BMJ Open. Healthcare utilization by pregnant asthma patients in South Korea: a cohort study using a nationwide claims data

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1 Healthcare utilization by pregnant asthma patients in South Korea: a cohort study using a nationwide claims data Journal: Manuscript ID: bmjopen-0-00 Article Type: Research Date Submitted by the Author: 0-Apr-0 Complete List of Authors: Lee, Chang-Hoon; Seoul National University Hospital, Department of Internal Medicine Kim, Jimin; National Evidence-based Healthcare Collaborating Agency, Division for Healthcare Technology Assessment Research Jang, Eun Jin; Andong National University, Department of Information Statistics Kim, Yun Jung; National Evidence-based Healthcare Collaborating Agency, Division for Healthcare Technology Assessment Research Choi, Seongmi; National Evidence-based Healthcare Collaborating Agency, Division for Healthcare Technology Assessment Research Lee, Joon-Ho; Seoul National University Hospital, Department of Obstetrics and Gynecology Kim, Deog Kyeom; Seoul Metropolitan Government-Seoul National University Boramae Medical Center, Department of Internal Medicine Yim, Jae-Joon; Seoul National University College of Medicine, Department of Internal Medicine Yoon, Hoil; Hoil Yoon, <b>primary Subject Heading</b>: Obstetrics and gynaecology Secondary Subject Heading: Obstetrics and gynaecology, Respiratory medicine Keywords: Asthma < THORACIC MEDICINE, EPIDEMIOLOGY, pregnancy, inhaled respiratory drugs : first published as 0./bmjopen-0-00 on November 0. Downloaded from on March 0 by guest. Protected by copyright.

2 Page of The prevalence and treatment of healthcare utilization of pregnant asthma patients: a cohort study using a nationwide claims data Chang-Hoon Lee, M.D.,, Jimin Kim, MPh., Eun Jin Jang, Ph.D.,, Yun Jung Kim, MPh., Seongmi Choi, Ph.D.,, Joon-Ho Lee, M.D., Ph.D., Deog Kyeom Kim, M.D., Ph.D.,, Jae-Joon Yim, M.D.,, *, Ho Il Yoon, M.D., Ph.D. National Evidence-based Healthcare Collaborating Agency, Seoul, Republic of Korea Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Hospital, Seoul, Republic of Korea Department of Information Statistics, Colloge of Natural Science, Andong National University, Andong, Republic of Korea Real Estate R&D Institute, Korea Appraisal Board, Daegu, Republic of Korea Department of Obstetrics and Gynecology, Seoul National University College of College of Medicine, Seoul National University Hospital, Seoul, Republic of Korea Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University College of College of Medicine, Seoul Metropolitan Government-Seoul National University Boramae Medical Center, Seoul, Republic of Korea Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam-Si, Republic of Korea * Corresponding author: Ho Il Yoon, M.D., Ph.D. - : first published as 0./bmjopen-0-00 on November 0. Downloaded from on March 0 by guest. Protected by copyright.

3 Page of Associate professor, Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital,, Gumi-Ro Beon-Gil, Bundang-Gu, Seongnam-Si, Gyeonggi-Do, -0, Republic of Korea. Tel: Fax: dextro@snu.ac.kr Key words: asthma; epidemiology; pregnancy; inhaled respiratory drugs of coauthors: Chang-Hoon Lee: kauri0@empal.com Jimin Kim: jimin@neca.re.kr Eun Jin Jang: jejstat@gmail.com Yun Jung Kim: indigo@neca.re.kr Seongmi Choi: edisil0@nate.com Joon-Ho Lee: doctor-joon@hanmail.net Deog Kyeom Kim: kimdkmd@gmail.com Jae-Joon Yim: yimjj@snu.ac.kr Word count:,0 - : first published as 0./bmjopen-0-00 on November 0. Downloaded from on March 0 by guest. Protected by copyright.

4 Page of ABSTRACT Objectives: Few nationwide population-based studies have been performed on the burden of asthma during pregnancy. We investigated the burden of asthma during pregnancy requiring healthcare utilization and its medical treatment in South Korea. Design: Cohort study Setting: Nationwide insurance claims database Participatns:,0, pregnant women who deliver in South Korea between 00 and 0 Outcomes: The prevalence and the exacerbation rates of asthma requiring healthcare utilization, and the prescription of anti-asthmatic drugs during pregnancy Results: The prevalence of asthma requiring healthcare utilization was 0.% among pregnant women. Among pregnant women with asthma requiring healthcare utilization,.% were hospitalized and treated with systemic steroids and short-acting β-agonists during pregnancy. Oral drugs were prescribed less during the rd trimester than during the st trimester (all P values for trends were <0.00). A significant number of patients with asthma were likely to stop taking anti-asthmatic drugs after becoming pregnant. Conclusions: The prevalence of asthma requiring healthcare utilization during pregnancy was not very high. However, a significant number of women were likely to stop taking antiasthmatic drugs and did experience exacerbations. - : first published as 0./bmjopen-0-00 on November 0. Downloaded from on March 0 by guest. Protected by copyright.

5 Page of STRENGTHS AND LIMITATIONS OF THIS STUDY - A study analyzing asthma requiring healthcare utilization during pregnancy with use of a large scale, nationwide database - A diagnosis of asthma was defined by ICD-0 code together with anti-asthmatic medication. - The results showed a significant number of patients were likely to stop taking drugs after becoming pregnant and the prescription of oral drugs were decreasing during pregnancy. - Asthma cases requiring healthcare utilization were only a part of the whole asthmatic pregnant women, but the results can show a real world healthcare utilization pattern of asthmatics during pregnancy. - : first published as 0./bmjopen-0-00 on November 0. Downloaded from on March 0 by guest. Protected by copyright.

