Challenges of evaluating and modelling vaccination in emerging infectious diseases.

Outbreaks of emerging pathogens pose unique methodological and practical challenges for the design, implementation, and evaluation of vaccine efficacy trials. Lessons learned from COVID-19 highlight the need for innovative and flexible study design and application to quickly identify promising candidate vaccines. Trial design strategies should be tailored to the dynamics of the specific pathogen, location of the outbreak, and vaccine prototypes, within the regional socioeconomic constraints. Mathematical and statistical models can assist investigators in designing infectious disease clinical trials. We introduce key challenges for planning, evaluating, and modelling vaccine efficacy trials for emerging pathogens.

Methods for external control groups for single arm trials or long-term uncontrolled extensions to randomized clinical trials.

PURPOSE: Clinical trials compare outcomes among patients receiving study treatment with comparators drawn from the same source. These internal controls are missing in single arm trials and from long-term extensions (LTE) of trials including only the treatment arm. An external control group derived from a different setting is then required to assess safety or effectiveness. METHODS: We present examples of external control groups that demonstrate some of the issues that arise and make recommendations to address them through careful assessment of the data source fitness for use, design, and analysis steps. RESULTS: Inclusion and exclusion criteria and context that produce a trial population may result in trial patients with different clinical characteristics than are present in an external comparison group. If these differences affect the risk of outcomes, then a comparison of outcome occurrence will be confounded. Further, patients who continue into LTE may differ from those initially entering the trial due to treatment effects. Application of appropriate methods is needed to make valid inferences when such treatment or selection effects are present. Outcome measures in a trial may be ascertained and defined differently from what can be obtained in an external comparison group. Differences in sensitivity and specificity for identification or measurement of study outcomes leads to information bias that can also invalidate inferences. CONCLUSION: This review concentrates on threats to the valid use of external control groups both in the scenarios of single arm trials and LTE of randomized controlled trials, along with methodological approaches to mitigate them.

Masking in Pragmatic Trials: Who, What, and When to Blind.

Masking (or blinding) of treatment assignment is routinely implemented in classical randomized clinical trials (RCTs) to isolate the effect of the intervention itself and to minimize the potential for bias that could occur with traditional trials. Such biases could be introduced with the conduct, assessment of endpoints, management of conditions, analysis, and reporting when the treatment assignments are known. However, masking of treatments is not only complex but it hinders how generalizable the findings are to the "real world" clinical setting. Pragmatic RCTs (pRCTs) are intended to evaluate the effects of interventions within routine medical care, and as such, do not typically mask treatment groups; moreover, pRCTs assess comparators that are available in routine medical practice, not masked placebos. Whether pRCTs should be masked if intended for regulatory or other purposes has recently been questioned. The literature on pRCTs, while extensive, does not address how much actual benefit is gained from masking outcomes and how masking may affect the "real world" nature of a study. Here, we propose an approach to evaluate sources of bias, describe stakeholders in the conduct of pRCTs who are most likely affected, and offer a framework for considering how masking may be implemented effectively while maintaining generalizability.

Data linkage in pharmacoepidemiology: A call for rigorous evaluation and reporting.

PURPOSE: The purpose of this paper is to provide guidance on the evaluation of data linkage quality through the development of a checklist for reporting key elements of the linkage process. METHODS: Responding to a call for manuscripts from the International Society for Pharmacoepidemiology (ISPE), a working group including international representation from the academic, industry, and contract research, and regulatory sectors was formed to develop a checklist for evaluation of data linkage performance and reporting data linkage specifically for pharmacoepidemiologic research. This checklist expands on the reporting of studies conducted using observational routinely collected health data specific to pharmacoepidemiology (RECORD-PE) guidelines. RESULTS: A key aspect of data linkage evaluation for pharmacoepidemiology is to articulate how a linkage process was performed and its accuracy in terms of validation and verification of the resulting linked data. This study generates a checklist, which covers domains including data sources, linkage variables, linkage methods, linkage results, and linkage evaluation. For each domain, specific recommendations provide a clear and transparent assessment of the linkage process. CONCLUSIONS: Linking data sources can help to enrich analytic databases to more accurately define study populations, enable adjustment for confounding, and improve the capture of health outcomes. Clear and transparent reporting of data linkage processes will help to increase confidence in the evidence generated from these data by allowing researchers and end users to critically assess the potential for bias owing to the data linkage process.

