Andrea V. Margulis

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.

Quality assessment of observational studies in a drug-safety systematic review, comparison of two tools: the Newcastle–Ottawa Scale and the RTI item bank

Background The study objective was to compare the Newcastle–Ottawa Scale (NOS) and the RTI item bank (RTI-IB) and estimate interrater agreement using the RTI-IB within a systematic review on the cardiovascular safety of glucose-lowering drugs. Methods We tailored both tools and added four questions to the RTI-IB. Two reviewers assessed the quality of the 44 included studies with both tools, (independently for the RTI-IB) and agreed on which responses conveyed low, unclear, or high risk of bias. For each question in the RTI-IB (n=31), the observed interrater agreement was calculated as the percentage of studies given the same bias assessment by both reviewers; chance-adjusted interrater agreement was estimated with the first-order agreement coefficient (AC1) statistic. Results The NOS required less tailoring and was easier to use than the RTI-IB, but the RTI-IB produced a more thorough assessment. The RTI-IB includes most of the domains measured in the NOS. Median observed interrater agreement for the RTI-IB was 75% (25th percentile [p25] =61%; p75 =89%); median AC1 statistic was 0.64 (p25 =0.51; p75 =0.86). Conclusion The RTI-IB facilitates a more complete quality assessment than the NOS but is more burdensome. The observed agreement and AC1 statistic in this study were higher than those reported by the RTI-IB’s developers.

Algorithms to estimate the beginning of pregnancy in administrative databases

The role of administrative databases for research on drug safety during pregnancy can be limited by their inaccurate assessment of the timing of exposure, as the gestational age at birth is typically unavailable. Therefore, we sought to develop and validate algorithms to estimate the gestational age at birth using information available in these databases.

Elevated Risk of Preeclampsia in Pregnant Women With Depression: Depression or Antidepressants?

A previous study suggested an increased risk of preeclampsia among women treated with selective serotonin reuptake inhibitors (SSRIs). Using population-based health-care utilization databases from British Columbia (1997-2006), the authors conducted a study of 69,448 pregnancies in women with depression. They compared risk of preeclampsia in women using SSRIs, serotonin-norepinephrine reuptake inhibitors (SNRIs), or tricyclic antidepressants (TCAs) between gestational weeks 10 and 20 with risk in depressed women not using antidepressants. Among prepregnancy antidepressant users, the authors compared the risk in women who continued antidepressants between gestational weeks 10 and 24 with the risk in those who discontinued. Relative risks and 95% confidence intervals were estimated. The risk of preeclampsia in depressed women not treated with antidepressants (2.4%) was similar to that in women without depression (2.3%). Compared with women with untreated depression, women treated with SSRI, SNRI, and TCA monotherapy had adjusted relative risks of 1.22 (95% confidence interval (CI): 0.97, 1.54), 1.95 (95% CI: 1.25, 3.03), and 3.23 (95% CI: 1.87, 5.59), respectively. Within prepregnancy antidepressant users, the relative risk for preeclampsia among continuers compared with discontinuers was 1.32 (95% CI: 0.95, 1.84) for SSRI, 3.43 (95% CI: 1.77, 6.65) for SNRI, and 3.26 (95% CI: 1.04, 10.24) for TCA monotherapy. Study results suggest that women who use antidepressants during pregnancy, especially SNRIs and TCAs, have an elevated risk of preeclampsia. These associations may reflect drug effects or more severe depression.

Positive predictive value of computerized medical records for uncomplicated and complicated upper gastrointestinal ulcer.

Computerized databases can be an efficient resource to study the epidemiology of peptic ulcer (PU) and upper gastrointestinal complications (UGIC) if we achieve a high positive predictive value (PPV) of outcome definitions. We assessed the PPV of diagnosis codes in THIN, a primary‐care medical‐record database, to ascertain individuals with uncomplicated PU, and to identify UGIC and Helicobacter pylori infection status (HPIS) among these patients.