6 Page of INTRODUCTION Asthma is an important health condition during pregnancy. Approximately % of pregnant women currently have asthma in US and.% of them experience an asthma attack. A prospective study also reported that the majority of pregnant women that seek respiratory specialists due to dyspnea are asthmatics or probable asthmatics. Asthma seems to increase the risk of low birth weight, pre-eclampsia, preterm delivery, and congenital malformations. There are also drug safety issues. For example, treatment with systemic corticosteroids during asthma could increase the risk of preeclampsia, low birth weight, and preterm delivery. Although several studies have reported that inhaled corticosteroids (ICSs) and β-agonists did not affect pregnancy outcomes, - many women commonly avoid asthma drugs during pregnancy because of these safety issues.,0 However, few nationwide population-based studies have been performed on the actual burden and treatment of asthma during pregnancy. In this study, we investigated the prevalence of patients with asthma who visited hospitals during pregnancy in South Korea, the incidence rates of exacerbations, and the actual medical treatment of these patients using a nationwide insurance claims database. - : first published as 0./bmjopen-0-00 on November 0. Downloaded from on March 0 by guest. Protected by copyright.

7 Page of METHODS Source of Data The Health Insurance Review and Assessment Service (HIRA, Seoul, Republic of Korea) is a governmental agency that examines the accuracy of claims for National Health Insurance (NHI) and National Medical Aid (NMA) in South Korea, which covers about the.% of the entire. million South Korean population. We used the HIRA database; the details regarding NHI and the NMA database were described elsewhere. Briefly, the HIRA database includes information regarding demographic variables and all the rendered medical services, along with diagnostic codes (International Statistical Classification of Diseases and Related Health Problems, 0 th edition code, ICD-0), and all the dispensed prescribed medications. The proportion of missing or out-of-range answers in terms of key fields, including drug names, quantity, date dispensed, and duration, was less than 0.% of the records. This study was approved by the ethics review committee of the National Evidencebased Healthcare Collaborating Agency, Seoul, Republic of Korea. Written informed consent was not provided by study subjects. Patient records/information was anonymized and deidentified before analysis. Analyses We defined a pregnancy if a claim about a delivery event was found. The initiation date of a pregnancy was calculated as the date 0 weeks before the delivery event. If a woman was pregnant more than once, only the first pregnancy was included in the analysis. In our study, we focused on patients with asthma requiring healthcare utilization (who visited hospitals and received physicians diagnosis and care). To increase the accuracy of diagnosis and to reduce - : first published as 0./bmjopen-0-00 on November 0. Downloaded from on March 0 by guest. Protected by copyright.

8 Page of a bias, asthma was defined in two ways: () definition : ICD-0 code J or J that should be repeated with at least a -month interval, and () definition : definition plus use of any asthma medication at least once. Asthma medication included inhaled corticosteroids (ICSs), ICS combined with inhaled long-acting β-agonists (ICS/LABAs), inhaled short-acting β- agonists (SABAs), leukotriene receptor antagonists (LTRAs), and theophylline. The prevelence of asthma requiring healthcare utilization during pregnancy were calculated as the number of asthma cases per 00 pregnancies (%). We also estimated the incidence rates of severe exacerbations of asthma. (the number of cases per pregnancy) We defined severe exacerbations in two ways: () a visit to the emergency room or hospitalization with a diagnosis of asthma, and () condition () plus treatment with systemic corticosteroids or SABAs. Asthma medications prescribed within weeks before the initiation date of pregnancy and those prescribed during each pregnancy trimester were also evaluated. All statistical analyses were performed using the SAS. software (SAS Institute, Cary, NC, US). - : first published as 0./bmjopen-0-00 on November 0. Downloaded from on March 0 by guest. Protected by copyright.

9 Page of RESULTS In total,,0, pregnant women (mean age, 0. ±.) were observed from 00 to 0. Of these,, asthma cases were diagnosed. (definition : the prevalence was 0.% in 00-00: 0.% in 00 and 0.% in 00) Among these, the number of asthma patients who were prescribed asthma drugs at least once during pregnancy was, (definition : the prevalence was 0.% in 00-00; 0.% in 00; and 0.% in 00). Table shows how many pregnant women with asthma experienced exacerbations. Among the total number of asthmatic pregnant women requiring healthcare utilization,.% visited the emergency department or the hospital due to asthma (incidence rate, 0. per pregnancy) and.% were treated with systemic steroids and SABA after visiting the emergency department or hospital due to asthma (incidence rate, 0.0 per pregnancy). Among the asthmatic pregnant women who were treated with asthma medications,.0% visited the ER or were hospitalized due to asthma (incidence rate, 0. per pregnancy) and 0.0% were treated with systemic steroids and SABA after visiting the emergency department or being hospitalized due to asthma (incidence rate, 0. per pregnancy). - : first published as 0./bmjopen-0-00 on November 0. Downloaded from on March 0 by guest. Protected by copyright.

10 Page of Table. The incidence of emergency room visits or hospitalization due to asthma exacerbation during pregnancy Definition : Among total pregnant women with asthma Number of patients with events (%) In the complete study period (n =,; 0.% among total pregnant women) () ER visit or hospitalization due to asthma () () + treated with systemic steroids or SABA In 00 (n =,; 0.% among total pregnant women) () ER visit or hospitalization due to asthma () () + treated with systemic steroids or SABA In 00 (n =,; 0.% among total pregnant women)) () ER visit or hospitalization due to asthma () () + treated with systemic steroids or SABA Definition : Definition AND treated with anti-asthma drugs In the complete study period (n =, ; 0.% among total pregnant women) () ER visit or hospitalization due to asthma () () + treated with systemic steroids or SABA In 00 (n =,; 0.% among total pregnant women) () ER visit or hospitalization due to asthma () () + treated with systemic steroids or SABA In 00 (n =,; 0.% among total pregnant women)) () ER visit or hospitalization due to asthma () () + treated with systemic steroids or SABA (.%) (.%) (.%) (.%) (.%) (.%) (.0%) (0.0%) (.%) (.%) 0 (.%) (0.%) Number of events Incidence rate (per pregnancy) : first published as 0./bmjopen-0-00 on November 0. Downloaded from on March 0 by guest. Protected by copyright.