Chronic obstructive pulmonary disease exacerbation episodes derived from electronic health record data validated using clinical trial data.

PURPOSE: To validate an algorithm for acute exacerbations of chronic obstructive pulmonary disease (AECOPD) episodes derived in an electronic health record (EHR) database, against AECOPD episodes collected in a randomized clinical trial using an electronic case report form (eCRF). METHODS: We analyzed two data sources from the Salford Lung Study in COPD: trial eCRF and the Salford Integrated Record, a linked primary-secondary routine care EHR database of all patients in Salford. For trial participants, AECOPD episodes reported in eCRF were compared with algorithmically derived moderate/severe AECOPD episodes identified in EHR. Episode characteristics (frequency, duration), sensitivity, and positive predictive value (PPV) were calculated. A match between eCRF and EHR episodes was defined as at least 1-day overlap. RESULTS: In the primary effectiveness analysis population (n = 2269), 3791 EHR episodes (mean [SD] length: 15.1 [3.59] days; range: 14-54) and 4403 moderate/severe AECOPD eCRF episodes (mean length: 13.8 [16.20] days; range: 1-372) were identified. eCRF episodes exceeding 28 days were usually broken up into shorter episodes in the EHR. Sensitivity was 63.6% and PPV 71.1%, where concordance was defined as at least 1-day overlap. CONCLUSIONS: The EHR algorithm performance was acceptable, indicating that EHR-derived AECOPD episodes may provide an efficient, valid method of data collection. Comparing EHR-derived AECOPD episodes with those collected by eCRF resulted in slightly fewer episodes, and eCRF episodes of extreme lengths were poorly captured in EHR. Analysis of routinely collected EHR data may be reasonable when relative, rather than absolute, rates of AECOPD are relevant for stakeholders' decision making.

Study investigating the generalisability of a COPD trial based in primary care (Salford Lung Study) and the presence of a Hawthorne effect.

INTRODUCTION: Traditional phase IIIb randomised trials may not reflect routine clinical practice. The Salford Lung Study in chronic obstructive pulmonary disease (SLS COPD) allowed broad inclusion criteria and followed patients in routine practice. We assessed whether SLS COPD approximated the England COPD population and evidence for a Hawthorne effect. METHODS: This observational cohort study compared patients with COPD in the usual care arm of SLS COPD (2012-2014) with matched non-trial patients with COPD in England from the Clinical Practice Research Datalink database. Generalisability was explored with baseline demographics, clinical and treatment variables; outcomes included COPD exacerbations in adjusted models and pretrial versus peritrial comparisons. RESULTS: Trial participants were younger (mean, 66.7 vs 71.1 years), more deprived (most deprived quintile, 51.5% vs 21.4%), more current smokers (47.5% vs 32.1%), with more severe Global initiative for chronic Obstructive Lung Disease stages but less comorbidity than non-trial patients. There were no material differences in other characteristics. Acute COPD exacerbation rates were high in the trial population (98.37th percentile). CONCLUSION: The trial population was similar to the non-trial COPD population. We observed some evidence of a Hawthorne effect, with more exacerbations recorded in trial patients; however, the largest effect was observed through behavioural changes in patients and general practitioner coding practices.

Patterns and management of chronic obstructive pulmonary disease in urban and rural China: a community-based survey of 25 000 adults across 10 regions.

INTRODUCTION: Chronic obstructive pulmonary disease (COPD) is the third leading cause of death worldwide, with COPD deaths in China accounting for one-third of all such deaths. However, there is limited available evidence on the management of COPD in China. METHODS: A random sample of 25 011 participants in the China Kadoorie Biobank, aged 38-87 years, from 10 regions in China was surveyed in 2013-2014. Data were collected using interviewer-administered questionnaires on the diagnosis ('doctor-diagnosed' or 'symptoms-based') and management of COPD (including use of medication and other healthcare resources), awareness of diagnosis and severity of symptoms in COPD cases. RESULTS: Overall, 6.3% of the study population were identified as COPD cases (doctor-diagnosed cases: 4.8% and symptom-based cases: 2.4%). The proportion having COPD was higher in men than in women (7.9% vs 5.3%) and varied by about threefold (3.7%-10.0%) across the 10 regions. Among those with COPD, 54% sought medical advice during the last 12 months, but <10% reported having received treatment for COPD. The rates of hospitalisation for COPD, use of oxygen therapy at home and influenza or pneumococcal vaccinations in the previous year were 15%, 3% and 4%, respectively. Of those with COPD, half had moderate or severe respiratory symptoms, and over 80% had limited understanding of their disease and need for treatment. CONCLUSION: Despite a high prevalence of COPD in China and its substantial impact on activities of daily living, knowledge about COPD and its management were limited.