The risk of heart failure associated with the use of noninsulin blood glucose-lowering drugs: systematic review and meta-analysis of published observational studies

BackgroundPatients with type 2 diabetes mellitus (T2DM) are at high risk of heart failure. A summary of the effects of blood glucose-lowering drugs other than glitazones on the risk of heart failure in routine clinical practice is lacking. The objective of this study was to conduct a systematic review and meta-analysis of observational studies on the risk of heart failure when using blood glucose-lowering drugs.MethodsWe systematically identified and reviewed cohort and case–control studies in which the main exposure of interest was noninsulin blood glucose-lowering medications in patients with T2DM. We searched Medline, Embase, and the Cochrane Library to identify publications meeting prespecified eligibility criteria. The quality of included studies was assessed with the Newcastle-Ottawa Scale and the RTI item bank. Results were combined using fixed and random-effects models when at least 3 independent data points were available for a drug-drug comparison.ResultsThe summary relative risk of heart failure in rosiglitazone users versus pioglitazone users (95% CI) was 1.16 (1.05-1.28) (5 cohort studies). Heterogeneity was present (I2 = 66%). For new users (n = 4) the summary relative risk was 1.21 (1.14-1.30) and the heterogeneity was reduced (I2 = 31%);. The summary relative risk for rosiglitazone versus metformin was 1.36 (95% CI, 1.17-1.59) (n = 3). The summary relative risk (95% CI) of heart failure in sulfonylureas users versus metformin users was 1.17 (95% CI, 1.06-1.29) (5 cohort studies; I2 = 24%) and 1.22 (1.02-1.46) when restricted to new users (2 studies).Information on other comparisons was very scarce. Information on dose and duration of treatment effects was lacking for most comparisons. Few studies accounted for disease severity; therefore, confounding by indication might be present in the majority of the within-study comparisons of this meta-analysis.ConclusionsUse of glitazones and sulfonylureas was associated with an increased risk of heart failure compared with metformin use. However, indication bias cannot be ruled out. Ongoing large multidatabase studies will help to evaluate the risk of heart failure in treated patients with diabetes, including those using newer blood glucose-lowering therapies.

Beginning and duration of pregnancy in automated health care databases: review of estimation methods and validation results

To describe methods reported in the literature to estimate the beginning or duration of pregnancy in automated health care data, and to present results of validation exercises where available.

Effects of gestational age at enrollment in pregnancy exposure registries

This study aims to explore the influence of gestational age at enrollment, and enrollment before or after prenatal screening, on the estimation of drug effects in pregnancy exposure registries.

Triggers of spontaneous preterm delivery--why today?

BACKGROUND Our goal is to study the triggers of spontaneous preterm delivery using a case-crossover design. METHODS In a pilot study, we enrolled 50 women with spontaneous preterm labour (PTL) and 50 with preterm premature rupture of membranes (PPROM) between 2011 and 2012. To assess non-transient risk factors, we also enrolled a control group of 158 pregnant women at their regular prenatal care visits matched to cases by gestational age and calendar time. The index time was defined as the onset of PTL/PPROM (for cases) or interview (for controls). Detailed data were collected through structured interviews regarding factors of interest during the 72 h that preceded the index time. Within case subjects, we compared the frequency of transient factors from 0 to 24 h before index time with that from 48 to 72 h before index time, and estimated matched odds ratios (OR) and 95% confidence intervals (CI). RESULTS Previously hypothesised chronic risk factors for spontaneous preterm delivery, including mood disorders and stressful events, were more common among cases than among controls. Within cases, skipped meals [OR 4.3, 95% CI 1.2, 15.2], disturbed sleep [OR 4.5, 95% CI 1.5, 13.3], sexual activity [OR 6.0, 95% CI 0.7, 69.8], and intake of spicy foods [OR 7.0, 95% CI 1.6, 30.8] were associated with an increased risk for PTL/PPROM within the subsequent 24 h. For physical exertion and other potential risk factors evaluated, the OR was close to the null. CONCLUSION Skipping meals and disturbed sleep may be associated with imminent PTL/PPROM; sexual activity and spicy food may trigger PTL/PPROM in susceptible women. Larger case-crossover studies will be able to evaluate the impact of modifiable risk factors and acute predictors of PTL/PPROM, and might help guide obstetrical management.

Variation in initiating secondary prevention after myocardial infarction by hospitals and physicians, 1997 through 2004

Myocardial infarction (MI) survivors benefit from receiving secondary prevention, including beta‐blockers, angiotensin‐blocking agents, and statins, as recommended by guidelines. Compliance with these guidelines is suboptimal. We sought to describe the initiation of secondary prevention in MI survivors, and to describe the variation in initiation by discharging the hospital, the physician, and the physician “responsible” for secondary prevention prescribing decisions in British Columbia in 1997–2004.