11 Page 0 of More than half of the pregnant women with asthma were prescribed either ICS/LABA (.%) or ICS alone (.%). The most commonly prescribed ICS/LABA was fluticasone/salmeterol (.%) and the most commonly used ICS was budesonide (.%). LTRA, theophylline, and systemic steroids were used in.0%,.%, and.% of cases, respectively. These oral drugs were less prescribed during the rd trimester than during the st trimester (all P values for trends were <0.00, Table ). Table. Asthma treatment among pregnant women with asthma (n =,) P for Total st trimester nd trimester** rd trimester*** trend n (%) n (%) n (%) n (%) ICS or LABA 0. Neither ICS nor LABA, (.%),0 (.%), (.0%),00 (.%) ICS with LABA,0 (.%) (.%) (.%) (.%) ICS without LABA,0 (.%) (.%) 0 (.%) (.%) LABA only (0.%) (0.%) (0.%) (0.%) ICS/LABA ICS LABA Fluticasone/salmeterol,0 (.%) (0.%) (0.%) 0 (.%) 0. Budesonide/formoterol (0.%) (.%) (.%) (.%) 0.0 Fluticasone (.%) 0 (0.%) (0.%) (0.%) 0. Budesonide, (.%) 0 (.%) (.%) (0.%) 0. other ICS (.%) (.0%) (.%) (.0%) 0. Salmeterol 0 (0.%) (0.%) (0.%) (0.%) 0.0 Formoterol (0.0%) 0 (0.0%) 0 (0.0%) (0.0%) 0. SABA,0 (.%) 0 (.%) (.%) (.%) 0.00 LTRA,0 (.0%),0 (.%) (.%) (.%) <0.00 Theophylline (.%) (.%) (.%) 0 (.%) <0.00 Systemic steroids 0 (.%) 0 (.%) (.%) 0 (.%) < : first published as 0./bmjopen-0-00 on November 0. Downloaded from on March 0 by guest. Protected by copyright.

12 Page of To evaluate how asthma patients changed their treatment after pregnancy, we also analyzed,0 patients who had been diagnosed with asthma (ICD-0 code J-J one time) within years before pregnancy from the total cohort. Compared with the period within weeks just before pregnancy, the percentages of asthma medications after pregnancy decreased markedly (Table ). - : first published as 0./bmjopen-0-00 on November 0. Downloaded from on March 0 by guest. Protected by copyright.

13 Page of Table. Asthma medication before and after pregnancy among asthma suspects (n =,0) During pregnancy Before pregnancy Total st trimester nd trimester rd trimester Before vs. n (%) n (%) n (%) n (%) n (%) During None, (.%), (.%) 0,0 (.%), (.%), (.%) < 0.00 <0.00 ICS,0 (.%) (0.%) (0.%) 0 (0.%) (0.%) < ICS+LABA,0 (.%) 0 (.0%) (0.%) (0.%) (0.%) < LTRA, (.%), (.%), (.%) (0.%) (0.%) < 0.00 <0.00 ICS+LTRA,0 (.%) (0.%) 0 (0.%) (0.%) (0.%) < 0.00 <0.00 ICS+LABA+LTRA, (.%) (0.%) (0.%) 0 (0.%) 0 (0.%) < 0.00 <0.00 on March 0 by guest. Protected by copyright. - P value Trend during pregnancy : first published as 0./bmjopen-0-00 on November 0. Downloaded from

14 Page of DISCUSSION The prevalence rate of asthma requiring healthcare utilization during pregnancy was 0.% in South Korea. In a field survey conducted more than 0 years ago with a randomly recruited general population from cities and rural areas in Korea, the prevalence of current asthma, defined as a case with current wheeze and positive bronchial hyperresponsiveness, in participants years old was about %. Considering that only a small percentage of patients visit healthcare services, the prevalence in our study may be reasonable. The prevalence of asthma during pregnancy was comparable to or slightly lower than that in the previous report in which, based on the insurance database, the prevalence of asthma in the Korean general population aged 0 years was reported as.. cases per,000 persons. Significant numbers of pregnant women with asthma experienced severe exacerbation in our study. Among the women who were diagnosed with asthma,.% visited the ER or were admitted to a hospital due to asthma and.% were also treated with systemic steroids and SABA, which is consistent with the results of previous studies. - This could be associated with the general low rate of asthma medication use during pregnancy. Among the,0 asthma suspects who were diagnosed with asthma within years before pregnancy, only.% were prescribed asthma drugs at least once. The most common drugs for asthma during pregnancy in South Korea were ICS or ICS/LABA, similar to those administered to non-pregnant patients with asthma. When ICS alone was used, budesonide was more commonly selected during pregnancy than fluticasone, although fluticasone/salmeterol was more widely chosen than budesonide/formoterol. This might be influenced by the result of a subgroup analysis of a randomized controlled trial in which the safety of budesonide during pregnancy was shown. - : first published as 0./bmjopen-0-00 on November 0. Downloaded from on March 0 by guest. Protected by copyright.

