Antibiotic exposure and adverse long-term health outcomes in children: a systematic review and meta-analysis

  • Quynh Anh Duong
    Affiliations
    Faculty of Science and Medicine, University of Fribourg, Fribourg, Switzerland
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  • Laure F Pittet
    Affiliations
    Department of Paediatrics, The University of Melbourne, Parkville, Australia

    Infectious Diseases Research Group, Murdoch Children's Research Institute, Parkville, Australia

    Infectious Diseases Unit, The Royal Children's Hospital Melbourne, Parkville, Australia

    Unit of Pediatric Infectious Diseases, Department of Pediatrics, Gynecology & Obstetrics, University Hospitals of Geneva and Faculty of Medicine, Geneva, Switzerland
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  • Nigel Curtis
    Affiliations
    Department of Paediatrics, The University of Melbourne, Parkville, Australia

    Infectious Diseases Research Group, Murdoch Children's Research Institute, Parkville, Australia

    Infectious Diseases Unit, The Royal Children's Hospital Melbourne, Parkville, Australia
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  • Petra Zimmermann
    Correspondence
    Address correspondence to: Dr Petra Zimmermann, Faculty of Science and Medicine, University of Fribourg, Fribourg, Route des Arsenaux 41, 1700 Fribourg, Switzerland. Tel: +41 26306 0000.
    Affiliations
    Faculty of Science and Medicine, University of Fribourg, Fribourg, Switzerland

    Infectious Diseases Research Group, Murdoch Children's Research Institute, Parkville, Australia

    Department of Paediatrics, Fribourg Hospital HFR, Fribourg, Switzerland
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Open AccessPublished:January 09, 2022DOI:https://doi.org/10.1016/j.jinf.2022.01.005

      Abstract

      Background

      Antibiotics are among the most commonly used drugs in children. In addition to inducing antibiotic resistance, antibiotic exposure has been associated with long-term adverse health outcomes.

      Methods

      A systematic search using PRISMA Guidelines to identify original studies reporting associations between antibiotic exposure and long-term adverse health outcomes in children. Overall pooled estimates of the odds ratios (ORs) were obtained using fixed or random-effects models.

      Results

      We identified 160 observational studies investigating 21 outcomes in 22,103,129 children. Antibiotic exposure was associated with an increased risk of atopic dermatitis (OR 1.40, 95% confidence interval (CI) 1.30-1.52, p<0.01), allergic symptoms (OR 1.93, 95%CI 1.66-2.26, p<0.01), food allergies (OR 1.35, 95%CI 1.20-1.52, p<0.01), allergic rhinoconjunctivitis (OR 1.66, 95%CI 1.51-1.83, p<0.01), wheezing (OR 1.81, 95%CI 1.65-1.97, p<0.01), asthma (OR 1.96, 95%CI 1.76-2.17, p<0.01), increased weight gain or overweight (OR 1.18, 95%CI 1.11-1.26, p<0.01), obesity (OR 1.21, 95%CI 1.05-1.40, p<0.01), juvenile idiopathic arthritis (OR 1.74, 95%CI 1.21-2.52, p<0.01), psoriasis (OR 1.75, 95%CI 1.44-2.11, p<0.01), autism spectrum disorders (OR 1.19, 95%CI 1.04-1.36, p=0.01) and neurodevelopment disorders (OR 1.29, 95%CI 1.09-1.53, p<0.01). Dose-response effects and stronger effects with broad-spectrum antibiotic were often reported. Antibiotic exposure was not associated with an altered risk of allergic sensitisation, infantile colic, abdominal pain, inflammatory bowel disease, celiac disease, type 1 diabetes, fluorosis, and attention deficit hyperactivity disorder.

      Conclusion

      Although a causal association cannot be determined from these studies, the results support the meticulous application of sound antibiotic stewardship to avoid potential adverse long-term health outcomes.

      Keywords

      Introduction

      Antibiotics belong to the greatest discoveries in medicine and among the most life-saving medical interventions. Their efficacy and presumed safety have led to their widespread use, which sometimes is irrational or even inappropriate.
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      Systematic review methods

      To identify original studies investigating the association between antibiotic exposure and adverse long-term health outcomes in children and adolescents (less than 18 years of age) MEDLINE (1946 to present) was searched in April 2021 using the Ovid interface with the search terms detailed in the supplementary data. Exclusion criteria were studies in which: (i) the effect of prenatal antibiotics was investigated; (ii) the timing of antibiotic exposure was not specified; (iii) antibiotic exposure occurred after the onset of the adverse health outcome and (iv) included preterm infants without adjusting values for prematurity. References of retrieved articles were hand-searched for additional publications. The following variables were extracted from the included studies: author, country, publication year, study design, cohort size, time of antibiotic exposure, specification of antibiotic treatment, age at outcome measure, number of cases, outcome definition and key findings. Review Manager (version 5.3) was used for the calculation of the odds ratios and the meta-analyses. If studies evaluated several time points, only the latest was included in the meta-analysis. Diversity in study design and reporting, which might result in selection and reporting bias, precluded quality evaluation according to the PRISMA guidelines. The ROBINS-1 tool was used to assess risk of bias.
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      Systematic review results