Excess risk of major vascular diseases associated with airflow obstruction: a 9-year prospective study of 0.5 million Chinese adults.

Background: China has high COPD rates, even among never-regular smokers. Little is known about nonrespiratory disease risks, especially vascular morbidity and mortality after developing airflow obstruction (AFO) in Chinese adults. Objective: We aimed to investigate the prospective association of prevalent AFO with major vascular morbidity and mortality. Materials and methods: In 2004-2008, a nationwide prospective cohort study recruited 512,891 men and women aged 30-79 years from 10 diverse localities across China, tracking cause-specific mortality and coded episodes of hospitalization for 9 years. Cox regression yielded adjusted HRs for vascular diseases comparing individuals with spirometry-defined prevalent AFO at baseline to those without. Results: Of 489,382 participants with no vascular disease at baseline, 6.8% had AFO, with prevalence rising steeply with age. Individuals with prevalent AFO had significantly increased vascular mortality (n=1,429, adjusted HR 1.29, 95% CI 1.21-1.36). There were also increased risks of hemorrhagic stroke (n=823, HR 1.18, 95% CI 1.09-1.27), major coronary events (n=635, HR 1.33, 95% CI 1.22-1.45), and heart failure (n=543, HR 2.19, 95% CI 1.98-2.41). For each outcome, the risk increased progressively with increasing COPD severity and persisted among never-regular smokers. Conclusion: Among adult Chinese, AFO was associated with significantly increased risks of major vascular morbidity and mortality. COPD management should be integrated with vascular disease prevention and treatment programs to improve long-term prognosis.

Physician perspectives on the burden and management of asthma in six countries: The Global Asthma Physician Survey (GAPS).

BACKGROUND: Despite recognition of asthma as a growing global issue and development of global guidelines, asthma treatment practices vary between countries. Several studies have reported patients' perspectives on asthma control. This study presents physicians' perspectives and strategies for asthma management. METHODS: Physicians seeing ≥4 adult patients with asthma per month in Australia, Canada, China, France, Germany, and Japan were surveyed (N=1809; ≈300 per country). A standardised questionnaire was developed for this study and administered by telephone, online or face-to-face. Statistics were weighted to account for the sampling scheme. RESULTS: Physicians estimated that 71% of their adult patients received maintenance medication, with adherence monitored by 76-97% of physicians. Perceived major barriers to patient adherence included: patients taking treatment as needed; acceptance of symptoms; and patients not perceiving treatment benefits. Written action plans (37%) and technology (15%) were seldom employed by physicians to aid patients' asthma management. Physicians rarely (10%) used validated patient-reported questionnaires to monitor asthma control, instead monitoring selected symptoms, exacerbations, and/or lung function measurements. Awareness of single maintenance and reliever therapy (SMART/MART) varied among countries (56-100%); although most physicians (72%) had prescribed SMART/MART, the majority (91%) co-prescribed a short-acting bronchodilator at least some of the time. CONCLUSIONS: These results show that physicians generally do not employ standardised tools to monitor asthma control or to manage its treatment and that despite high awareness of SMART/MART, the strategy appears to be commonly misapplied. Better education for patients and physicians is required to improve asthma management and resulting patient outcomes.

Asthma and Chronic Obstructive Pulmonary Disease Overlap: The Effect of Definitions on Measures of Burden.