15 Page of About one-third of these patients with asthma took anti-asthma drugs within weeks before pregnancy. Asthmatic women could have stopped anti-asthma drugs because asthmatic symptoms improve during pregnancy. However, it is well known that the percentages of people with improved, same, and worsened asthmatic symptoms during pregnancy are similar. Thus, many women may have stopped taking anti-asthma drugs after becoming pregnant, possibly due to concerns that these drugs could affect pregnancy outcomes, although it is widely accepted that it is safer for pregnant women with asthma to be treated with asthma medications than to continue to have asthma symptoms and exacerbations. Although no drug can, in fact, be considered completely safe, 0 the major anti-asthma drugs are generally regarded as safe - and uncontrolled asthma may be associated with poorer pregnancy outcomes.,, In fact, the guidelines state that poorly controlled asthma and exacerbations cause a much greater risk to the baby than current asthma treatments do. 0 Limitations of our study include that asthma cases requiring healthcare utilization were only a part of the whole asthmatic pregnant women. Because this study was not a survey but was based on a claims database, some mild asthmatic pregnant women who did not need to seek medical attention may not have been included in our analysis. But the results can show a real world healthcare utilization pattern of asthmatics during pregnancy. In conclusion, in this analysis by a nationwide insurance claims database, the prevalence of asthma requiring healthcare utilization during pregnancy was not very high. However, a significant number of women were likely to stop anti-asthmatic drugs and did experience exacerbations. - : first published as 0./bmjopen-0-00 on November 0. Downloaded from on March 0 by guest. Protected by copyright.

16 Page of ACKNOWLEDGEMENTS CONTRIBUTORS CHL, JK, and JHL wrote the manuscript. JK, YJK, EJJ, AND SMC analyzed data. DKK and JJY participated in study design. CHL and HIY planned the study. FUNDING This study was supported by the National Evidence-Based Healthcare Collaborating Agency (NA-00), which contributed to the study s design, conduct, and reporting. COMPETING INTERESTS There are no conflicts of interest to be declared. ETHICS APPROVAL This study was approved by the ethics review committee of the National Evidence-based Healthcare Collaborating Agency, Seoul, Republic of Korea. DATA SHARING STATEMENT No additional data available. - : first published as 0./bmjopen-0-00 on November 0. Downloaded from on March 0 by guest. Protected by copyright.

17 Page of REFERENCES. Kwon HL, Triche EW, Belanger K, et al. The epidemiology of asthma during pregnancy: prevalence, diagnosis, and symptoms. Immunol Allergy Clin North Am 00; :-. Bidad K, Heidarnazhad H, Pourpak Z, et al. Frequency of asthma as the cause of dyspnea in pregnancy. Int J Gynaecol Obstet 00; :0-. Murphy VE, Namazy JA, Powell H, et al. A meta-analysis of adverse perinatal outcomes in women with asthma. BJOG 0; :-. Murphy VE, Wang G, Namazy JA, et al. The risk of congenital malformations, perinatal mortality and neonatal hospitalisation among pregnant women with asthma: a systematic review and meta-analysis. BJOG 0; 0:-. Schatz M, Dombrowski MP, Wise R, et al. The relationship of asthma medication use to perinatal outcomes. J Allergy Clin Immunol 00; :00-. Pauwels RA, Pedersen S, Busse WW, et al. Early intervention with budesonide in mild persistent asthma: a randomised, double-blind trial. Lancet 00; :0-. Silverman M, Sheffer A, Diaz PV, et al. Outcome of pregnancy in a randomized controlled study of patients with asthma exposed to budesonide. Ann Allergy Asthma Immunol 00; :-0. Tata LJ, Lewis SA, McKeever TM, et al. Effect of maternal asthma, exacerbations and asthma medication use on congenital malformations in offspring: a UK populationbased study. Thorax 00; :-. Malm H, Martikainen J, Klaukka T, et al. Prescription of hazardous drugs during pregnancy. Drug Saf 00; :-0 0. Vlastarakos PV, Manolopoulos L, Ferekidis E, et al. Treating common problems of the - : first published as 0./bmjopen-0-00 on November 0. Downloaded from on March 0 by guest. Protected by copyright.

18 Page of nose and throat in pregnancy: what is safe? Eur Arch Otorhinolaryngol 00; :-0. Lee CH, Kim K, Hyun MK, et al. Use of inhaled corticosteroids and the risk of tuberculosis. Thorax 0; :0-. Kim YK, Kim SH, Tak YJ, et al. High prevalence of current asthma and active smoking effect among the elderly. Clin Exp Allergy 00; :0-. Park HS, Choi GS, Cho JS, et al. Epidemiology and current status of allergic rhinitis, asthma, and associated allergic diseases in Korea: ARIA Asia-Pacific workshop report. Asian Pac J Allergy Immunol 00; :-. Schatz M, Dombrowski MP, Wise R, et al. Asthma morbidity during pregnancy can be predicted by severity classification. J Allergy Clin Immunol 00; :-. Stenius-Aarniala BS, Hedman J, Teramo KA. Acute asthma during pregnancy. Thorax ; :-. Firoozi F, Ducharme FM, Lemiere C, et al. Effect of fetal gender on maternal asthma exacerbations in pregnant asthmatic women. Respir Med 00; 0:-. Bakhireva LN, Schatz M, Jones KL, et al. Asthma control during pregnancy and the risk of preterm delivery or impaired fetal growth. Ann Allergy Asthma Immunol 00; 0:-. Gluck JC. The change of asthma course during pregnancy. Clin Rev Allergy Immunol 00; :-0. Dombrowski MP, Schatz M, Bulletins-Obstetrics ACoP. ACOG practice bulletin: clinical management guidelines for obstetrician-gynecologists number 0, February 00: asthma in pregnancy. Obstet Gynecol 00; :- 0. Global Initiative for Asthma. Global strategy for asthma management and prevention : first published as 0./bmjopen-0-00 on November 0. Downloaded from on March 0 by guest. Protected by copyright.

