The feasibility of using multiple databases to study rare outcomes: the potential effect of long-acting beta agonists with inhaled corticosteroid therapy on asthma mortality.

PURPOSE: Long-acting beta agonists (LABAs) when used without concomitant inhaled corticosteroids (ICS) increase the risk of asthma-related deaths, but the effect on asthma-related death of LABA used in combination with ICS therapy is unknown. To address this question, we explored the feasibility of conducting an observational study using multiple US health care data sources. METHODS: Retrospective cohort study to evaluate the likelihood of getting an upper 95% confidence limit ≤1.4 for the asthma mortality rate ratio and ≤0.40 per 10 000 person-years for the mortality rate difference, assuming no effect of new use of combined LABA + ICS (versus non-LABA maintenance therapy) on asthma mortality. Ten research institutions executed centrally distributed analytic code based on a standard protocol using an extracted (2000-2010) persistent asthma cohort (asthma diagnosis and ≥4 asthma medications in 12 months). Pooled results were analyzed by the coordinating center. Asthma deaths were ascertained by linkage with the National Death Index. RESULTS: In a cohort of 994 627 persistent asthma patients (2.4 million person-years; 278 asthma deaths), probabilities of the upper 95% confidence limit for effect estimates being less than targeted values, assuming a null relation, were about 0.05. Modifications in cohort and exposure definitions increased exposed person-time and outcome events, but study size remained insufficient to attain study goals. CONCLUSIONS: Even with 10 data sources and a 10-year study period, the rarity of asthma deaths among patients using certain medications made it infeasible to study the association between combined LABA + ICS and asthma mortality with our targeted level of study precision. Copyright © 2016 John Wiley & Sons, Ltd.

Topiramate use during pregnancy and major congenital malformations in multiple populations.

BACKGROUND: We measured birth prevalence of major congenital malformations (MCMs) after topiramate use during pregnancy to screen for a possible signal of increased risk. METHODS: Using four healthcare databases, we identified three cohorts of pregnant women: cohort 1, used topiramate during the first trimester; cohort 2, used topiramate or another antiepileptic drug previously but not during pregnancy; and cohort 3, were pregnant and did not use topiramate but had indications for use individually matched to those of users. Cohort 1 was compared with cohorts 2 and 3. MCMs were a code for any major congenital malformation dated within 30 days of the delivery date on the mother's claims or within 365 days after infant birth date, excluding a genetic or syndromic basis, and with procedure or healthcare usage consistent with the MCM diagnosis code in the 365 days after infant birth. RESULTS: Of the 10 specific common MCMs evaluated, 1 (conotruncal heart defects) had a prevalence ratio greater than 1.5 for both primary comparisons, and 4 (ventricular septal defect, atrial septal defect, hypospadias, coarctation of the aorta) had a prevalence ratio greater than 1.5 for one of the two comparisons. Following screening of organ systems with elevated MCMs, the prevalence ratio was greater than 1.5 for patent ductus arteriosus in both comparisons and for obstructive genitourinary defects in one comparison. CONCLUSION: To evaluate a large number of MCMs across many pregnancies, we used crude methods for detecting potential signals. Therefore, these results should be seen as potential signals, not causal.

Advantages and problems with pregnancy registries: observations and surprises throughout the life of the International Lamotrigine Pregnancy Registry.

PURPOSE: The International Lamotrigine Pregnancy Registry monitored for a signal of a substantial increase in the frequency of major congenital malformations associated with lamotrigine exposures in pregnancy over an 18-year period. Key methodological lessons are discussed. METHODS: The strengths and weaknesses of the Registry were assessed using quantifiable methodological and operational parameters including enrollment, completeness of exposure and outcome data reporting, and lost to follow-up. The choice of comparator groups and stopping rules for registry closure were critically evaluated. RESULTS: The reliance on voluntary reporting was associated with a clustered geographical distribution of registered pregnancies. The enrollment rate increased over time with new approvals and indications for lamotrigine and publication of interim data. Reporter burden was minimized through a streamlined data collection approach resulting in a high level of completeness of exposure and primary outcome data. Lost to follow-up rates were high (28.5% overall) representing a major limitation; incentives to increase the completeness of reporting failed to reduce rates. A lack of an internal comparator group complicated data interpretation; but external comparisons with multiple external groups allowed an assessment of consistency of outcome data across multiple data sources. A lack of a priori closure criteria prolonged the life of the Registry, and consideration of regulatory guidelines on this subject is encouraged at the time of conception of future registries. CONCLUSIONS: A successful pregnancy exposure registry requires ongoing flexibility and continuous re-assessment of enrollment, recruitment, and retention methods and the availability of comparison data, throughout its lifecycle.