      Our search identified 23,225 studies. Of these, 150 fulfilled the inclusion criteria.
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      • Rutter CE
      • Silverwood RJ
      • Williams HC
      • et al.
      Are Environmental Factors for Atopic Eczema in ISAAC Phase Three due to Reverse Causation?.
      • Saari A
      • Virta LJ
      • Sankilampi U
      • Dunkel L
      • Saxen H.
      Antibiotic exposure in infancy and risk of being overweight in the first 24 months of life.
      • Sandini U
      • Kukkonen AK
      • Poussa T
      • Sandini L
      • Savilahti E
      • Kuitunen M.
      Protective and risk factors for allergic diseases in high-risk children at the ages of two and five years.
      • Schmitt J
      • Schmitt NM
      • Kirch W
      • Meurer M.
      Early exposure to antibiotics and infections and the incidence of atopic eczema: a population-based cohort study.
      • Schwartz BS
      • Pollak J
      • Bailey-Davis L
      • et al.
      Antibiotic use and childhood body mass index trajectory.
      • Scott FI
      • Horton DB
      • Mamtani R
      • et al.
      Administration of Antibiotics to Children Before Age 2 Years Increases Risk for Childhood Obesity.
      • Semic-Jusufagic A
      • Belgrave D
      • Pickles A
      • et al.
      Assessing the association of early life antibiotic prescription with asthma exacerbations, impaired antiviral immunity, and genetic variants in 17q21: a population-based birth cohort study.
      • Shaw SY
      • Blanchard JF
      • Bernstein CN.
      Association between the use of antibiotics in the first year of life and pediatric inflammatory bowel disease.
      • Simon MR
      • Havstad SL
      • Wegienka GR
      • Ownby DR
      • Johnson CC.
      Risk factors associated with transient wheezing in young children.
      • Singh S
      • Sharma BB
      • Salvi S
      • et al.
      Allergic rhinitis, rhinoconjunctivitis, and eczema: prevalence and associated factors in children.
      • Slykerman RF
      • Coomarasamy C
      • Wickens K
      • et al.
      Exposure to antibiotics in the first 24 months of life and neurocognitive outcomes at 11 years of age.
      • Smith-Brown P
      • Morrison M
      • Krause L
      • Davies PSW.
      Microbiota and Body Composition During the Period of Complementary Feeding.
      • Soto-Martinez ME
      • Yock-Corrales A
      • Camacho-Badilla K
      • et al.
      The current prevalence of asthma, allergic rhinitis, and eczema related symptoms in school-aged children in Costa Rica.
      • Stark CM
      • Susi A
      • Emerick J
      • Nylund CM.
      Antibiotic and acid-suppression medications during early childhood are associated with obesity.
      • Stromberg Celind F
      • Wennergren G
      • Vasileiadou S
      • Alm B
      • Goksor E.
      Antibiotics in the first week of life were associated with atopic asthma at 12 years of age.
      • Su Y
      • Rothers J
      • Stern DA
      • Halonen M
      • Wright AL.
      Relation of early antibiotic use to childhood asthma: confounding by indication?.
      • Sultesz M
      • Katona G
      • Hirschberg A
      • Galffy G.
      Prevalence and risk factors for allergic rhinitis in primary schoolchildren in Budapest.
      • Sun W
      • Svendsen ER
      • Karmaus WJ
      • Kuehr J
      • Forster J.
      Early-life antibiotic use is associated with wheezing among children with high atopic risk: a prospective European study.
      • Tamay Z
      • Akcay A
      • Ergin A
      • Guler N.
      Prevalence of allergic rhinitis and risk factors in 6- to 7-yearold children in Istanbul.
      • Tamay Z
      • Akcay A
      • Ones U
      • Guler N
      • Kilic G
      • Zencir M.
      Prevalence and risk factors for allergic rhinitis in primary school children.
      • Tapia G
      • Stordal K
      • Marild K
      • et al.
      Antibiotics, acetaminophen and infections during prenatal and early life in relation to type 1 diabetes.
      • Taylor-Robinson DC
      • Williams H
      • Pearce A
      • Law C
      • Hope S.
      Do early-life exposures explain why more advantaged children get eczema? Findings from the U.K. Millennium Cohort Study.
      • Thomsen SF
      • Ulrik CS
      • Porsbjerg C
      • Backer V.
      Early life exposures and risk of atopy among Danish children.
      • Trasande L
      • Blustein J
      • Liu M
      • Corwin E
      • Cox LM
      • Blaser MJ.
      Infant antibiotic exposures and early-life body mass.
      • Uusijarvi A
      • Bergstrom A
      • Simren M
      • et al.
      Use of antibiotics in infancy and childhood and risk of recurrent abdominal pain–a Swedish birth cohort study.
      • Uzan-Yulzari A
      • Turta O
      • Belogolovski A
      • et al.
      Neonatal antibiotic exposure impairs child growth during the first six years of life by perturbing intestinal microbial colonization.
      • Verhulst SL
      • Vael C
      • Beunckens C
      • Nelen V
      • Goossens H
      • Desager K.
      A longitudinal analysis on the association between antibiotic use, intestinal microflora, and wheezing during the first year of life.
      • Ville AP
      • Heyman MB
      • Medrano R
      • Wojcicki JM.
      Early Antibiotic Exposure and Risk of Childhood Obesity in Latinos.
      • Virta L
      • Auvinen A
      • Helenius H
      • Huovinen P
      • Kolho KL.
      Association of repeated exposure to antibiotics with the development of pediatric Crohn's disease–a nationwide, register-based finnish case-control study.
      • von Mutius E
      • Illi S
      • Hirsch T
      • Leupold W
      • Keil U
      • Weiland SK.
      Frequency of infections and risk of asthma, atopy and airway hyperresponsiveness in children.
      • Wang JY
      • Liu LF
      • Chen CY
      • Huang YW
      • Hsiung CA
      • Tsai HJ.
      Acetaminophen and/or antibiotic use in early life and the development of childhood allergic diseases.
      • Wang X
      • Liu W
      • Hu Y
      • Zou Z
      • Shen L
      • Huang C.
      Home environment, lifestyles behaviors, and rhinitis in childhood.
      • Wernroth ML
      • 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.
      • Wickens K
      • Ingham T
      • Epton M
      • et al.
      The association of early life exposure to antibiotics and the development of asthma, eczema and atopy in a birth cohort: confounding or causality?.
      • Wickens K
      • Pearce N
      • Crane J
      • Beasley R.
      Antibiotic use in early childhood and the development of asthma.
      • Wjst M
      • Hoelscher B
      • Frye C
      • Wichmann HE
      • Dold S
      • Heinrich J.
      Early antibiotic treatment and later asthma.
      • Wu P
      • Feldman AS
      • Rosas-Salazar C
      • et al.
      Relative Importance and Additive Effects of Maternal and Infant Risk Factors on Childhood Asthma.
      • Yamamoto-Hanada K
      • Yang L
      • Narita M
      • Saito H
      • Ohya Y
      Influence of antibiotic use in early childhood on asthma and allergic diseases at age 5.
      • Yang SI
      • Lee E
      • Jung YH
      • et al.
      Effect of antibiotic use and mold exposure in infancy on allergic rhinitis in susceptible adolescents.
      • Yeh KW
      • Ou LS
      • Yao TC
      • et al.
      Prevalence and risk factors for early presentation of asthma among preschool children in Taiwan.
      • Yoshida S
      • Ide K
      • Takeuchi M
      • Kawakami K.
      Prenatal and early-life antibiotic use and risk of childhood asthma: A retrospective cohort study.
      • Zou Z
      • Liu W
      • Huang C
      • Sun C
      • Zhang J.
      First-Year Antibiotics Exposure in Relation to Childhood Asthma, Allergies, and Airway Illnesses.
      An additional 10 relevant studies were identified by hand searching of references.
      • Karimi M
      • Mirzaei M.
      Antibiotic use and symptoms of asthma, allergic rhinitis and eczema in children.
      • Love BL
      • Mann JR
      • Hardin JW
      • Lu ZK
      • Cox C
      • Amrol DJ.
      Antibiotic prescription and food allergy in young children.
      • Lapin B
      • Piorkowski J
      • Ownby D
      • et al.
      The relationship of early-life antibiotic use with asthma in at-risk children.
      • Kwon JW
      • Kim BJ
      • Song Y
      • et al.
      Changes in the prevalence of childhood asthma in seoul from 1995 to 2008 and its risk factors.
      • Sharma SK
      • Banga A.
      Prevalence and risk factors for wheezing in children from rural areas of north India.
      • Illi S
      • von Mutius E
      • Lau S
      • et al.
      Early childhood infectious diseases and the development of asthma up to school age: a birth cohort study.
      • Khalkhali HR
      • Oshnouei S
      • Salarilak S
      • Rahimi Rad M
      • Karamyar M
      • Khashabi J
      Effects of antibiotic consumption on children 2-8 years of age developing asthma.
      • Lee E
      • Kwon JW
      • Kim HB
      • et al.
      Association Between Antibiotic Exposure, Bronchiolitis, and TLR4 (rs1927911) Polymorphisms in Childhood Asthma.
      • Sejersen TS
      • Vinding RK
      • Stokholm J
      • et al.
      Antibiotic exposure in infancy and development of BMI and body composition in childhood.
      • Antvorskov JC
      • Morgen CS
      • Buschard K
      • Jess T
      • Allin KH
      • Josefsen K
      Antibiotic treatment during early childhood and risk of type 1 diabetes in children: A national birth cohort study.
      The selection of included studies is summarised in figure 1. The 160 studies included in this review investigated 21 outcomes in 22,103,129 children; 159 were observational studies (23 registry-based studies, 69 cohort studies, 34 cross-sectional studies, 11 case-control studies, and 22 retrospective studies) and one was a secondary analysis of data from a randomised control trial;
      • Edmonson MB
      • Eickhoff JC.
      Weight Gain and Obesity in Infants and Young Children Exposed to Prolonged Antibiotic Prophylaxis.
      145 of the studies were done in industrialised countries. The number of participants in each study ranged from 50 to 9,400,000 (median 3,944, mean 138,146). Exposure to antibiotics was captured through registries, medical and prescription records or parent questionnaires; studies included any course of antibiotic received, antibiotic exposure during an early-life period (e.g. first week, months or first years of life) or during a certain time before diagnosis. Outcomes were defined by validated questionnaires, diagnostic codes, parent-reported symptoms, or diagnosis, or clinical or laboratory evaluation. The results of these studies are summarised in table 1. In addition to the overall antibiotic exposure, 17 studies investigated the effect of the number of antibiotic courses received, 17 studies compared the effect of different types of antibiotics and 41 studies both. The risk of bias summary of studies included in the review can be found in table 2.
      Table 1Summary of studies investigating the effect of antibiotic exposure on health outcomes in children
      AuthorCountry Publication yearStudy type (Level of evidence)No of cases; cohort sizeNo of cases in children with antibiotics; no of children with antibioticsNo of cases in children without antibiotics; no of children without antibioticsTime of antibiotic exposure (age unless otherwise specified)Antibiotic specifiedEvaluation of antibiotic exposureAge at outcome measureOutcome definitionMain findingsFactors adjusted for
      Atopic dermatitis
      Aversa et al.
      • Aversa Z
      • Atkinson EJ
      • Schafer MJ
      • et al.
      Association of Infant Antibiotic Exposure With Childhood Health Outcomes.


