Prevalence of prescription opioid use during pregnancy in eight US health plans during 2001-2014.

PURPOSE: To estimate prevalence of prescription opioid use during pregnancy in eight US health plans during 2001-2014. METHODS: We conducted a cohort study of singleton live birth deliveries. Maternal characteristics were ascertained from health plan and/or birth certificate data and opioids dispensed during pregnancy from health plan pharmacy records. Prevalence of prescription opioid use during pregnancy was calculated for any use, cumulative days of use, and number of dispensings. RESULTS: We examined prevalence of prescription opioid use during pregnancy in each health plan. Tennessee Medicaid had appreciably greater prevalence of use compared to the seven other health plans. Thus, results for the two groups were reported separately. In the seven health plans (n = 587 093 deliveries), prevalence of use during pregnancy was relatively stable at 9%-11% throughout 2001-2014. In Tennessee Medicaid (n = 256 724 deliveries), prevalence increased from 29% in 2001 to a peak of 36%-37% in 2004-2010, and then declined to 28% in 2014. Use for ≥30 days during pregnancy was stable at 1% in the seven health plans and increased from 2% to 7% in Tennessee Medicaid during 2001-2014. Receipt of ≥5 opioid dispensings during pregnancy increased in the seven health plans (0.3%-0.6%) and Tennessee Medicaid (3%-5%) during 2001-2014. CONCLUSION: During 2001-2014, prescription opioid use during pregnancy was more common in Tennessee Medicaid (peak prevalence in late 2000s) compared to the seven health plans (relatively stable prevalence). Although a small percentage of women had opioid use during pregnancy for ≥30 days or ≥ 5 dispensings, they represent thousands of women during 2001-2014.

Validity of diagnosis and procedure codes for identifying neural tube defects in infants.

PURPOSE: The use of validated criteria to identify birth defects in electronic healthcare databases can avoid the cost and time-intensive efforts required to conduct chart reviews to confirm outcomes. This study evaluated the validity of various case-finding methodologies to identify neural tube defects (NTDs) in infants using an electronic healthcare database. METHODS: This analysis used data generated from a study whose primary aim was to evaluate the association between first-trimester maternal prescription opioid use and NTDs. The study was conducted within the Medication Exposure in Pregnancy Risk Evaluation Program. A broad approach was used to identify potential NTDs including diagnosis and procedure codes from inpatient and outpatient settings, death certificates and birth defect flags in birth certificates. Potential NTD cases were chart abstracted and confirmed by clinical experts. Positive predictive values (PPVs) and 95% confidence intervals (95% CI) are reported. RESULTS: The cohort included 113 168 singleton live-born infants: 55 960 infants with opioid exposure in pregnancy and 57 208 infants unexposed in pregnancy. Seventy-three potential NTD cases were available for the validation analysis. The overall PPV was 41% using all diagnosis and procedure codes plus birth certificates. Restricting approaches to codes recorded in the infants' medical record or to birth certificate flags increased the PPVs (72% and 80%, respectively) but missed a substantial proportion of confirmed NTDs. CONCLUSIONS: Codes in electronic healthcare data did not accurately identify confirmed NTDs. These results indicate that chart review with adjudication of outcomes is important when conducting observational studies of NTDs using electronic healthcare data.

Unmet Patient Need in Statin Intolerance: the Clinical Characteristics and Management.

PURPOSE: A substantial percentage of patients report intolerance or side effects of statin treatment leading to treatment changes or discontinuation. The purpose of this study was to examine statin therapy changes and subsequent effects on low-density lipoprotein cholesterol (LDL-C) among patients with statin intolerance (SI). METHODS: We identified 45,037 adults from Kaiser Permanente Southern California with SI documented between 2006 and 2012. Changes in statin therapy in the year before and after the SI index date were examined. We categorized patients into those who initiated statin therapy, discontinued, up-titrated, down-titrated, or did not switch therapy. We calculated the percentage change in LDL-C from the year before to the year after SI, and the percentage of patients attaining LDL-C < 100 and < 70 mg/dL. RESULTS: In the year prior to the SI date, 77.8% of patients filled a statin prescription. Following SI, 44.6% had no treatment change, 25.5% discontinued, and 30.0% altered their statin therapy. Of those who altered statin therapy, 52.6% down-titrated and 17.2% up-titrated their dose. Rhabdomyolysis was documented in < 1% of the cohort. The largest changes in LDL-C were experienced by patients who were on a high-intensity statin then discontinued treatment (35.6% increase) and those who initiated a high-intensity statin (25.5% decrease). The proportion of patients achieving LDL-C < 100 mg/dL and LDL-C < 70 mg/dL was the lowest among those who discontinued therapy. CONCLUSIONS: Although adjustments to the statin dosage may be appropriate upon documentation of SI, many of these patients will have high LDL-C. Strategies for LDL-C reduction in patients with SI may be necessary.

