Antibiotic Exposures and the Likelihood of Developing Pediatric Autoimmune Diseases: a Register-based Matched Case-control Study

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Using national registers (special reimbursement and drug purchase register), this matched case-control study aims to discover whether antibiotic exposures are related to development of ADs in general. From a cohort of 11,407 children (born 2000-2005, followed-up until December 2018), 242 children with ADs (type 1 diabetes (DM), autoimmune thyroiditis (AIT), juvenile idiopathic arthritis (JIA), and inflammatory bowel diseases (IBD)) generated the case group. Each case was matched with one to four child(ren) with similar age, sex, residential area, gestational age, and delivery mode, generating 708 matched controls. Number of antibiotic purchases throughout childhood was unrelated to the development of the studied ADs as one group, nor with DM, AIT, or IBD individually. While antibiotic exposures in infancy did not increase the likelihood of ADs, exposures to macrolides within two years before diagnosis showed minor association (OR 1.24, 95% CI 1.01-1.51). Exposures to cephalosporins, macrolides, and amoxicillin-clavulanic acid throughout childhood may increase the likelihood of JIA (OR 1.25, 95% CI 1.03-1.52; OR 1.21, 95% CI 1.06-1.38; OR 1.19, 95% CI 1.02-1.39, respectively). Regardless of frequent use in childhood (40% of all antibiotics), penicillins were not associated with the onset of any ADs. Conclusion: Occasional use of antibiotics are relatively safe regarding overall development of ADs. Penicillins are unlikely to be associated with any ADs, while broad-spectrum antibiotics (including macrolides) should be used considerately as they may associate with an increased likelihood of ADs, especially JIA. Pediatrics antibiotics autoimmune thyroiditis inflammatory bowel diseases juvenile idiopathic arthritis macrolide type 1 diabetes Figures Figure 1 Figure 2 Figure 3 What is known Role of antibiotics and/or infections in triggering autoimmune diseases have been speculated Antibiotic exposures in early childhood have been associated with the development of juvenile idiopathic arthritis (JIA) and inflammatory bowel diseases (IBD), while in type 1 diabetes (DM) the association is controversial The role of antibiotic exposures as a potential mutual risk factor for several autoimmune diseases is unclear What is new Number of antibiotic courses in the first year of life are unlikely to be associated with overall development of pediatric autoimmune diseases Exposures to broad-spectrum antibiotics, particularly in early childhood, may increase the likelihood of developing JIA Exposures to macrolides may be associated with the development of autoimmune diseases in general, while exposures to penicillins did not seem to be Introduction Autoimmune diseases (ADs) are disorders in which the immune system attacks normal tissues. Some ADs such as type 1 diabetes (DM), autoimmune thyroiditis (AIT), juvenile idiopathic arthritis (JIA), and inflammatory bowel diseases (IBD) may have overlapping genetic pathways [ 1 , 2 ] and similarities in their pathogenesis [ 3 – 7 ]. For unknown reasons, the incidences of these four chronic ADs in pediatric population in Finland have been particularly high, presuming a presence of mutual environmental risk factors [ 8 ]. Since Finnish children have used more antibiotics in the first and second year of life compared with Estonian or Russian Karelian children, and since the incidence of ADs in Finland are higher than in eastern Europe, this study focuses on the potential relationship between antibiotics and ADs [ 9 – 13 ]. Previous studies have connected antibiotic exposures (especially in early childhood) with the onset of JIA and Crohn’s disease, while findings regarding DM were controversial [ 14 – 19 ]. AIT has been related to tetracycline use in adolescence, but the mechanism remained unspecified [ 20 ]. Most of previous studies addressed each disease individually in different settings, making it challenging to estimate whether antibiotic exposures could be associated with the development of pediatric autoimmunity in general, yet manifesting as different diseases. The aim of this register-based matched case-control study is to investigate whether ADs (represented by DM, AIT, JIA, and IBD) might be associated with: (1) number of antibiotic exposures during different periods in childhood; (2) exposures to particular types of. antibiotics. Methods Data sources for the study population The study population was derived from Finnish Health in Teens (Fin-HIT) cohort – a nationwide prospective school-based cohort to address health behaviors of Finnish children and adolescents, comprising over 11,000 children (born 2000-2005) without specific exclusion criteria. More details on recruitment process and characteristics of the cohort have been described elsewhere [21]. The cohort represents children from densely populated areas across Finland, with relatively high maternal socioeconomic status [8]. Using a unique personal identity code of every Finnish resident, children in the Fin-HIT cohort were linked to three well established national registers: (1) the Special Reimbursement Register (SRR) – containing records on patients with chronic diseases requiring medication (including entry dates and physician verified diagnosis), who are entitled to drug refunds (i.e. special reimbursements) regardless of their socioeconomic status; (2) the Drug Purchase Register (DPR) – containing data on all purchased drugs by prescriptions in Finland (including dispensation dates and pharmaceutical information); and (3) the Medical Birth Register (MBR) – containing information on gestational age, delivery modes, and postnatal antibiotic treatment before discharge. These registers are maintained by the Finnish Social Insurance Institution (SRR and DPR) and Finnish Institute for Health and Welfare (MBR). Identifying children eligible for the matched case-control study The outcome of this study was the diagnosis of at least one AD at the end of the follow-up (31 December 2018). DM, JIA, and IBD (including Crohn’s disease, ulcerative colitis, and IBD unclassified) diagnoses were obtained from the SRR using ICD-10 codes (International Classification of Diseases (ICD), 10 th revision): E10 for DM; M08 for JIA; K50 (CD) and K51 (UC/IBDU) for IBD. AIT diagnoses were obtained from the DPR using ATC (Anatomical Therapeutic Chemical) code H03AA01 for thyroxin – the prescription-only drug used for AIT. The excellent coverage of these registers has been described previously [22, 23]. DPR was chosen for identifying AIT because thyroxin is inexpensive and not everyone using this medication is registered in the SRR. Of over 11,000 children in the Fin-HIT cohort, 242 developed a primary AD after first year of life and generated the case group. Depending on the availability of potential controls, each child in the case group was matched with one to four children from the same cohort with similar age (0-4 days of age difference), sex, and residential area. Since preterm birth has been identified as a potential risk factor for ADs, gestational age (preterm/term), and delivery mode (cesarean section/vaginal delivery) were also considered in the matching [8]. Due to the limited number of potential controls, most children born preterm and/or with cesarean section had only one matching control. Number and types of antibiotic purchases Data on perinatal antibiotic treatment in birth hospital were collected from the MBR and outpatient antibiotic purchases from the DPR with ATC codes starting with J01. The data was collected from birth until two months prior to index date (date of diagnosis for children with ADs/ compatible date for their matched controls). The two-month period was chosen to reduce the possibility of including antibiotic purchases during exacerbation phase of ADs. Antibiotic exposures were analyzed in several observation periods based on age distribution of antibiotic purchases (Figure 1 a): (1) throughout childhood – from birth to the date of diagnosis / the index date; (2) infancy – during the first year of life; (3) toddler phase – from the age 1 up to 3 rd birthday/index date (in those who were diagnosed <3 years old); (4) preschool to adolescence – from the age of 3 years to the index date; and (5) within two years before the index date. Due to observed nonlinear associations between antibiotic exposures and ADs, the numbers of antibiotic purchases in each observation periods were first categorized into quartiles and then modified accordingly: no purchases or 0 to Q1 (when the number of children without antibiotic purchases in that specific observation period is low), Q2, and combined Q3-Q4. The odds of developing an AD in relation to the number of antibiotic exposures in each observation period (while exposures in earlier periods were disregarded) were analyzed individually. Different types of antibiotics were categorized based on level 4 ATC codes (Supplementary Table 1) into 5 groups: (A) penicillins; (B) macrolides; (C) cephalosporines; (D) amoxicillin-clavulanic acid; and (E) sulphonamides and trimethoprim. Clindamycin, tetracyclines, fluoroquinolones and other antibiotics such as nitrofurantoin and metronidazole were considered in the analysis regarding the total number of antibiotic purchases but dismissed from the subgroup analysis due to low frequency of usage. Purchases of different antibiotic subgroups were also analyzed in the same observation periods as above (1-5). Statistical methods The background data of cases and controls are presented as mean and standard deviation (SD) or number/proportion (%). The likelihood of developing an AD was obtained by comparing each case and matched control(s) using conditional logistic regression. Results were presented with Odds Ratio (OR) and 95% confidence interval (CI). The software used was IBM SPSS Statistics 26.0 and a 5% statistical significance level was adopted. Results The background characteristics of the 242 children who developed ADs (cases) and 708 children who did not (matched controls) are presented in Table 1 . Throughout childhood, only 14 (5.8%) children in the case group and 34 (4.8%) in the matched control group had no record of antibiotic purchases (p=0.596). Age at and the type of the first antibiotic exposure did not differ between cases and matched controls (Supplementary Table 2). Penicillins were the most common purchased antibiotics (40% of all antibiotics, of which over 80% were amoxicillin), followed by macrolides (20% of all antibiotics, of which over 80% were azithromycin) (Supplementary Table 1). Table 1 Background characteristics of children in the study population. DM (N=102) AIT (N=68) JIA (N=54) IBD (N=27) Cases a (N=242) Matched controls b (N=708) Age at the end of follow-up (years), mean±SD 16.5±1.6 17.1±1.1 16.6±1.3 16.8±1.2 16.7±1.4 16.8±1.4 Sex, N (%) - Girl 41 (40.2) 47 (69.1) 43 (79.6) 13 (48.1) 140 (57.9) 407 (57.5) - Boy 61 (59.8) 21 (30.9) 11 (20.4) 14 (51.9) 102 (42.1) 301 (42.5) Residential area, N (%) - Capital (South) 34 (33.3) 20 (29.4) 10 (18.5) 11 (40.7) 72 (29.8) 248 (35.0) - Inner South 6 (5.9) 7 (10.3) 13 (24.1) 4 (14.8) 30 (12.4) 93 (13.1) - West 9 (8.8) 18 (26.5) 10 (18.5) 2 (7.4) 36 (14.9) 92 (13.0) - East 33 (32.4) 18 (26.5) 9 (16.7) 5 (18.5) 63 (26.0) 161 (22.7) - North 20 (19.6) 5 (7.4) 12 (22.2) 5 (18.5) 41 (16.9) 114 (16.1) Age of diagnosis/ age at the index date e , N (%) - 12 years 24 (23.5) 44 (64.7) 17 (31.5) 14 (51.9) 95 (39.3) 281 (39.7) Gestational age, N (%) - Term (≥ 37 weeks) 90 (88.2) 63 (92.6) 49 (90.7) 24 (88.9) 217 (89.7) 682 (96.3) - Preterm (<37 weeks) 9 (8.9) 4 (5.9) 4 (7.4) 3 (11.1) 20 (8.3) 26 (3.7) - Missing 3 (2.9) 1 (1.5) 1 (1.9) 0 5 (2.0) 0 Delivery mode, N(%) - Vaginal 80 (78.4) 58 (85.3) 47 (87.0) 21 (77.8) 198 (81.8) 644 (91.0) - Cesarean section 19 (18.6) 9 (13.2) 7 (13.0) 6 (22.2) 40 (16.5) 64 (9.0) - Missing 3 (2.9) 1 (1.5) 0 0 4 (1.7) 0 Maternal antibiotic purchase during pregnancy, N(%) - None 79 (77.5) 58 (85.3) 45 (83.3) 23 (85.2) 198 (81.8) 776 (80.9) - Up to 60 days before delivery 5 (4.9) 1 (1.5) 0 0 6 (2.5) 36 (3.8) - > 60 days before delivery 18 (17.6) 9 (13.2) 9 (16.7) 4 (14.8) 38 (15.7) 147 (15.3) a Cases=children with autoimmune diseases (represented with DM (type 1 diabetes mellitus), AIT (autoimmune thyroiditis), JIA (juvenile idiopathic arthritis), and IBD (inflammatory bowel diseases)). Nine chidren have two diagnoses. b Each child in the case group were matched with one to four children with similar age, sex, residential area, gestational age (preterm/term), delivery mode (cesarean section/vaginal). Due to limited potential controls, most children born preterm/with cesarean section have only one control instead of four. Table 2 Association between numbers of antibiotic purchases in different periods and the development of an autoimmune disease (DM, AIT, JIA, or IBD) a . Antibiotic purchases at different ages, N(%) Cases a (N=242) Matched controls b (N=708) Odds Ratio (95%CI) c Throughout childhood (From birth to the index date d ) AD 8 courses 107 (44.2) 311 (43.9) 1.22 (0.79-1.88) DM 8 courses 38 (37.3) 98 (35.0) 1.27 (0.69-2.36) AIT 8 courses 33 (48.5) 113 (59.5) 0.68 (0.29-1.60) JIA 8 courses 29 (53.7) 55 (35.3) 6.60 (2.12-20.5) IBD 8 courses 13 (48.1) 41 (56.2) 0.69 (0.17-2.79) Infancy (<age of 1 year) AD None 128 (52.9) 356 (50.3) 1.00 (0.72-1.38) 1-2 courses 85 (35.1) 262 (37.0) 1.00 (Ref) ≥3 courses 29 (12.0) 90 (12.7) 0.88 (0.54-1.44) DM None 59 (57.8) 147 (52.5) 1.09 (0.65-1.83) 1-2 courses 34 (33.3) 102 (36.4) 1.00 (Ref) ≥3 courses 9 (8.8) 31 (11.1) 0.66 (0.26-1.65) AIT None 37 (54.4) 89 (46.8) 1.37 (0.71-2.62) 1-2 courses 22 (32.4) 73 (38.4) 1.00 (Ref) ≥3 courses 9 (13.2) 28 (14.7) 1.00 (0.41-2.44) JIA None 24 (44.4) 82 (52.6) 0.76 (0.37-1.54) 1-2 courses 19 (35.2) 56 (35.9) 1.00 (Ref) ≥3 courses 11 (20.4) 18 (11.5) 1.71 (0.72-4.11) IBD None 14 (51.9) 31 (42.5) 1.01 (0.42-2.45) 1-2 courses 12 (44.4) 29 (39.7) 1.00 (Ref) ≥3 courses 1 (3.7) 13 (17.8) 0.21 (0.03-1.77) Toddler phase (From age of 1 up to third birthday/ the index date e ) AD None 45 (23.3) 146 (20.6) 0.98 (0.65-1.50) 1-2 courses 73 (30.2) 216 (30.5) 1.00 (Ref) ≥3 courses 124 (51.2) 346 (48.9) 1.63 (1.14-2.34) DM None 21 (20.6) 56 (20.0) 1.25 (0.66-2.34) 1-2 courses 27 (26.5) 96 (34.3) 1.00 (Ref) ≥3 courses 54 (52.9) 128 (45.7) 1.74 (1.01-3.00) AIT None 11 (16.2) 40 (21.1) 0.60 (0.26-1.37) 1-2 courses 25 (36.8) 44 (23.2) 1.00 (Ref) ≥3 courses 32 (26.4) 106 (55.8) 0.81 (0.41-1.60) JIA None 13 (24.1) 35 (22.4) 1.47 (0.61-3.47) 1-2 courses 12 (22.2) 57 (36.5) 1.00 (Ref) ≥3 courses 29 (53.7) 64 (41.0) 4.80 (1.90-12.1) IBD None 2 (7.4) 10 (13.7) 0.24 (0.03-1.96) 1-2 courses 9 (33.3) 17 (23.3) 1.00 (Ref) ≥3 courses 16 (59.3) 46 (63.0) 1.67 (0.65-4.30) Preschool to adolsescence (From age of 3 years to index date) AD None 33 (13.6) 96 (13.6) 1.23 (0.68-2.23) 1-2 courses 38 (15.7) 147 (20.8) 1.00 (Ref) ≥3 courses 151 (62.3) 40 (57.3) 1.56 (1.01-2.43) Index date <3 years 20 (8.3) 59 (8.3) DM None 20 (19.6) 54 (19.3) 1.75 (0.69-4.39) 1-2 courses 13 (12.7) 71 (25.4) 1.00 (Ref) ≥3 courses 57 (55.9) 126 (45.0) 2.63 (1.29-5.57) Index date <3 years 12 (11.8) 29 (10.4) AIT None 7 (10.3) 13 (6.8) 1.81 (0.54-6.05) 1-2 courses 10 (14.7)) 29 (15.3) 1.00 (Ref) ≥3 courses 51 (75.0) 148 (77.9) 1.15 (0.49-2.70) Index date <3 years 0 0 JIA None 6 (11.1) 27 (17.3) 0.53 (0.15-1.91) 1-2 courses 9 (16.7) 35 (22.4) 1.00 (Ref) ≥3 courses 33 (61.1) 72 (46.2) 2.09 (0.82-5.31) Index date <3 years 6 (11.1) 22 (14.1) IBD None 1 (3.7) 2 (2.7) 0.86 (0.06-13.2) 1-2 courses 6 (16.2) 12 (16.4) 1.00 (Ref) ≥3 courses 18 (66.7) 52 (71.2) 0.69 (0.21-2.22) Index date <3 years 2 (7.4) 7 (9.6) Purchases within 2 years before index date Autoimmune diseases None 120 (49.6) 371 (52.4) 1.02 (0.71-1.45) 1-2 courses 70 (28.9) 235 (33.2) 1.00 (Ref) ≥3 courses 52 (21.5) 102 (14.4) 1.81 (1.14-2.86) DM None 54 (52.9) 153 (54.6) 1.07 (0.61-1.88) 1-2 courses 27 (26.5) 83 (29.6) 1.00 (Ref) ≥3 courses 21 (20.6) 44 (15.7) 1.43 (0.66-3.11) AIT None 39 (57.4) 101 (53.2) 1.06 (0.39-2.84) 1-2 courses 21 (30.9) 64 (33.7) 1.00 (Ref) ≥3 courses 8 (11.8) 25 (13.2) 1.10 (0.58-2.09) JIA None 24 (44.4) 76 (48.7) 1.14 (0.49-2.64) 1-2 courses 14 (25.9) 56 (35.9) 1.00 (Ref) ≥3 courses 16 (29.6) 24 (15.4) 2.67 (1.16-6.16) IBD None 10 (37.0) 37 (50.7) 0.69 (0.25-1.90) 1-2 courses 9 (33.3) 27 (37.0) 1.00 (Ref) ≥3 courses 8 (29.6) 9 (12.3) 2.87 (0.72-11.5) a AD=autoimmune diseases. Cases=children with ADs, N=242 (represented with DM (type 1 diabetes mellitus), N=102; AIT (autoimmune thyroiditis), N=68; JIA (juvenile idiopathic arthritis), N=54; and IBD (inflammatory bowel diseases), N=27). Nine children had two diagnoses. b Each child in the case group were matched with one to four children with similar age, sex, residential area, gestational age (preterm/term), and delivery mode (cesarean section/vaginal). Due to limited potential controls, most children born preterm/with cesarean section have only one control instead of four. c Odds ratio and CI (95% Confidence Interval) was obtained using conditional logistic regression. d Throughout childhood, only 14 children in the case group and 34 in the control group had no records of antibiotic purchases. Index date= date of diagnosis for children who developed autoimmune diseases and compatible date for their matching controls. e When the age of diagnosis were between the age of 1 and 3 years. Total number of antibiotic purchases throughout childhood (from birth to the date of diagnosis/index date) was not associated with the development of the studied ADs as one group, nor with DM, AIT, and IBD individually. Of all purchased antibiotics, 44.3% (n=3,825) were bought before the age of 3 years. Concerning antibiotic purchases in each age, the only significant difference between cases and matched controls was seen during the second year of life: children who later developed ADs purchased more antibiotics than those who did not develop ADs (OR 1.11, 95%CI 1.03-1.20) (Figure 1 ). As for antibiotic types, penicillins were not associated with the development of any ADs, while purchases of macrolides within two years before the index date were associated with the onset of ADs in general. Moreover, purchases of broader-spectrum antibiotics (macrolides, cephalosporins, or amoxicillin-clavulanic acid) throughout childhood (but particularly during infancy and toddler phase) increased the likelihood of developing JIA. Number of antibiotic purchases The relationship between the total number of antibiotic purchases before the index date and the proportion of ADs was non-linear and required categorized analyses (Figure 2 ). The highest odds for developing ADs in general (not associated with any specific diagnosis) were observed in children with frequent antibiotic purchases (≥ 3 courses) when compared with those without antibiotic purchases (OR 1.72, 95%CI 1.08-2.74) within the two years before the index date (Supplementary Table 3). Regarding particular diagnosis, children receiving 4-8 courses and >8 courses had an increased likelihood of developing JIA (OR 2.91, 95% CI 1.05-8.05 and OR 6.60, 95% CI 2.12-20.5 – respectively) compared with those receiving <4 antibiotic courses throughout childhood. The likelihood of developing JIA was also increased after frequent antibiotic purchases during toddler phase (OR 4.80, 95% CI 1.90-12.1) and within 2 years before the index date (OR 2.67 95% CI 1.16-6.16) when compared with infrequent antibiotic purchases (1-2 courses) in both of these periods. Furthermore, JIA was more common in children with frequent antibiotic purchases (OR 3.94, 95% CI 1.16-13.4) than in those without antibiotic purchases during preschool to adolescence (Supplementary Table 3). As for other ADs, frequent antibiotic purchases (≥ 3 courses) in toddler phase (OR 1.74, 95% CI 1.01-3.00) and from preschool to adolescence (OR 2.63, 95% CI 1.29-5.57) increased the odds of developing DM when compared with infrequent antibiotic purchases during these periods. Types of antibiotic purchases When purchases of the five most common antibiotic types in the study population (penicillins, macrolides, cephalosporins, amoxicillin-clavulanic acid, and sulphonamides and trimethoprim) throughout childhood were analyzed individually, none of them was associated with the onset of the four ADs as one group (Supplementary Table 4). The likelihood of JIA was increasing with the number broader-spectrum antibiotics (cephalosporins, macrolides, and amoxicillin-clavulanic acid) purchases, particularly in infancy (OR 2.54, 95%CI 1.01-6.38; OR 1.80, 95%CI 1.08-3.01; and OR 1.03, 95%CI 1.12-3.32 – respectively) and in toddler phase (OR 1.69, 95%CI 1.15-2.48; OR 1.40, 95% CI 1.09-1.79; and OR 1.43, 95%CI 1.03-2.00 – respectively). However, this finding was inconspicuous regarding DM, AIT, and IBD – as their odds were low after purchases of broader-spectrum antibiotics in infancy. Furthermore, purchases of sulphonamides and trimethoprim from preschool to adolescence was associated with DM (OR 1.35, 95%CI 1.03-1.77). Finally, purchases of macrolides within two years before the index date was associated with the development of ADs in general (OR 1.24, 95%CI 1.01-1.51) (Figure 3 , Supplementary Table 4), while purchases of penicillin were scarcely ever associated with any types of ADs in this study. Discussion Our study is the first to investigate the association between number and types of antibiotic exposures in different stages of childhood and the onset of four common pediatric ADs (DM, AIT, JIA, or IBD) in a mutual setting. We showed that the relationship between the number of antibiotic exposures and the onset of ADs seems to be non-linear. In addition, the likelihood of developing ADs after antibiotic exposures in infancy remained low, especially regarding DM, AIT, and IBD. Despite of being the most common antibiotic used in childhood, penicillins (predominantly amoxicillin) would be relatively safe to use at any age in relation with the development of ADs, while exposures to macrolides within the two years prior to diagnosis may present minor association. Regarding specific diagnosis, the number of antibiotic exposures throughout childhood was mainly associated with JIA. Even then, exposures to penicillin group antibiotics did not increase the likelihood of JIA, while exposures to cephalosporin, macrolide, and amoxicillin-clavulanic (especially before the age of three) might moderately do so. In our study, antibiotic exposures in infancy did not increase the likelihood of developing any ADs. Furthermore, we showed that frequent antibiotic exposures after first year of life may be related with ADs when compared with occasional exposures, but not when compared with those having no records of antibiotic purchases in each observation period. However, this finding seems to be predominantly related to JIA and DM, but not with AIT and IBD. How do these findings align with previous studies? A Swedish register-based study presented a connection between prescribed antibiotics during infancy and the onset of DM [ 18 ], while studies from which countries have not reported significant association between early childhood antibiotic exposures and DM [ 19 , 24 ]. Studies from United Kingdom and Finland have associated both lifetime and early life antibiotic exposures and the onset of JIA [ 14 , 15 ]. As for IBD, early antibiotic exposures have been related with Crohn’s disease but not with ulcerative colitis [ 17 , 25 ]. Most of these studies assumed a linear association between antibiotic exposures and the onset of a particular AD, thus assuming that the lowest risk for ADs is retained by those without previous antibiotic exposures. Our study challenges this presumption. Since infancy is the most susceptible period for common infectious diseases and is the period of most frequent antibiotic use [ 26 ], it is reassuring that antibiotics used in early childhood hardly increased the likelihood of developing pediatric ADs. Beyond first year of life, occasional antibiotic courses (approximately 1-2 courses per year) can generally be seen as a low-risk approach in relation to the development of ADs. We showed that exposures to macrolides within the two years before obtaining diagnosis may be related with the overall development of ADs. In addition, exposures to antibiotics with broader spectrum (cephalosporine, macrolide, and amoxicillin-clavulanic acid), particularly before the age of three years, were moderately associated with JIA. On the contrary, penicillins (as the most common antibiotic type used to treat infections throughout childhood) were not related to the development of any ADs at any age. Hence, the relationship between antibiotics and ADs could not solely be explained by number of infections, as often speculated. Several studies have reported an association between gut dysbiosis and autoimmune diseases [ 27 – 30 ]. Since antibiotics have been shown to have an influence on gut microbial homeostasis [ 31 ], antibiotic exposures could as well be related to ADs through facilitating gut dysbiosis. Variations in magnitude and specificity of gut microbiota modification by different antibiotics have been reported, hence requiring variable recovery time after exposures [ 32 – 34 ]. For example, macrolides have both a broad spectrum and long-term influence on gut microbiota that may persist even for several years [ 35 , 36 ]. In our study, azithromycin was the most often used antibiotic among macrolides. Azithromycin has a broad bacteriostatic spectrum, a marked tissue penetration, a high stability and a low clearance rate due to its long half-life, which enable it to reach a higher cellular concentration compared to penicillin [ 37 ]. These characteristics may explain the long-term influences of azithromycin (as a macrolide) on gut microbiota compared with penicillin. Furthermore, previous Fin-HIT study showed that azithromycin presented the strongest inverse association with salivary microbiota diversity [ 38 ]. Since dysbiosis of gut and salivary microbiota have also been associated with ADs [ 39 ], we suggest that macrolides might catalyze longer-term dysbiosis, explaining their association with the development of ADs, particularly up to two years prior to diagnosis, while penicillin was not associated with any type of ADs at any ages. Further studies to examine the potential link between the use of broad-spectrum antibiotics, the time of their influence on gut microbiota, gut dysbiosis, and the onset of ADs is warranted. The strength of our study lies in the comprehensive longitudinal data from national registers. For example, we were able to trace purchased antibiotics as outpatients rather than just prescribed. In addition, we studied several ADs in a mutual setting, using rather homogenous Fin-HIT cohort with small variations in socioeconomic status as the source of study population[ 8 ]. The control population was matched with details based on age (with only up to 4 days of age difference), sex, residential area, gestational age, and delivery method to limit the number of potential confounding factors. Therefore, our study setting made it possible to examine the association between childhood antibiotic exposures and onsets of the four pediatric ADs together, and to reliably compare one disease to another in this subject. As for limitations, we lack the information on the children’s genetic susceptibility to infections or to ADs. We also did not know why the antibiotics were purchased – for treating infections (and if so, for what kind of infection) or for prophylactic purposes – and on whether secondary antibiotic courses for the same infection were needed. In addition, we had no access on the length of purchased antibiotic courses nor on the antibiotics given during inpatient care. Yet, antibiotic treatments during hospitalization are often continued orally after discharge, and our data cover these post-discharge antibiotic purchases. Conclusion Use of antibiotics in the first year of life and occasional use throughout childhood can be considered relatively safe in relation with the development of pediatric autoimmunity. Antibiotics in the penicillin group are unlikely to be associated with the development of any ADs. In contrast, broad-spectrum antibiotics (including macrolides) should be used considerately as they may associate with an increased likelihood of ADs, especially JIA. Abbreviations AD Autoimmune disease AIT Autoimmune Thyroiditis ATC Anatomical Therapeutic Chemical DM Type 1 Diabetes DPR Drug Purchase Register Fin-HIT Finnish Health in Teens IBD Inflammatory Bowel Diseases JIA Juvenile Idiopathic Arthritis MBR Maternal Birth Register SRR Special Reimbursement Register Declarations Funding The project has received financial support from the Swedish Cultural Foundation in Finland, Folkhälsan Research Foundation, to accommodate the work of HV and EE. LR is under the employment of Tampere University, faculty of medicine and received research grant from Tampere University Hospital, department of pediatrics. KLK received Helsinki University Grant. There were no other specific grants from any public, commercial, or non-profit sectors relevant to this article to disclose. The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. Conflict of interest The authors have no conflicts of interest to declare, nor have any affiliations with financial or non-financial interest in subjects relevant to the content of this manuscript. Ethics approval The Fin-HIT study protocol was approved by the Ethics Committee of the Hospital District of Helsinki and Uusimaa (decision number 169/13/03/00/10). Consent to participate The children and a guardian provided a written informed consent for the register linkage. Consent for publication All authors approved the final manuscript as submitted, and agreed to be accountable for all aspects of the work. Availability of data and material Data available upon request. Code availability N/A Contributions LR, EE, HV, KLK conceptualized the study. HV participated in data collection. LR carried out the analyses and interpreted the results with the help of RS and SK, and wrote the initial manuscript, and made the figures and tables. LR and SK searched the literatures. HV and KLK supervised the study. All authors critically reviewed and revised the manuscript for important intellectual content. Acknowledgements We thank prof Per Ashorn and Valma Harjutsalo for valuable comments, Binu Matthews for helping with data management. References Lees CW, Barrett JC, Parkes M, et al. New IBD genetics: common pathways with other diseases . Gut. 2011;60: 1739-1753. Richard-Miceli C, Criswell LA. Emerging patterns of genetic overlap across autoimmune disorders . Genome Med. 2012;4:6. Paschou SA, Papadopoulou-Marketou N, Chrousos G, et al. (2017) On type 1 diabetes mellitus pathogenesis . Endocr. connect. 7. 2017;7:R38-R46. Pugliese A. Autoreactive T cells in type 1 diabetes . J. Clin. Investig. 2017;127: 2881-2891. Antonelli A, Ferrari SM, Corrado A, et al. Autoimmune thyroid disorders . Autoimmun. Rev. 2014;14: 174-180. Martini A, Prakken B, Albani S, et al. Arthritis 3 Juvenile idiopathic arthritis . Lancet. 2011;377: 2138-49. Giuffrida P, Corazza GR, Di Sabatino A. Old and New Lymphocyte Players in Inflammatory Bowel Disease . Dig Dis Sci. 2017;63: 277-288. Räisänen L, Viljakainen H, Sarkkola C, et al. Perinatal risk factors for pediatric onset type 1 diabetes, autoimmune thyroiditis, juvenile idiopathic arthritis, and inflammatory bowel diseases . Eur J Pediatr. 2021;180(7): 2115-2123. Mustonen N, Siljander H, Peet A, et al. Early childhood infections and the use of antibiotics and antipyretic-analgesics in Finland, Estonia and Russian Karelia . Acta Paediatr Int J Paediatr. 2019;108: 2075-2082. Mobasseri M, Shirmohammadi M, Amiri T, et al. Prevalence and incidence of type 1 diabetes in the world: a systematic review and meta-analysis . Health Promot Perspect. 2020;10:98-115. Savolainen E, Kaipiainen-Seppänen O, Kröger L, et al. Total Incidence and Distribution of Inflammatory Joint Diseases in a Defined Population: Results from the Kuopio 2000 Arthritis Survey . J Rheumatol. 2003;30: 2460-2468. Pruunsild C, Uibo K, Liivamägi H, et al. Incidence of juvenile idiopathic arthritis in children in Estonia: A prospective population-based study . Scand J Rheumatol. 