19 Page of Section/Topic Item # STROBE 00 (v) Statement Checklist of items that should be included in reports of cohort studies Recommendation Reported on page # Title and abstract (a) Indicate the study s design with a commonly used term in the title or the abstract #, # Introduction (b) Provide in the abstract an informative and balanced summary of what was done and what was found # Background/rationale Explain the scientific background and rationale for the investigation being reported # Objectives State specific objectives, including any prespecified hypotheses # Methods Study design Present key elements of study design early in the paper # Setting Describe the setting, locations, and relevant dates, including periods of recruitment, exposure, follow-up, and data collection Participants (a) Give the eligibility criteria, and the sources and methods of selection of participants. Describe methods of follow-up # (b) For matched studies, give matching criteria and number of exposed and unexposed Variables Clearly define all outcomes, exposures, predictors, potential confounders, and effect modifiers. Give diagnostic criteria, if Data sources/ measurement applicable * For each variable of interest, give sources of data and details of methods of assessment (measurement). Describe comparability of assessment methods if there is more than one group Bias Describe any efforts to address potential sources of bias #- Study size 0 Explain how the study size was arrived at N/A (just a Quantitative variables Explain how quantitative variables were handled in the analyses. If applicable, describe which groupings were chosen and why Statistical methods (a) Describe all statistical methods, including those used to control for confounding # on March 0 by guest. Protected by copyright. (b) Describe any methods used to examine subgroups and interactions - # N/A # #- nationwide data) # N/A (we did not apply any subgroup analysis or analysis to find interactions) : first published as 0./bmjopen-0-00 on November 0. Downloaded from

20 Page of Results Participants Descriptive data (c) Explain how missing data were addressed N/A (we could not identify if missing exists ) (d) If applicable, explain how loss to follow-up was addressed (e) Describe any sensitivity analyses * (a) Report numbers of individuals at each stage of study eg numbers potentially eligible, examined for eligibility, confirmed eligible, included in the study, completing follow-up, and analysed N/A N/A (our results are only descriptive) # (b) Give reasons for non-participation at each stage # (c) Consider use of a flow diagram We did not use a flow diagram * (a) Give characteristics of study participants (eg demographic, clinical, social) and information on exposures and potential # confounders (b) Indicate number of participants with missing data for each variable of interest N/A (we could not identify if missing exists ) (c) Summarise follow-up time (eg, average and total amount) # Outcome data * Report numbers of outcome events or summary measures over time #- Main results (a) Give unadjusted estimates and, if applicable, confounder-adjusted estimates and their precision (eg, % confidence #- interval). Make clear which confounders were adjusted for and why they were included (b) Report category boundaries when continuous variables were categorized #- (c) If relevant, consider translating estimates of relative risk into absolute risk for a meaningful time period Other analyses Report other analyses done eg analyses of subgroups and interactions, and sensitivity analyses N/A Discussion Key results Summarise key results with reference to study objectives # Limitations Interpretation 0 Give a cautious overall interpretation of results considering objectives, limitations, multiplicity of analyses, results from #- similar studies, and other relevant evidence Generalisability Discuss the generalisability (external validity) of the study results # - : first published as 0./bmjopen-0-00 on November 0. Downloaded from on March 0 by guest. Protected by copyright. N/A

21 Page 0 of Other information Funding Give the source of funding and the role of the funders for the present study and, if applicable, for the original study on # which the present article is based *Give information separately for cases and controls in case-control studies and, if applicable, for exposed and unexposed groups in cohort and cross-sectional studies. Note: An Explanation and Elaboration article discusses each checklist item and gives methodological background and published examples of transparent reporting. The STROBE checklist is best used in conjunction with this article (freely available on the Web sites of PLoS Medicine at Annals of Internal Medicine at and Epidemiology at Information on the STROBE Initiative is available at : first published as 0./bmjopen-0-00 on November 0. Downloaded from on March 0 by guest. Protected by copyright.

22 Healthcare utilization by pregnant asthma patients in South Korea: a cohort study using a nationwide claims data Journal: Manuscript ID bmjopen-0-00.r Article Type: Research Date Submitted by the Author: -Aug-0 Complete List of Authors: Lee, Chang-Hoon; Seoul National University Hospital, Department of Internal Medicine Kim, Jimin; National Evidence-based Healthcare Collaborating Agency, Division for Healthcare Technology Assessment Research Jang, Eun Jin; Andong National University, Department of Information Statistics Kim, Yun Jung; National Evidence-based Healthcare Collaborating Agency, Division for Healthcare Technology Assessment Research Choi, Seongmi; National Evidence-based Healthcare Collaborating Agency, Division for Healthcare Technology Assessment Research Lee, Joon-Ho; Seoul National University Hospital, Department of Obstetrics and Gynecology Kim, Deog Kyeom; Seoul Metropolitan Government-Seoul National University Boramae Medical Center, Department of Internal Medicine Yim, Jae-Joon; Seoul National University College of Medicine, Department of Internal Medicine Yoon, Hoil; Hoil Yoon, <b>primary Subject Heading</b>: Obstetrics and gynaecology Secondary Subject Heading: Obstetrics and gynaecology, Respiratory medicine Keywords: Asthma < THORACIC MEDICINE, EPIDEMIOLOGY, pregnancy, inhaled respiratory drugs : first published as 0./bmjopen-0-00 on November 0. Downloaded from on March 0 by guest. Protected by copyright.

