Obstetric Complications and Birth Outcomes After Antenatal Coronavirus Disease 2019 (COVID-19) Vaccination.

OBJECTIVE: To evaluate the association between antenatal messenger RNA (mRNA) coronavirus disease 2019 (COVID-19) vaccination and risk of adverse pregnancy outcomes. METHODS: This was a retrospective cohort study of individuals with singleton pregnancies with live deliveries between June 1, 2021, and January 31, 2022, with data available from eight integrated health care systems in the Vaccine Safety Datalink. Vaccine exposure was defined as receipt of one or two mRNA COVID-19 vaccine doses (primary series) during pregnancy. Outcomes were preterm birth (PTB) before 37 weeks of gestation, small-for-gestational age (SGA) neonates, gestational diabetes mellitus (GDM), gestational hypertension, and preeclampsia-eclampsia-HELLP (hemolysis, elevated liver enzymes, and low platelet count) syndrome. Outcomes in individuals vaccinated were compared with those in propensity-matched individuals with unexposed pregnancies. Adjusted hazard ratios (aHRs) and 95% CIs were estimated for PTB and SGA using a time-dependent covariate Cox model, and adjusted relative risks (aRRs) were estimated for GDM, gestational hypertension, and preeclampsia-eclampsia-HELLP syndrome using Poisson regression with robust variance. RESULTS: Among 55,591 individuals eligible for inclusion, 23,517 (42.3%) received one or two mRNA COVID-19 vaccine doses during pregnancy. Receipt of mRNA COVID-19 vaccination varied by maternal age, race, Hispanic ethnicity, and history of COVID-19. Compared with no vaccination, mRNA COVID-19 vaccination was associated with a decreased risk of PTB (rate: 6.4 [vaccinated] vs 7.7 [unvaccinated] per 100, aHR 0.89; 95% CI, 0.83-0.94). Messenger RNA COVID-19 vaccination was not associated with SGA (8.3 vs 7.4 per 100; aHR 1.06, 95% CI, 0.99-1.13), GDM (11.9 vs 10.6 per 100; aRR 1.00, 95% CI, 0.90-1.10), gestational hypertension (10.8 vs 9.9 per 100; aRR 1.08, 95% CI, 0.96-1.22), or preeclampsia-eclampsia-HELLP syndrome (8.9 vs 8.4 per 100; aRR 1.10, 95% CI, 0.97-1.24). CONCLUSION: Receipt of an mRNA COVID-19 vaccine during pregnancy was not associated with an increased risk of adverse pregnancy outcomes; this information will be helpful for patients and clinicians when considering COVID-19 vaccination in pregnancy.

Validity of inpatient electronic health record-based measures of oxygen-related therapy in the United States: Lessons applicable for studying COVID-19 endpoints.

INTRODUCTION: During the COVID-19 pandemic, inpatient electronic health records (EHRs) have been used to conduct public health surveillance and assess treatments and outcomes. Invasive mechanical ventilation (MV) and supplemental oxygen (O2) use are markers of severe illness in hospitalized COVID-19 patients. In a large US system (n = 142 hospitals), we assessed documentation of MV and O2 use during COVID-19 hospitalization in administrative data versus nursing documentation. METHODS: We identified 319 553 adult hospitalizations with a COVID-19 diagnosis, February 2020-October 2022, and extracted coded, administrative data for MV or O2. Separately, we developed classification rules for MV or O2 supplementation from semi-structured nursing documentation. We assessed MV and O2 supplementation in administrative data versus nursing documentation and calculated ordinal endpoints of decreasing COVID-19 disease severity. Nursing documentation was considered the gold standard in sensitivity and positive predictive value (PPV) analyses. RESULTS: In nursing documentation, the prevalence of MV and O2 supplementation among COVID-19 hospitalizations was 14% and 75%, respectively. The sensitivity of administrative data was 83% for MV and 41% for O2, with both PPVs above 91%. Concordance between sources was 97% for MV (κ = 0.85), and 54% for O2 (κ = 0.21). For ordinal endpoints, administrative data accurately identified intensive care and MV but underestimated hospitalizations with O2 requirements (42% vs. 18%). CONCLUSIONS: In comparison to nursing documentation, administrative data under-ascertained O2 supplementation but accurately estimated severe endpoints such as MV. Nursing documentation improved ascertainment of O2 among COVID-19 hospitalizations and can capture oxygen requirements in adults hospitalized with COVID-19 or other respiratory illnesses.