Trends in Statin Use 2009-2015 in a Large Integrated Health System: Pre- and Post-2013 ACC/AHA Guideline on Treatment of Blood Cholesterol.

PURPOSE: Implementation of the 2013 ACC/AHA cholesterol treatment guideline is likely to vary by statin benefit group. The aim of this study was to document trends in statin use before and after introduction of the ACC/AHA guideline. METHODS: We conducted a retrospective study with annual cohorts from 2009 to 2015 among members of Kaiser Permanente Southern California aged ≥ 21 years. Members were categorized into four mutually exclusive statin benefit groups: atherosclerotic cardiovascular disease (ASCVD), LDL-C ≥ 190 mg/dL in the last year, diabetes (aged 40-75 years), and 10-year ASCVD risk ≥ 7.5% (aged 40-75 years). RESULTS: The cohorts ranged from 1,993,755 members in 2009 to 2,440,429 in 2015. Approximately 5% of patients had ASCVD, 1% had LDL-C ≥ 190 mg/dL, 6% had diabetes, and 10% had a 10-year ASCVD risk ≥ 7.5% each year. Trends in statin use were stable for adults with ASCVD (2009 78%; 2015 80%), recent LDL-C ≥ 190 mg/dL (2009 45%; 2015 44%), and diabetes (2009 74%; 2015 73%), but increased for patients with 10-year ASCVD risk ≥ 7.5% (2009 36%; 2015 47%). High-intensity statin use also increased 142% and 54% among patients with LDL-C ≥ 190 mg/dL and those with ASCVD ≤ 75 years of age, respectively. Moderate-to-high intensity statin utilization increased over 50% among those with a 10-year ASCVD risk ≥ 7.5%. CONCLUSIONS: Statin use increased substantially among patients with 10-year ASCVD risk ≥ 7.5% and use of appropriate statin dosage increased in each of the four statin benefit groups between 2009 and 2015; however, there is room for improvement.

Outcomes of Dabigatran and Warfarin for Atrial Fibrillation in Contemporary Practice: A Retrospective Cohort Study.

BACKGROUND: Dabigatran (150 mg twice daily) has been associated with lower rates of stroke than warfarin in trials of atrial fibrillation, but large-scale evaluations in clinical practice are limited. OBJECTIVE: To compare incidence of stroke, bleeding, and myocardial infarction in patients receiving dabigatran versus warfarin in practice. DESIGN: Retrospective cohort. SETTING: National U.S. Food and Drug Administration Sentinel network. PATIENTS: Adults with atrial fibrillation initiating dabigatran or warfarin therapy between November 2010 and May 2014. MEASUREMENTS: Ischemic stroke, intracranial hemorrhage, extracranial bleeding, and myocardial infarction identified from hospital claims among propensity score-matched patients starting treatment with dabigatran or warfarin. RESULTS: Among 25 289 patients starting dabigatran therapy and 25 289 propensity score-matched patients starting warfarin therapy, those receiving dabigatran did not have significantly different rates of ischemic stroke (0.80 vs. 0.94 events per 100 person-years; hazard ratio [HR], 0.92 [95% CI, 0.65 to 1.28]) or extracranial hemorrhage (2.12 vs. 2.63 events per 100 person-years; HR, 0.89 [CI, 0.72 to 1.09]) but were less likely to have intracranial bleeding (0.39 vs. 0.77 events per 100 person-years; HR, 0.51 [CI, 0.33 to 0.79]) and more likely to have myocardial infarction (0.77 vs. 0.43 events per 100 person-years; HR, 1.88 [CI, 1.22 to 2.90]). However, the strength and significance of the association between dabigatran use and myocardial infarction varied in sensitivity analyses and by exposure definition (HR range, 1.13 [CI, 0.78 to 1.64] to 1.43 [CI, 0.99 to 2.08]). Older patients and those with kidney disease had higher gastrointestinal bleeding rates with dabigatran. LIMITATION: Inability to examine outcomes by dabigatran dose (unacceptable covariate balance between matched patients) or quality of warfarin anticoagulation (few patients receiving warfarin had available international normalized ratio values). CONCLUSION: In matched adults with atrial fibrillation treated in practice, the incidences of stroke and bleeding with dabigatran versus warfarin were consistent with those seen in trials. The possible relationship between dabigatran and myocardial infarction warrants further investigation. PRIMARY FUNDING SOURCE: U.S. Food and Drug Administration.