Background: Although the overlap between asthma and COPD has been recognized for years this overlap has only recently been given a name, asthma-COPD overlap syndrome (ACOS), and better defined. Different definitions of the component diseases can affect prevalence and outcome measures of ACOS. Methods: We used data from the National Health and Nutrition Examination Survey (NHANES) from 2007-2012 to determine the population estimates of ACOS in U.S. adults using 2 different definitions of ACOS (ACOS1= self-reported COPD and current asthma; ACOS2 = spirometric-confirmed COPD [pre-bronchodilator FEV1/FVC < 70%] and current asthma) and to describe variation in other factors, such as lung function impairment and health care utilization, by ACOS definitions. Results: Among U.S. adults aged 20 and older, 1.6% had ACOS1, and 1.9% had ACOS2. Both case definitions were similar with regard to symptoms and impairment of lung function. ACOS1 individuals were more likely to have one or more overnight hospital stays relative to those with neither asthma nor COPD, (odds ratio [OR] 3.4, 95% confidence interval [CI] 2.5, 4.6) than ACOS2 (OR 1.6, 95% CI 0.9, 2.9). Conclusions: Different definitions of ACOS in population-based studies affect both estimates of disease prevalence and outcomes related to the disease. These definitions need to be carefully considered in the design of epidemiologic studies and clinical trials.

Disease Burden of Patients with Asthma/COPD Overlap in a US Claims Database: Impact of ICD-9 Coding-based Definitions.

The inclusion of an asthma/chronic obstructive pulmonary disease (COPD) overlap syndrome (ACOS) population in the 2015 Global Initiative for Chronic Obstructive Lung Disease strategic documents has raised questions about the profile of these patients in clinical practice, as they are mostly excluded from asthma and COPD clinical trials. We estimated the disease burden, co-morbidities, and respiratory treatments of patients with asthma/COPD overlap, utilizing the Truven MarketScan commercial and Medicare databases. Patients with ≥1 COPD or chronic obstructive asthma diagnostic code were identified between January 1, 2008, and December 31, 2011. The asthma/COPD overlap group was defined and stratified based upon type and frequency of asthma diagnostic code (chronic obstructive asthma only, COPD and chronic obstructive asthma, and COPD and ≥1 asthma code). 1,488,613 patients were identified; of these, 1,171,626 were diagnosed with COPD alone and 316,987 with asthma/COPD overlap. Patients with asthma and COPD had higher disease burden indicators and inhaled corticosteroid/long-acting beta-agonist use compared with COPD alone. This trend was consistent for all definitions of asthma/COPD overlap. Patients with obstructive asthma and COPD tended to be older, with greater disease burden compared with other definitions; this population may represent a more severe form of asthma/COPD overlap. Disease burden and treatment also varied based on the codes defining asthma/COPD overlap, indicating possible phenotypic differences. More clinical insight and detailed phenotyping is needed to determine the reasons for coding variation in asthma/COPD overlap, with implications for further research to address unmet needs.

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.

Intranasal Fluticasone Propionate Observational Cohort Safety Studies: Reviewing Evidence from Databases on Two Continents.

PURPOSE: Our objective was to highlight the importance of database selection in observational research and to determine the incidence of corticosteroid-related events in patients exposed to fluticasone propionate intranasal spray (FPNS) compared with other intranasal steroids (INS). METHODS: After a feasibility study using an electronic medical record database in the UK (1990-2002), a retrospective cohort study was conducted using a large administrative claims database in the USA from 1994 to 2002 comparing the incidence and rate ratios of steroid-related events among intermittent, sub-chronic, and chronic FPNS use and other INS use episodes. RESULTS: Most patients used INS intermittently; power was low to evaluate risk associated with chronic use. Significantly elevated adjusted rate ratios were observed in the US study comparing FPNS with other INS for hypercorticism, sinusitis, abscess, and empyema, as well as a significantly decreased rate ratio for cataracts. The US claims database provided greater granularity on covariates and markers of severity to improve control of confounding for this study and time period, but neither database was able to assess the indication for prescription and the UK study could not address the use of INS without a prescription. CONCLUSIONS: The FPNS results were consistent with the risk profile for INS and did not raise any new safety signals at the time of study conduct, which is consistent with the current safety profile. We were not able to discern the extent of potential off-label use of FPNS or other INS. Differences in the available data and healthcare systems highlight important considerations for database selection in the feasibility phase to assess the precision and limitations prior to formal risk evaluation.

Pharmacoepidemiological Study of Long-Acting ß-agonist/Inhaled Corticosteroid Therapy and Asthma Mortality: Clinical Implications.