Attitudes Toward COVID-19 Vaccines Among Pregnant and Recently Pregnant Individuals.

Importance: Pregnant people and infants are at high risk of severe COVID-19 outcomes. Understanding changes in attitudes toward COVID-19 vaccines among pregnant and recently pregnant people is important for public health messaging. Objective: To assess attitudinal trends regarding COVID-19 vaccines by (1) vaccination status and (2) race, ethnicity, and language among samples of pregnant and recently pregnant Vaccine Safety Datalink (VSD) members from 2021 to 2023. Design, Setting, and Participants: This cross-sectional surveye study included pregnant or recently pregnant members of the VSD, a collaboration of 13 health care systems and the US Centers for Disease Control and Prevention. Unvaccinated, non-Hispanic Black, and Spanish-speaking members were oversampled. Wave 1 took place from October 2021 to February 2022, and wave 2 took place from November 2022 to February 2023. Data were analyzed from May 2022 to September 2023. Exposures: Self-reported or electronic health record (EHR)-derived race, ethnicity, and preferred language. Main Outcomes and Measures: Self-reported vaccination status and attitudes toward monovalent (wave 1) or bivalent Omicron booster (wave 2) COVID-19 vaccines. Sample- and response-weighted analyses assessed attitudes by vaccination status and 3 race, ethnicity, and language groupings of interest. Results: There were 1227 respondents; all identified as female, the mean (SD) age was 31.7 (5.6) years, 356 (29.0%) identified as Black race, 555 (45.2%) identified as Hispanic ethnicity, and 445 (36.3%) preferred the Spanish language. Response rates were 43.5% for wave 1 (652 of 1500 individuals sampled) and 39.5% for wave 2 (575 of 1456 individuals sampled). Respondents were more likely than nonrespondents to be White, non-Hispanic, and vaccinated per EHR. Overall, 76.8% (95% CI, 71.5%-82.2%) reported 1 or more COVID-19 vaccinations; Spanish-speaking Hispanic respondents had the highest weighted proportion of respondents with 1 or more vaccination. Weighted estimates of somewhat or strongly agreeing that COVID-19 vaccines are safe decreased from wave 1 to 2 for respondents who reported 1 or more vaccinations (76% vs 50%; χ21 = 7.8; P < .001), non-Hispanic White respondents (72% vs 43%; χ21 = 5.4; P = .02), and Spanish-speaking Hispanic respondents (76% vs 53%; χ21 = 22.8; P = .002). Conclusions and Relevance: Decreasing confidence in COVID-19 vaccine safety in a large, diverse pregnant and recently pregnant insured population is a public health concern.

Treatment and care received by children hospitalized with COVID-19 in a large hospital network in the United States, February 2020 to September 2021.