Risk of Breast Cancer With Long-Term Use of Calcium Channel Blockers or Angiotensin-Converting Enzyme Inhibitors Among Older Women.

Controversy exists about breast cancer risk associated with long-term use of calcium channel blockers (CCBs) or angiotensin-converting enzyme inhibitors (ACEis), respectively. Our objective in this study was to separately evaluate associations between duration of CCB or ACEi use and breast cancer in hypertensive women aged ≥55 years at 3 sites in the Kaiser Permanente health-care system (1997­2012). Exposures included CCB or ACEi use of 1­12 years' duration, determined from pharmacy dispensings. Outcomes included invasive lobular or ductal carcinoma. Statistical methods included discrete-time survival analyses. The cohort included 19,674 (17.9%) CCB users and 90,078 (82.1%) ACEi users. Two percent (n = 397) of CCB users and 1.9% (n = 1,733) of ACEi users developed breast cancer. Compared with 1­<2 years of use, in adjusted analysis, there was no association between CCB use for 2­<12 years and breast cancer: All 95% confidence intervals included 1. Increasing duration of ACEi use was associated with reduced breast cancer risk: Compared with 1­<2 years of use, the adjusted hazard ratio was 0.76 (95% confidence interval: 0.63, 0.92) for 5­<6 years of use and 0.63 (95% confidence interval: 0.43, 0.93) for 9­<10 years of use. We conclude that among older women with hypertension, long-term CCB use does not increase breast cancer risk and long-term treatment with ACEis may confer protection against breast cancer.

First Trimester Influenza Vaccination and Risks for Major Structural Birth Defects in Offspring.

OBJECTIVE: To examine risks for major structural birth defects in infants after first trimester inactivated influenza vaccine (IIV) exposures. STUDY DESIGN: In this observational study, we used electronic health data from 7 Vaccine Safety Datalink sites to examine risks for selected major structural defects in infants after maternal IIV exposure. Vaccine exposures for women with continuous insurance enrollment through pregnancy who delivered singleton live births between 2004 and 2013 were identified from standardized files. Infants with continuous insurance enrollment were followed to 1 year of age. We excluded mother-infant pairs with other exposures that potentially increased their background risk for birth defects. Selected cardiac, orofacial or respiratory, neurologic, ophthalmologic or otologic, gastrointestinal, genitourinary and muscular or limb defects were identified from diagnostic codes in infant medical records using validated algorithms. Propensity score adjusted generalized estimating equations were used to estimate prevalence ratios (PRs). RESULTS: We identified 52 856 infants with maternal first trimester IIV exposure and 373 088 infants whose mothers were unexposed to IIV during first trimester. Prevalence (per 100 live births) for selected major structural birth defects was 1.6 among first trimester IIV exposed versus 1.5 among unexposed mothers. The adjusted PR was 1.02 (95% CI 0.94-1.10). Organ system-specific PRs were similar to the overall PR. CONCLUSION: First trimester maternal IIV exposure was not associated with an increased risk for selected major structural birth defects in this large cohort of singleton live births.

Identifying birth defects in automated data sources in the Vaccine Safety Datalink.