RATIONALE: The increased risk of asthma mortality in association with long-acting ß2-agonist (LABA) monotherapy is well documented but the risk associated with LABA plus inhaled corticosteroid (ICS) therapy remains unclear. OBJECTIVE: We assessed the feasibility of a large pharmacoepidemiological study to compare the effect of combined LABA + ICS therapy with non-LABA maintenance therapy on the risk of asthma mortality. METHODS: This observational retrospective study used electronic data from ten US data partners to construct a cohort of patients with persistent asthma (defined as: four or more asthma maintenance medication dispensings in 12 months and a code diagnosis of asthma). Asthma deaths were determined by linking patient data with the National Death Index. RESULTS: From 5,881,438 asthma patients, a cohort of 994,627 met the criteria for persistent asthma and provided 2.4 million person-years of follow-up. The total number of deaths was 278 with only three of these occurring after incident exposure to an asthma maintenance medication. The overall pooled asthma mortality rate, standardized by age and data partner, was 1.16 [95 % confidence interval (CI) 0.98-1.34] per 10,000 person-years; crude mortality rates (per 10,000 person-years) increased with age and were higher in female individuals (1.34; 95 % CI 1.15-1.55) than in male individuals (0.92; 95 % CI 0.74-1.12). CONCLUSIONS: Despite a cohort size of almost 1 million asthma patients, the asthma mortality risk associated with combined LABA + ICS therapy could not be determined. This study showed that very few patients with persistent asthma have asthma-related deaths, and confirmed that those who die are more likely to be older and female.

Health behaviors and their correlates among participants in the Continuing to Confront COPD International Patient Survey.

BACKGROUND AND AIMS: We used data from the Continuing to Confront COPD International Patient Survey to test the hypothesis that patients with COPD who report less engagement with their disease management are also more likely to report greater impact of the disease. METHODS: This was a population-based, cross-sectional survey of 4,343 subjects aged ≥40 years from 12 countries, fulfilling a case definition of COPD based on self-reported physician diagnosis or symptomatology. The impact of COPD was measured with COPD Assessment Test, modified Medical Research Council Dyspnea Scale, and hospital admissions and emergency department visits for COPD in the prior year. The 13-item Patient Activation Measure (PAM-13) instrument and the 8-item Morisky Medication Adherence Scale (MMAS-8) were used to measure patient disease engagement and medication adherence, respectively. RESULTS: Twenty-eight percent of subjects reported being either disengaged or struggling with their disease (low engagement: PAM-13 levels 1 and 2), and 35% reported poor adherence (MMAS-8 <6). In univariate analyses, lower PAM-13 and MMAS-8 scores were significantly associated with poorer COPD-specific health status, greater breathlessness and lower BMI (PAM-13 only), less satisfaction with their doctor's management of COPD, and more emergency department visits. In multivariate regression models, poor satisfaction with their doctor's management of COPD was significantly associated with both low PAM-13 and MMAS-8 scores; low PAM-13 scores were additionally independently associated with higher COPD Assessment Test and modified Medical Research Council scores and low BMI (underweight). CONCLUSION: Poor patient engagement and medication adherence are frequent and associated with worse COPD-specific health status, higher health care utilization, and lower satisfaction with health care providers. More research will be needed to better understand what factors can be modified to improve medication adherence and patient engagement.

Validity of COPD diagnoses reported through nationwide health insurance systems in the People's Republic of China.

BACKGROUND: COPD is the fourth leading cause of death worldwide, with particularly high rates in the People's Republic of China, even among never smokers. Large population-based cohort studies should allow for reliable assessment of the determinants of diseases, which is dependent on the quality of disease diagnoses. We assessed the validity of COPD diagnoses collected through electronic health records in the People's Republic of China. METHODS: The CKB study recruited 0.5 million adults aged 30-79 years from ten diverse regions in the People's Republic of China during the period 2004-2008. During 7 years of follow-up, 11,800 COPD cases were identified by linkage with mortality registries and the national health insurance system. We randomly selected ~10% of the reported COPD cases and then undertook an independent adjudication of retrieved hospital medical records in 1,069 cases. RESULTS: Overall, these 1,069 cases were accrued over a 9-year period (2004-2013) involving 153 hospitals across ten regions. A diagnosis of COPD was confirmed in 911 (85%) cases, corresponding to a positive predictive value of 85% (95% confidence interval [CI]: 83%-87%), even though spirometry testing was not widely used (14%) in routine hospital care. The positive predictive value for COPD did not vary significantly by hospital ranking or calendar period, but was higher in men than women (89% vs 79%), at age ≥70 years than in younger people (88%, 95% CI: 85%-91%), and when the cases were reported from both death registry and health insurance systems (97%, 95% CI: 94%-100%). Among the remaining cases, 87 (8.1%) had other respiratory diseases (chiefly pneumonia and asthma; n=85) and 71 (6.6%) cases showed no evidence of any respiratory disease on their clinical records. CONCLUSION: In the People's Republic of China, COPD diagnoses obtained from electronic health records are of good quality and suitable for large population-based studies and do not warrant systematic adjudication of all the reported cases.