We described care received by hospitalized children with COVID-19 or multi-system inflammatory syndrome (MIS-C) prior to the 2021 COVID-19 Omicron variant surge in the US. We identified hospitalized children <18 years of age with a COVID-19 or MIS-C diagnosis (COVID-19 not required), separately, from February 2020-September 2021 (n = 126 hospitals). We described high-risk conditions, inpatient treatments, and complications among these groups. Among 383,083 pediatric hospitalizations, 2,186 had COVID-19 and 395 had MIS-C diagnosis. Less than 1% had both COVID-19 and MIS-C diagnosis (n = 154). Over half were >6 years old (54% COVID-19, 70% MIS-C). High-risk conditions included asthma (14% COVID-19, 11% MIS-C), and obesity (9% COVID-19, 10% MIS-C). Pulmonary complications in children with COVID-19 included viral pneumonia (24%) and acute respiratory failure (11%). In reference to children with COVID-19, those with MIS-C had more hematological disorders (62% vs 34%), sepsis (16% vs 6%), pericarditis (13% vs 2%), myocarditis (8% vs 1%). Few were ventilated or died, but some required oxygen support (38% COVID-19, 45% MIS-C) or intensive care (42% COVID-19, 69% MIS-C). Treatments included: methylprednisolone (34% COVID-19, 75% MIS-C), dexamethasone (25% COVID-19, 15% MIS-C), remdesivir (13% COVID-19, 5% MIS-C). Antibiotics (50% COVID-19, 68% MIS-C) and low-molecular weight heparin (17% COVID-19, 34% MIS-C) were frequently administered. Markers of illness severity among hospitalized children with COVID-19 prior to the 2021 Omicron surge are consistent with previous studies. We report important trends on treatments in hospitalized children with COVID-19 to improve the understanding of real-world treatment patterns in this population.

Medically Attended Acute Adverse Events in Pregnant People After Coronavirus Disease 2019 (COVID-19) Booster Vaccination.

In this multisite, observational, matched cohort study of more than 80,000 pregnant people, receipt of an mRNA monovalent coronavirus disease 2019 (COVID-19) booster vaccination in pregnancy was not associated with increased risk for thrombocytopenia, myocarditis, venous thromboembolism, ischemic stroke, or other serious adverse events within 21 or 42 days after booster vaccination. The mRNA monovalent COVID-19 booster in pregnancy was associated with an increased risk for medically attended malaise or fatigue within 7 days of vaccination (adjusted rate ratio [aRR] 3.64, 95% CI 2.42-5.48) and lymphadenopathy or lymphadenitis within 21 days (aRR 3.25, 95% CI 1.67-6.30) or 42 days (aRR 2.18, 95% CI 1.33-3.58) of vaccination. Our findings are consistent with prior evaluations of the primary COVID-19 vaccine series and are reassuring with respect to COVID-19 booster vaccination in pregnancy.

COVID-19 Vaccine Safety Surveillance in Early Pregnancy in the United States: Design Factors Affecting the Association Between Vaccine and Spontaneous Abortion.

In the Vaccine Safety Datalink (VSD), we previously reported no association between coronavirus disease 2019 (COVID-19) vaccination in early pregnancy and spontaneous abortion (SAB). The present study aims to understand how time since vaccine rollout or other methodological factors could affect results. Using a case-control design and generalized estimating equations, we estimated the odds ratios (ORs) of COVID-19 vaccination in the 28 days before a SAB or last date of the surveillance period (index date) in ongoing pregnancies and occurrence of SAB, across cumulative 4-week periods from December 2020 through June 2021. Using data from a single site, we evaluated alternative methodological approaches: increasing the exposure window to 42 days, modifying the index date from the last day to the midpoint of the surveillance period, and constructing a cohort design with a time-dependent exposure model. A protective effect (OR = 0.78, 95% confidence interval: 0.69, 0.89), observed with 3-cumulative periods ending March 8, 2021, was attenuated when surveillance extended to June 28, 2021 (OR = 1.02, 95% confidence interval: 0.96, 1.08). We observed a lower OR for a 42-day window compared with a 28-day window. The time-dependent model showed no association. Timing of the surveillance appears to be an important factor affecting the observed vaccine-SAB association.

Receipt of COVID-19 Vaccine During Pregnancy and Preterm or Small-for-Gestational-Age at Birth - Eight Integrated Health Care Organizations, United States, December 15, 2020-July 22, 2021.

