This retrospective population‐based cohort study used the Longitudinal Health Insurance Database 2005 (LHID 2005) released by the Taiwan National Health Research Institutes (NHRI) for research purposes. The National Health Insurance (NHI) Program implemented on March 1, 1995 covers more than 99% of the 23.74 million population of Taiwan. The LHID2005 comprises a random sample of 1 million of those, and includes the demographic data of enrollees. The LHID 2005 contains the demographic data of enrollees; service records and expenditure claims from outpatient, inpatient, and ambulatory care; and data associated with contracted pharmacies for reimbursement purposes. The International Classification of Disease, 9th Revision, Clinical Modification (ICD-9-CM) codes was used to identify diseases in this study. The accuracy of diagnoses in the NHIRD has been verified in previous articles. The study was approved by the Institutional Review Board of the Ditmanson Medical Foundation Chia-Yi Christian Hospital, Taiwan (CYCH-IRB No: 2018078).
We conducted a retrospective cohort study on the period from January 1, 1996 to December 31, 2013. Patients newly diagnosed with IDA (ICD-9-CM: 280) were selected from the period between January 1, 2000 and December 31, 2012. We selected cases 20 or more years of age with a first diagnosis of IDA from the LHID 2005 between 2000 and 2012. The patients diagnosed with anxiety disorders, depression, psychotic disorders, bipolar disorders, sleep disorders, RLS, dementia before 2000, or before the first visit for IDA, were excluded. In order to increase the validity of IDA diagnoses, this study only included cases that have had at least two diagnoses of IDA in their medical claims prior to their index date as IDA cases. The iron supplementary medication were also collected. Individuals who had missing data, and those who were diagnosed without blood tests were excluded. Moreover, on the basis of the clinical guidelines and health insurance regulations under the NHI, patients suspected of having IDA might receive a diagnosis of unspecified anemia (ICD-9-CM: 285) on the first visit. However in order to a definite diagnosis of IDA the patient must be confirmed by receiving the laboratory test (decreased serum iron and ferritin, increased total iron binding capacity [TIBC]). We matched IDA and non-IDA subjects according to age and gender in a 1:2 ratio.
Patients in both the IDA and non-IDA groups were followed up from the index date until the end of December 31, 2013 or until one of the following events occurred: diagnosis with psychiatric disorders, including anxiety disorders ICD-9-CM: 300), depression (ICD-9-CM: 296.2-296.3, 300.4 and 311), psychotic disorders (ICD-9-CM: 295 and 297-298), bipolar disorders (ICD-9-CM: 296.0, 296.4-296.8), sleep disorders (ICD-9-CM: 307.4 and 780.5), RLS (ICD-9-CM: 333.90 and 333.99), and dementia (ICD-9-CM: 290, 294.1, and 331.0) withdrawal from the NHI program, or death, whichever came first.
Baseline characteristics and comorbidities
The general characteristics of individuals were comprised age, gender, insurable salary (in New Taiwan Dollars [NT$]; <19,100, 19,100 – 41,999, ≥ 42,000) and urbanization level of residence (levels 1 – 4). The covariates of comorbidities that were selected in this study included hypertension (ICD-9-CM: 401 – 405), diabetes mellitus (DM, ICD-9-CM: 250), dyslipidemia (ICD-9-CM: 272), hyperthyroidism (ICD-9-CM: 242), hypothyroidism (ICD-9-CM: 244), chronic pulmonary disease (COPD, ICD-9-CM: 490 – 496) , stroke (ICD-9-CM: 430 – 438), coronary artery disease (CAD, ICD-9-CM: 410 – 414), chronic kidney disease (CKD, ICD-9-CM: 585) and liver cirrhosis (ICD-9-CM: 571.2, 571.5, and 571.6).
Demographic characteristics was expressed using means and standard deviations (SD) for continuous variables, presented as number and percentage for categorical variables. The differences in continuous variables were estimated using t-tests, and differences between categorical variables were analyzed using the chi-square test or Fisher exact test, as appropriate. The incidence rate was calculated as the number of first diagnoses of psychiatric disorders per 1,000 person-years. Hazard ratios (HRs) and 95% confidence interval (CI) for developing outcomes (including overall events and dementia, anxiety disorders, depression, bipolar disorders, sleep disorders, RLS, and psychotic disorders, respectively) were calculated using univariate and multivariate Cox proportional hazards models. Multivariable Cox proportional hazards models were used to explore the associations between IDA and risk of psychiatric disorders, controlling for age, gender, and medical comorbidities. We used the Kaplan-Meier method and log-rank test to estimate the cumulative risks of psychiatric disorders between the IDA and non-IDA groups. A 2-tailed p-value of < 0.05 was considered significant. The SPSS for Windows version 21.0 (IBM Corp., Armonk, NY, USA) was used for the statistical analysis of the results. Statistical graphs were plotted with R version 3.5.1, with the KMsurv, survfit and survival packages.