PURPOSE: The Vaccine Safety Datalink (VSD), a collaboration between the Centers for Disease Control and Prevention and several large healthcare organizations, aims to monitor safety of vaccines administered in the USA. We present definitions and prevalence estimates for major structural birth defects to be used in studies of maternal vaccine safety. METHODS: In this observational study, we created and refined algorithms for identifying major structural birth defects from electronic healthcare data, conducted formal chart reviews for severe cardiac defects, and conducted limited chart validation for other defects. We estimated prevalence for selected defects by VSD site and birth year and compared these estimates to those in a US and European surveillance system. RESULTS: We developed algorithms to enumerate >50 major structural birth defects from standardized administrative and healthcare data based on utilization patterns and expert opinion, applying criteria for number, timing, and setting of diagnoses. Our birth cohort included 497 894 infants across seven sites. The period prevalence for all selected major birth defects in the VSD from 2004 to 2013 was 1.7 per 100 live births. Cardiac defects were most common (65.4 per 10 000 live births), with one-fourth classified as severe, requiring emergent intervention. For most major structural birth defects, prevalence estimates were stable over time and across sites and similar to those reported in other population-based surveillance systems. CONCLUSIONS: Our algorithms can efficiently identify many major structural birth defects in large healthcare datasets and can be used in studies evaluating the safety of vaccines administered to pregnant women. Copyright © 2017 John Wiley & Sons, Ltd.

Effectiveness of bisphosphonate use and risk of contralateral breast cancer and recurrence in women with early-stage breast cancer treated with tamoxifen.

The effectiveness of bisphosphonates (BP) in reducing risk of second breast cancer and recurrence in observational studies has been minimally studied. We examined the association of oral BP use on risk of contralateral breast cancer (CBC) and recurrence in 16,781 women diagnosed with early-stage breast cancer from 1996 to 2007, treated with tamoxifen, and followed through December 31, 2009 at Kaiser Permanente Northern California (KPNC, n = 8857) and Southern California (KPSC, n = 7924). Sociodemographic, clinical, and pharmacy information were extracted from electronic medical records and cancer registries. CBC was identified from cancer registries, and recurrences from electronic health records and chart reviews. Multivariate Cox regression models were used to estimate hazard ratios (HR) and 95 % confidence intervals (CI) treating BP use and hormonal therapy as time-varying variables. After mean 6.4 years of follow-up, 494 (3.0 %) women developed CBC. BP use post-breast cancer diagnosis (>93 % alendronate) ranged from 14.5 to 24.9 % at both study sites. Overall, there was no association of BP use with reduced risk of CBC (ever use, HR = 0.96; 95 % CI 0.67-1.38 and continuous use, HR = 1.03; 95 % CI 0.88, 1.20). Similar null associations were observed for recurrence (ever use, HR = 0.98; 95 % CI 0.82, 1.17 and continuous use, HR = 1.00; 95 % CI 0.92, 1.09). Associations varied somewhat by site yet confidence intervals overlapped. BP use was not associated with reduced risk of recurrence or new primary disease among women diagnosed with early breast cancer and treated with tamoxifen.

Trimethoprim-sulfonamide use during the first trimester of pregnancy and the risk of congenital anomalies.

BACKGROUND: Sulfonamide antibacterials are widely used in pregnancy, but evidence about their safety is mixed. The objective of this study was to assess the association between first-trimester sulfonamide exposure and risk of specific congenital malformations. METHODS: Mother-infant pairs were selected from a cohort of 1.2 million live-born deliveries (2001-2008) at 11 US health plans comprising the Medication Exposure in Pregnancy Risk Evaluation Program. Mothers with first-trimester trimethoprim-sulfonamide (TMP-SUL) exposures were randomly matched 1:1 to (i) a primary comparison group (mothers exposed to penicillins and/or cephalosporins) and (ii) a secondary comparison group (mothers with no dispensing of an antibacterial, antiprotozoal, or antimalarial medication during the same time period). The outcomes were cardiovascular abnormalities, cleft palate/lip, clubfoot, and urinary tract abnormalities. RESULTS: We first identified 7615 infants in the TMP-SUL exposure group, of which 7595 (99%) were exposed to a combination of TMP-SUL and the remaining 1% to sulfonamides alone. After matching (1:1) to the comparator groups and only including those with complete data on covariates, there were 20 064 (n = 6688 per group) in the primary analyses. Overall, cardiovascular defects (1.52%) were the most common and cleft lip/palate (0.10%) the least common that were evaluated. Compared with penicillin/cephalosporin exposure, and no antibacterial exposure, TMP-SUL exposure was not associated with statistically significant elevated risks for cardiovascular, cleft lip/palate, clubfoot, or urinary system defects. CONCLUSIONS: First-trimester TMP-SUL exposure was not associated with a higher risk of the congenital anomalies studied, compared with exposure to penicillins and/or cephalosporins, or no exposure to antibacterials.