Topiramate use in pregnancy and the birth prevalence of oral clefts.

PURPOSE: First marketed in the USA in 1996, topiramate (TPM) is an antiepileptic drug later approved for migraine prophylaxis, and in 2012 for weight loss in combination with phentermine. Some studies indicate an elevated prevalence of oral cleft (OC) in infants exposed to TPM in utero. We evaluated the association between TPM use in early pregnancy and the risk of OC. METHODS: This retrospective cohort study used 1997-2011 automated data from four sources: HealthCore and OptumInsight (commercial insurance claims), Truven Health (Medicaid claims), and Kaiser Permanente Northern California Region (electronic medical records). We compared the prevalence of OCs in infants of women exposed to TPM in the first trimester (TPM cohort) with the prevalence in infants of women formerly exposed to TPM or other antiepileptic drugs (formerly exposed [FE] cohort) and infants of women with similar medical profiles (SMPs) to the TPM cohort that were not exposed to TPM (SMP cohort). To control for confounding, we used stratification and standardization for individual variables and propensity score deciles. RESULTS: The birth prevalence of OCs was 0.36% (7/1945) in the TPM cohort, 0.14% (20/13 512) in the FE cohort, and 0.07% (9/13 614) in the SMP cohort. Standardized by site, the prevalence ratio (PR) for TPM versus FE was 2.5 (95% CI: 1.0-6.0) and for TPM versus SMP was 5.4 (95% CI: 2.0-14.6). Adjustment for covariates one at a time or by propensity score yielded similar results. CONCLUSION: Consistent with other recent epidemiologic research, first-trimester TPM exposure was associated with an elevated birth prevalence of OC.

A US postmarketing evaluation of the frequency and safety of live attenuated influenza vaccine use in nonrecommended children younger than 5 years: 2009-2010 season.

The 2007 US approval for use of Ann Arbor strain live attenuated influenza vaccine (LAIV) in children aged 24 through 59 months included precautions against use in (1) children <24 months and children aged 24 through 59 months with (2) asthma, (3) recurrent wheezing, and (4) altered immunocompetence. Results from the third season (2009-2010) of a 3-year study postmarketing commitment to monitor LAIV vaccination rates and frequency of hospitalizations or emergency department visits within 42 days after LAIV are reported here. As in the first 2 seasons, LAIV usage in cohorts 1, 2, and 4 were low relative to those in LAIV-recommended populations. The only numerically increased risk observed was for respiratory events in children aged <24 months administered LAIV, compared to those administered trivalent inactivated influenza vaccine (TIV). The number of children vaccinated with LAIV was small and precluded precise quantification of rare event.

Incidence of osteonecrosis of the jaw among users of bisphosphonates with selected cancers or osteoporosis.

PURPOSE: To quantify the incidence of osteonecrosis of the jaw (ONJ) by bisphosphonate exposure among two cohorts of patients. METHODS: In a retrospective cohort study, we identified cohort members via health insurance claim diagnosis codes and identified potential cases of ONJ that were confirmed with medical record review. One cohort included patients aged ≥40 years with breast or prostate cancer or multiple myeloma; the other cohort included men aged ≥60 years and women ≥50 years with osteoporosis. For each cohort, we calculated sex- and age-standardized incidence of ONJ by exposure to oral bisphosphonates and intravenous bisphosphonates. RESULTS: In the cancer cohort (n = 46 542), sex- and age-standardized incidence of ONJ (n = 26 probable or possible cases) adjusted for abstraction proportion was 0.29 per 1000 person-years (95% confidence interval [CI], 0.07-0.52) among those unexposed to bisphosphonates and 5.3 (95%CI, 1.9-8.7) after intravenous bisphosphonate use. Controlling for covariates, the rate ratio for intravenous use versus no use was 8.8 (95%CI, 2.0-38). Patients with multiple myeloma had a rate 4.5 times that of patients with breast cancer. In the osteoporosis cohort (n = 31 244), sex- and age-standardized ONJ (n = 11 probable or possible cases) incidence was 0.26 per 1000 person-years (95%CI, 0.06-0.47) among those unexposed to bisphosphonate and 0.15 (95%CI, 0.00-0.36) after oral bisphosphonate use. CONCLUSION: Among patients with selected cancers, incidence of ONJ was higher among those with multiple myeloma and users of intravenous bisphosphonates.

Healthcare utilization and comorbidity burden among children and young adults in the United States with systemic lupus erythematosus or inflammatory bowel disease.