      USA

      2021
      Multicentre prospective cohort study (2b)297; 14,572

      231; 10,220

      66; 4,352
      < 2 y

      Yes

      Medical records
      6-11 yICD-9 and ICD-10 codesExposure to AB in first 2 y of life associated with increased risk.

      aHR 1.47 (95%CI 1.12-1.94), p<0.01

      Girls

      • penicillins: HR 1.27 (95%CI 0.87-1.87), p=0.22

      • cephalosporins: HR 1.69 (95%CI 1.14-2.52), p=0.01

      • macrolides: HR 0.59 (95%CI 0.37-0.92), p=0.02

      •sulfonamides: HR 0.98 (95%CI 0.49-1.96), p=0.95

      Boys

      • penicillins: HR 1.40 (95%CI 0.96-2.03), p=0.08

      • cephalosporins: HR 1.29 (95%CI 0.90-1.84), p=0.17

      • macrolides: HR 0.83 (95%CI 0.57-1.19), p=0.30

      •sulfonamides: HR 1.37 (95%CI 0.75-2.51), p=0.30
      Sex, ethnicity, maternal age, education and smoking, antibiotic use during pregnancy, birth weight, delivery mode
      Zou et al.
      • Zou Z
      • Liu W
      • Huang C
      • Sun C
      • Zhang J.
      First-Year Antibiotics Exposure in Relation to Childhood Asthma, Allergies, and Airway Illnesses.


      China

      2020
      Multicentre cross-sectional study (3b)2,752; 12,667

      772; 3,049

      1,980; 9,618
      < 1 y

      No

      Parent questionnaire
      4-6 yQuestionnaire for atopic dermatitis symptoms (ISAAC)Exposure to AB in first y of life associated with increased risk.

      aOR 1.17 (95%CI 1.05-1.31), p<0.01
      Age, sex, living area, family history of atopy, breastfeeding, home decoration, pet, smoke and home dampness-related exposure
      Levin et al.
      • Levin ME
      • Botha M
      • Basera W
      • et al.
      Environmental factors associated with allergy in urban and rural children from the South African Food Allergy (SAFFA) cohort.


      South-Africa

      2020
      Multicentre prospective cohort study (2b)301; 1,185

      182; 654

      119; 531
      < 1 y

      No

      Parent questionnaire
      12-36 mCriteria by American Academy of DermatologyExposure to AB in first y of life associated with increased risk in urban cohort.

      OR 1.33 (95%CI 1.02-1.74), p=0.03
      calculated from reported data
      8; 398

      7; 347

      1; 51
      Exposure to AB in first y of life not associated with increased risk in rural cohort.

      • OR 1.03 (95%CI 0.12-8.54), p=0.98
      calculated from reported data
      Rutter et al.
      • Rutter CE
      • Silverwood RJ
      • Williams HC
      • et al.
      Are Environmental Factors for Atopic Eczema in ISAAC Phase Three due to Reverse Causation?.


      UK

      2019
      Multicentre cross-sectional study (3b)15,152; 120,799

      13,108
      calculated from reported data
      ; 97,631

      2,044
      calculated from reported data
      ; 23,168
      < 1 y

      No

      Parent questionnaire
      6-7 yQuestionnaire for atopic dermatitis symptoms (ISAAC)Exposure to AB in first y of life associated with increased risk.

      aOR 1.41 (95%CI 1.34-1.48), p=nr
      Sex, maternal education and smoking, medication use, open fire cooking
      Metzler et al.
      • Metzler S
      • Frei R
      • Schmauser-Hechfellner E
      • et al.
      Association between antibiotic treatment during pregnancy and infancy and the development of allergic diseases.


      Switzerland

      2019
      Multicentre prospective cohort study (2b)275; 1,019

      154; 419

      121; 600
      < 1 y

      No

      Parent questionnaire
      < 6 yParent-reported physician's diagnosisExposure to AB in first y of life associated with increased risk.

      aOR 1.91 (95%CI 1.36‐2.67), p<0.05

      • 1 AB course: aOR 1.60 (95%CI nr), p=nr

      • 2 AB courses: aOR 2.06 (95%CI nr), p=nr

      • ≥ 3 AB courses: aOR 7.25 (95%CI nr), p=nr
      Sex, family history of atopy, number of siblings, living area, smoking and pet exposure during pregnancy, delivery mode, duration of breastfeeding, pet exposure
      Gao et al.
      • Gao X
      • Yan Y
      • Zeng G
      • et al.
      Influence of prenatal and early-life exposures on food allergy and eczema in infancy: a birth cohort study.


      China

      2019
      Single-centre prospective cohort study (2b)226; 903

      26; 184

      200; 719
      < 1 y

      No

      Parent questionnaire
      12 mParent-reported atopic dermatitis symptomsExposure to AB in first y of life associated with decreased risk.

      aOR 0.44 (95%CI 0.28-0.70), p<0.01
      Sex, family history of atopy, antibiotic use during pregnancy, season of birth, egg and milk consumption
      Ho et al.
      • Ho CL
      • Chang LI
      • Wu WF.
      The prevalence and risk factors of atopic dermatitis in 6-8 year-old first graders in Taipei.


      Taiwan

      2019
      Multicentre cross-sectional study (3b)2,625; 23,908

      562; 3,691

      2,063; 20,217
      < 1 y

      No

      Parent questionnaire
      6-8 yQuestionnaire for atopic dermatitis symptoms (ISAAC)Exposure to AB in first y of life associated with increased risk.

      aOR 1.37 (95%CI 1.22-1.53), p<0.01
      Sex, number of siblings, number of LRTIs, duration of breastfeeding, timing of solid food introduction, pet and home dampness-related exposure
      Norbäck et al.
      • Norback D
      • Lu C
      • Zhang Y
      • et al.
      Sources of indoor particulate matter (PM) and outdoor air pollution in China in relation to asthma, wheeze, rhinitis and eczema among pre-school children: Synergistic effects between antibiotics use and PM10and second hand smoke.


      China

      2019
      Multicentre retrospective cohort study (2b)9,573; 39,782

      7,497; 29,303

      2,076; 10,479
      < 1 y

      No

      Parent questionnaire
      3-6 yParent-reported physician's diagnosisExposure to AB in first y of life associated with increased risk.

      aOR 1.20 (95%CI 1.11-1.30), p<0.01

      • 1 AB course: aOR 1.15 (95%CI 1.07-1.24), p<0.01

      • > 1 AB courses: aOR 1.45 (95%CI 1.36-1.56), p<0.01
      Living city, temperature in each city, time spend outdoors, air pollution
      Oosterloo et al.
      • Oosterloo BC
      • van Elburg RM
      • Rutten NB
      • et al.
      Wheezing and infantile colic are associated with neonatal antibiotic treatment.


      Netherlands

      2018
      Multicentre prospective cohort study (2b)156; 436

      57; 151

      99; 285
      < 1 w

      No

      Parent questionnaire
      0-1 yParent-reported atopic dermatitis symptomsExposure to AB in first w of life not associated with increased risk.

      • aOR 1.09 (95%CI 0.70-1.70), p=0.70
      Family history of atopy, parental education, day care, number of siblings, smoking during pregnancy, delivery mode, duration of breastfeeding, household smoking
      Mitre et al.
      • Mitre E
      • Susi A
      • Kropp LE
      • Schwartz DJ
      • Gorman GH
      • Nylund CM.
      Association Between Use of Acid-Suppressive Medications and Antibiotics During Infancy and Allergic Diseases in Early Childhood.