COVID-19 vaccines are recommended during pregnancy to prevent severe maternal morbidity and adverse birth outcomes; however, vaccination coverage among pregnant women has been low (1). Concerns among pregnant women regarding vaccine safety are a persistent barrier to vaccine acceptance during pregnancy. Previous studies of maternal COVID-19 vaccination and birth outcomes have been limited by small sample size (2) or lack of an unvaccinated comparison group (3). In this retrospective cohort study of live births from eight Vaccine Safety Datalink (VSD) health care organizations, risks for preterm birth (<37 weeks' gestation) and small-for-gestational-age (SGA) at birth (birthweight <10th percentile for gestational age) after COVID-19 vaccination (receipt of ≥1 COVID-19 vaccine doses) during pregnancy were evaluated. Risks for preterm and SGA at birth among vaccinated and unvaccinated pregnant women were compared, accounting for time-dependent vaccine exposures and propensity to be vaccinated. Single-gestation pregnancies with estimated start or last menstrual period during May 17-October 24, 2020, were eligible for inclusion. Among 46,079 pregnant women with live births and gestational age available, 10,064 (21.8%) received ≥1 COVID-19 vaccine doses during pregnancy and during December 15, 2020-July 22, 2021; nearly all (9,892; 98.3%) were vaccinated during the second or third trimester. COVID-19 vaccination during pregnancy was not associated with preterm birth (adjusted hazard ratio [aHR] = 0.91; 95% CI = 0.82-1.01). Among 40,627 live births with birthweight available, COVID-19 vaccination in pregnancy was not associated with SGA at birth (aHR = 0.95; 95% CI = 0.87-1.03). Results consistently showed no increased risk when stratified by mRNA COVID-19 vaccine dose, or by second or third trimester vaccination, compared with risk among unvaccinated pregnant women. Because of the small number of first-trimester exposures, aHRs for first-trimester vaccination could not be calculated. These data add to the evidence supporting the safety of COVID-19 vaccination during pregnancy. To reduce the risk for severe COVID-19-associated illness, CDC recommends COVID-19 vaccination for women who are pregnant, recently pregnant (including those who are lactating), who are trying to become pregnant now, or who might become pregnant in the future (4).

Using inpatient electronic medical records to study influenza for pandemic preparedness.

BACKGROUND: We assessed the ability to identify key data relevant to influenza and other respiratory virus surveillance in a large-scale US-based hospital electronic medical record (EMR) dataset using seasonal influenza as a use case. We describe characteristics and outcomes of hospitalized influenza cases across three seasons. METHODS: We identified patients with an influenza diagnosis between March 2017 and March 2020 in 140 US hospitals as part of the US FDA's Sentinel System. We calculated descriptive statistics on the presence of high-risk conditions, influenza antiviral administrations, and severity endpoints. RESULTS: Among 5.1 million hospitalizations, we identified 29,520 hospitalizations with an influenza diagnosis; 64% were treated with an influenza antiviral within 2 days of admission, and 25% were treated >2 days after admission. Patients treated >2 days after admission had more comorbidities than patients treated within 2 days of admission. Patients never treated during hospitalization had more documentation of cardiovascular and other diseases than treated patients. We observed more severe endpoints in patients never treated (death = 3%, mechanical ventilation [MV] = 9%, intensive care unit [ICU] = 26%) or patients treated >2 days after admission (death = 2%, MV = 14%, ICU = 32%) than in patients treated earlier (treated on admission: death = 1%, MV = 5%, ICU = 23%, treated within 2 days of admission: death = 1%, MV = 7%, ICU = 27%). CONCLUSIONS: We identified important trends in influenza severity related to treatment timing in a large inpatient dataset, laying the groundwork for the use of this and other inpatient EMR data for influenza and other respiratory virus surveillance.

Self-controlled assessment of thromboembolic event (TEE) risk following intravenous immune globulin (IGIV) in the U.S. (2006-2012).