2007; 36: 7-13. Burisch J, Jess T, Martinato M, et al. The burden of inflammatory bowel disease in Europe . J Crohn Colitis, 2013;7: 322-337. Horton DB, Scott FI, Haynes K, et al. Antibiotic exposure and juvenile idiopathic arthritis: a case-control study . Pediatrics (Evanston) 136: e333-e343. Arvonen, Miika. Virta, Lauri. Pokka, Tytti. Kröger, Liisa. Vähäsalo, Paula. Repeated exposure to antibiotics in infancy: a predisposing factor for juvenile idiopathic arthritis or a sign of this group's greater susceptibility to infections? J.Rheumatol. 2015;42(3): 521-526. Kronman MP, Zaoutis TE, Haynes K, et al. Antibiotic Exposure and IBD Development Among Children: A Population-Based Cohort Study . Pediatrics 130: e794-e803. Virta L, Auvinen A, Helenius H, et al. Association of Repeated Exposure to Antibiotics With the Development of Pediatric Crohn's Disease--A Nationwide, Register-based Finnish Case-Control Study . Am. J. Epidemiol. 2012;175: 775-784. Wernroth M, Fall K, Svennblad B, et al. Early Childhood Antibiotic Treatment for Otitis Media and Other Respiratory Tract Infections Is Associated With Risk of Type 1 Diabetes: A Nationwide Register- Based Study With Sibling Analysis . Diabetes Care. 2020;43(5):991-999. Kemppainen KM, Vehik K, Lynch KF, et al. Association Between Early-Life Antibiotic Use and the Risk of Islet or Celiac Disease Autoimmunity . JAMA Pediatrics. 2017;171: 1217-1225. Pollock AJ, MD, Seibert, Tasa, MD, MPH, Allen DB, MD. Severe and Persistent Thyroid Dysfunction Associated with Tetracycline-Antibiotic Treatment in Youth . J. Pediatr. 2016;173: 232-234. Figueiredo, Rejane Augusta de Oliveira, Simola-Ström S, Rounge TB, et al. Cohort Profile: The Finnish Health in Teens (Fin-HIT) study: a population-based study . Int. J. Epidemiol. 2019;48: 23-24h. Niemelä H. Social Security in Finland: Helsinki, Finland: Social Insurance Institution (KELA), Finnish Centre for Pensions (ETK), Finnish Pension Alliance (TELA), and Finnish Ministry of Social Affairs and Health. 2006. Furu K, Wettermark B, Andersen M, et al. The Nordic Countries as a Cohort for Pharmacoepidemiological Research . Basic ClinPharmacol Toxicol. 2010;106: 86-94. Mikkelsen KH, Knop FK, Vilsbøll T, et al. Use of antibiotics in childhood and risk of Type 1 diabetes: a population-based case-control study . Diabet Med. 2017;34: 272. Shaw SY, Blanchard JF, Bernstein CN. Association Between the Use of Antibiotics in the First Year of Life and Pediatric Inflammatory Bowel Disease . Am. J. Gastroenterol. 2010;105: 2687-2692. Simon AK, Hollander GA, McMichael A. Evolution of the immune system in humans from infancy to old age . Proc Biol Sci. 2015;282: 20143085. Han H, Li Y, Fang J, et al. Gut Microbiota and Type 1 Diabetes . Int. J. Mol. Sci. 2018 ; 19: 995. Virili C, Fallahi P, Antonelli A, et al.) Gut microbiota and Hashimoto's thyroiditis . Rev Endocr Metab Dis .2018.19: 293-300. Arvonen M, Berntson L, Pokka T, et al. Gut microbiota-host interactions and juvenile idiopathic arthritis . Pediatr. Rheumatol. Online J. 2016;14: 44. Comito D, Romano C. Dysbiosis in the Pathogenesis of Pediatric Inflammatory Bowel Diseases . Int. J Inflamm. 2012: 687143-7. Neuman H, Forsythe P, Uzan A, et al. Antibiotics in early life: dysbiosis and the damage done . FEMS Microbiology Rev.2018; 42: 489-499. Gerber JS, Hersh AL, Kronman MP, et al. Development and Application of an Antibiotic Spectrum Index for Benchmarking Antibiotic Selection Patterns Across Hospitals . Infect Control Hosp Epidemiol. 2017;38: 993-997. Iizumi T, Battaglia T, Ruiz V, et al. Gut Microbiome and Antibiotics . Arch Med Res. 2017;48: 727-734. Rinninella E, Raoul P, Cintoni M, et al. What is the Healthy Gut Microbiota Composition? A Changing Ecosystem across Age, Environment, Diet, and Diseases . Microorganisms. 2019;7:14. Elvers KT, Wilson VJ, Hammond A, et al. Antibiotic-induced changes in the human gut microbiota for the most commonly prescribed antibiotics in primary care in the UK: a systematic review . BMJ Open 10. Korpela K, Salonen A, Virta LJ, et al. Intestinal microbiome is related to lifetime antibiotic use in Finnish pre-school children . Nature communications. 2016;7: 10410. Van Bambeke F, Tulkens PM. (2001) Macrolides: pharmacokinetics and pharmacodynamics . Int J Antimicrob Agents. 2001;18: 17-23. Raju SC, Viljakainen H, Figueiredo RAO, et al. Antimicrobial drug use in the first decade of life influences saliva microbiota diversity and composition . Microbiome. 2020;8: 1-121. Xun Z, Zhang Q, Xu T, et al. Dysbiosis and ecotypes of the salivary microbiome associated with inflammatory bowel diseases and the assistance in diagnosis of diseases using oral bacterial profiles . Front Microbiol. 2018; 9:1136. Supplementary Files SupplementsAbandautoimmunediseasesRaisanen.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-1110501","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":71182755,"identity":"56f5354d-1634-4e55-b083-2a7ed4b9d434","order_by":0,"name":"Laura Räisänen","email":"","orcid":"https://orcid.org/0000-0002-4892-5710","institution":"Tampere University: Tampereen Yliopisto","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Laura","middleName":"","lastName":"Räisänen","suffix":""},{"id":71182756,"identity":"3d8dd64d-f30b-43e1-a309-62532a902edd","order_by":1,"name":"Sohvi Kääriäinen","email":"","orcid":"","institution":"Finnish Institute for Health and Welfare: Terveyden ja hyvinvoinnin laitos","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Sohvi","middleName":"","lastName":"Kääriäinen","suffix":""},{"id":71182757,"identity":"fddf350b-efbd-4a53-ba62-0e7842e3459d","order_by":2,"name":"Reijo Sund","email":"","orcid":"","institution":"University of Eastern Finland Faculty of Health Sciences: Ita-Suomen yliopisto Terveystieteiden tiedekunta","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Reijo","middleName":"","lastName":"Sund","suffix":""},{"id":71182758,"identity":"da1d9995-0cc3-4b7c-ba02-b23582df52a6","order_by":3,"name":"Elina Engberg","email":"","orcid":"","institution":"Folkhälsan research center","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Elina","middleName":"","lastName":"Engberg","suffix":""},{"id":71182759,"identity":"efb0a41f-55c7-4095-a6d5-e7c90717807f","order_by":4,"name":"Heli Viljakainen","email":"data:image/png;base64,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","orcid":"","institution":"Samfundet Folkhälsan: Samfundet Folkhalsan","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Heli","middleName":"","lastName":"Viljakainen","suffix":""},{"id":71182760,"identity":"cde17895-984b-4705-8b5d-c29d36e23499","order_by":5,"name":"Kaija-Leena Kolho","email":"","orcid":"","institution":"University of Helsinki: Helsingin Yliopisto","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Kaija-Leena","middleName":"","lastName":"Kolho","suffix":""}],"badges":[],"createdAt":"2021-11-24 11:21:45","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-1110501/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-1110501/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":16667813,"identity":"2b17994e-bea7-4ba4-a69a-cf58a8202cb9","added_by":"auto","created_at":"2021-12-21 23:54:57","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":93154,"visible":true,"origin":"","legend":"\u003cp\u003ePurchased antibiotic courses before index date\u003csup\u003ea\u003c/sup\u003e in the matched case-control\u003csup\u003eb\u003c/sup\u003e study. Number of tetracyclin, clindamycin, fluoroquinolone, and other antibiotics courses were relatively low.\u003c/p\u003e\u003cp\u003e\u003csup\u003ea\u003c/sup\u003e Index date= Date of diagnosis for children who developed autoimmune diseases (type 1 diabetes, autoimmune thyroiditis, juvenile idiopathic arthritis, and inflammatory bowel diseases) and compatible date for their matching controls\u003c/p\u003e\u003cp\u003e\u003csup\u003eb \u003c/sup\u003eCases= 242 children who developed autoimmune diseases by the end of follow-up (31 December 2018). Each child in the case group was matched with one to four children with similar age, sex, residential area, gestational age (preterm/term), and delivery mode (cesarean section/vaginal), comprising control group of 708 children.\u003c/p\u003e","description":"","filename":"Fig1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-1110501/v1/06057150295011a908335388.jpg"},{"id":16667814,"identity":"9e1f5891-fa55-4b51-8cf0-5825d57092f0","added_by":"auto","created_at":"2021-12-21 23:54:57","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":36556,"visible":true,"origin":"","legend":"\u003cp\u003eProportion of autoimmune diseases\u003csup\u003ea\u003c/sup\u003e in groups of children with different number of antibiotic purchases in different periods of childhood.\u003c/p\u003e\u003cp\u003e\u003csup\u003ea\u003c/sup\u003e Autoimmune diseases in this study were type 1 diabetes, autoimmune thyroiditis, juvenile idiopathic arthritis, and inflammatory bowel diseases. Index date = Date of diagnosis for children who developed autoimmune diseases and compatible date for their age, sex, residential areas, gestational age (preterm/term), and delivery method (Cesarean section/vaginal delivery) matched controls.\u003c/p\u003e","description":"","filename":"Fig2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-1110501/v1/2071bc5236f91eedeec71c89.jpg"},{"id":16667957,"identity":"a5d25bce-2c7d-4159-b35e-321eacd31bcd","added_by":"auto","created_at":"2021-12-21 23:57:57","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":84102,"visible":true,"origin":"","legend":"\u003cp\u003eAssociation between types of antibiotic purchases\u0026nbsp;in different periods and the development of an autoimmune disease (DM, AIT, JIA, or\u0026nbsp;IBD)\u003csup\u003ea\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003e\u003csup\u003ea\u0026nbsp;\u003c/sup\u003eAD=autoimmune diseases.\u0026nbsp;Cases=children with\u0026nbsp;ADs\u0026nbsp;(represented with DM (type 1 diabetes mellitus), AIT (autoimmune thyroiditis), JIA (juvenile idiopathic arthritis), and IBD (inflammatory bowel diseases)). Nine children have two diagnoses.\u0026nbsp;OR=Odds ratio,\u0026nbsp;CI=Confidence Interval. Analyses was performed using conditional logistic regression.\u0026nbsp;Index date= age of diagnosis for children who developed autoimmune diseases and compatible date for their matching controls.\u003c/p\u003e","description":"","filename":"Fig3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-1110501/v1/6455d623f76398e82650633d.jpg"},{"id":17787047,"identity":"8f5d6c42-2a60-406e-8f86-2c22e2ac418c","added_by":"auto","created_at":"2022-01-30 18:18:05","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":684136,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-1110501/v1/e4f5a53f-70bd-4c02-ab57-5a684c4fc217.pdf"},{"id":16667816,"identity":"81e52b63-24f1-4053-a083-3477c2f1ed6f","added_by":"auto","created_at":"2021-12-21 23:54:57","extension":"docx","order_by":7,"title":"","display":"","copyAsset":false,"role":"supplement","size":114662,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementsAbandautoimmunediseasesRaisanen.docx","url":"https://assets-eu.researchsquare.com/files/rs-1110501/v1/7516f0c43b76cbfbce2df925.docx"}],"financialInterests":"","formattedTitle":"\u003cp\u003eAntibiotic Exposures and the Likelihood of Developing Pediatric Autoimmune Diseases: a Register-based Matched Case-control Study\u003c/p\u003e","fulltext":[{"header":"What is known","content":"\u003cul\u003e\n\u003cli\u003e\n\u003cp\u003eRole of antibiotics and/or infections in triggering autoimmune diseases have been speculated\u003c/p\u003e\n\u003c/li\u003e\n\u003cli\u003e\n\u003cp\u003eAntibiotic exposures in early childhood have been associated with the development of juvenile idiopathic arthritis (JIA) and inflammatory bowel diseases (IBD), while in type 1 diabetes (DM) the association is controversial\u003c/p\u003e\n\u003c/li\u003e\n\u003cli\u003e\n\u003cp\u003eThe role of antibiotic exposures as a potential mutual risk factor for several autoimmune diseases is unclear\u003c/p\u003e\n\u003c/li\u003e\n\u003c/ul\u003e"},{"header":"What is new","content":"\u003cul\u003e\n\u003cli\u003e\n\u003cp\u003eNumber of antibiotic courses in the first year of life are unlikely to be associated with overall development of pediatric autoimmune diseases\u003c/p\u003e\n\u003c/li\u003e\n\u003cli\u003e\n\u003cp\u003eExposures to broad-spectrum antibiotics, particularly in early childhood, may increase the likelihood of developing JIA\u003c/p\u003e\n\u003c/li\u003e\n\u003cli\u003e\n\u003cp\u003eExposures to macrolides may be associated with the development of autoimmune diseases in general, while exposures to penicillins did not seem to be\u003c/p\u003e\n\u003c/li\u003e\n\u003c/ul\u003e"},{"header":"Introduction","content":"\u003cp\u003eAutoimmune diseases (ADs) are disorders in which the immune system attacks normal tissues. Some ADs such as type 1 diabetes (DM), autoimmune thyroiditis (AIT), juvenile idiopathic arthritis (JIA), and inflammatory bowel diseases (IBD) may have overlapping genetic pathways [\u003cspan class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e2\u003c/span\u003e] and similarities in their pathogenesis [\u003cspan class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e7\u003c/span\u003e]. For unknown reasons, the incidences of these four chronic ADs in pediatric population in Finland have been particularly high, presuming a presence of mutual environmental risk factors [\u003cspan class=\"CitationRef\"\u003e8\u003c/span\u003e]. Since Finnish children have used more antibiotics in the first and second year of life compared with Estonian or Russian Karelian children, and since the incidence of ADs in Finland are higher than in eastern Europe, this study focuses on the potential relationship between antibiotics and ADs [\u003cspan class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e13\u003c/span\u003e].\u003c/p\u003e\n\u003cp\u003ePrevious studies have connected antibiotic exposures (especially in early childhood) with the onset of JIA and Crohn\u0026rsquo;s disease, while findings regarding DM were controversial [\u003cspan class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e19\u003c/span\u003e]. AIT has been related to tetracycline use in adolescence, but the mechanism remained unspecified [\u003cspan class=\"CitationRef\"\u003e20\u003c/span\u003e]. Most of previous studies addressed each disease individually in different settings, making it challenging to estimate whether antibiotic exposures could be associated with the development of pediatric autoimmunity in general, yet manifesting as different diseases. The aim of this register-based matched case-control study is to investigate whether ADs (represented by DM, AIT, JIA, and IBD) might be associated with: (1) number of antibiotic exposures during different periods in childhood; (2) exposures to particular types of. antibiotics.\u003c/p\u003e"},{"header":"Methods","content":"\u003ch2\u003eData sources for the study population\u003c/h2\u003e\n\u003cp\u003eThe study population was derived from Finnish Health in Teens (Fin-HIT) cohort \u0026ndash; a nationwide prospective school-based cohort to address health behaviors of Finnish children and adolescents, comprising over 11,000 children (born 2000-2005) without specific exclusion criteria.\u0026nbsp;More details on recruitment process and characteristics of the cohort have been\u0026nbsp;described elsewhere\u0026nbsp;[21].\u0026nbsp;The cohort represents children from densely populated areas across Finland, with relatively high maternal socioeconomic status\u0026nbsp;[8].\u003csup\u003e\u0026nbsp;\u003c/sup\u003eUsing a unique personal identity code of every Finnish resident, children in the Fin-HIT cohort were linked to three well established national registers: (1) the Special Reimbursement Register (SRR) \u0026ndash; containing records on patients with chronic diseases requiring medication (including entry dates and physician verified diagnosis), who are entitled to drug refunds (i.e. special reimbursements) regardless of their socioeconomic status; \u0026nbsp;(2) the Drug Purchase Register (DPR) \u0026ndash; containing data on all purchased drugs by prescriptions in Finland (including dispensation dates and pharmaceutical information); and (3) the Medical Birth Register (MBR) \u0026ndash; containing information on gestational age, delivery modes, and postnatal antibiotic treatment before discharge. These registers are maintained by the Finnish Social Insurance Institution (SRR and DPR) and Finnish Institute for Health and Welfare (MBR).