      USA

      2018
      Multicentre retrospective cohort study (2b)112,608; 792,130

      21,638; 131,708

      90,970; 660,422
      < 6 m

      No

      Registry
      1-6 yICD-9-CM codesExposure to AB in first 6 m of life associated with increased risk.

      aHR 1.18 (95%CI 1.16-1.19), p=nr
      Sex, prematurity, delivery mode, medication (incl. anti-reflux medication) use
      Singh et al.
      • Singh S
      • Sharma BB
      • Salvi S
      • et al.
      Allergic rhinitis, rhinoconjunctivitis, and eczema: prevalence and associated factors in children.


      India

      2018
      Multicentre cross-sectional study (3b)1,249; 44,928

      nr; nr

      nr; nr
      < 1 y

      No

      Parent questionnaire
      6-7 yQuestionnaire for atopic dermatitis symptoms (ISAAC)Exposure to AB in first y of life associated with increased risk.

      OR 1.80 (95%CI 1.60-2.00), p<0.01
      Yamamoto-Hanada et al.
      • Yamamoto-Hanada K
      • Yang L
      • Narita M
      • Saito H
      • Ohya Y
      Influence of antibiotic use in early childhood on asthma and allergic diseases at age 5.


      Japan

      2017
      Multicentre prospective cohort study (2b)194; 902

      107; 436

      87; 466
      < 2 y

      Yes

      Parent questionnaire
      5 yQuestionnaire for atopic dermatitis symptoms (ISAAC) plus medical recordsExposure to AB in first 2 y of life associated with increased risk.

      aOR 1.40 (95%CI 1.01-1.94), p=0.04

      • penicillins: aOR 1.41 (95%CI 0.82-2.43), p=0.22

      • cephem: aOR 1.37 (95%CI 0.94-1.99), p=0.10

      • macrolides: aOR 1.58 (95%CI 1.07-2.33), p=0.02
      Sex, maternal age, maternal parity, maternal BMI, maternal history of atopy, day care, maternal education, smoking during pregnancy, gestational age, delivery mode, number of LRTIs
      Park et al.
      • Park YM
      • Lee SY
      • Kim WK
      • et al.
      Risk factors of atopic dermatitis in Korean schoolchildren: 2010 international study of asthma and allergies in childhood.


      Korea

      2016
      Multicentre cross-sectional study (3b)1,424; 4,003

      607; 1585
      calculated from reported data


      817; 2418
      calculated from reported data
      < 1 y

      No

      Parent questionnaire
      6-7 yQuestionnaire for atopic dermatitis symptoms (ISAAC)Exposure to AB in first y of life not associated with increased risk.

      • aOR 1.09 (95%CI 0.88-1.39), p=0.70
      Age, sex, family history of atopy, living area, atopy
      981; 4,112

      288; 1090
      calculated from reported data


      693; 3022
      calculated from reported data
      12-13 yExposure to AB in first y of life not associated with increased risk.

      • aOR 1.04 (95%CI 0.86-1.34), p=0.70
      Taylor-Robinson et al.
      • Taylor-Robinson DC
      • Williams H
      • Pearce A
      • Law C
      • Hope S.
      Do early-life exposures explain why more advantaged children get eczema? Findings from the U.K. Millennium Cohort Study.


      UK

      2016
      Multicentre prospective cohort study (2b)3,489; 12,917

      1,909; 5,678

      1,580; 7,239
      < 1 y

      No

      Registry
      5 yQuestionnaire for atopic dermatitis symptoms (ISAAC)Exposure to AB in first y of life associated with increased risk.

      aOR 1.28 (95%CI 1.16-1.42), p<0.01
      Sex, ethnicity, maternal age, maternal BMI, maternal history of atopy, day care, number of siblings, maternal education, maternal smoking and alcohol consumption during pregnancy, birth weight, delivery mode, breastfeeding, timing of solid food and cow's milk introduction, smoke and grime exposure
      Loo et al.
      • Loo EX
      • Shek LP
      • Goh A
      • et al.
      Atopic Dermatitis in Early Life: Evidence for at Least Three Phenotypes? Results from the GUSTO Study.


      Singapore

      2015
      Multicentre prospective cohort study (2b)43; 792

      nr; nr

      nr; nr
      < 6 m

      No

      Parent questionnaire
      6 m-1 yParents-reported physician's diagnosisExposure to AB in first 6 m of life not associated with increased risk.

      • aOR 3.19 (95%CI 0.72-14.11), p=0.13
      Sex, sibling history of atopy, living area, age of child at outcome measurement
      47; 792

      nr; nr

      nr; nr
      1-1.5 yExposure to AB in first 6 m of life associated with increased risk.

      aOR 3.11 (95%CI 1.10-8.76), p=0.03
      Hoskin-Parr et al.
      • Hoskin-Parr L
      • Teyhan A
      • Blocker A
      • Henderson AJ.
      Antibiotic exposure in the first two years of life and development of asthma and other allergic diseases by 7.5 yr: a dose-dependent relationship.


      UK

      2013
      Single-centre prospective cohort study (2b)994; 5,780

      494
      calculated from reported data
      ; 2,659

      500
      calculated from reported data
      ; 3,121
      < 2 y

      No

      Parent questionnaire
      7.5 y (mean)Parents-reported physician's diagnosisExposure to AB in first 2 y of life associated with increased risk.

      aOR 1.20 (95%CI 1.02-1.41), p=nr

      • 1 AB course: aOR 1.05 (95%CI 0.85-1.29), p=nr

      • 2 AB courses: aOR 1.23 (95%CI 1.00-1.51), p=nr

      • 3 AB courses: aOR 1.17 (95%CI 0.93-1.47), p=nr

      • ≥ 4 AB courses: aOR 1.41 (95%CI 1.14-1.74), p=nr
      Age, sex, maternal age, parental marital status, home ownership status, degree of difficulty in paying for food, maternal education, smoking and disinfectant use during pregnancy, gestational age, birth weight, delivery mode, age of child at outcome measurement, breastfeeding, time spend outdoors, pet exposure
      Wang et al.
      • Wang JY
      • Liu LF
      • Chen CY
      • Huang YW
      • Hsiung CA
      • Tsai HJ.
      Acetaminophen and/or antibiotic use in early life and the development of childhood allergic diseases.


      Taiwan

      2013
      Multicentre prospective cohort study (2b)19,015; 263,620

      nr; 15,663

      nr; 247,957
      < 1 y

      Yes

      Medical records
      2-6 yICD-9-CM codesExposure to AB in first y of life associated with increased risk.

      aHR 1.61 (95%CI 1.53-1.70), p<0.05

      Results according to antibiotic class nr
      Living area, socioeconomic status, healthcare use
      Sandini et al.
      • Sandini U
      • Kukkonen AK
      • Poussa T
      • Sandini L
      • Savilahti E
      • Kuitunen M.
      Protective and risk factors for allergic diseases in high-risk children at the ages of two and five years.


      Finland

      2011
      Single-centre prospective cohort study (2b)270; 925

      nr; nr

      nr; nr
      < 6 m

      No

      Parent questionnaire
      2 yWilliam's criteriaExposure to AB in first 6 m of life not associated with increased risk.

      • OR 1.18 (95%CI 0.77-1.81), p=0.44
      368; 891

      nr; nr

      nr; nr
      5 yExposure to AB in first 6 m of life not associated with increased risk.

      • OR 1.20 (95%CI 0.79-1.81), p=0.39
      Schmitt et al.
      • Schmitt J
      • Schmitt NM
      • Kirch W
      • Meurer M.
      Early exposure to antibiotics and infections and the incidence of atopic eczema: a population-based cohort study.


      Germany

      2010
      Multicentre prospective cohort study (2b)44; 370

      24; 155

      20; 215
      < 1 y

      Yes

      Registry
      2 yICD-10 codes plus prescription recordsExposure to AB in first y of life associated with increased risk, significant only for ≥ 2 AB courses.