Since 2013, the U.S. Food and Drug administration (FDA) has required that intravenous immune globulin (IGIV) products carry a boxed warning concerning the risk of thromboembolic events (TEEs). This study assessed the incidence of TEEs attributable to IGIV in a large population-based cohort. A self-controlled risk interval design was used to quantify the transient increase in TEE risk during the risk interval (days 0-2 and 0-13 following IGIV for arterial and venous TEEs, respectively) relative to a later control interval (days 14-27 following IGIV). Potential IGIV-exposed TEE cases from 2006 to 2012 were identified from the FDA-sponsored Sentinel Distributed Database and confirmed through medical record review. Inpatient IGIV exposures were not included in the venous TEE analysis due to concerns about time-varying confounding. 19,069 new users of IGIV who received 93,555 treatment episodes were included. Charts were retrieved for 62% and 70% of potential venous and arterial cases, respectively. There was a transient increase in the risk of arterial TEEs during days 0-2 following IGIV treatment (RR = 4.69; 95% CI 1.87, 11.90; absolute increase in risk = 8.86 events per 10,000 patients, 95% CI 3.25, 14.6), but no significant increase in venous TEE risk during days 0-13 following outpatient IGIV treatments (RR = 1.07, 95% CI 0.34, 3.48). Our results suggest there is a small increase in the absolute risk of arterial TEEs following IGIV. However, lower-than-expected chart retrieval rates and the possibility of time-varying confounding mean that our results should be interpreted cautiously. Continued pharmacovigilance efforts are warranted.

A COVID-19-ready public health surveillance system: The Food and Drug Administration's Sentinel System.

The US Food and Drug Administration's Sentinel System was established in 2009 to use routinely collected electronic health data for improving the national capability to assess post-market medical product safety. Over more than a decade, Sentinel has become an integral part of FDA's surveillance capabilities and has been used to conduct analyses that have contributed to regulatory decisions. FDA's role in the COVID-19 pandemic response has necessitated an expansion and enhancement of Sentinel. Here we describe how the Sentinel System has supported FDA's response to the COVID-19 pandemic. We highlight new capabilities developed, key data generated to date, and lessons learned, particularly with respect to working with inpatient electronic health record data. Early in the pandemic, Sentinel developed a multi-pronged approach to support FDA's anticipated data and analytic needs. It incorporated new data sources, created a rapidly refreshed database, developed protocols to assess the natural history of COVID-19, validated a diagnosis-code based algorithm for identifying patients with COVID-19 in administrative claims data, and coordinated with other national and international initiatives. Sentinel is poised to answer important questions about the natural history of COVID-19 and is positioned to use this information to study the use, safety, and potentially the effectiveness of medical products used for COVID-19 prevention and treatment.

Medical chart validation of inpatient diagnosis codes for transfusion-related acute lung injury 2013-2015.

INTRODUCTION: Transfusion-related acute lung injury (TRALI), an adverse event occurring during or within 6 hours of transfusion, is a leading cause of transfusion-associated fatalities reported to the US Food and Drug Administration. There is limited information on the validity of diagnosis codes for TRALI recorded in inpatient electronic medical records (EMRs). STUDY DESIGNS AND METHODS: We conducted a validation study to establish the positive predictive value (PPV) of TRALI International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) diagnosis codes recorded within a large hospital system between 2013 and 2015. A physician with critical care expertise confirmed the TRALI diagnosis. As TRALI is likely underdiagnosed, we used the specific code (518.7), and codes for respiratory failure (518.82) in combination with transfusion reaction (999.80, 999.89, E934.7). RESULTS: Among almost four million inpatient stays, we identified 208 potential TRALI cases with ICD-9-CM codes and reviewed 195 medical records; 68 (35%) met clinical definitions for TRALI (26 [38%] definitive, 15 [22%] possible, 27 [40%] delayed). Overall, the PPV for all inpatient TRALI diagnoses was 35% (95% confidence interval (CI), 28-42). The PPV for the TRALI-specific code was 44% (95% CI, 35-54). CONCLUSION: We observed low PPVs (<50%) for TRALI ICD-9-CM diagnosis codes as validated by medical charts, which may relate to inconsistent code use, incomplete medical records, or other factors. Future studies using TRALI diagnosis codes in EMR databases may consider confirming diagnoses with medical records, assessing TRALI ICD, Tenth Revision, Clinical Modification codes, or exploring alternative ways for of accurately identifying TRALI in EMR databases. KEY POINTS: In 169 hospitals, we identified 208 potential TRALI cases, reviewed 195 charts, and confirmed 68 (35%) cases met TRALI clinical definitions. As many potential TRALI cases identified with diagnosis codes did not meet clinical definitions, medical record confirmation may be prudent.