OBJECTIVE: We sought to assess the feasibility of using a health insurance claims database to estimate the prevalence and health care utilization and costs among children diagnosed with systemic lupus erythematosus (SLE) and inflammatory bowel disease (IBD). STUDY DESIGN: This was a retrospective analysis of the LifeLink insurance claims database for the years 2000-2006. Children (0-15 years) and young adults (16-25 years) with ≥ 2 diagnosis claims for SLE or IBD were selected as the 2 cohorts of interest. For each member of the SLE and IBD cohorts, 2 individuals were randomly selected for a matched comparison group. All the analyses were descriptive in nature, CI for differences between means and 2 proportions for measures including health care utilization, comorbidity burden were based on t tests and 2-group tests of proportions. RESULTS: We identified 278 patients with SLE (prevalence estimate: 7.9 per/100000 population) and 1174 patients with IBD (33.2 per/100000 population). The mean annual total medical costs was substantially higher for the SLE (difference: $22223; 95% CI: $14961-$29485) and IBD (difference: $16238; 95% CI: $14395-$18082) cohorts compared with those of the comparator cohort. We observed higher comorbidity burdens in the SLE and IBD cohorts than we saw in the comparator cohort. CONCLUSIONS: Administrative claims data can be a useful tool for assessing the comparative prevalence and associated resource utilization of rare conditions such as SLE and IBD.

Maternal outcomes among pregnant women receiving live attenuated influenza vaccine.

BACKGROUND: Although the live attenuated influenza vaccine (LAIV) prescribing information contains warnings/precautions against use during pregnancy, administration of LAIV to pregnant women does occur. Data regarding maternal outcomes after LAIV administration during pregnancy are limited. OBJECTIVES: Maternal outcomes after LAIV vaccination during pregnancy were examined. METHODS: Data from a health insurance claims database that covers approximately 50 million individuals were analyzed for the six influenza seasons from 2003-2004 through 2008-2009. Emergency department (ED) visits and hospitalizations occurring within 42 days of vaccination were analyzed by primary diagnosis; outcomes were categorized as cardiopulmonary, obstetric, and other. Cohort characteristics were analyzed using descriptive statistics. RESULTS: Of 834,999 pregnancies identified, 138 (0·017%) were among women who received LAIV vaccinations. Of the 138 pregnant women, 13% were ≤19 years, 67% were 20-34 years, and 20% were ≥35 years of age. Eight events occurred within 42 days of vaccination: one ED visit for bronchitis, two hospitalizations for hyperemesis gravidarum and premature labor, and five ED visits/hospitalizations for common medical conditions. All outcomes identified after LAIV exposure occurred at rates similar to rates in unvaccinated pregnant women reported in the medical literature. CONCLUSIONS: Administration of LAIV to pregnant women is rare; the rate has remained constant since 2004-2005. In this cohort, there was no evidence of significant maternal adverse outcomes after receipt of LAIV. These data may offer some reassurance to providers and pregnant women in the event of inadvertent LAIV administration, but do not support the routine use of LAIV in pregnant women.

A postmarketing evaluation of the frequency of use and safety of live attenuated influenza vaccine use in nonrecommended children younger than 5 years.

The 2007 US approval for use of live attenuated influenza vaccine (LAIV) in children aged 24-59 months included precautions against use in (1) children <24 months and children aged 24-59 months with (2) asthma, (3) recurrent wheezing, and (4) altered immunocompetence. A postmarketing commitment was initiated to monitor LAIV use and the frequency of select safety outcomes in these cohorts. Vaccination rates and the frequency of hospitalizations or emergency department visits within 42 days after LAIV and trivalent inactivated influenza vaccine (TIV) administration were estimated from 2007 to 2009 claims data from a health insurance database. Rates of LAIV use per 10,000 child-days among cohorts 1, 2, and 4 were low relative to rates among the LAIV-recommended population (2007-2008; 0.03-0.78 vs. 1.32, 2008-2009; 0.08-3.26 vs. 5.94). However, rates of LAIV use per 10,000 child-days in cohort 3 were similar to rates among the LAIV-recommended population (2007-2008; 1.55 vs. 1.32, 2008-2009; 5.01 vs. 5.94). The rate of emergency department visits/hospitalizations within 42 days of vaccination with LAIV was the same as or less than the rate within 42 days of vaccination with TIV. Less restricted LAIV use in children with past wheezing may be related to the broad definition of recurrent wheezing used in national guidelines and the current study. In the small number of nonrecommended children receiving LAIV, no safety signals were identified.

Cancer risk in asthmatic populations.