      • OR 1.79 (95%CI 0.95-3.37), p=0.07
      calculated from reported data


      • 1 AB course: RR 1.45 (95%CI 0.76-2.75), p=nr

      • ≥ 2 AB courses: RR 2.11 (95%CI 1.05-4.22), p=nr

      • penicillins: RR 0.88 (95%CI 0.37-2.12), p=nr

      • cephalosporins: RR 1.93 (95%CI 1.07-3.49), p=nr

      • macrolides: RR 2.15 (95%CI 1.18-3.91), p=nr
      Su et al.
      • Su Y
      • Rothers J
      • Stern DA
      • Halonen M
      • Wright AL.
      Relation of early antibiotic use to childhood asthma: confounding by indication?.


      USA

      2010
      Single-centre prospective cohort study (2b)134; 424

      49; 136

      85; 288
      < 9 m

      No

      Parent questionnaire
      1-5 yParent-reported physician's diagnosisExposure to AB in first 9 m of life not associated with increased risk.

      • OR 1.35 (95%CI 0.87-2.07), p=0.18
      calculated from reported data
      Dom et al.
      • Dom S
      • Droste JH
      • Sariachvili MA
      • et al.
      Pre- and post-natal exposure to antibiotics and the development of eczema, recurrent wheezing and atopic sensitization in children up to the age of 4 years.


      Belgium

      2010
      Multicentre prospective cohort study (2b)243; 670

      192; 564

      51; 106
      < 4 y

      No

      Parent questionnaire
      < 4 yQuestionnaire for atopic dermatitis symptoms (ISAAC)Exposure to AB in first 4 y of life associated with decreased risk.

      OR 0.56 (95%CI 0.37-0.85), p<0.01
      calculated from reported data


      Exposure to AB in first y of life associated with decreased risk.

      • aOR 0.61 (95%CI 0.36-1.01), p=0.05

      Exposure to AB in second to fourth y of life with decreased risk.

      aOR 0.11 (95%CI 0.05-0.23), p<0.01
      Sex, maternal age, family history of atopy, day care, number of siblings, parental education, smoking during and pet exposure during pregnancy, birth weight, number of LRTIs, breastfeeding, household smoking, pet exposure
      Mai et al.
      • Mai XM
      • Kull I
      • Wickman M
      • Bergström A.
      Antibiotic use in early life and development of allergic diseases: respiratory infection as the explanation.


      Sweden

      2010
      Single-centre prospective cohort study (2b)663; 3,306

      318; 1,420

      345; 1,886
      < 1 y

      No

      Parent questionnaire
      4 yQuestionnaire for atopic dermatitis symptoms (BAMSE based on ISAAC)Exposure to AB in first y of life associated with increased risk.

      • aOR 1.30 (95%CI 1.10-1.50), p=nr
      Sex, maternal age, family history of atopy, number of siblings, breastfeeding, maternal smoking
      523; 3,306

      255; 1,420

      268; 1,886
      8 yExposure to AB in first y of life associated with increased risk.

      • aOR 1.30 (95%CI 1.10-1.60), p=nr
      Garcia-Marcos et al.
      • Garcia-Marcos L
      • Gonzalez-Diaz C
      • Garvajal-Uruena I
      • et al.
      Early exposure to paracetamol or to antibiotics and eczema at school age: modification by asthma and rhinoconjunctivitis.


      Spain

      2010
      Multicentre retrospective case-control study (3b)922; 13,325

      589; 6,831

      333; 6,494
      < 1 y

      No

      Parent questionnaire
      6-7 yQuestionnaire for atopic dermatitis symptoms (ISAAC)Exposure to AB in first y of life associated with increased risk.

      aOR 1.66 (95%CI 1.43-1.92), p<0.01
      Age, sex, number of siblings, living area, maternal education, maternal smoking, pet and traffic exposure
      Karimi et al.
      • Karimi M
      • Mirzaei M.
      Antibiotic use and symptoms of asthma, allergic rhinitis and eczema in children.


      Iran

      2009
      Multicentre cross-sectional study (3b)90; 1,476

      63; 952
      calculated from reported data


      27; 524
      calculated from reported data
      < 1 y

      No

      nr
      6-7 yQuestionnaire for atopic dermatitis symptoms (ISAAC)Exposure to AB in first y of life not associated with increased risk.

      • OR 1.30 (95%CI 0.79-2.13), p=0.20
      Foliaki et al.
      • Foliaki S
      • Pearce N
      • Bjorksten B
      • et al.
      Antibiotic use in infancy and symptoms of asthma, rhinoconjunctivitis, and eczema in children 6 and 7 years old: International Study of Asthma and Allergies in Childhood Phase III.


      Sweden

      2009
      Multicentre retrospective cross-sectional study (3b)nr; 193,412

      nr; 135,775

      nr; 57,637
      < 1 y

      No

      Parent questionnaire
      6-7 yQuestionnaire for atopic dermatitis symptoms (ISAAC)Exposure to AB in first y of life associated with increased risk.

      aOR 1.58 (95%CI 1.33-1.51), p=nr
      Sex, language, living area, income
      Wickens et al.
      • Wickens K
      • Ingham T
      • Epton M
      • et al.
      The association of early life exposure to antibiotics and the development of asthma, eczema and atopy in a birth cohort: confounding or causality?.


      New Zealand

      2008
      Multicentre

      prospective cohort study (2b)
      398; 1,064

      52
      calculated from reported data
      ; 148

      346
      calculated from reported data
      ; 916
      < 3 m

      No

      Parent questionnaire
      15 mQuestionnaire for atopic dermatitis symptoms (ISAAC)Exposure to AB in first 3 m of life not associated with increased risk.

      • aOR 0.84 (95%CI 0.57-1.22), p=0.35
      Number of LRTIs
      305; 1,011

      242
      calculated from reported data
      ; 722

      63
      calculated from reported data
      ; 289
      < 15 m

      4 yExposure to AB in first 15 m of life associated with increased risk.

      aOR 1.75 (95% CI, 1.03-2.96), p=0.04
      Kusel et al.
      • Kusel MM
      • de Klerk N
      • Holt PG
      • Sly PD.
      Antibiotic use in the first year of life and risk of atopic disease in early childhood.


      Australia

      2008
      Multicentre prospective cohort study (2b)62; 198

      37
      calculated from reported data
      ; 107

      25
      calculated from reported data
      ; 91
      < 1 y

      Yes

      Parent questionnaire
      0-5 yHanifin and Rajka criteriaExposure to AB in first y of life not associated with increased risk.

      • aOR 1.50 (95%CI 0.70-3.30), p=nr

      Results according to antibiotic class nr
      Sex, day care, number of GP visits, pet exposure
      Kummeling et al.
      • Kummeling I
      • Stelma FF
      • Dagnelie PC
      • et al.
      Early life exposure to antibiotics and the subsequent development of eczema, wheeze, and allergic sensitization in the first 2 years of life: the KOALA Birth Cohort Study.


      Netherlands

      2007
      Multicentre prospective cohort study (2b)817; 2,462

      145; 489

      672; 1,973
      < 6 m

      No

      Parent questionnaire
      < 2 yQuestionnaire for atopic dermatitis symptoms (ISAAC)Exposure to AB in first 6 m not associated with increased risk.

      • aOR 0.94 (95%CI 0.75-1.18), p=nr
      Sex, family history of atopy, day care, number of siblings, delivery mode, vaccination status, fever, breastfeeding, pet and smoke exposure
      Mullooly et al.
      • Mullooly JP
      • Schuler R
      • Barrett M
      • Maher JE.
      Vaccines, antibiotics, and atopy.


      USA

      2007
      Single-centre retrospective case-control study (3b)58; 844

      nr; nr

      nr; nr
      < 2 y

      No

      Medical records
      10.3 y (mean)Parent-reported physician's diagnosisExposure to AB in first 2 y of life not associated with increased risk.

      • aOR 1.03 (95%CI 0.96-1.10), p=nr
      Sex, ethnicity, maternal age, birth weight, age of child at time of outcome, breastfeeding, household smoking
      Floistrup et al.
      • Floistrup H
      • Swartz J
      • Bergstrom A
      • et al.
      Allergic disease and sensitization in Steiner school children.