Developing a Standardized and Reusable Method to Link Distributed Health Plan Databases to the National Death Index: Methods Development Study Protocol.

BACKGROUND: Certain medications may increase the risk of death or death from specific causes (eg, sudden cardiac death), but these risks may not be identified in premarket randomized trials. Having the capacity to examine death in postmarket safety surveillance activities is important to the US Food and Drug Administration's (FDA) mission to protect public health. Distributed networks of electronic health plan databases used by the FDA to conduct multicenter research or medical product safety surveillance studies often do not systematically include death or cause-of-death information. OBJECTIVE: This study aims to develop reusable, generalizable methods for linking multiple health plan databases with the Centers for Disease Control and Prevention's National Death Index Plus (NDI+) data. METHODS: We will develop efficient administrative workflows to facilitate multicenter institutional review board (IRB) review and approval within a distributed network of 6 health plans. The study will create a distributed NDI+ linkage process that avoids sharing of identifiable patient information between health plans or with a central coordinating center. We will develop standardized criteria for selecting and retaining NDI+ matches and methods for harmonizing linked information across multiple health plans. We will test our processes within a use case comprising users and nonusers of antiarrhythmic medications. RESULTS: We will use the linked health plan and NDI+ data sets to estimate the incidences and incidence rates of mortality and specific causes of death within the study use case and compare the results with reported estimates. These comparisons provide an opportunity to assess the performance of the developed NDI+ linkage approach and lessons for future studies requiring NDI+ linkage in distributed database settings. This study is approved by the IRB at Harvard Pilgrim Health Care in Boston, MA. Results will be presented to the FDA at academic conferences and published in peer-reviewed journals. CONCLUSIONS: This study will develop and test a reusable distributed NDI+ linkage approach with the goal of providing tested NDI+ linkage methods for use in future studies within distributed data networks. Having standardized and reusable methods for systematically obtaining death and cause-of-death information from NDI+ would enhance the FDA's ability to assess mortality-related safety questions in the postmarket, real-world setting. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/21811.

Evaluation of the US Food and Drug Administration Sentinel Analysis Tools Using a Comparator with a Different Indication: Comparing the Rates of Gastrointestinal Bleeding in Warfarin and Statin Users.

BACKGROUND: The US Food and Drug Administration's Sentinel System was established to monitor safety of regulated medical products. Sentinel investigators identified known associations between drugs and adverse events to test reusable analytic tools developed for Sentinel. This test case used a comparator with a different indication. OBJECTIVE: We tested the ability of Sentinel's reusable analytic tools to identify the known association between warfarin and gastrointestinal bleeding (GIB). Statins, expected to have no effect on GIB, were the comparator. We further explored the impact of analytic features, including matching ratio and stratifying Cox regression analyses, on matched pairs. METHODS: This evaluation included data from 14 Sentinel Data Partners. New users of warfarin and statins, aged 18 years and older, who had not received other anticoagulants or had recent GIB were matched on propensity score using 1:1 and 1:n variable ratio matching, matching statin users with warfarin users to estimate the average treatment effect in warfarin-treated patients. We compared the risk of GIB using Cox proportional hazards regression, following patients for the duration of their observed continuous treatment or until a GIB. For the 1:1 matched cohort, we conducted analyses with and without stratification on matched pair. The variable ratio matched cohort analysis was stratified on the matched set. RESULTS: We identified 141,398 new users of warfarin and 2,275,694 new users of statins. In analyses stratified on matched pair/set, the hazard ratios (HR) for GIB in warfarin users compared with statin users were 2.78 (95% confidence interval [CI] 2.36-3.28) in the 1:1 matched cohort and 3.10 (95% CI 2.76-3.49) in the variable ratio matched cohort. The HR was lower in the analysis of the 1:1 matched cohort not stratified by matched pair (2.22, 95% CI 1.97-2.49), and highest early in treatment. Follow-up for warfarin users tended to be shorter than for statin users. CONCLUSIONS: This study identified the expected GIB risk with warfarin compared with statins using an analytic tool developed for Sentinel. Our findings suggest that comparators with different indications may be useful in surveillance in select circumstances. Finally, in the presence of differential censoring, stratification by matched pair may reduce the potential for bias in Cox regression analyses.