Lower Total Knee Arthroplasty Revision Risk Associated With Bisphosphonate Use, Even in Patients With Normal Bone Density.

BACKGROUND: Bisphosphonates (BPs) are associated with lower total knee arthroplasty (TKA) revision risk, but the effect of bone mineral density has not been evaluated. METHODS: A cohort of 34,116 primary TKA patients was evaluated with revision surgery and periprosthetic fractures as end points. BP usage was the exposure of interest. Bone quality (normal, osteopenia, and osteoporosis) and patient age (<65 vs ≥65 years) were evaluated as effect modifiers of risk estimates. RESULTS: Of the patients, 19.6% were BP users. In BP users, 0.5% underwent an aseptic revision; and 0.6%, a periprosthetic fracture. In non-BP users, 1.6% underwent aseptic revision; and 0.1%, a periprosthetic fracture. CONCLUSION: Bisphosphonate use was associated with lower risk of revision in all bone quality categories in those older than 65 years. The risk of periprosthetic fractures was higher for patients on BP.

Patient and clinical characteristics associated with gout flares in an integrated healthcare system.

Gout flares have been challenging to identify in retrospective databases due to gout flares not being well documented by diagnosis codes, making it difficult to conduct accurate database studies. Previous studies have used different algorithms, and in this study, we used a computer-based method to identify gout flares. The objectives of this study were to identify gout flares in gout patients newly initiated on urate-lowering therapy and evaluate factors associated with a patient experiencing gout flares after starting drug treatment. This was a retrospective cohort study identifying gout patients newly initiated on a urate-lowering therapy (ULT) during the study time period of January 1, 2007-December 31, 2010. The index date was the first dispensed ULT prescription during the study time period. Patients had to be ≥18 years of age on index date, have no history of prior ULT prescription during 12 months before index date, and were required to have 12 months of continuous membership with drug benefit during pre-/post-index. Electronic chart notes were reviewed to identify gout flares; these reviews helped create a validated computer-based method to further identify patients with gout flares and were categorized into 0 gout flares, 1-2 gout flares, and ≥3 gout flares during the 12 months post-index period. Multivariable logistic regression was used to examine patient and clinical factors associated with gout flares during the 12-month follow-up period. There were 8905 patients identified as the final cohort and 68 % of these patients had one or more gout flares during the 12-month follow-up: 2797 patients (31 %) had 0 gout flares, 4836 (54 %) had 1-2 gout flares, and 1272 patients (14 %) had ≥3 gout flares. Using a multivariate regression analyses, factors independently associated with 1-2 gout flares and ≥3 gout flares versus no gout flares were similar, however, with slight differences, such as younger patients were more likely to have 1-2 gout flares and patients ≥65 years of age had ≥3 gout flares. Factors such as male gender, not attaining sUA goal, having ≥3 comorbidities, diuretics use, no changes in initial ULT dose, and not adhering to ULT all were associated with gout flares versus no gout flares. Using a new method to identify gout flares, we had the opportunity to compare our findings with the previous studies. Our study findings echo other previous studies where older patients, male, diuretics, having a greater number of comorbidities, and non-adherence are more likely to have more gout flares during the first year of newly initiating ULT. There is an unmet need for patients with gout to be educated and managed more closely, especially during the first year.

Genital herpes and its treatment in relation to preterm delivery.

To examine the risks of genital herpes and antiherpes treatment during pregnancy in relation to preterm delivery (PTD), we conducted a multicenter, member-based cohort study within 4 Kaiser Permanente regions: northern and southern California, Colorado, and Georgia. The study included 662,913 mother-newborn pairs from 1997 to 2010. Pregnant women were classified into 3 groups based on genital herpes diagnosis and treatment: genital herpes without treatment, genital herpes with antiherpes treatment, and no herpes diagnosis or treatment (unexposed controls). After controlling for potential confounders, we found that compared with being unexposed, having untreated genital herpes during first or second trimester was associated with more than double the risk of PTD (odds ratio (OR) = 2.23, 95% confidence interval (CI): 1.80, 2.76). The association was stronger for PTD due to premature rupture of membrane (OR = 3.57, 95% CI: 2.53, 5.06) and for early PTD (≤35 weeks gestation) (OR = 2.87, 95% CI: 2.22, 3.71). In contrast, undergoing antiherpes treatment during pregnancy was associated with a lower risk of PTD compared with not being treated, and the PTD risk was similar to that observed in the unexposed controls (OR = 1.11, 95% CI: 0.89, 1.38). The present study revealed increased risk of PTD associated with genital herpes infection if left untreated and a potential benefit of antiherpes medications in mitigating the effect of genital herpes infection on the risk of PTD.