\u003c/p\u003e\n\u003ch2\u003eIdentifying children eligible for the matched case-control study\u003c/h2\u003e\n\u003cp\u003eThe outcome of this study was the diagnosis of at least one AD at the end of the follow-up (31 December 2018).\u0026nbsp;DM, JIA, and IBD\u0026nbsp;(including Crohn\u0026rsquo;s disease, ulcerative colitis, and IBD unclassified)\u0026nbsp;diagnoses were obtained from the SRR using ICD-10 codes\u0026nbsp;(International Classification of Diseases (ICD), 10\u003csup\u003eth\u003c/sup\u003e revision): E10 for DM; M08 for JIA; K50 (CD) and K51 (UC/IBDU) for IBD. AIT diagnoses were obtained from the DPR using ATC (Anatomical Therapeutic Chemical) code H03AA01 for thyroxin \u0026ndash; the prescription-only drug used for AIT. The excellent coverage of these registers has been described previously [22, 23]. DPR was chosen for identifying AIT because thyroxin is inexpensive and not everyone using this medication is registered in the SRR.\u003c/p\u003e\n\u003cp\u003eOf over 11,000 children in the Fin-HIT cohort, 242 developed a primary AD after first year of life and generated the case group. \u0026nbsp;Depending on the availability of potential controls, each child in the case group was matched with one to four children from the same cohort with similar age (0-4 days of age difference), sex, and residential area. Since preterm birth has been identified as a potential risk factor for ADs, gestational age (preterm/term), and delivery mode (cesarean section/vaginal delivery) were also considered in the matching [8]. Due to the limited number of potential controls, most children born preterm and/or with cesarean section had only one matching control.\u003c/p\u003e\n\u003ch2\u003eNumber and types of antibiotic purchases\u003c/h2\u003e\n\u003cp\u003eData on perinatal antibiotic treatment in birth hospital were collected from the MBR and outpatient antibiotic purchases from the DPR with ATC codes starting with J01. The data was collected from birth until two months prior to index date (date of diagnosis for children with ADs/ compatible date for their matched controls). The two-month period was chosen to reduce the possibility of including antibiotic purchases during exacerbation phase of ADs.\u003c/p\u003e\n\u003cp\u003eAntibiotic exposures were analyzed in several observation periods based on age distribution of antibiotic purchases (Figure 1 a): (1) throughout childhood \u0026ndash; from birth to the date of diagnosis / the index date; (2) infancy \u0026ndash; during the first year of life; (3) toddler phase \u0026ndash; from the age 1 up to 3\u003csup\u003erd\u003c/sup\u003e birthday/index date (in those who were diagnosed \u0026lt;3 years old); (4) preschool to adolescence \u0026ndash; from the age of 3 years to the index date; and (5) within two years before the index date. Due to observed nonlinear associations between antibiotic exposures and ADs, the numbers of antibiotic purchases in each observation periods were first categorized into quartiles and then modified accordingly: no purchases or 0 to Q1 (when the number of children without antibiotic purchases in that specific observation period is low), Q2, and combined Q3-Q4. The odds of developing an AD in relation to the number of antibiotic exposures in each observation period (while exposures in earlier periods were disregarded) were analyzed individually.\u003c/p\u003e\n\u003cp\u003eDifferent types of antibiotics were categorized based on level 4 ATC codes (Supplementary Table 1) into 5 groups: (A)\u003cem\u003e\u0026nbsp;\u003c/em\u003epenicillins; (B) macrolides; (C) cephalosporines; (D) amoxicillin-clavulanic acid; and (E) sulphonamides and trimethoprim. Clindamycin, tetracyclines, fluoroquinolones and other antibiotics such as nitrofurantoin and metronidazole were considered in the analysis regarding the total number of antibiotic purchases but dismissed from the subgroup analysis due to low frequency of usage. Purchases of different antibiotic subgroups were also analyzed in the same observation periods as above (1-5).\u003c/p\u003e\n\u003ch2\u003eStatistical methods\u003c/h2\u003e\n\u003cp\u003eThe background data of cases and controls are presented as mean and standard deviation (SD) or number/proportion (%). The likelihood of developing an AD was obtained by comparing each case and matched control(s) using conditional logistic regression. Results were presented with Odds Ratio (OR) and 95% confidence interval (CI). The software used was IBM SPSS Statistics 26.0 and a 5% statistical significance level was adopted.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eThe background characteristics of the 242 children who developed ADs (cases) and 708 children who did not (matched controls) are presented in Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e. Throughout childhood, only 14 (5.8%) children in the case group and 34 (4.8%) in the matched control group had no record of antibiotic purchases (p=0.596). Age at and the type of the first antibiotic exposure did not differ between cases and matched controls (Supplementary Table 2). Penicillins were the most common purchased antibiotics (40% of all antibiotics, of which over 80% were amoxicillin), followed by macrolides (20% of all antibiotics, of which over 80% were azithromycin) (Supplementary Table 1).\u003c/p\u003e\n\u003ctable id=\"Tab1\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eBackground characteristics of children in the study population.\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\u003ccolgroup\u003e\u003c/colgroup\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eDM\u003c/p\u003e\n\u003cp\u003e(N=102)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eAIT\u003c/p\u003e\n\u003cp\u003e(N=68)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eJIA\u003c/p\u003e\n\u003cp\u003e(N=54)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eIBD\u003c/p\u003e\n\u003cp\u003e(N=27)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eCases\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003e(N=242)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eMatched controls\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003e(N=708)\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eAge at the end of follow-up (years), mean\u0026plusmn;SD\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e16.5\u0026plusmn;1.6\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e17.1\u0026plusmn;1.1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e16.6\u0026plusmn;1.3\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e16.8\u0026plusmn;1.2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e16.7\u0026plusmn;1.4\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e16.8\u0026plusmn;1.4\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eSex, N (%)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e- Girl\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e41 (40.2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e47 (69.1)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e43 (79.6)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e13 (48.1)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e140 (57.9)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e407 (57.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e- Boy\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e61 (59.8)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e21 (30.9)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e11 (20.4)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e14 (51.9)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e102 (42.1)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e301 (42.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eResidential area, N (%)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e- Capital (South)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e34 (33.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e20 (29.4)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e10 (18.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e11 (40.7)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e72 (29.8)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e248 (35.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e- Inner South\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e6 (5.9)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e7 (10.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e13 (24.1)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4 (14.8)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e30 (12.4)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e93 (13.1)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e- West\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e9 (8.8)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e18 (26.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e10 (18.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2 (7.4)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e36 (14.9)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e92 (13.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e- East\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e33 (32.4)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e18 (26.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e9 (16.7)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e5 (18.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e63 (26.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e161 (22.7)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e- North\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e20 (19.6)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e5 (7.4)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e12 (22.2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e5 (18.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e41 (16.9)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e114 (16.1)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eAge of diagnosis/\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eage at the index date\u003c/strong\u003e\u003csup\u003e\u003cstrong\u003ee\u003c/strong\u003e\u003c/sup\u003e, \u003cstrong\u003eN (%)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e- \u0026lt;6 years\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e36 (35.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3 (4.4)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e19 (35.2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2 (7.4)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e59 (24.4)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e154 (21.8)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e- 6-12 years\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e42 (41.2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e21 (30.9)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e18 (33.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e11 (40.7)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e88 (36.4)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e273 (38.6)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e- \u0026gt;12 years\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e24 (23.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e44 (64.7)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e17 (31.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e14 (51.9)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e95 (39.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e281 (39.7)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eGestational age, N (%)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e- Term (\u0026ge; 37 weeks)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e90 (88.2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e63 (92.6)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e49 (90.7)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e24 (88.9)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e217 (89.7)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e682 (96.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e- Preterm (\u0026lt;37 weeks)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e9 (8.9)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4 (5.9)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4 (7.4)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3 (11.1)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e20 (8.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e26 (3.7)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e- Missing\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3 (2.9)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1 (1.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1 (1.9)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e5 (2.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eDelivery mode, N(%)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e- Vaginal\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e80 (78.4)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e58 (85.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e47 (87.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e21 (77.8)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e198 (81.8)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e644 (91.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e- Cesarean section\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e19 (18.6)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e9 (13.2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e7 (13.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e6 (22.2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e40 (16.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e64 (9.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e- Missing\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3 (2.9)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1 (1.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4 (1.7)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eMaternal antibiotic purchase during pregnancy, N(%)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e- None\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e79 (77.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e58 (85.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e45 (83.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e23 (85.2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e198 (81.8)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e776 (80.9)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e- Up to 60 days before delivery\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e5 (4.9)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1 (1.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e6 (2.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e36 (3.8)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e- \u0026gt; 60 days before delivery\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e18 (17.6)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e9 (13.2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e9 (16.7)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4 (14.8)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e38 (15.7)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e147 (15.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003ctfoot\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"7\"\u003e\u003csup\u003ea\u003c/sup\u003e Cases=children with autoimmune diseases (represented with DM (type 1 diabetes mellitus), AIT (autoimmune thyroiditis), JIA (juvenile idiopathic arthritis), and IBD (inflammatory bowel diseases)). Nine chidren have two diagnoses. \u003csup\u003eb\u003c/sup\u003e Each child in the case group were matched with one to four children with similar age, sex, residential area, gestational age (preterm/term), delivery mode (cesarean section/vaginal). Due to limited potential controls, most children born preterm/with cesarean section have only one control instead of four.