OBJECTIVE: To conduct a meta-analysis of epidemiologic studies to derive a pooled estimate of the association between asthma and cancer incidence and between allergy and cancer incidence. DATA SOURCES: Five cohort studies and 1 case-control study of cancer incidence in asthma, 4 studies of cancer mortality in asthma, and 3 studies of cancer incidence in allergy. STUDY SELECTION: We searched the National Library of Medicine Gateway to identify observational studies of cancer incidence in asthma and included any case-control or cohort study of incident cancers or of cancer mortality that met the predefined inclusion criteria. RESULTS: There was no significant association between asthma and cancer incidence. A single large cohort study demonstrated a protective effect of asthma; the remaining cohort studies demonstrated a slightly elevated risk of cancer associated with asthma. Inconsistencies in study design features included control of smoking in analyses, use of a control group, and methods to identify asthma status. CONCLUSIONS: The method of asthma identification affects the validity of asthma classification and the severity of asthma examined. The inconsistency in study designs could have contributed to the variability in results and the underestimation of the impact of asthma on cancer incidence.

Lamotrigine and the risk of malformations in pregnancy.

OBJECTIVE: To report the frequency of major malformations in lamotrigine-exposed pregnancies from September 1, 1992, through March 31, 2004, in the International Lamotrigine Pregnancy Registry. METHODS: Health care professionals throughout the world can voluntarily enroll lamotrigine-exposed pregnancies in this observational study. Only pregnancies with unknown outcomes at the time of enrollment were included in the analysis. The percentage of outcomes with major birth defects was calculated as the total number of outcomes with major birth defects divided by the sum of the number of outcomes with major birth defects + the number of live births without defects. RESULTS: Among 414 first-trimester exposures to lamotrigine monotherapy, 12 outcomes with major birth defects were reported (2.9%, 95% CI 1.6% to 5.1%). Among the 88 first-trimester exposures to lamotrigine polytherapy including valproate, 11 outcomes with major birth defects were reported (12.5%; 95% CI 6.7% to 21.7%). Among 182 first-trimester exposures to lamotrigine polytherapy excluding valproate, 5 outcomes with major birth defects were reported (2.7%, 95% CI 1.0% to 6.6%). No distinctive pattern of major birth defects was apparent among the offspring exposed to lamotrigine monotherapy or polytherapy. CONCLUSIONS: The risk of all major birth defects after first-trimester exposure to lamotrigine monotherapy (2.9%) was similar to that in the general population and in other registries enrolling women exposed to antiepileptic monotherapy (3.3% to 4.5%). However, the sample size was too small to detect any but very large increases in specific birth defects.

Preliminary results on pregnancy outcomes in women using lamotrigine.

PURPOSE: In 1992, the International Lamotrigine Pregnancy Registry was initiated to enroll prospectively and to monitor pregnancies exposed to lamotrigine (LTG) for the occurrence of major birth defects. This study presents results as of September 2001 on 168 outcomes exposed to LTG monotherapy and 166 outcomes after pregnancies exposed to LTG polytherapy during the first trimester. METHODS: LTG pregnancy exposures are voluntarily reported to the registry by health care providers before they are aware of each pregnancy outcome. Pregnancy-outcome ascertainment is obtained through subsequent follow-up with the reporting health care provider, and each reported birth defect is reviewed by an expert pediatrician. The percentage with major birth defects in pregnancies with known birth defect status was calculated for LTG monotherapy and for polytherapy stratified by trimester of exposure. RESULTS: The registry identified 334 first-trimester LTG pregnancy outcomes exposed to LTG monotherapy or polytherapy during the first trimester and involving either a live birth with or without a major birth defect or an abortion with a major birth defect. After exposure to LTG monotherapy, the percentage with major birth defects exposed to LTG monotherapy was three (1.8%) of 168 [95% confidence interval (CI), 0.5-5.5%]. There were five (10%) major birth defects observed in 50 outcomes after LTG polytherapy involving valproic acid (VPA; 95% CI, 3.7-22.6%) during the first trimester. The observed proportion of major defects after LTG polytherapy without VPA during the first trimester was five (4.3%) of 116 (95% CI, 1.6-10.3%). No specific patterns of major birth defects in any subgroup or within the registry as a whole were observed. CONCLUSIONS: The sample sizes for individual regimens are too small to rule out small increases in frequency of all major birth defects or even large increases in frequency of rare major birth defects. However, the percentage of outcomes with major birth defects after LTG monotherapy in this study and in another similar pregnancy registry in the United Kingdom did not differ from that reported in the recent literature for women with epilepsy receiving antiepileptic drug monotherapy (4%). The frequency of major malformations after exposures of LTG-VPA is higher than that after the LTG monotherapy or LTG polytherapy regimens without VPA. Although there are published data on frequency of major malformations after VPA exposures in pregnancy, between-study differences in methods and source populations and the wide confidence intervals around the estimate for LTG and VPA limit the utility of comparison with such data, and no conclusions are made at this time about this combination. The continued registration of exposed pregnancies to an exposure registry as early as possible in the pregnancy before any knowledge of the outcome, and before any prenatal testing, will enhance the power of such data.