ADHD drugs and serious cardiovascular events in children and young adults.

BACKGROUND: Adverse-event reports from North America have raised concern that the use of drugs for attention deficit-hyperactivity disorder (ADHD) increases the risk of serious cardiovascular events. METHODS: We conducted a retrospective cohort study with automated data from four health plans (Tennessee Medicaid, Washington State Medicaid, Kaiser Permanente California, and OptumInsight Epidemiology), with 1,200,438 children and young adults between the ages of 2 and 24 years and 2,579,104 person-years of follow-up, including 373,667 person-years of current use of ADHD drugs. We identified serious cardiovascular events (sudden cardiac death, acute myocardial infarction, and stroke) from health-plan data and vital records, with end points validated by medical-record review. We estimated the relative risk of end points among current users, as compared with nonusers, with hazard ratios from Cox regression models. RESULTS: Cohort members had 81 serious cardiovascular events (3.1 per 100,000 person-years). Current users of ADHD drugs were not at increased risk for serious cardiovascular events (adjusted hazard ratio, 0.75; 95% confidence interval [CI], 0.31 to 1.85). Risk was not increased for any of the individual end points, or for current users as compared with former users (adjusted hazard ratio, 0.70; 95% CI, 0.29 to 1.72). Alternative analyses addressing several study assumptions also showed no significant association between the use of an ADHD drug and the risk of a study end point. CONCLUSIONS: This large study showed no evidence that current use of an ADHD drug was associated with an increased risk of serious cardiovascular events, although the upper limit of the 95% confidence interval indicated that a doubling of the risk could not be ruled out. However, the absolute magnitude of such an increased risk would be low. (Funded by the Agency for Healthcare Research and Quality and the Food and Drug Administration.).

Receipt of pertussis vaccine during pregnancy across 7 Vaccine Safety Datalink sites.

OBJECTIVE: In response to widespread pertussis outbreaks and infant deaths, in 2010, the California Department of Health (CDPH) and in 2011 the Advisory Committee on Immunization Practices (ACIP) advised that the tetanus toxoid, reduced diphtheria toxoid and acellular pertussis (Tdap) vaccine be administered during pregnancy. The goals of this study were to describe Tdap coverage among pregnant women following these recommendations. METHODS: In this observational cohort study, we utilized electronic medical record and claims data from seven Vaccine Safety Datalink sites to identify pregnancies and Tdap administrations. All Tdap doses were classified as pre-pregnancy, during pregnancy or post-pregnancy/postpartum. For pregnancies ending in a live birth, we evaluated factors associated with Tdap vaccination. RESULTS: Among 289,141 live births at the California VSD sites, receipt of Tdap during pregnancy increased substantially in the years 2010, 2011, and 2012, when coverage was 15.9, 30.0 and 19.5%, respectively. Among 82,398 women with live births at the Oregon, Washington, Colorado, Wisconsin and Minnesota VSD sites, receipt of Tdap during pregnancy first increased in 2012, at 16.0%. Women receiving early prenatal care and other vaccine(s) during pregnancy had higher Tdap coverage. CONCLUSION: We observed substantial increases in Tdap coverage during pregnancy following CDPH and ACIP recommendations.

An automated causality assessment algorithm to detect drug-induced liver injury in electronic medical record data.