      Netherlands, Austria, Germany, Sweden, Switzerland

      2006
      Multicentre cross-sectional study (3b)520; 4,606

      126
      calculated from reported data
      ; 788

      394
      calculated from reported data
      ; 3,818
      < 1 y

      No

      Parent questionnaire
      7-11 yParent-reported physician's diagnosisExposure to AB in first y of life associated with increased risk.

      aOR 1.63 (95%CI 1.22-2.17), p=nr
      Age, sex, family history of atopy, number of siblings, living country, parental education, measles infection, vaccination status, medication use, smoking during pregnancy, diet, household smoking, pet exposure
      Purvis et al.
      • Purvis DJ
      • Thompson JM
      • Clark PM
      • et al.
      Risk factors for atopic dermatitis in New Zealand children at 3.5 years of age.


      New Zealand

      2005
      Multicentric, prospective case-control study (3b)87; 550

      57; 369

      30; 181
      < 1 y

      No

      Parent questionnaire
      3.5-4 yQuestionnaire for atopic dermatitis symptoms (ISAAC) plus serum IgE (environmental allergens)Exposure to AB in first y of life not associated with increased risk.

      • OR 1.18 (95%CI, 0.61-2.26), p=0.62
      Cohet et al.
      • Cohet C
      • Cheng S
      • MacDonald C
      • et al.
      Infections, medication use, and the prevalence of symptoms of asthma, rhinitis, and eczema in childhood.


      New Zealand

      2004
      Single-centre retrospective case-control study (3b)1,549; 3,927

      1,130; 2,684

      419; 1,243
      < 1 y

      No

      Parent questionnaire
      6-7 yQuestionnaire for atopic dermatitis symptoms (ISAAC)Exposure to AB in first y of life associated with increased risk.

      OR 1.40 (95%CI 1.21-1.62), p=nr
      Celedon et al.
      • Celedon JC
      • Litonjua AA
      • Ryan L
      • Weiss ST
      • Gold DR.
      Lack of association between antibiotic use in the first year of life and asthma, allergic rhinitis, or eczema at age 5 years.


      USA

      2002
      Multicentre prospective cohort study (2b)22; 448

      16; 302

      6; 146
      < 1 y

      No

      Parent questionnaire
      5 yParent-reported physician's diagnosisExposure to AB in first y of life not associated with increased risk.

      • 1 AB course: aOR 0.90 (95%CI 0.30-3.40), p=nr

      • ≥ 2 AB courses: aOR 1.10 (95%CI 0.40-3.10), p=nr
      Sex, family history of atopy, income
      Bohme et al.
      • Böhme M
      • Lannerö E
      • Wickman M
      • Nordvall SL
      • Wahlgren CF.
      Atopic dermatitis and concomitant disease patterns in children up to two years of age.


      Sweden

      2002
      Multicentre prospective cohort study (2b)952; 3,786

      ≥ 2 AB courses: 450; 1,586

      502; 2,200
      1-2 y

      No

      Parent questionnaire
      2 yQuestionnaire for atopic dermatitis symptoms (BAMSE)Exposure to ≥ 2 AB courses in first 2 y of life associated with increased risk.

      aRP 1.29 (95%CI 1.07-1.56), p=nr
      Sex, maternal age, family history of atopy, parental education, gestational age, age of child at time of outcome, breastfeeding duration, maternal smoking
      McKeever et al.
      • McKeever TM
      • Lewis SA
      • Smith C
      • et al.
      Early exposure to infections and antibiotics and the incidence of allergic disease: a birth cohort study with the West Midlands General Practice Research Database.


      UK

      2002
      Single-centre prospective cohort study (2b)3,580; 19,133

      nr; 12,497

      nr; 6,636
      < 1 y

      Yes

      Medical records
      < 11 y

      2.2 y (mean)
      Oxford Medical Information System (OXMIS), ICD-8 or Read codesExposure to AB in first y of life associated with increased risk.

      • 1 AB course: aHR 1.22 (95%CI 1.12-1.34), p=nr

      • 2 AB courses: aHR 1.21 (95%CI 1.09-1.35), p=nr

      • 3 AB courses: aHR 1.22 (95%CI 1.08-1.38), p=nr

      • 4 AB courses: aHR 1.11 (95%CI 0.95-1.28), p=nr

      • > 4 AB courses: aHR 1.01 (95%CI 0.88-1.17), p=nr

      • penicillin: aHR 1.07 (95%CI 0.97-1.18), p=nr

      • amoxicillin: aHR 1.09 (95%CI 1.01-1.17), p=nr

      • amoxicillin/clavulanic acid: aHR 1.16 (95%CI 0.98-1.38), p=nr

      • cephalosporins: aHR 0.90 (95%CI 0.80-1.02), p=nr

      • macrolides: aHR 0.96 (95%CI 0.89-1.04), p=nr
      Number of GP visits
      Wjst et al.
      • Wjst M
      • Hoelscher B
      • Frye C
      • Wichmann HE
      • Dold S
      • Heinrich J.
      Early antibiotic treatment and later asthma.


      Germany

      2001
      Multicentre cross-sectional study (3b)768; 2,512

      nr; 2,025

      nr; 487
      < 5-14 y

      No

      Medical records
      5-14 yQuestionnaire for atopic dermatitis symptoms (ISAAC)Exposure to AB between the fifth and fourteenth y of life not associated with increased risk.

      • aOR 1.30 (95%CI 0.80-2.20), p=0.27
      Age, sex, family history of atopy, season, parental education
      Droste et al.
      • Droste JH
      • Wieringa MH
      • Weyler JJ
      • Nelen VJ
      • Vermeire PA
      • Van Bever HP.
      Does the use of antibiotics in early childhood increase the risk of asthma and allergic disease?.


      Belgium

      2000
      Multicentre retrospective cross-sectional study (3b)233; 1,180

      85; 375

      148; 805
      < 1 y

      No

      Parent questionnaire
      7-8 yQuestionnaire for atopic dermatitis symptoms (ISAAC)Exposure to AB in first y of life associated with increased risk in high-risk children.

      • aOR 1.30 (95%CI 1.00-1.80), p=0.05
      Sex, family history of atopy, number of siblings, living area, smoking during pregnancy, smoke exposure
      Von Mutius et al.
      • von Mutius E
      • Illi S
      • Hirsch T
      • Leupold W
      • Keil U
      • Weiland SK.
      Frequency of infections and risk of asthma, atopy and airway hyperresponsiveness in children.


      Germany

      1999
      Single-centre cross-sectional study (3b)812; 5,006

      673; 3,904

      139; 1,102
      < 3 y

      No

      Medical records
      5-7 yQuestionnaire for atopic dermatitis symptoms (ISAAC)Exposure to AB in first 3 y of life associated with increased risk.

      OR 1.44 (95%CI 1.19-1.76), p<0.01
      calculated from reported data
      865; 5,267

      701; 4006

      164; 1261
      9-11 yExposure to AB in first 3 y of life associated with increased risk.

      OR 1.42 (95%CI 1.18-1.70), p<0.01
      calculated from reported data
      Wickens et al.
      • Wickens K
      • Pearce N
      • Crane J
      • Beasley R.
      Antibiotic use in early childhood and the development of asthma.


      New Zealand

      1999
      Multicentre retrospective cross-sectional study (3b)125; 447

      98; 334

      27; 113
      < 10 y

      No

      Parent questionnaire
      5-10 yQuestionnaire for atopic dermatitis symptoms (ISAAC)Exposure to AB in first 10 y of life not associated with increased risk.

      • aOR 1.23 (95%CI 0.71-2.13), p=nr
      Age, sex, ethnicity, family history of atopy, household size, parental smoking
      Farooqi et al.
      • Farooqi IS
      • Hopkin JM.
      Early childhood infection and atopic disorder.


      UK

      1998
      Single-centre retrospective cohort study (2b)367; 1,855

      287
      calculated from reported data
      ; 1,237

      80
      calculated from reported data
      ; 618
      < 2 y

      Yes

      Medical records
      6-12 yPhysician's diagnosisExposure to AB in first 2 y of life associated with increased risk.