Overall and cause-specific mortality in the Sentinel system: A power analysis.

PURPOSE: Mortality data within the Sentinel Death Tables remain generally uncharacterized. Assessment of mortality data within Sentinel will help inform its utility for medical product safety studies. METHODS: To determine if Sentinel contains sufficient all-cause and cause-specific mortality events to power postmarketing safety studies. We calculated crude rates of all-cause mortality and suicide and proportional mortality from suicide from 2004 to 2012 in seven Sentinel data partners. Results were stratified by data partner, sex, age group, and calendar year and compared with national estimates from Centers for Disease Control and Prevention Wide-ranging ONline Data for Epidemiologic Research. We performed sample size estimations for all-cause mortality and 10 leading causes of death. RESULTS: We observed 479 694 deaths, including 5811 suicides, during 68 million person-years of follow-up. Pooled mean death and suicide rates in the data partners were 710 and 8.6 per 100 000 person-years, respectively (vs 810 and 11.8 nationally). The mean proportional mortality from suicide among the data partners was 1.2%, compared with 1.5% nationally. National trends of decreasing overall mortality and increasing proportional mortality for suicide were reflected within Sentinel. We estimated that detecting hazard ratios of 1.25 and 3 would require 16 442 and 460 exposed patients, respectively, for overall mortality, and 1.3 million and 37 411, respectively, for suicide. CONCLUSIONS: This was the first study to investigate mortality data in the Sentinel death tables. We found that all-cause mortality appeared well powered for use as a safety outcome and cause-specific mortality outcomes may be adequately powered in certain circumstances. Further investigation into the quality of the Sentinel death data is needed.

A mHealth-based care model for improving hypertension control in stroke survivors: Pilot RCT.

PURPOSE: Hypertension (HTN) is significantly under-treated in stroke survivors. We examined usability and efficacy of a mHealth -based care model for improving post-stroke HTN control (Funding: AHRQ R21HS021794). METHODS: We used a RCT design. Planned study duration was 90 days. Intervention arm (IA) participants measured their BP daily using a smart phone and wireless BP monitor. This was transmitted automatically to the study database. Investigators (Physician + PharmD) made bi-weekly medication adjustments to achieve the BP goal. Control arm (CA) participants received a digital BP monitor and usual care. We examined Usability (measured with Marshfield System Usability Survey) and HTN control efficacy using an ITT (intent-to-treat) and as-treated (AT) analyses. RESULTS: Fifty participants (IA = 28; CA = 22) completed the study. The Marshfield survey question, "I thought the system was easy to use" mean score was 4.6, (5 = strongly agree). Mean SBP declined significantly between enrollment and study completion in the IA. In ITT, IA SBP declined 9.88 mm, p = 0.005. In AT, IA SBP declined 10.81 mm, p = 0.0036. CA SBP decline was 5-6 mm Hg (not significant). In the ITT, baseline HTN control (SBP < 140 mm Hg) was 50% in IA and CA. At study completion, HTN was controlled in 82% (23/28) of IA and 64% (14/22) of CA (p = 0.14). In the AT, HTN was controlled in 89% (23/26) of IA and 58% (14/24) of CA, (p = 0.015). CONCLUSION: A mHealth-based HTN care model had excellent usability and provided better HTN control than usual care in stroke survivors. CLINICAL TRIAL: gov: NCT01875094.

Chart validation of inpatient International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) administrative diagnosis codes for venous thromboembolism (VTE) among intravenous immune globulin (IGIV) users in the Sentinel Distributed Database.