PURPOSE: The aim of this study was to develop an automated causality assessment algorithm to identify drug-induced liver injury. METHODS: The Roussel Uclaf Causality Assessment Method (RUCAM) is an algorithm for determining the causal association between a drug and liver injury. In collaboration with hepatology experts, definitions were developed for the RUCAM criteria to operationalize an electronic RUCAM (eRUCAM). The eRUCAM was tested in a population of patients taking 14 drugs with a characteristic phenotype for liver injury. Quality assurance for programming specifications involved comparisons between scores generated by the eRUCAM, for probable and highly probable cases, and expert manual RUCAM (n = 20). Concordance between eRUCAM and manual RUCAM subscores and total score was tested using the Wilcoxon signed rank test. RESULTS: Causality scores were the same for 6 of 20 patients (30%) by manual and eRUCAM algorithms. Analysis of subscores revealed ≥80% concordance between manual and eRUCAM for five of the seven criteria. In general, the total scores tended to be higher for the eRUCAM compared with the manual RUCAM. Programming issues were identified for criterion 5 'non-drug causes of liver injury' where significant differences existed between manual and eRUCAM scoring (p = 0.001). For criterion 5, identical scores occurred in 9 of 20 patients (45%), and manual review identified additional codes, timing criteria, and laboratory results for improving subsequent eRUCAM revisions. CONCLUSION: The eRUCAM had generally good concordance with manual RUCAM scoring. These preliminary findings suggest that the eRUCAM algorithm is feasible and could have application in clinical practice and drug safety surveillance.

Validation of the Osteoporosis-Specific Morisky Medication Adherence Scale in long-term users of bisphosphonates.

PURPOSE: To examine the psychometric properties and validity of the 8-item Osteoporosis-Specific Morisky Medication Adherence Scale (OS-MMAS-8) in postmenopausal women prescribed bisphosphonates (BPs) for at least 15 months. METHODS: A random sample of women aged ≥55 years with osteoporosis prescribed daily or weekly BPs was identified. Pharmacy fill data were extracted to calculate the medication possession ratio (MPR). Eligible women were stratified by low (<0.50), medium (0.50-0.79), or high (≥0.80) MPR, with the a priori goal of recruiting 133 participants in each group. OS-MMAS-8 scores can range from 0 to 8 and were categorized as low (<6), medium (6 to <8), and high (8) adherence. Internal consistency reliability (Cronbach's alpha), test-retest reliability [intraclass correlation coefficients (ICCs)] and convergent validity (correlating OS-MMAS-8 with MPR and other self-reported measures) were assessed. RESULTS: A total of 400 women out of 449 respondents reported that they were still taking their BPs at the time of the survey and completed OS-MMAS-8. Overall, 38.5, 34.3, and 27.3% of participants had low, medium, and high OS-MMAS-8 scores, respectively. The mean (SD) MPRs according to OS-MMAS-8 scores (<6, 6 to <8 and 8) were 56.9 (22.6), 69.0 (24.9), and 76.7 (26.4), respectively. The correlation between OS-MMAS-8 and MPR was 0.36; p < 0.0001. Cronbach's alpha was 0.74, and the ICC was 0.83 (95% CI 0.76-0.88). CONCLUSIONS: OS-MMAS-8 has acceptable psychometric properties for assessing medication adherence in postmenopausal women prescribed therapy for osteoporosis. Additional studies are needed to investigate the psychometric properties of OS-MMAS-8 in other settings and populations.

Evaluation of the association of maternal pertussis vaccination with obstetric events and birth outcomes.

IMPORTANCE: In 2010, due to a pertussis outbreak and neonatal deaths, the California Department of Health recommended that the tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccine (Tdap) be administered during pregnancy. Tdap is now recommended by the Advisory Committee on Immunization Practices for all pregnant women, preferably between 27 and 36 weeks' gestation. Limited data exist on Tdap safety during pregnancy. OBJECTIVE: To evaluate whether maternal Tdap vaccination during pregnancy is associated with increased risks of adverse obstetric events or adverse birth outcomes. DESIGN AND SETTING: Retrospective, observational cohort study using administrative health care databases from 2 California Vaccine Safety Datalink sites. PARTICIPANTS AND EXPOSURES: Of 123,494 women with singleton pregnancies ending in a live birth between January 1, 2010, and November 15, 2012, 26,229 (21%) received Tdap during pregnancy and 97,265 did not. MAIN OUTCOMES AND MEASURES: Risks of small-for-gestational-age (SGA) births (<10th percentile), chorioamnionitis, preterm birth (<37 weeks' gestation), and hypertensive disorders of pregnancy were evaluated. Relative risk (RR) estimates were adjusted for site, receipt of another vaccine during pregnancy, and propensity to receive Tdap during pregnancy. Cox regression was used for preterm delivery, and Poisson regression for other outcomes. RESULTS: Vaccination was not associated with increased risks of adverse birth outcomes: crude estimates for preterm delivery were 6.3% of vaccinated and 7.8% of unvaccinated women (adjusted RR, 1.03; 95% CI, 0.97-1.09); 8.4% of vaccinated and 8.3% of unvaccinated had an SGA birth (adjusted RR, 1.00; 95% CI, 0.96-1.06). Receipt of Tdap before 20 weeks was not associated with hypertensive disorder of pregnancy (adjusted RR, 1.09; 95% CI, 0.99-1.20); chorioamnionitis was diagnosed in 6.1% of vaccinated and 5.5% of unvaccinated women (adjusted RR, 1.19; 95% CI, 1.13-1.26). CONCLUSIONS AND RELEVANCE: In this cohort of women with singleton pregnancies that ended in live birth, receipt of Tdap during pregnancy was not associated with increased risk of hypertensive disorders of pregnancy or preterm or SGA birth, although a small but statistically significant increased risk of chorioamnionitis diagnosis was observed.