      OR 2.04 (95%CI 1.53-2.73), p<0.01

      Results according to antibiotic class nr
      Allergic sensitisation
      Levin et al.
      • Levin ME
      • Botha M
      • Basera W
      • et al.
      Environmental factors associated with allergy in urban and rural children from the South African Food Allergy (SAFFA) cohort.


      South-Africa

      2020
      Multicentre prospective cohort study (2b)107; 1,185

      64; 654

      43; 531
      < 1 y

      No

      Parent questionnaire
      12-36 mSPT (food and inhalant allergens)Exposure to AB in first y of life not associated with increased risk.

      • OR 1.23 (95%CI 0.82-1.85), p=0.31
      calculated from reported data
      11; 398

      11; 347

      0; 51
      Exposure to AB in first y of life not associated with increased risk in rural cohort.

      • OR 3.52 (95%CI 0.20-60.65), p=0.39
      calculated from reported data
      Metzler et al.
      • Metzler S
      • Frei R
      • Schmauser-Hechfellner E
      • et al.
      Association between antibiotic treatment during pregnancy and infancy and the development of allergic diseases.


      Switzerland

      2019
      Multicentre prospective cohort study (2b)388; 1,019

      167; 419

      221; 600
      < 1 y

      No

      Parent questionnaire
      < 6 ySerum IgE (seasonal, perennial and food allergens)Exposure to AB in first y of life not associated with increased risk.

      • aOR 1.06 (95%CI 0.70-1.60), p=nr
      Sex, family history of atopy, number of siblings, living area, smoking during pregnancy, pet exposure during pregnancy, delivery mode, duration of breastfeeding, pet exposure
      Oosterloo et al.
      • Oosterloo BC
      • van Elburg RM
      • Rutten NB
      • et al.
      Wheezing and infantile colic are associated with neonatal antibiotic treatment.


      Netherlands

      2018
      Multicentre prospective cohort study (2b)18; 205

      9; 77

      9; 128
      < 1 w

      No

      Parent questionnaire
      0-1 ySerum IgE (food and inhalant allergens)Exposure to AB in first w of life not associated with increased risk.

      • aOR 3.26 (95%CI 0.95-11.13), p=0.06
      Family history of atopy, parental education, day care, number of siblings, smoking during pregnancy, delivery mode, duration of breastfeeding, household smoking
      Batool et al.
      • Batool T
      • Reece PL
      • Schulze KM
      • et al.
      Prenatal and early-life predictors of atopy and allergic disease in Canadian children: results of the Family Atherosclerosis Monitoring In earLY life (FAMILY) Study.


      Canada

      2016
      Multicentre prospective cohort study (2b)141; 576

      63; 205

      78; 371
      < 1 y

      No

      Parent questionnaire
      1 ySPT (food and inhalant allergens)Exposure to AB in first y of life associated with increased risk.

      OR 1.67 (95%CI 1-13-2.46), p<0.01
      calculated from reported data
      Azad et al.
      • Azad MB
      • Konya T
      • Guttman DS
      • et al.
      Infant gut microbiota and food sensitization: associations in the first year of life.


      Canada

      2015
      Multicentre prospective cohort study (2b)12; 166

      6; 78

      6; 88
      < 3 m

      No

      Medical records
      1 ySPT (food allergens)Exposure to AB in first 3 m of life not associated with increased risk.

      • OR 1.14 (95%CI 0.35-3.69), p=0.83
      calculated from reported data
      12; 166

      9; 105

      3; 61
      < 1 y

      No

      Medical records
      Exposure to AB in first y of life not associated with increased risk.

      • OR 1.81 (95%CI 0.47-6.97), p=0.39
      calculated from reported data
      Loo et al.
      • Loo EX
      • Shek LP
      • Goh A
      • et al.
      Atopic Dermatitis in Early Life: Evidence for at Least Three Phenotypes? Results from the GUSTO Study.


      Singapore

      2015
      Multicentre prospective cohort study (2b)94; 696

      nr; nr

      nr; nr
      < 6 m

      No

      Parent questionnaire
      1.5 ySPT (food and inhalant allergens)Exposure to AB in first 6 m of life not associated with increased risk.

      • aOR 11.44 (95%CI 0.50-260.29), p=0.13
      Sex, living area, family history of atopy, age of child at time of outcome
      Semic-Jusufagic et al.
      • Semic-Jusufagic A
      • Belgrave D
      • Pickles A
      • et al.
      Assessing the association of early life antibiotic prescription with asthma exacerbations, impaired antiviral immunity, and genetic variants in 17q21: a population-based birth cohort study.


      UK

      2014
      Multicentre prospective cohort study (2b)209; 800

      nr; 564

      nr; 236
      < 1 y

      No

      Parent questionnaire
      1-11 ySPT (food and inhalant allergens)Exposure to AB in first y of life not associated with increased risk.

      • HR 1.02 (95%CI 0.60-1.78), p=0.92
      Hoskin-Parr et al.
      • Hoskin-Parr L
      • Teyhan A
      • Blocker A
      • Henderson AJ.
      Antibiotic exposure in the first two years of life and development of asthma and other allergic diseases by 7.5 yr: a dose-dependent relationship.


      UK

      2013
      Single-centre prospective cohort study (2b)830; 5,780

      386
      calculated from reported data
      ; 2,659

      444
      calculated from reported data
      ; 3,121
      < 2 y

      No

      Parent questionnaire
      7.5 y (mean)SPT (inhalant allergens)Exposure to AB in first 2 y of life not associated with increased risk.

      • aOR 1.02 (95%CI 0.85-1.22), p=nr

      • 1 AB course: aOR 1.00 (95%CI 0.80-1.25), p=nr

      • 2 AB courses: aOR 1.10 (95%CI 0.89-1.39), p=nr

      • 3 AB courses: aOR 0.96 (95%CI 0.74-1.24), p=nr

      • ≥ 4 AB courses: aOR 1.00 (95%CI 0.79-1.27), p=nr
      Age, sex, maternal age, parental marital status, home ownership status, degree of difficulty in paying for food, maternal education, smoking during pregnancy, disinfectant use during pregnancy, gestational age, birth weight, delivery mode, age of child at outcome measurement, breastfeeding, time spend outdoors, pet exposure
      Risnes et al.
      • Risnes KR
      • Belanger K
      • Murk W
      • Bracken MB.
      Antibiotic exposure by 6 months and asthma and allergy at 6 years: Findings in a cohort of 1,401 US children.


      USA

      2011
      Multicentric prospective cohort study (2b)151; 1,401

      71
      calculated from reported data
      ; 464

      80
      calculated from reported data
      ; 937
      < 6 m

      No

      Parent questionnaire
      6 ySPT (food and inhalant allergens)Exposure to AB in first 6 m of life associated with increased risk.

      aOR 1.59 (95% CI, 1.10-2.28), p=nr
      Maternal age, family history of atopy, number of LRTIs
      Sandini et al.
      • Sandini U
      • Kukkonen AK
      • Poussa T
      • Sandini L
      • Savilahti E
      • Kuitunen M.
      Protective and risk factors for allergic diseases in high-risk children at the ages of two and five years.


      Finland

      2011
      Single-centre prospective cohort study (2b)271; 916

      nr; nr

      nr; nr
      < 6 m

      No

      Parent questionnaire
      2 ySPT or serum IgE (food and inhalant allergens)Exposure to AB in first 6 m of life not associated with increased risk.

      • OR 1.22 (95%CI 0.79-1.88), p=0.37
      367; 889

      nr; nr

      nr; nr
      5 yExposure to AB in first 6 m of life not associated with increased risk.

      • OR 0.82 (95%CI 0.54-1.25), p=0.35
      Dom et al.
      • Dom S
      • Droste JH
      • Sariachvili MA
      • et al.
      Pre- and post-natal exposure to antibiotics and the development of eczema, recurrent wheezing and atopic sensitization in children up to the age of 4 years.