The Sentinel Distributed Database (SDD) is a database of patient administrative healthcare records, derived from insurance claims and electronic health records, sponsored by the US Food and Drug Administration for evaluation of medical product outcomes. There is limited information on the validity of diagnosis codes for acute venous thromboembolism (VTE) in the SDD and administrative healthcare data more generally.In this chart validation study, we report on the positive predictive value (PPV) of inpatient administrative diagnosis codes for acute VTE-pulmonary embolism (PE) or lower-extremity or site-unspecified deep vein thrombosis (DVT)-within the SDD. As part of an assessment of thromboembolic adverse event risk following treatment with intravenous immune globulin (IGIV), charts were obtained for 75 potential VTE cases, abstracted, and physician-adjudicated.VTE status was determined for 62 potential cases. PPVs for lower-extremity DVT and/or PE were 90% (95% CI: 73-98%) for principal-position diagnoses, 80% (95% CI: 28-99%) for secondary diagnoses, and 26% (95% CI: 11-46%) for position-unspecified diagnoses (originating from physician claims associated with an inpatient stay). Average symptom onset was 1.5 days prior to hospital admission (range: 19 days prior to 4 days after admission).PPVs for principal and secondary VTE discharge diagnoses were similar to prior study estimates. Position-unspecified diagnoses were less likely to represent true acute VTE cases.

Chart validation of inpatient ICD-9-CM administrative diagnosis codes for acute myocardial infarction (AMI) among intravenous immune globulin (IGIV) users in the Sentinel Distributed Database.

BACKGROUND: The Sentinel Distributed Database (SDD) is a large database of patient-level administrative health care records, primarily derived from insurance claims and electronic health records, and is sponsored by the US Food and Drug Administration for medical product safety evaluations. Acute myocardial infarction (AMI) is a common study endpoint for drug safety studies that rely on health records from the SDD and other administrative databases. PURPOSE: In this chart validation study, we report on the positive predictive value (PPV) of inpatient International Classification of Diseases, Ninth Revision, Clinical Modification AMI administrative diagnosis codes (410.x1 and 410.x0) in the SDD. METHODS: As part of an assessment of thromboembolic adverse event risk following treatment with intravenous immune globulin, charts were obtained for 103 potential post-intravenous immune globulin AMI cases. Charts were abstracted by trained nurses and physician-adjudicated based on prespecified diagnostic criteria. RESULTS: Acute myocardial infarction status could be determined for 89 potential cases. The PPVs for the inpatient AMI diagnoses recorded in the SDD were 75% overall (95% CI, 65-84%), 93% (95% CI, 78-99%) for principal-position diagnoses, 88% (95% CI, 72-97%) for secondary diagnoses, and 38% (95% CI, 20-59%) for position-unspecified diagnoses (eg, diagnoses originating from separate physician claims associated with an inpatient stay). Of the confirmed AMI cases, demand ischemia was the suspected etiology more often for those coded in secondary or unspecified positions (72% and 40%, respectively) than for principal-position AMI diagnoses (21%). CONCLUSIONS: The PPVs for principal and secondary AMI diagnoses were high and similar to estimates from prior chart validation studies. Position-unspecified diagnosis codes were less likely to represent true AMI cases.

Development and application of two semi-automated tools for targeted medical product surveillance in a distributed data network.

PURPOSE OF REVIEW: An important component of the Food and Drug Administration's Sentinel Initiative is the active post-market risk identification and analysis (ARIA) system, which utilizes semi-automated, parameterized computer programs to implement propensity-score adjusted and self-controlled risk interval designs to conduct targeted surveillance of medical products in the Sentinel Distributed Database. In this manuscript, we review literature relevant to the development of these programs and describe their application within the Sentinel Initiative. RECENT FINDINGS: These quality-checked and publicly available tools have been successfully used to conduct rapid, replicable, and targeted safety analyses of several medical products. In addition to speed and reproducibility, use of semi-automated tools allows investigators to focus on decisions regarding key methodological parameters. We also identified challenges associated with the use of these methods in distributed and prospective datasets like the Sentinel Distributed Database, namely uncertainty regarding the optimal approach to estimating propensity scores in dynamic data among data partners of heterogeneous size. SUMMARY: Future research should focus on the methodological challenges raised by these applications as well as developing new modular programs for targeted surveillance of medical products.