Noncommunicable Lung Disease in Sub-Saharan Africa. A Community-based Cross-Sectional Study of Adults in Urban Malawi.

RATIONALE: Noncommunicable diseases are major causes of morbidity and mortality in sub-Saharan Africa (sSA). Valid burden of disease estimates are lacking for noncommunicable lung disease in sSA. OBJECTIVES: We performed a community-based survey to determine the prevalence of chronic lung disease among adults 18 years or older in Malawi, using American Thoracic Society standard spirometry, internationally validated respiratory symptom and exposure questionnaires, and an assessment of HIV status. METHODS: An age- and sex-stratified random sample of 2,000 adults was taken from the population of the Chilomoni district of Blantyre, Malawi. Fieldworkers collected questionnaire data, conducted HIV testing, and performed pre- and post-bronchodilator spirometry on eligible participants. Survey-weighted population prevalence estimates of respiratory symptoms and spirometric abnormalities were computed, and bivariate and multivariable regression were used to identify associated variables. MEASUREMENTS AND MAIN RESULTS: Questionnaire data, HIV status, and standard spirometry were obtained from 1,059, 933, and 749 participants, respectively. Current respiratory symptoms, exposure to biomass, and ever-smoking were reported by 11.8, 85.2, and 10.4% of participants, respectively. HIV prevalence was 24.2%. Moderate to severe airway obstruction was seen in 3.6%. The prevalence of spirometric restriction was 38.6% using National Health and Nutrition Examination Survey III reference ranges and 9.0% using local reference ranges. Age was positively associated with obstruction, whereas low body mass index was associated with restriction. CONCLUSIONS: More than 40% of the Malawian adults in our urban population sample had abnormal lung function (mostly restrictive) in the context of widespread exposure to biomass smoke and a high prevalence of HIV. These findings potentially have major public health implications for Malawi and the broader sSA region.

Safety of Fluticasone Propionate Prescribed for Asthma During Pregnancy: A UK Population-Based Cohort Study.

BACKGROUND: Asthma is commonly treated during pregnancy, yet data on the safety of asthma medicines used during pregnancy are sparse. OBJECTIVE: The objective of this study was to evaluate the safety of the inhaled corticosteroid (ICS) fluticasone propionate (FP), alone and in fixed-dose combination with salmeterol (FSC) in terms of the risk of all major congenital malformations (MCMs), compared with all other non-FP ICS. METHODS: Women with asthma who had a pregnancy between January 1, 2000, and December 31, 2010, were identified in the United Kingdom's Clinical Practice Research Datalink. Exposure to asthma medicines during the first trimester of pregnancy was based on issued prescriptions. The mothers' and infants' medical records were linked where possible, and pregnancy outcomes with an MCM diagnosed by age 1 year were identified based on medical codes in the mother's and infant's medical records, including those MCMs prenatally diagnosed that ended in an induced pregnancy termination. The absolute and relative risks of an MCM after different ICS exposures, stratified by the asthma treatment intensity level, were calculated. RESULTS: A total of 14,654 mother-infant pairs were identified, of which 6,174 received an ICS prescription during the first trimester, in addition to 13 first trimester ICS exposed pregnancies that ended in an induced termination after a prenatal MCM diagnosis. In total, 5,362 pregnancies were eligible for the primary analysis at age 1 year. The absolute risk of an MCM after any first trimester FP exposure was 2.4% (CI95 0.8-4.1) and 2.7% (CI95 1.8-3.6) for the "moderate" and "considerable/severe" asthma treatment intensity levels, respectively. The adjusted odds ratios when compared with non-FP ICS were 1.1 (CI95 0.5-2.3) and 1.2 (CI95 0.7-2.0) for the "moderate" and "considerable/severe" intensity levels; risks for any FP and for FSC did not differ substantially. CONCLUSION: No increase in the overall risk of MCMs was identified after first trimester FP exposure compared with non-FP ICS.