23 Page of Healthcare utilization by pregnant asthma patients in South Korea: a cohort study using a nationwide claims data Chang-Hoon Lee, M.D.,, Jimin Kim, MPh., Eun Jin Jang, Ph.D.,, Yun Jung Kim, MPh., Seongmi Choi, Ph.D.,, Joon-Ho Lee, M.D., Ph.D., Deog Kyeom Kim, M.D., Ph.D.,, Jae-Joon Yim, M.D.,, *, Ho Il Yoon, M.D., Ph.D. National Evidence-based Healthcare Collaborating Agency, Seoul, Republic of Korea Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Hospital, Seoul, Republic of Korea Department of Information Statistics, Colloge of Natural Science, Andong National University, Andong, Republic of Korea Real Estate R&D Institute, Korea Appraisal Board, Daegu, Republic of Korea Department of Obstetrics and Gynecology, Seoul National University College of College of Medicine, Seoul National University Hospital, Seoul, Republic of Korea Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University College of College of Medicine, Seoul Metropolitan Government-Seoul National University Boramae Medical Center, Seoul, Republic of Korea Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam-Si, Republic of Korea * Corresponding author: Ho Il Yoon, M.D., Ph.D. - : first published as 0./bmjopen-0-00 on November 0. Downloaded from on March 0 by guest. Protected by copyright.

24 Page of Associate professor, Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital,, Gumi-Ro Beon-Gil, Bundang-Gu, Seongnam-Si, Gyeonggi-Do, -0, Republic of Korea. Tel: Fax: dextro@snu.ac.kr Key words asthma; epidemiology; pregnancy; inhaled respiratory drugs of coauthors: Chang-Hoon Lee: kauri0@empal.com Jimin Kim: jimin@neca.re.kr Eun Jin Jang: jejstat@gmail.com Yun Jung Kim: indigo@neca.re.kr Seongmi Choi: edisil0@nate.com Joon-Ho Lee: doctor-joon@hanmail.net Deog Kyeom Kim: kimdkmd@gmail.com Jae-Joon Yim: yimjj@snu.ac.kr - : first published as 0./bmjopen-0-00 on November 0. Downloaded from on March 0 by guest. Protected by copyright.

25 Page of ABSTRACT Objectives: Few nationwide population-based studies have examined the burden of asthma during pregnancy. Here we investigated the burden and medical treatment of asthma during pregnancy requiring healthcare utilization in South Korea. Design: Cohort study Setting: Nationwide insurance claims database Participants: A total of,0, pregnant women who delivered in South Korea in 00 0 Outcomes: The prevalence and exacerbation rates of asthma requiring healthcare utilization, and the prescription of anti-asthmatic drugs during pregnancy Results: The prevalence of asthma requiring healthcare utilization was 0.% among pregnant women. Among those with asthma requiring healthcare utilization,.% were hospitalized and treated with systemic steroids and short-acting β -agonists during pregnancy. Oral drugs were prescribed less during the rd trimester than during the st trimester (all P values for trends were <0.00). A significant number of patients with asthma were likely to stop taking anti-asthmatic drugs after becoming pregnant. Conclusions: The prevalence of asthma requiring healthcare utilization during pregnancy was not very high. However, a significant number of women were likely to stop taking antiasthmatic drugs, and those who did tended to experience exacerbations. - : first published as 0./bmjopen-0-00 on November 0. Downloaded from on March 0 by guest. Protected by copyright.

26 Page of STRENGTHS AND LIMITATIONS OF THIS STUDY - A study analysing asthma requiring healthcare utilization during pregnancy using a largescale nationwide database - The diagnosis of asthma was defined as its ICD-0 code together with the patient s use of anti-asthmatic medication. - The results showed that a significant number of patients were likely to stop taking drugs after becoming pregnant and that the prescription of oral drugs decreased during pregnancy. - Although only a portion of the asthmatic pregnant women required healthcare utilization, our results showed a real world healthcare utilization pattern of asthmatics during pregnancy. - : first published as 0./bmjopen-0-00 on November 0. Downloaded from on March 0 by guest. Protected by copyright.

27 Page of INTRODUCTION Asthma is an important health condition during pregnancy. Approximately % of pregnant women in the US currently have asthma, and.% of them experience at least one asthma attack. One prospective study also reported that the majority of pregnant women who seek respiratory specialist care for dyspnoea are asthmatics or probable asthmatics. Asthma seems to increase the risk of low birth weight, pre-eclampsia, preterm delivery, and congenital malformations. Patients with asthma are also susceptible to drug safety issues. For example, treatment with systemic corticosteroids during asthma could increase the risk of preeclampsia, low birth weight, and preterm delivery. Although several studies have reported that inhaled corticosteroids (ICSs) and β-agonists did not affect pregnancy outcomes, - many women commonly avoid taking asthma drugs during pregnancy because of these safety issues.,0 However, few nationwide population-based studies have been performed of the actual burden and treatment of asthma during pregnancy. The national insurance program of South Korea covers more than % of Koreans. Although the prevalence of asthma among people aged 0 years old is reportedly 0. %,, that of asthma among pregnant women has never been investigated. In this study, we investigated the prevalence of asthma requiring healthcare utilization during pregnancy in South Korea, incidence of severe asthma exacerbations, and actual medical treatment of these patients using a nationwide insurance claims database. - : first published as 0./bmjopen-0-00 on November 0. Downloaded from on March 0 by guest. Protected by copyright.

28 Page of METHODS Data Source The Health Insurance Review and Assessment Service (HIRA, Seoul, Republic of Korea) is a governmental agency that examines the accuracy of claims submitted to the National Health Insurance (NHI) and National Medical Aid (NMA) in South Korea, which covers approximately.% of the entire. million South Korean population. We used the HIRA database, which includes information regarding demographic variables and all of the rendered medical services along with diagnostic codes (International Statistical Classification of Diseases and Related Health Problems, 0 th edition code, ICD-0), and all of the dispensed prescribed medications. The proportion of missing or out-of-range answers in terms of key fields, including drug names, quantity, date dispensed, and duration, comprised <0.% of the records. This study was approved by the ethics review committee of the National Evidencebased Healthcare Collaborating Agency, Seoul, Republic of Korea. Written informed consent was not required due to the study s retrospective nature. Patient records and information were anonymized and de-identified prior to the analysis. Analyses We identified a pregnancy whenever a claim about a delivery event was found. The initiation pregnancy date was calculated as the date 0 weeks before the delivery event. If a woman was pregnant more than once, only the first pregnancy was included in the analysis. In our study, we focused on patients with asthma that required healthcare utilization (who visited hospitals and received a physician s diagnosis and care). To increase the diagnostic accuracy and reduce bias, asthma was defined in two ways: () definition : ICD-0 code J or J - : first published as 0./bmjopen-0-00 on November 0. Downloaded from on March 0 by guest. Protected by copyright.