Characterizing phenotypes and outcomes of drug-associated liver injury using electronic medical record data.

PURPOSE: To evaluate the incidence, phenotypes, and outcomes of drug-associated liver injury identified in electronic medical record (EMR) data using standardized criteria for drug-induced liver injury (DILI). METHODS: This retrospective cohort study used EMR data from a large integrated healthcare system. Study inclusion required 18 years of age or older, ≥1 prescription fill for any of 14 medications associated with hepatotoxicity between 1 January 2003 and 30 June 2009, and ≥12 months of membership prior to the drug exposure. Patients with underlying non-drug causes of liver injury were excluded to minimize capture of liver injury events unrelated to drugs. Drug-associated liver injuries were identified by liver chemistry elevations temporally associated with drug use based on standardized criteria for DILI. Cases were classified by clinical pattern and severity. Outcomes of liver transplant and all-cause and liver-related death were examined. RESULTS: A total of 1 053 979 drug exposures were identified in 601 125 patients. We identified 265 drug-associated liver injuries (32.8 per 100 000 persons) occurring in 250 patients. Isoniazid exhibited the highest incidence rate of 606 per 100 000 persons. Of the 265 cases, 41% were mild; 12% exhibited moderate drug-associated liver injury (with concomitant ALT ≥ 5× ULN and bilirubin ≥2× ULN); and 17% exhibited coagulopathy, ascites, encephalopathy, or other organ failure. Last, seven cases (3%) were associated with death, and there were no liver transplants. CONCLUSIONS: Study results align with earlier prospective studies, supporting the value of standardized methodology to identify drug-associated liver injury in the EMR. These methods can potentially enhance safety and clinical outcomes.

Near real-time adverse drug reaction surveillance within population-based health networks: methodology considerations for data accrual.

PURPOSE: This study describes practical considerations for implementation of near real-time medical product safety surveillance in a distributed health data network. METHODS: We conducted pilot active safety surveillance comparing generic divalproex sodium to historical branded product at four health plans from April to October 2009. Outcomes reported are all-cause emergency room visits and fractures. One retrospective data extract was completed (January 2002-June 2008), followed by seven prospective monthly extracts (January 2008-November 2009). To evaluate delays in claims processing, we used three analytic approaches: near real-time sequential analysis, sequential analysis with 1.5 month delay, and nonsequential (using final retrospective data). Sequential analyses used the maximized sequential probability ratio test. Procedural and logistical barriers to active surveillance were documented. RESULTS: We identified 6586 new users of generic divalproex sodium and 43,960 new users of the branded product. Quality control methods identified 16 extract errors, which were corrected. Near real-time extracts captured 87.5% of emergency room visits and 50.0% of fractures, which improved to 98.3% and 68.7% respectively with 1.5 month delay. We did not identify signals for either outcome regardless of extract timeframe, and slight differences in the test statistic and relative risk estimates were found. CONCLUSIONS: Near real-time sequential safety surveillance is feasible, but several barriers warrant attention. Data quality review of each data extract was necessary. Although signal detection was not affected by delay in analysis, when using a historical control group differential accrual between exposure and outcomes may theoretically bias near real-time risk estimates towards the null, causing failure to detect a signal.