\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tfoot\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"1\" width=\"0\"\u003e\u003ccaption\u003e\n\u003cp\u003eTable 2\u003c/p\u003e\n\u003cp\u003eAssociation between numbers of antibiotic purchases in different periods and the development of an autoimmune disease (DM, AIT, JIA, or IBD)\u003csup\u003ea\u003c/sup\u003e.\u003c/p\u003e\n\u003c/caption\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"2\" width=\"263\"\u003e\n\u003cp\u003e\u003cstrong\u003eAntibiotic purchases at different ages, N(%)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"103\"\u003e\n\u003cp\u003e\u003cstrong\u003eCases\u003csup\u003ea\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e(N=242)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"144\"\u003e\n\u003cp\u003e\u003cstrong\u003eMatched controls\u003csup\u003eb\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e(N=708)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"170\"\u003e\n\u003cp\u003e\u003cstrong\u003eOdds Ratio (95%CI)\u003csup\u003ec\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd rowspan=\"20\" width=\"127\"\u003e\n\u003cp\u003e\u003cstrong\u003eThroughout childhood\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e(From birth to the index date\u003csup\u003ed\u003c/sup\u003e)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"136\"\u003e\n\u003cp\u003e\u003cstrong\u003eAD\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"103\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"144\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"170\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"136\"\u003e\n\u003cp\u003e\u0026lt;4 courses\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"103\"\u003e\n\u003cp\u003e\u0026nbsp;53 (21.9)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"144\"\u003e\n\u003cp\u003e174 (24.6)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"170\"\u003e\n\u003cp\u003e1.00 (Ref)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"136\"\u003e\n\u003cp\u003e4-8 courses\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"103\"\u003e\n\u003cp\u003e\u0026nbsp;82 (33.9)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"144\"\u003e\n\u003cp\u003e223 (31.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"170\"\u003e\n\u003cp\u003e1.32 (0.87-2.01)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"136\"\u003e\n\u003cp\u003e\u0026gt;8 courses\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"103\"\u003e\n\u003cp\u003e107 (44.2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"144\"\u003e\n\u003cp\u003e311 (43.9)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"170\"\u003e\n\u003cp\u003e1.22 (0.79-1.88)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"136\"\u003e\n\u003cp\u003e\u003cstrong\u003eDM\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"103\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"144\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"170\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"136\"\u003e\n\u003cp\u003e\u0026lt;4 courses\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"103\"\u003e\n\u003cp\u003e28 (27.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"144\"\u003e\n\u003cp\u003e\u0026nbsp; 81 (28.9)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"170\"\u003e\n\u003cp\u003e1.00 (Ref)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"136\"\u003e\n\u003cp\u003e4-8 courses\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"103\"\u003e\n\u003cp\u003e36 (35.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"144\"\u003e\n\u003cp\u003e101 (36.1)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"170\"\u003e\n\u003cp\u003e1.07 (0.60-1.93)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"136\"\u003e\n\u003cp\u003e\u0026gt;8 courses\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"103\"\u003e\n\u003cp\u003e38 (37.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"144\"\u003e\n\u003cp\u003e\u0026nbsp;98 (35.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"170\"\u003e\n\u003cp\u003e1.27 (0.69-2.36)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"136\"\u003e\n\u003cp\u003e\u003cstrong\u003eAIT\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"103\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"144\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"170\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"136\"\u003e\n\u003cp\u003e\u0026lt;4 courses\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"103\"\u003e\n\u003cp\u003e11 (16.2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"144\"\u003e\n\u003cp\u003e\u0026nbsp;25 (13.2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"170\"\u003e\n\u003cp\u003e1.00 (Ref)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"136\"\u003e\n\u003cp\u003e4-8 courses\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"103\"\u003e\n\u003cp\u003e24 (35.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"144\"\u003e\n\u003cp\u003e\u0026nbsp;52 (27.4)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"170\"\u003e\n\u003cp\u003e1.08 (0.45-2.58)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"136\"\u003e\n\u003cp\u003e\u0026gt;8 courses\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"103\"\u003e\n\u003cp\u003e33 (48.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"144\"\u003e\n\u003cp\u003e113 (59.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"170\"\u003e\n\u003cp\u003e0.68 (0.29-1.60)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"136\"\u003e\n\u003cp\u003e\u003cstrong\u003eJIA\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"103\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"144\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"170\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"136\"\u003e\n\u003cp\u003e\u0026lt;4 courses\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"103\"\u003e\n\u003cp\u003e10 (18.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"144\"\u003e\n\u003cp\u003e56 (35.9)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"170\"\u003e\n\u003cp\u003e1.00 (Ref)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"136\"\u003e\n\u003cp\u003e4-8 courses\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"103\"\u003e\n\u003cp\u003e15 (27.8)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"144\"\u003e\n\u003cp\u003e45 (28.8)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"170\"\u003e\n\u003cp\u003e\u003cem\u003e2.91 (1.05-8.05)\u003c/em\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"136\"\u003e\n\u003cp\u003e\u0026gt;8 courses\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"103\"\u003e\n\u003cp\u003e29 (53.7)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"144\"\u003e\n\u003cp\u003e55 (35.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"170\"\u003e\n\u003cp\u003e\u003cem\u003e6.60 (2.12-20.5)\u003c/em\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"136\"\u003e\n\u003cp\u003e\u003cstrong\u003eIBD\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"103\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"144\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"170\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"136\"\u003e\n\u003cp\u003e\u0026lt;4 courses\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"103\"\u003e\n\u003cp\u003e\u0026nbsp; 5 (18.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"144\"\u003e\n\u003cp\u003e11 (15.1)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"170\"\u003e\n\u003cp\u003e1.00 (Ref)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"136\"\u003e\n\u003cp\u003e4-8 courses\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"103\"\u003e\n\u003cp\u003e\u0026nbsp; 9 (33.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"144\"\u003e\n\u003cp\u003e21 (28.8)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"170\"\u003e\n\u003cp\u003e0.90 (0.21-3.86)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"136\"\u003e\n\u003cp\u003e\u0026gt;8 courses\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"103\"\u003e\n\u003cp\u003e13 (48.1)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"144\"\u003e\n\u003cp\u003e41 (56.2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"170\"\u003e\n\u003cp\u003e0.69 (0.17-2.79)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd rowspan=\"20\" width=\"127\"\u003e\n\u003cp\u003e\u003cstrong\u003eInfancy \u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e(\u0026lt;age of 1 year)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"136\"\u003e\n\u003cp\u003e\u003cstrong\u003eAD\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"103\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"144\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"170\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"136\"\u003e\n\u003cp\u003eNone\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"103\"\u003e\n\u003cp\u003e128 (52.9)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"144\"\u003e\n\u003cp\u003e356 (50.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"170\"\u003e\n\u003cp\u003e1.00 (0.72-1.38)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"136\"\u003e\n\u003cp\u003e1-2 courses\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"103\"\u003e\n\u003cp\u003e\u0026nbsp; 85 (35.1)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"144\"\u003e\n\u003cp\u003e262 (37.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"170\"\u003e\n\u003cp\u003e1.00 (Ref)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"136\"\u003e\n\u003cp\u003e\u0026ge;3 courses\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"103\"\u003e\n\u003cp\u003e\u0026nbsp; 29 (12.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"144\"\u003e\n\u003cp\u003e\u0026nbsp; 90 (12.7)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"170\"\u003e\n\u003cp\u003e0.88 (0.54-1.44)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"136\"\u003e\n\u003cp\u003e\u003cstrong\u003eDM\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"103\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"144\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"170\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"136\"\u003e\n\u003cp\u003eNone\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"103\"\u003e\n\u003cp\u003e\u0026nbsp; 59 (57.8)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"144\"\u003e\n\u003cp\u003e147 (52.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"170\"\u003e\n\u003cp\u003e1.09 (0.65-1.83)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"136\"\u003e\n\u003cp\u003e1-2 courses\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"103\"\u003e\n\u003cp\u003e\u0026nbsp; 34 (33.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"144\"\u003e\n\u003cp\u003e102 (36.4)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"170\"\u003e\n\u003cp\u003e1.00 (Ref)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"136\"\u003e\n\u003cp\u003e\u0026ge;3 courses\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"103\"\u003e\n\u003cp\u003e\u0026nbsp;\u0026nbsp; 9\u0026nbsp;\u0026nbsp; (8.8)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"144\"\u003e\n\u003cp\u003e\u0026nbsp; 31 (11.1)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"170\"\u003e\n\u003cp\u003e0.66 (0.26-1.65)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"136\"\u003e\n\u003cp\u003e\u003cstrong\u003eAIT\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"103\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"144\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"170\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"136\"\u003e\n\u003cp\u003eNone\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"103\"\u003e\n\u003cp\u003e\u0026nbsp;37 (54.4)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"144\"\u003e\n\u003cp\u003e89 (46.8)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"170\"\u003e\n\u003cp\u003e1.37 (0.71-2.62)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"136\"\u003e\n\u003cp\u003e1-2 courses\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"103\"\u003e\n\u003cp\u003e\u0026nbsp;22 (32.4)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"144\"\u003e\n\u003cp\u003e73 (38.4)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"170\"\u003e\n\u003cp\u003e1.00 (Ref)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"136\"\u003e\n\u003cp\u003e\u0026ge;3 courses\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"103\"\u003e\n\u003cp\u003e\u0026nbsp;\u0026nbsp; 9 (13.2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"144\"\u003e\n\u003cp\u003e28 (14.7)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"170\"\u003e\n\u003cp\u003e1.00 (0.41-2.44)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"136\"\u003e\n\u003cp\u003e\u003cstrong\u003eJIA\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"103\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"144\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"170\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"136\"\u003e\n\u003cp\u003eNone\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"103\"\u003e\n\u003cp\u003e24 (44.4)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"144\"\u003e\n\u003cp\u003e82 (52.6)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"170\"\u003e\n\u003cp\u003e0.76 (0.37-1.54)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"136\"\u003e\n\u003cp\u003e1-2 courses\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"103\"\u003e\n\u003cp\u003e19 (35.2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"144\"\u003e\n\u003cp\u003e56 (35.9)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"170\"\u003e\n\u003cp\u003e1.00 (Ref)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"136\"\u003e\n\u003cp\u003e\u0026ge;3 courses\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"103\"\u003e\n\u003cp\u003e11 (20.4)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"144\"\u003e\n\u003cp\u003e18 (11.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"170\"\u003e\n\u003cp\u003e1.71 (0.72-4.11)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"136\"\u003e\n\u003cp\u003e\u003cstrong\u003eIBD\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"103\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"144\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"170\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"136\"\u003e\n\u003cp\u003eNone\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"103\"\u003e\n\u003cp\u003e14 (51.9)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"144\"\u003e\n\u003cp\u003e31 (42.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"170\"\u003e\n\u003cp\u003e1.01 (0.42-2.45)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"136\"\u003e\n\u003cp\u003e1-2 courses\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"103\"\u003e\n\u003cp\u003e12 (44.4)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"144\"\u003e\n\u003cp\u003e29 (39.7)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"170\"\u003e\n\u003cp\u003e1.00 (Ref)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"136\"\u003e\n\u003cp\u003e\u0026ge;3 courses\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"103\"\u003e\n\u003cp\u003e\u0026nbsp; 1\u0026nbsp;\u0026nbsp; (3.7)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"144\"\u003e\n\u003cp\u003e13 (17.8)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"170\"\u003e\n\u003cp\u003e0.21 (0.03-1.77)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd rowspan=\"20\" width=\"127\"\u003e\n\u003cp\u003e\u003cstrong\u003eToddler phase\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e(From age of 1 up to third birthday/ the index date\u003csup\u003ee\u003c/sup\u003e)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"136\"\u003e\n\u003cp\u003e\u003cstrong\u003eAD\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"103\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"144\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"170\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"136\"\u003e\n\u003cp\u003eNone\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"103\"\u003e\n\u003cp\u003e45 (23.