29 Page of that was repeated with at least a -month interval; and () definition : definition plus use of any asthma medication at least once. Asthma medication included ICSs, ICS combined with inhaled long-acting β-agonists (ICS/LABAs), inhaled short-acting β-agonists (SABAs), leukotriene receptor antagonists (LTRAs), and theophylline. The prevalence of asthma requiring healthcare utilization during pregnancy was calculated as the number of asthma cases per 00 pregnancies (%). We also estimated the incidence rates of severe exacerbations of asthma (number of cases per pregnancy). We defined severe exacerbations in two ways: () a visit to the emergency room or hospitalization with a diagnosis of asthma and () condition plus treatment with systemic corticosteroids or SABAs. Asthma medications prescribed within weeks before the initiation date of pregnancy and those prescribed during each pregnancy trimester were also evaluated. We evaluated whether there were significant trends across trimesters in the use of medications using Mantel-Haenszel statistics. All analyses were performed using SAS. software (SAS Institute, Cary, NC, US) and Stata. software (StataCorp, College Station, TX, US). - : first published as 0./bmjopen-0-00 on November 0. Downloaded from on March 0 by guest. Protected by copyright.

30 Page of RESULTS A total of,0, pregnant women (mean age, 0. ±. years) were observed in Of them,, were diagnosed with asthma (definition prevalence of 0.% in 00 00: 0.% in 00, 0.% in 00). Among them,, were prescribed asthma drugs at least once during pregnancy (definition prevalence of 0.% in 00 00: 0.% in 00 and 0.% in 00). Table shows how many pregnant women with asthma experienced exacerbations. Among the total number of asthmatic pregnant women requiring healthcare utilization,.% visited the emergency department or were admitted to the hospital for asthma treatment (incidence, 0. per pregnancy) and.% were treated with systemic steroids and SABA after visiting the emergency department or hospitalized for asthma treatment (incidence, 0.0 per pregnancy). Among the asthmatic pregnant women who were treated with asthma medications,.0% visited the emergency department or were hospitalized for asthma treatment (incidence, 0. per pregnancy) and 0.0% were treated with systemic steroids and SABA after visiting the emergency department or being hospitalized for asthma treatment (incidence, 0. per pregnancy). - : first published as 0./bmjopen-0-00 on November 0. Downloaded from on March 0 by guest. Protected by copyright.

31 Page of Table. The incidence of emergency room visits or hospitalization for asthma exacerbations during pregnancy Definition : Among all pregnant women with asthma Number of patients with events (%) In the complete study period (n =,; 0.% among all pregnant women) () ER visit or hospitalization for asthma treatment () condition + treatment with systemic steroids or SABA In 00 (n =,; 0.% of all pregnant women) () ER visit or hospitalization due to asthma () condition + treatment with systemic steroids or SABA In 00 (n =,; 0.% of all pregnant women) () ER visit or hospitalization for asthma treatment () condition + treatment with systemic steroids or SABA Definition : Definition AND treatment with anti-asthmatic drugs In the complete study period (n =,; 0.% of all pregnant women) () ER visit or hospitalization due to asthma () condition + treatment with systemic steroids or SABA In 00 (n =,; 0.% of all pregnant women) () ER visit or hospitalization for asthma treatment () condition + treatment with systemic steroids or SABA In 00 (n =,; 0.% of all pregnant women) () ER visit or hospitalization due to asthma () condition + treatment with systemic steroids or SABA ER: emergency room, SABA: short-acting β-agonists (.%) (.%) (.%) (.%) (.%) (.%) (.0%) (0.0%) (.%) (.%) 0 (.%) (0.%) Number of events Incidence (per pregnancy) : first published as 0./bmjopen-0-00 on November 0. Downloaded from on March 0 by guest. Protected by copyright.

32 Page 0 of More than half of the pregnant women with asthma were prescribed either ICS/LABA (.%) or ICS alone (.%). The most commonly prescribed ICS/LABA was fluticasone/salmeterol (.%), while the most commonly used ICS was budesonide (.%). LTRA, theophylline, and systemic steroids were used in.0%,.%, and.% of cases, respectively. These oral drugs were less prescribed during the rd trimester than during the st trimester (all P values for trends were <0.00; Table ). Table. Asthma treatment among pregnant women with asthma (n =,) Total st trimester nd trimester** rd P for trimester*** trend n (%) n (%) n (%) n (%) ICS or LABA 0. Neither ICS nor LABA, (.%),0 (.%), (.0%),00 (.%) LABA only (0.%) (0.%) (0.%) (0.%) ICS without LABA,0 (.%) (.%) 0 (.%) (.%) ICS with LABA,0 (.%) (.%) (.%) (.%) ICS/LABA ICS LABA Fluticasone/salmeterol,0 (.%) (0.%) (0.%) 0 (.%) 0. Budesonide/formoterol (0.%) (.%) (.%) (.%) 0.0 Fluticasone (.%) 0 (0.%) (0.%) (0.%) 0. Budesonide, (.%) 0 (.%) (.%) (0.%) 0. Other ICS (.%) (.0%) (.%) (.0%) 0. Salmeterol 0 (0.%) (0.%) (0.%) (0.%) 0.0 Formoterol (0.0%) 0 (0.0%) 0 (0.0%) (0.0%) 0. SABA,0 (.%) 0 (.%) (.%) (.%) 0.00 LTRA,0 (.0%),0 (.%) (.%) (.%) <0.00 Theophylline (.%) (.%) (.%) 0 (.%) <0.00 Systemic steroids 0 (.%) 0 (.%) (.%) 0 (.%) <0.00 ICS: inhaled corticosteroids, LABA: long-acting β-agonists, SABA: short-acting β-agonists, LTRA: leukotriene receptor antagonists - : first published as 0./bmjopen-0-00 on November 0. Downloaded from on March 0 by guest. Protected by copyright.

