifetime history of migraine and other headaches lasting 4 or more hours were obtained for race and gender groups. A cross-sectional analysis was done to assess the relationship between headache type, by aura status, and various sociodemographic and health-related indices. RESULTS: Compared to education beyond high school, having completed less than 12 years of education was significantly associated with an increased occurrence of migraine with aura (prevalence odds ratio [POR], 1.47; 95% confidence interval [CI], 1.08 to 2.01). Family income less than $16 000, compared to family income of $75 000 or greater, was significantly associated with migraine with aura (POR, 1.68; 95% CI, 1.07 to 2.64), migraine without aura (POR, 1.56; 95% CI, 1.14 to 2.14), and other headaches with aura (POR, 1.89; 95% CI, 1.14 to 3.13). The prevalence odds ratio was higher in each headache category, particularly for those with an aura, for those with hypertension versus normotension and for those who perceived their general health as poor compared to those whose perception was excellent. CONCLUSIONS: A lifetime history of migraine with aura and other headaches with aura was more common among whites, women, and younger participants. Further investigation of headaches lasting 4 or more hours, particularly by aura status, is warranted.