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"144\"\u003e\n\u003cp\u003e146 (20.6)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"170\"\u003e\n\u003cp\u003e0.98 (0.65-1.50)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"136\"\u003e\n\u003cp\u003e1-2 courses\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"103\"\u003e\n\u003cp\u003e73 (30.2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"144\"\u003e\n\u003cp\u003e216 (30.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"170\"\u003e\n\u003cp\u003e1.00 (Ref)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"136\"\u003e\n\u003cp\u003e\u0026ge;3 courses\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"103\"\u003e\n\u003cp\u003e124 (51.2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"144\"\u003e\n\u003cp\u003e346 (48.9)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"170\"\u003e\n\u003cp\u003e\u003cem\u003e1.63 (1.14-2.34)\u003c/em\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"136\"\u003e\n\u003cp\u003e\u003cstrong\u003eDM\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"103\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"144\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"170\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"136\"\u003e\n\u003cp\u003eNone\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"103\"\u003e\n\u003cp\u003e21 (20.6)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"144\"\u003e\n\u003cp\u003e\u0026nbsp;56 (20.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"170\"\u003e\n\u003cp\u003e1.25 (0.66-2.34)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"136\"\u003e\n\u003cp\u003e1-2 courses\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"103\"\u003e\n\u003cp\u003e27 (26.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"144\"\u003e\n\u003cp\u003e\u0026nbsp;96 (34.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"170\"\u003e\n\u003cp\u003e1.00 (Ref)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"136\"\u003e\n\u003cp\u003e\u0026ge;3 courses\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"103\"\u003e\n\u003cp\u003e54 (52.9)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"144\"\u003e\n\u003cp\u003e128 (45.7)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"170\"\u003e\n\u003cp\u003e\u003cem\u003e1.74 (1.01-3.00)\u003c/em\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"136\"\u003e\n\u003cp\u003e\u003cstrong\u003eAIT\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"103\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"144\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"170\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"136\"\u003e\n\u003cp\u003eNone\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"103\"\u003e\n\u003cp\u003e11 (16.2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"144\"\u003e\n\u003cp\u003e\u0026nbsp; 40 (21.1)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"170\"\u003e\n\u003cp\u003e0.60 (0.26-1.37)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"136\"\u003e\n\u003cp\u003e1-2 courses\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"103\"\u003e\n\u003cp\u003e25 (36.8)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"144\"\u003e\n\u003cp\u003e\u0026nbsp; 44 (23.2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"170\"\u003e\n\u003cp\u003e1.00 (Ref)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"136\"\u003e\n\u003cp\u003e\u0026ge;3 courses\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"103\"\u003e\n\u003cp\u003e32 (26.4)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"144\"\u003e\n\u003cp\u003e106 (55.8)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"170\"\u003e\n\u003cp\u003e0.81 (0.41-1.60)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"136\"\u003e\n\u003cp\u003e\u003cstrong\u003eJIA\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"103\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"144\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"170\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"136\"\u003e\n\u003cp\u003eNone\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"103\"\u003e\n\u003cp\u003e13 (24.1)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"144\"\u003e\n\u003cp\u003e35 (22.4)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"170\"\u003e\n\u003cp\u003e1.47 (0.61-3.47)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"136\"\u003e\n\u003cp\u003e1-2 courses\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"103\"\u003e\n\u003cp\u003e12 (22.2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"144\"\u003e\n\u003cp\u003e57 (36.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"170\"\u003e\n\u003cp\u003e1.00 (Ref)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"136\"\u003e\n\u003cp\u003e\u0026ge;3 courses\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"103\"\u003e\n\u003cp\u003e29 (53.7)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"144\"\u003e\n\u003cp\u003e64 (41.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"170\"\u003e\n\u003cp\u003e\u003cem\u003e4.80 (1.90-12.1)\u003c/em\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"136\"\u003e\n\u003cp\u003e\u003cstrong\u003eIBD\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"103\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"144\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"170\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"136\"\u003e\n\u003cp\u003eNone\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"103\"\u003e\n\u003cp\u003e\u0026nbsp;\u0026nbsp; 2\u0026nbsp; (7.4)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"144\"\u003e\n\u003cp\u003e10 (13.7)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"170\"\u003e\n\u003cp\u003e0.24 (0.03-1.96)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"136\"\u003e\n\u003cp\u003e1-2 courses\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"103\"\u003e\n\u003cp\u003e\u0026nbsp; 9 (33.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"144\"\u003e\n\u003cp\u003e17 (23.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"170\"\u003e\n\u003cp\u003e1.00 (Ref)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"136\"\u003e\n\u003cp\u003e\u0026ge;3 courses\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"103\"\u003e\n\u003cp\u003e16 (59.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"144\"\u003e\n\u003cp\u003e46 (63.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"170\"\u003e\n\u003cp\u003e1.67 (0.65-4.30)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd rowspan=\"24\" width=\"127\"\u003e\n\u003cp\u003e\u003cstrong\u003ePreschool to adolsescence\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e(From age of 3 years to index date)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"136\"\u003e\n\u003cp\u003e\u003cstrong\u003eAD\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"103\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"144\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"170\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"136\"\u003e\n\u003cp\u003eNone\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"103\"\u003e\n\u003cp\u003e\u0026nbsp; 33 (13.6)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"144\"\u003e\n\u003cp\u003e\u0026nbsp; 96 (13.6)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"170\"\u003e\n\u003cp\u003e1.23 (0.68-2.23)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"136\"\u003e\n\u003cp\u003e1-2 courses\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"103\"\u003e\n\u003cp\u003e\u0026nbsp; 38 (15.7)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"144\"\u003e\n\u003cp\u003e147 (20.8)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"170\"\u003e\n\u003cp\u003e1.00 (Ref)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"136\"\u003e\n\u003cp\u003e\u0026ge;3 courses\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"103\"\u003e\n\u003cp\u003e151 (62.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"144\"\u003e\n\u003cp\u003e\u0026nbsp; 40 (57.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"170\"\u003e\n\u003cp\u003e\u003cem\u003e1.56 (1.01-2.43)\u003c/em\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"136\"\u003e\n\u003cp\u003eIndex date \u0026lt;3 years\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"103\"\u003e\n\u003cp\u003e\u0026nbsp; 20\u0026nbsp;\u0026nbsp; (8.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"144\"\u003e\n\u003cp\u003e\u0026nbsp; 59\u0026nbsp;\u0026nbsp; (8.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"170\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"136\"\u003e\n\u003cp\u003e\u003cstrong\u003eDM\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"103\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"144\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"170\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"136\"\u003e\n\u003cp\u003eNone\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"103\"\u003e\n\u003cp\u003e20 (19.6)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"144\"\u003e\n\u003cp\u003e\u0026nbsp;54 (19.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"170\"\u003e\n\u003cp\u003e1.75 (0.69-4.39)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"136\"\u003e\n\u003cp\u003e1-2 courses\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"103\"\u003e\n\u003cp\u003e13 (12.7)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"144\"\u003e\n\u003cp\u003e\u0026nbsp;71 (25.4)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"170\"\u003e\n\u003cp\u003e1.00 (Ref)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"136\"\u003e\n\u003cp\u003e\u0026ge;3 courses\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"103\"\u003e\n\u003cp\u003e57 (55.9)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"144\"\u003e\n\u003cp\u003e126 (45.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"170\"\u003e\n\u003cp\u003e\u003cem\u003e2.63 (1.29-5.57)\u003c/em\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"136\"\u003e\n\u003cp\u003eIndex date \u0026lt;3 years\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"103\"\u003e\n\u003cp\u003e12 (11.8)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"144\"\u003e\n\u003cp\u003e\u0026nbsp; 29 (10.4)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"170\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"136\"\u003e\n\u003cp\u003e\u003cstrong\u003eAIT\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"103\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"144\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"170\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"136\"\u003e\n\u003cp\u003eNone\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"103\"\u003e\n\u003cp\u003e7 (10.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"144\"\u003e\n\u003cp\u003e13\u0026nbsp;\u0026nbsp; (6.8)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"170\"\u003e\n\u003cp\u003e1.81 (0.54-6.05)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"136\"\u003e\n\u003cp\u003e1-2 courses\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"103\"\u003e\n\u003cp\u003e10 (14.7))\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"144\"\u003e\n\u003cp\u003e29 (15.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"170\"\u003e\n\u003cp\u003e1.00 (Ref)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"136\"\u003e\n\u003cp\u003e\u0026ge;3 courses\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"103\"\u003e\n\u003cp\u003e51 (75.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"144\"\u003e\n\u003cp\u003e148 (77.9)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"170\"\u003e\n\u003cp\u003e1.15 (0.49-2.70)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"136\"\u003e\n\u003cp\u003eIndex date \u0026lt;3 years\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"103\"\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"144\"\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"170\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"136\"\u003e\n\u003cp\u003e\u003cstrong\u003eJIA\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"103\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"144\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"170\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"136\"\u003e\n\u003cp\u003eNone\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"103\"\u003e\n\u003cp\u003e6 (11.1)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"144\"\u003e\n\u003cp\u003e27 (17.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"170\"\u003e\n\u003cp\u003e0.53 (0.15-1.91)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"136\"\u003e\n\u003cp\u003e1-2 courses\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"103\"\u003e\n\u003cp\u003e9 (16.7)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"144\"\u003e\n\u003cp\u003e35 (22.4)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"170\"\u003e\n\u003cp\u003e1.00 (Ref)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"136\"\u003e\n\u003cp\u003e\u0026ge;3 courses\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"103\"\u003e\n\u003cp\u003e33 (61.1)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"144\"\u003e\n\u003cp\u003e72 (46.2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"170\"\u003e\n\u003cp\u003e2.09 (0.82-5.31)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"136\"\u003e\n\u003cp\u003eIndex date \u0026lt;3 years\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"103\"\u003e\n\u003cp\u003e6 (11.1)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"144\"\u003e\n\u003cp\u003e22 (14.1)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"170\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"136\"\u003e\n\u003cp\u003e\u003cstrong\u003eIBD\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"103\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"144\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"170\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"136\"\u003e\n\u003cp\u003eNone\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"103\"\u003e\n\u003cp\u003e1\u0026nbsp;\u0026nbsp; (3.7)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"144\"\u003e\n\u003cp\u003e\u0026nbsp;2\u0026nbsp;\u0026nbsp; (2.7)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"170\"\u003e\n\u003cp\u003e0.86 (0.06-13.2)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"136\"\u003e\n\u003cp\u003e1-2 courses\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"103\"\u003e\n\u003cp\u003e6 (16.2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"144\"\u003e\n\u003cp\u003e12 (16.4)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"170\"\u003e\n\u003cp\u003e1.00 (Ref)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"136\"\u003e\n\u003cp\u003e\u0026ge;3 courses\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"103\"\u003e\n\u003cp\u003e18 (66.7)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"144\"\u003e\n\u003cp\u003e52 (71.2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"170\"\u003e\n\u003cp\u003e0.69 (0.21-2.22)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"127\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"136\"\u003e\n\u003cp\u003eIndex date \u0026lt;3 years\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"103\"\u003e\n\u003cp\u003e2\u0026nbsp;\u0026nbsp; (7.4)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"144\"\u003e\n\u003cp\u003e\u0026nbsp; 7\u0026nbsp;\u0026nbsp; (9.6)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"170\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd rowspan=\"20\" width=\"127\"\u003e\n\u003cp\u003e\u003cstrong\u003ePurchases within 2 years before index date\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"136\"\u003e\n\u003cp\u003e\u003cstrong\u003eAutoimmune diseases\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"103\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"144\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"170\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"136\"\u003e\n\u003cp\u003eNone\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"103\"\u003e\n\u003cp\u003e120 (49.6)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"144\"\u003e\n\u003cp\u003e371 (52.4)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"170\"\u003e\n\u003cp\u003e1.02 (0.71-1.45)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"136\"\u003e\n\u003cp\u003e1-2 courses\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"103\"\u003e\n\u003cp\u003e70 (28.9)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"144\"\u003e\n\u003cp\u003e235 (33.2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"170\"\u003e\n\u003cp\u003e1.00 (Ref)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"136\"\u003e\n\u003cp\u003e\u0026ge;3 courses\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"103\"\u003e\n\u003cp\u003e52 (21.