33 Page of To evaluate how asthma patients changed their treatment compliance after pregnancy, we also analysed,0 patients from the overall cohort who were diagnosed with asthma (ICD-0 code J-J on at least one occasion) within years before pregnancy. Compared with the period within weeks just before pregnancy, the date of asthma medication use during pregnancy was markedly decreased (Table ). - : first published as 0./bmjopen-0-00 on November 0. Downloaded from on March 0 by guest. Protected by copyright.

34 Page of Table. Asthma medication before and after pregnancy among asthma suspects (n =,0) During pregnancy Before pregnancy Total st trimester nd trimester rd trimester Before vs. n (%) n (%) n (%) n (%) n (%) During None, (.%), (.%) 0,0 (.%), (.%), (.%) < 0.00 <0.00 ICS,0 (.%) (0.%) (0.%) 0 (0.%) (0.%) < ICS+LABA,0 (.%) 0 (.0%) (0.%) (0.%) (0.%) < LTRA, (.%), (.%), (.%) (0.%) (0.%) < 0.00 <0.00 ICS+LTRA,0 (.%) (0.%) 0 (0.%) (0.%) (0.%) < 0.00 <0.00 ICS+LABA+LTRA, (.%) (0.%) (0.%) 0 (0.%) 0 (0.%) < 0.00 <0.00 ICS: inhaled corticosteroids, LABA: long-acting β-agonists, SABA: short-acting β-agonists, LTRA: leukotriene receptor antagonists on March 0 by guest. Protected by copyright. - P value Trend during pregnancy : first published as 0./bmjopen-0-00 on November 0. Downloaded from

35 Page of DISCUSSION This study showed a prevalence of asthma requiring healthcare utilization during pregnancy of 0.% in South Korea. In a field survey conducted more than 0 years ago of a randomly recruited general population from cities and rural areas in Korea, the prevalence of current asthma, defined as current wheezing and positive bronchial hyper-responsiveness, in participants years old was approximately %. Considering that only a small percentage of patients seek healthcare services, the prevalence in our study may be reasonable. The prevalence of asthma during pregnancy was comparable to or slightly lower than that in the previous report in which, based on the insurance database, the prevalence of asthma in the Korean general population aged 0 years was reportedly.. cases per,000 persons. Significant numbers of pregnant women with asthma experienced severe exacerbations in our study. Among the women who were diagnosed with asthma,.% visited the emergency room or were admitted to a hospital for asthma treatment, while.% were also treated with systemic steroids and SABA, findings that are consistent with the results of previous studies. - This finding could be associated with the general low rate of asthma medication use during pregnancy. Among the,0 patients with suspected asthma who were diagnosed with asthma within years before pregnancy, only.% were prescribed asthma drugs at least once. The most common drugs prescribed for asthma during pregnancy in South Korea were ICS or ICS/LABA, similar to those administered to non-pregnant patients with asthma. When ICS alone was used, budesonide was more commonly selected during pregnancy than fluticasone, although fluticasone/salmeterol was more widely chosen than budesonide/formoterol. This phenomenon might be influenced by the result of a subgroup analysis of a randomized controlled trial in which the safety of budesonide during pregnancy - : first published as 0./bmjopen-0-00 on November 0. Downloaded from on March 0 by guest. Protected by copyright.

36 Page of was demonstrated. The adherence rate with prescription drugs is relatively low,,0 and pregnant women with asthma are no exception., In our study, many women may have stopped taking antiasthmatic drugs after becoming pregnant, possibly due to concerns that they could affect pregnancy outcomes. In fact, the US Food and Drug Administration categorizes the majority of asthma drugs including fluticasone, salmeterol, fluticasone/salmeterol, formoterol, budesonide/formoterol, salbutamol, theophylline, and prednisolone into category C (risk not ruled out). However, it is widely accepted that it is safer for pregnant women with asthma to be treated with asthma medications than continue to have asthma symptoms and exacerbations. Although no drug can be considered completely safe, 0 the major antiasthmatic drugs are generally considered safe - and uncontrolled asthma may be associated with poorer pregnancy outcomes.,, In fact, the guidelines state that poorly controlled asthma and exacerbations put babies at much greater risk than do current asthma treatments. In our study, a significant number of women were likely to stop anti-asthmatic drugs and substantial number of asthmatic pregnant women did experience exacerbations, which might indirectly support the guidelines emphasis on the adherence for asthma treatment during pregnancy. The limitations of our study include that only a portion of our pregnant cohort had asthma requiring healthcare utilization. Because this study was based on a claims database and not a survey, some pregnant women with mild or well-controlled asthma who did not need to seek medical attention may not have been included in the analysis. It is well known that similar percentages of women have improved, unchanged, and worsened asthmatic symptoms during pregnancy. In addition, pregnant women who were not covered by NHI or NMA were not included in this study. Moreover, our data should be cautiously interpreted. First, the analyses - : first published as 0./bmjopen-0-00 on November 0. Downloaded from on March 0 by guest. Protected by copyright.