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"144\"\u003e\n\u003cp\u003e102 (14.4)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"170\"\u003e\n\u003cp\u003e\u003cem\u003e1.81 (1.14-2.86)\u003c/em\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"136\"\u003e\n\u003cp\u003e\u003cstrong\u003eDM\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"103\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"144\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"170\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"136\"\u003e\n\u003cp\u003eNone\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"103\"\u003e\n\u003cp\u003e54 (52.9)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"144\"\u003e\n\u003cp\u003e153 (54.6)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"170\"\u003e\n\u003cp\u003e1.07 (0.61-1.88)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"136\"\u003e\n\u003cp\u003e1-2 courses\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"103\"\u003e\n\u003cp\u003e27 (26.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"144\"\u003e\n\u003cp\u003e\u0026nbsp; 83 (29.6)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"170\"\u003e\n\u003cp\u003e1.00 (Ref)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"136\"\u003e\n\u003cp\u003e\u0026ge;3 courses\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"103\"\u003e\n\u003cp\u003e21 (20.6)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"144\"\u003e\n\u003cp\u003e\u0026nbsp; 44 (15.7)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"170\"\u003e\n\u003cp\u003e1.43 (0.66-3.11)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"136\"\u003e\n\u003cp\u003e\u003cstrong\u003eAIT\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"103\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"144\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"170\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"136\"\u003e\n\u003cp\u003eNone\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"103\"\u003e\n\u003cp\u003e39 (57.4)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"144\"\u003e\n\u003cp\u003e101 (53.2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"170\"\u003e\n\u003cp\u003e1.06 (0.39-2.84)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"136\"\u003e\n\u003cp\u003e1-2 courses\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"103\"\u003e\n\u003cp\u003e21 (30.9)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"144\"\u003e\n\u003cp\u003e\u0026nbsp; 64 (33.7)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"170\"\u003e\n\u003cp\u003e1.00 (Ref)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"136\"\u003e\n\u003cp\u003e\u0026ge;3 courses\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"103\"\u003e\n\u003cp\u003e\u0026nbsp; 8 (11.8)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"144\"\u003e\n\u003cp\u003e\u0026nbsp; 25 (13.2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"170\"\u003e\n\u003cp\u003e1.10 (0.58-2.09)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"136\"\u003e\n\u003cp\u003e\u003cstrong\u003eJIA\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"103\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"144\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"170\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"136\"\u003e\n\u003cp\u003eNone\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"103\"\u003e\n\u003cp\u003e24 (44.4)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"144\"\u003e\n\u003cp\u003e76 (48.7)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"170\"\u003e\n\u003cp\u003e1.14 (0.49-2.64)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"136\"\u003e\n\u003cp\u003e1-2 courses\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"103\"\u003e\n\u003cp\u003e14 (25.9)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"144\"\u003e\n\u003cp\u003e56 (35.9)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"170\"\u003e\n\u003cp\u003e1.00 (Ref)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"136\"\u003e\n\u003cp\u003e\u0026ge;3 courses\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"103\"\u003e\n\u003cp\u003e16 (29.6)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"144\"\u003e\n\u003cp\u003e24 (15.4)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"170\"\u003e\n\u003cp\u003e\u003cem\u003e2.67 (1.16-6.16)\u003c/em\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"136\"\u003e\n\u003cp\u003e\u003cstrong\u003eIBD\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"103\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"144\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"170\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"136\"\u003e\n\u003cp\u003eNone\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"103\"\u003e\n\u003cp\u003e10 (37.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"144\"\u003e\n\u003cp\u003e37 (50.7)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"170\"\u003e\n\u003cp\u003e0.69 (0.25-1.90)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"136\"\u003e\n\u003cp\u003e1-2 courses\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"103\"\u003e\n\u003cp\u003e\u0026nbsp; 9 (33.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"144\"\u003e\n\u003cp\u003e27 (37.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"170\"\u003e\n\u003cp\u003e1.00 (Ref)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"136\"\u003e\n\u003cp\u003e\u0026ge;3 courses\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"103\"\u003e\n\u003cp\u003e\u0026nbsp; 8 (29.6)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"144\"\u003e\n\u003cp\u003e\u0026nbsp; 9 (12.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"170\"\u003e\n\u003cp\u003e2.87 (0.72-11.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"7\" width=\"170\"\u003e\n\u003cp\u003e\u003csup\u003ea \u003c/sup\u003eAD=autoimmune diseases. Cases=children with ADs, N=242 (represented with DM (type 1 diabetes mellitus), N=102; AIT (autoimmune thyroiditis), N=68; JIA (juvenile idiopathic arthritis), N=54; and IBD (inflammatory bowel diseases), N=27). Nine children had two diagnoses.\u003c/p\u003e\n\u003cp\u003e\u003csup\u003eb \u003c/sup\u003eEach child in the case group were matched with one to four children with similar age, sex, residential area, gestational age (preterm/term), and delivery mode (cesarean section/vaginal). Due to limited potential controls, most children born preterm/with cesarean section have only one control instead of four.\u003c/p\u003e\n\u003cp\u003e\u003csup\u003ec \u003c/sup\u003eOdds ratio and CI (95% Confidence Interval) was obtained using conditional logistic regression.\u003c/p\u003e\n\u003cp\u003e\u003csup\u003ed \u003c/sup\u003eThroughout childhood, only 14 children in the case group and 34 in the control group had no records of antibiotic purchases.\u003c/p\u003e\n\u003cp\u003eIndex date= date of diagnosis for children who developed autoimmune diseases and compatible date for their matching controls.\u003c/p\u003e\n\u003cp\u003e\u003csup\u003ee \u003c/sup\u003eWhen the age of diagnosis were between the age of 1 and 3 years.\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTotal number of antibiotic purchases throughout childhood (from birth to the date of diagnosis/index date) was not associated with the development of the studied ADs as one group, nor with DM, AIT, and IBD individually. Of all purchased antibiotics, 44.3% (n=3,825) were bought before the age of 3 years. Concerning antibiotic purchases in each age, the only significant difference between cases and matched controls was seen during the second year of life: children who later developed ADs purchased more antibiotics than those who did not develop ADs (OR 1.11, 95%CI 1.03-1.20) (Figure \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e). As for antibiotic types, penicillins were not associated with the development of any ADs, while purchases of macrolides within two years before the index date were associated with the onset of ADs in general. Moreover, purchases of broader-spectrum antibiotics (macrolides, cephalosporins, or amoxicillin-clavulanic acid) throughout childhood (but particularly during infancy and toddler phase) increased the likelihood of developing JIA.\u003c/p\u003e\n\u003ch2\u003eNumber of antibiotic purchases\u003c/h2\u003e\n\u003cp\u003eThe relationship between the total number of antibiotic purchases before the index date and the proportion of ADs was non-linear and required categorized analyses (Figure \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e). The highest odds for developing ADs in general (not associated with any specific diagnosis) were observed in children with frequent antibiotic purchases (\u0026ge; 3 courses) when compared with those without antibiotic purchases (OR 1.72, 95%CI 1.08-2.74) within the two years before the index date (Supplementary Table 3).\u003c/p\u003e\n\u003cp\u003eRegarding particular diagnosis, children receiving 4-8 courses and \u0026gt;8 courses had an increased likelihood of developing JIA (OR 2.91, 95% CI 1.05-8.05 and OR 6.60, 95% CI 2.12-20.5 \u0026ndash; respectively) compared with those receiving \u0026lt;4 antibiotic courses throughout childhood. The likelihood of developing JIA was also increased after frequent antibiotic purchases during toddler phase (OR 4.80, 95% CI 1.90-12.1) and within 2 years before the index date (OR 2.67 95% CI 1.16-6.16) when compared with infrequent antibiotic purchases (1-2 courses) in both of these periods. Furthermore, JIA was more common in children with frequent antibiotic purchases (OR 3.94, 95% CI 1.16-13.4) than in those without antibiotic purchases during preschool to adolescence (Supplementary Table 3). As for other ADs, frequent antibiotic purchases (\u0026ge; 3 courses) in toddler phase (OR 1.74, 95% CI 1.01-3.00) and from preschool to adolescence (OR 2.63, 95% CI 1.29-5.57) increased the odds of developing DM when compared with infrequent antibiotic purchases during these periods.\u003c/p\u003e\n\u003ch2\u003eTypes of antibiotic purchases\u003c/h2\u003e\n\u003cp\u003eWhen purchases of the five most common antibiotic types in the study population (penicillins, macrolides, cephalosporins, amoxicillin-clavulanic acid, and sulphonamides and trimethoprim) throughout childhood were analyzed individually, none of them was associated with the onset of the four ADs as one group (Supplementary Table 4). The likelihood of JIA was increasing with the number broader-spectrum antibiotics (cephalosporins, macrolides, and amoxicillin-clavulanic acid) purchases, particularly in infancy (OR 2.54, 95%CI 1.01-6.38; OR 1.80, 95%CI 1.08-3.01; and OR 1.03, 95%CI 1.12-3.32 \u0026ndash; respectively) and in toddler phase (OR 1.69, 95%CI 1.15-2.48; OR 1.40, 95% CI 1.09-1.79; and OR 1.43, 95%CI 1.03-2.00 \u0026ndash; respectively). However, this finding was inconspicuous regarding DM, AIT, and IBD \u0026ndash; as their odds were low after purchases of broader-spectrum antibiotics in infancy. Furthermore, purchases of sulphonamides and trimethoprim from preschool to adolescence was associated with DM (OR 1.35, 95%CI 1.03-1.77). Finally, purchases of macrolides within two years before the index date was associated with the development of ADs in general (OR 1.24, 95%CI 1.01-1.51) (Figure \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e, Supplementary Table 4), while purchases of penicillin were scarcely ever associated with any types of ADs in this study.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eOur study is the first to investigate the association between number and types of antibiotic exposures in different stages of childhood and the onset of four common pediatric ADs (DM, AIT, JIA, or IBD) in a mutual setting. We showed that the relationship between the number of antibiotic exposures and the onset of ADs seems to be non-linear. In addition, the likelihood of developing ADs after antibiotic exposures in infancy remained low, especially regarding DM, AIT, and IBD. Despite of being the most common antibiotic used in childhood, penicillins (predominantly amoxicillin) would be relatively safe to use at any age in relation with the development of ADs, while exposures to macrolides within the two years prior to diagnosis may present minor association. Regarding specific diagnosis, the number of antibiotic exposures throughout childhood was mainly associated with JIA. Even then, exposures to penicillin group antibiotics did not increase the likelihood of JIA, while exposures to cephalosporin, macrolide, and amoxicillin-clavulanic (especially before the age of three) might moderately do so.\u003c/p\u003e \u003cp\u003eIn our study, antibiotic exposures in infancy did not increase the likelihood of developing any ADs. Furthermore, we showed that frequent antibiotic exposures after first year of life may be related with ADs when compared with occasional exposures, but not when compared with those having no records of antibiotic purchases in each observation period. However, this finding seems to be predominantly related to JIA and DM, but not with AIT and IBD. How do these findings align with previous studies? A Swedish register-based study presented a connection between prescribed antibiotics during infancy and the onset of DM [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e], while studies from which countries have not reported significant association between early childhood antibiotic exposures and DM [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. Studies from United Kingdom and Finland have associated both lifetime and early life antibiotic exposures and the onset of JIA [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. As for IBD, early antibiotic exposures have been related with Crohn\u0026rsquo;s disease but not with ulcerative colitis [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. Most of these studies assumed a linear association between antibiotic exposures and the onset of a particular AD, thus assuming that the lowest risk for ADs is retained by those without previous antibiotic exposures. Our study challenges this presumption. Since infancy is the most susceptible period for common infectious diseases and is the period of most frequent antibiotic use [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e], it is reassuring that antibiotics used in early childhood hardly increased the likelihood of developing pediatric ADs. Beyond first year of life, occasional antibiotic courses (approximately 1-2 courses per year) can generally be seen as a low-risk approach in relation to the development of ADs.\u003c/p\u003e \u003cp\u003eWe showed that exposures to macrolides within the two years before obtaining diagnosis may be related with the overall development of ADs. In addition, exposures to antibiotics with broader spectrum (cephalosporine, macrolide, and amoxicillin-clavulanic acid), particularly before the age of three years, were moderately associated with JIA. On the contrary, penicillins (as the most common antibiotic type used to treat infections throughout childhood) were not related to the development of any ADs at any age. Hence, the relationship between antibiotics and ADs could not solely be explained by number of infections, as often speculated.\u003c/p\u003e \u003cp\u003eSeveral studies have reported an association between gut dysbiosis and autoimmune diseases [\u003cspan additionalcitationids=\"CR28 CR29\" citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. Since antibiotics have been shown to have an influence on gut microbial homeostasis [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e], antibiotic exposures could as well be related to ADs through facilitating gut dysbiosis. Variations in magnitude and specificity of gut microbiota modification by different antibiotics have been reported, hence requiring variable recovery time after exposures [\u003cspan additionalcitationids=\"CR33\" citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. For example, macrolides have both a broad spectrum and long-term influence on gut microbiota that may persist even for several years [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]. In our study, azithromycin was the most often used antibiotic among macrolides. Azithromycin has a broad bacteriostatic spectrum, a marked tissue penetration, a high stability and a low clearance rate due to its long half-life, which enable it to reach a higher cellular concentration compared to penicillin [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]. These characteristics may explain the long-term influences of azithromycin (as a macrolide) on gut microbiota compared with penicillin. Furthermore, previous Fin-HIT study showed that azithromycin presented the strongest inverse association with salivary microbiota diversity [\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e]. Since dysbiosis of gut and salivary microbiota have also been associated with ADs [\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e], we suggest that macrolides might catalyze longer-term dysbiosis, explaining their association with the development of ADs, particularly up to two years prior to diagnosis, while penicillin was not associated with any type of ADs at any ages. Further studies to examine the potential link between the use of broad-spectrum antibiotics, the time of their influence on gut microbiota, gut dysbiosis, and the onset of ADs is warranted.\u003c/p\u003e \u003cp\u003eThe strength of our study lies in the comprehensive longitudinal data from national registers. For example, we were able to trace purchased antibiotics as outpatients rather than just prescribed. In addition, we studied several ADs in a mutual setting, using rather homogenous Fin-HIT cohort with small variations in socioeconomic status as the source of study population[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. The control population was matched with details based on age (with only up to 4 days of age difference), sex, residential area, gestational age, and delivery method to limit the number of potential confounding factors. Therefore, our study setting made it possible to examine the association between childhood antibiotic exposures and onsets of the four pediatric ADs together, and to reliably compare one disease to another in this subject.\u003c/p\u003e \u003cp\u003eAs for limitations, we lack the information on the children\u0026rsquo;s genetic susceptibility to infections or to ADs. We also did not know why the antibiotics were purchased \u0026ndash; for treating infections (and if so, for what kind of infection) or for prophylactic purposes \u0026ndash; and on whether secondary antibiotic courses for the same infection were needed. In addition, we had no access on the length of purchased antibiotic courses nor on the antibiotics given during inpatient care. Yet, antibiotic treatments during hospitalization are often continued orally after discharge, and our data cover these post-discharge antibiotic purchases.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eUse of antibiotics in the first year of life and occasional use throughout childhood can be considered relatively safe in relation with the development of pediatric autoimmunity. Antibiotics in the penicillin group are unlikely to be associated with the development of any ADs. In contrast, broad-spectrum antibiotics (including macrolides) should be used considerately as they may associate with an increased likelihood of ADs, especially JIA.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003e\u003cstrong\u003eAD \u003c/strong\u003eAutoimmune disease\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAIT\u003c/strong\u003e Autoimmune Thyroiditis\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eATC \u003c/strong\u003eAnatomical Therapeutic Chemical\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDM \u003c/strong\u003e Type 1 Diabetes\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDPR\u003c/strong\u003e Drug Purchase Register\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFin-HIT \u003c/strong\u003e Finnish Health in Teens\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eIBD\u003c/strong\u003e Inflammatory Bowel Diseases\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eJIA \u003c/strong\u003eJuvenile Idiopathic Arthritis\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMBR \u003c/strong\u003eMaternal Birth Register\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSRR\u003c/strong\u003e Special Reimbursement Register\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe project has received financial support from the Swedish Cultural Foundation in Finland, Folkh\u0026auml;lsan Research Foundation, to accommodate the work of HV and EE. LR is under the employment of Tampere University, faculty of medicine and received research grant from Tampere University Hospital, department of pediatrics. KLK received Helsinki University Grant. There were no other specific grants from any public, commercial, or non-profit sectors relevant to this article to disclose. The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors have no conflicts of interest to declare, nor have any affiliations with financial or non-financial interest in subjects relevant to the content of this manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe Fin-HIT study protocol was approved by the Ethics Committee of the Hospital District of Helsinki and Uusimaa (decision number 169/13/03/00/10).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe children and a guardian provided a written informed consent for the register linkage.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors approved the final manuscript as submitted, and agreed to be accountable for all aspects of the work.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and material\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eData available upon request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCode availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eN/A\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eContributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eLR, EE, HV, KLK conceptualized the study. HV participated in data collection. LR carried out the analyses and interpreted the results with the help of RS and SK, and wrote the initial manuscript, and made the figures and tables. LR and SK searched the literatures. HV and KLK supervised the study. All authors critically reviewed and revised the manuscript for important intellectual content.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe thank prof Per Ashorn and Valma Harjutsalo for valuable comments, Binu Matthews for helping with data management.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eLees CW, Barrett JC, Parkes M, et al. New IBD genetics: common pathways with other diseases\u003cem\u003e. Gut.\u0026nbsp;\u003c/em\u003e2011;60: 1739-1753.\u003c/li\u003e\n \u003cli\u003eRichard-Miceli C, Criswell LA. Emerging patterns of genetic overlap across autoimmune disorders\u003cem\u003e. 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Antibiotic Exposure and IBD Development Among Children: A Population-Based Cohort Study\u003cem\u003e.\u0026nbsp;\u003c/em\u003e\u003cem\u003ePediatrics\u003c/em\u003e 130: e794-e803.\u003c/li\u003e\n \u003cli\u003eVirta L, Auvinen A, Helenius H, et al. Association of Repeated Exposure to Antibiotics With the Development of Pediatric Crohn\u0026apos;s Disease--A Nationwide, Register-based Finnish Case-Control Study\u003cem\u003e. Am. J. Epidemiol.\u003c/em\u003e 2012;175: 775-784.\u003c/li\u003e\n \u003cli\u003eWernroth M, Fall K, Svennblad B, et al. Early Childhood Antibiotic Treatment for Otitis Media and Other Respiratory Tract Infections Is Associated With Risk of Type 1 Diabetes: A Nationwide Register- Based Study With Sibling Analysis\u003cem\u003e. Diabetes Care.\u003c/em\u003e 2020;43(5):991-999.\u003c/li\u003e\n \u003cli\u003eKemppainen KM, Vehik K, Lynch KF, et al. Association Between Early-Life Antibiotic Use and the Risk of Islet or Celiac Disease Autoimmunity\u003cem\u003e. JAMA Pediatrics.\u003c/em\u003e2017;171: 1217-1225.\u003c/li\u003e\n \u003cli\u003ePollock AJ, MD, Seibert, Tasa, MD, MPH, Allen DB, MD. Severe and Persistent Thyroid Dysfunction Associated with Tetracycline-Antibiotic Treatment in Youth\u003cem\u003e. J. Pediatr.\u003c/em\u003e 2016;173: 232-234.\u003c/li\u003e\n \u003cli\u003eFigueiredo, Rejane Augusta de Oliveira, Simola-Str\u0026ouml;m S, Rounge TB, et al. Cohort Profile: The Finnish Health in Teens (Fin-HIT) study: a population-based study\u003cem\u003e. Int. J. Epidemiol.\u0026nbsp;\u003c/em\u003e2019;48: 23-24h.\u003c/li\u003e\n \u003cli\u003eNiemel\u0026auml; H. Social Security in Finland: Helsinki, Finland: Social Insurance Institution (KELA), Finnish Centre for Pensions (ETK), Finnish Pension Alliance (TELA), and Finnish Ministry of Social Affairs and Health. 2006.\u003c/li\u003e\n \u003cli\u003eFuru K, Wettermark B, Andersen M, et al. The Nordic Countries as a Cohort for Pharmacoepidemiological Research\u003cem\u003e. Basic ClinPharmacol Toxicol.\u003c/em\u003e 2010;106: 86-94.\u003c/li\u003e\n \u003cli\u003eMikkelsen KH, Knop FK, Vilsb\u0026oslash;ll T, et al. Use of antibiotics in childhood and risk of Type 1 diabetes: a population-based case-control study\u003cem\u003e. Diabet Med.\u003c/em\u003e 2017;34: 272.\u003c/li\u003e\n \u003cli\u003eShaw SY, Blanchard JF, Bernstein CN. Association Between the Use of Antibiotics in the First Year of Life and Pediatric Inflammatory Bowel Disease\u003cem\u003e. Am. J. Gastroenterol.\u0026nbsp;\u003c/em\u003e2010;105: 2687-2692.\u003c/li\u003e\n \u003cli\u003eSimon AK, Hollander GA, McMichael A. Evolution of the immune system in humans from infancy to old age\u003cem\u003e.\u0026nbsp;\u003c/em\u003e\u003cem\u003eProc Biol Sci.\u003c/em\u003e2015;282: 20143085.\u003c/li\u003e\n \u003cli\u003eHan H, Li Y, Fang J, et al. Gut Microbiota and Type 1 Diabetes\u003cem\u003e. Int. J. Mol. Sci.\u003c/em\u003e2018\u003cem\u003e;\u003c/em\u003e19: 995.\u003c/li\u003e\n \u003cli\u003eVirili C, Fallahi P, Antonelli A, et al.) Gut microbiota and Hashimoto\u0026apos;s thyroiditis\u003cem\u003e.\u0026nbsp;\u003c/em\u003e\u003cem\u003eRev Endocr Metab Dis\u003c/em\u003e.2018.19: 293-300.\u003c/li\u003e\n \u003cli\u003eArvonen M, Berntson L, Pokka T, et al. Gut microbiota-host interactions and juvenile idiopathic arthritis\u003cem\u003e. Pediatr. Rheumatol. Online J.\u003c/em\u003e2016;14: 44.\u003c/li\u003e\n \u003cli\u003eComito D, Romano C. Dysbiosis in the Pathogenesis of Pediatric Inflammatory Bowel Diseases\u003cem\u003e. Int. J Inflamm.\u003c/em\u003e 2012: 687143-7.\u003c/li\u003e\n \u003cli\u003eNeuman H, Forsythe P, Uzan A, et al. Antibiotics in early life: dysbiosis and the damage done\u003cem\u003e. FEMS Microbiology Rev.2018;\u003c/em\u003e 42: 489-499.\u003c/li\u003e\n \u003cli\u003eGerber JS, Hersh AL, Kronman MP, et al. Development and Application of an Antibiotic Spectrum Index for Benchmarking Antibiotic Selection Patterns Across Hospitals\u003cem\u003e. Infect Control Hosp Epidemiol.\u0026nbsp;\u003c/em\u003e2017;38: 993-997.\u003c/li\u003e\n \u003cli\u003eIizumi T, Battaglia T, Ruiz V, et al. Gut Microbiome and Antibiotics\u003cem\u003e. Arch Med Res.\u003c/em\u003e2017;48: 727-734.\u003c/li\u003e\n \u003cli\u003eRinninella E, Raoul P, Cintoni M, et al. What is the Healthy Gut Microbiota Composition? A Changing Ecosystem across Age, Environment, Diet, and Diseases\u003cem\u003e. Microorganisms.\u003c/em\u003e 2019;7:14.\u003c/li\u003e\n \u003cli\u003eElvers KT, Wilson VJ, Hammond A, et al. Antibiotic-induced changes in the human gut microbiota for the most commonly prescribed antibiotics in primary care in the UK: a systematic review\u003cem\u003e.\u0026nbsp;\u003c/em\u003e\u003cem\u003eBMJ Open\u003c/em\u003e 10.\u003c/li\u003e\n \u003cli\u003eKorpela K, Salonen A, Virta LJ, et al. Intestinal microbiome is related to lifetime antibiotic use in Finnish pre-school children\u003cem\u003e. Nature communications.\u003c/em\u003e 2016;7: 10410.\u003c/li\u003e\n \u003cli\u003eVan Bambeke F, Tulkens PM. (2001) Macrolides: pharmacokinetics and pharmacodynamics\u003cem\u003e. Int J Antimicrob Agents.\u003c/em\u003e 2001;18: 17-23.\u003c/li\u003e\n \u003cli\u003eRaju SC, Viljakainen H, Figueiredo RAO, et al. Antimicrobial drug use in the first decade of life influences saliva microbiota diversity and composition\u003cem\u003e. Microbiome.\u003c/em\u003e 2020;8: 1-121.\u003c/li\u003e\n \u003cli\u003eXun Z, Zhang Q, Xu T, et al. Dysbiosis and ecotypes of the salivary microbiome associated with inflammatory bowel diseases and the assistance in diagnosis of diseases using oral bacterial profiles\u003cem\u003e. Front Microbiol.\u003c/em\u003e 2018; 9:1136.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"antibiotics, autoimmune thyroiditis, inflammatory bowel diseases, juvenile idiopathic arthritis, macrolide, type 1 diabetes","lastPublishedDoi":"10.21203/rs.3.rs-1110501/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-1110501/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eIncidences of pediatric autoimmune diseases (ADs) have been increasing without clearly identified environmental risk factors. Using national registers (special reimbursement and drug purchase register), this matched case-control study aims to discover whether antibiotic exposures are related to development of ADs in general. From a cohort of 11,407 children (born 2000-2005, followed-up until December 2018), 242 children with ADs (type 1 diabetes (DM), autoimmune thyroiditis (AIT), juvenile idiopathic arthritis (JIA), and inflammatory bowel diseases (IBD)) generated the case group. Each case was matched with one to four child(ren) with similar age, sex, residential area, gestational age, and delivery mode, generating 708 matched controls. Number of antibiotic purchases throughout childhood was unrelated to the development of the studied ADs as one group, nor with DM, AIT, or IBD individually. While antibiotic exposures in infancy did not increase the likelihood of ADs, exposures to macrolides within two years before diagnosis showed minor association (OR 1.24, 95% CI 1.01-1.51). Exposures to cephalosporins, macrolides, and amoxicillin-clavulanic acid throughout childhood may increase the likelihood of JIA (OR 1.25, 95% CI 1.03-1.52; OR 1.21, 95% CI 1.06-1.38; OR 1.19, 95% CI 1.02-1.39, respectively). Regardless of frequent use in childhood (40% of all antibiotics), penicillins were not associated with the onset of any ADs.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003e\u003cem\u003eConclusion:\u003c/em\u003e\u003c/strong\u003e Occasional use of antibiotics are relatively safe regarding overall development of ADs. Penicillins are unlikely to be associated with any ADs, while broad-spectrum antibiotics (including macrolides) should be used considerately as they may associate with an increased likelihood of ADs, especially JIA.\u003c/p\u003e","manuscriptTitle":"Antibiotic Exposures and the Likelihood of Developing Pediatric Autoimmune Diseases: a Register-based Matched Case-control Study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2021-12-21 23:54:56","doi":"10.21203/rs.3.rs-1110501/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"d9a056ba-c55a-4a75-948c-38fd740c7e9e","owner":[],"postedDate":"December 21st, 2021","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":9288398,"name":"Pediatrics"}],"tags":[],"updatedAt":"2022-01-30T18:17:55+00:00","versionOfRecord":[],"versionCreatedAt":"2021-12-21 23:54:56","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-1110501","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-1110501","identity":"rs-1110501","version":["v1"]},"buildId":"7rjqhiLT3MXkJMwkYKINL","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}