      Belgium

      2010
      Multicentre prospective cohort study (2b)160; 450

      121; 384

      39; 66
      < 4 y

      No

      Parent questionnaire
      < 4 ySerum IgE (food and inhalant allergens)Exposure to AB before first 4 y of life associated with decreased risk.

      OR 0.32 (95%CI 0.19-0.54), p<0.01
      calculated from reported data
      Sex, maternal age, family history of atopy, day care, number of siblings, parental education, smoking during pregnancy, pet exposure during pregnancy, birth weight, number of LRTIs, breastfeeding, household smoking, pet exposure
      Mai et al.
      • Mai XM
      • Kull I
      • Wickman M
      • Bergström A.
      Antibiotic use in early life and development of allergic diseases: respiratory infection as the explanation.


      Sweden

      2010
      Single-centre prospective cohort study (2b)579; 3,306

      244; 1,420

      335; 1,886
      < 1 y

      No

      Parent questionnaire
      4 ySerum IgE (food and inhalant allergens)Exposure to AB in first y of life not associated with increased risk.

      • aOR 0.90 (95%CI 0.70-1.10), p=nr
      Sex, maternal age, family history of atopy, number of siblings, breastfeeding, maternal smoking
      828; 3,306

      358; 1,420

      470; 1,886
      8 yExposure to AB in first y of life not associated with increased risk.

      • aOR 1.00 (95%CI 0.80-1.20), p=nr
      Su et al.
      • Su Y
      • Rothers J
      • Stern DA
      • Halonen M
      • Wright AL.
      Relation of early antibiotic use to childhood asthma: confounding by indication?.


      USA

      2010
      Single-centre prospective cohort study (2b)202; 398

      65; 136

      137; 262
      < 9 m

      No

      Parent questionnaire
      1-5 ySerum IgE (food and inhalant allergens)Exposure to AB in first 9 m of life not associated with increased risk.

      • OR 0.84 (95%CI 0.55-1.26), p=0.39
      calculated from reported data
      Kusel et al.
      • Kusel MM
      • de Klerk N
      • Holt PG
      • Sly PD.
      Antibiotic use in the first year of life and risk of atopic disease in early childhood.


      Australia

      2008
      Multicentre prospective cohort study (2b)67; 198

      36
      calculated from reported data
      ; 107

      31
      calculated from reported data
      ; 91
      < 1 y

      Yes

      Parent questionnaire
      0-5 ySPT plus serum IgE (food and inhalant allergens)Exposure to AB in first y of life not associated with increased risk.

      • aOR 1.00 (95%CI 0.50-2.10), p=nr

      Results according to antibiotic class nr
      Sex, day care, number of GP visits, pet exposure
      Wickens et al.
      • Wickens K
      • Ingham T
      • Epton M
      • et al.
      The association of early life exposure to antibiotics and the development of asthma, eczema and atopy in a birth cohort: confounding or causality?.


      New Zealand

      2008
      Multicentre

      prospective cohort study (2b)
      249; 1,064

      44
      calculated from reported data
      ; 148

      205
      calculated from reported data
      ; 916
      < 3 m

      No

      Parent questionnaire
      15 mSPT (food and inhalant allergens)Exposure to AB before 3 m of life not associated with increased risk.

      • aOR 1.36 (95% CI, 0.91-2.05), p=0.14
      Number of LRTIs
      Harris et al.
      • Harris JM
      • Mills P
      • White C
      • Moffat S
      • Newman Taylor AJ
      • Cullinan P
      Recorded infections and antibiotics in early life: associations with allergy in UK children and their parents.


      UK

      2007
      Single-centre prospective cohort study (2b)104; 490

      27; nr

      77; nr
      < 5 y

      No

      Medical records
      8 ySPT (inhalant allergens)Exposure to AB in first 5 y of life not associated with increased risk.

      • aOR 1.00 (95%CI 0.97-1.03), p=0.86
      Family history of atopy, birth order, smoke exposure
      Majkowska-Wojciechowska et al.
      • Majkowska-Wojciechowska B
      • Pelka J
      • Korzon L
      • et al.
      Prevalence of allergy, patterns of allergic sensitization and allergy risk factors in rural and urban children.


      Poland

      2007
      Multicentre prospective cohort study (2b)128; 201

      8
      calculated from reported data
      ; 10

      120
      calculated from reported data
      ; 191
      nr

      No

      Parent questionnaire
      12-16 ySPTEarly-life exposure to AB associated with increased risk.

      OR 2.12 (95%CI 1.16-3.85), p=0.02
      Kummeling et al.
      • Kummeling I
      • Stelma FF
      • Dagnelie PC
      • et al.
      Early life exposure to antibiotics and the subsequent development of eczema, wheeze, and allergic sensitization in the first 2 years of life: the KOALA Birth Cohort Study.


      Netherlands

      2007
      Multicentre prospective cohort study (2b)223; 2,462

      44; 489

      179; 1,973
      < 6 m

      No

      Parent questionnaire
      2 ySerum IgE (food and inhalant allergens)Exposure to AB in first 6 m of life not associated with increased risk.

      • aOR 1.32 (95%CI 0.86-2.02), p=nr
      Sex, family history of atopy, day care, number of siblings, delivery mode, vaccination status, fever, breastfeeding, pet and smoke exposure
      Floistrup et al.
      • Floistrup H
      • Swartz J
      • Bergstrom A
      • et al.
      Allergic disease and sensitization in Steiner school children.


      Netherlands, Austria, Germany, Sweden, Switzerland

      2006
      Multicentre cross-sectional study (3b)1,487; 4,606

      264
      calculated from reported data
      ; 788

      1,223
      calculated from reported data
      ; 3,818
      < 1 y

      No

      Parent questionnaire
      7-11 ySerum IgE (food and inhalant allergens)Exposure to AB in first y of life not associated with increased risk.

      • aOR 0.91 (95%CI 0.60-1.37), p=nr
      Age, sex, family history of atopy, number of siblings, living country, parental education, measles infection, vaccination status, medication use, smoking during pregnancy, diet, parental smoking, pet exposure
      Johnson et al.
      • Johnson CC
      • Ownby DR
      • Alford SH
      • et al.
      Antibiotic exposure in early infancy and risk for childhood atopy.


      USA

      2005
      Multicentre prospective cohort study (2b)157; 448

      83
      calculated from reported data
      ; 221

      74
      calculated from reported data
      ; 227
      < 6 m

      No

      Medical records
      6-7 yClinical evaluation plus SPTExposure to AB in first 6 m of life not associated with increased risk.

      • aOR 1.48 (95%CI 0.94-2.34), p=0.09
      Family history of atopy, number of LRTIs, duration of breastfeeding, pet exposure
      Wjst et al.
      • Wjst M
      • Hoelscher B
      • Frye C
      • Wichmann HE
      • Dold S
      • Heinrich J.
      Early antibiotic treatment and later asthma.


      Germany

      2001
      Multicentre cross-sectional study (3b)1,944; 2,512

      nr; 2,025

      nr; 487
      < 5-14 y

      No

      Medical records
      5-14 ySPT (food and inhalant allergens)Exposure to AB in first y of life not associated with increased risk.

      • aOR 0.90 (95%CI 0.60-1.40), p=0.71
      Age, sex, family history of atopy, season, parental education
      Droste et al.
      • Droste JH
      • Wieringa MH
      • Weyler JJ
      • Nelen VJ
      • Vermeire PA
      • Van Bever HP.
      Does the use of antibiotics in early childhood increase the risk of asthma and allergic disease?.


      Belgium

      2000
      Multicentre cross-sectional study (3b)130; 660

      45; 210

      85; 450
      < 1 y

      No

      Parent questionnaire
      7-8 ySPT (inhalant allergens)Exposure to AB in first y of life not associated with increased risk in high-risk children.

      • aOR 1.10 (95%CI 0.70-1.70), p=0.10
      Sex, family history of atopy, number of siblings, living area, smoking during pregnancy, smoke exposure
      Von Mutius et al.
      • von Mutius E
      • Illi S
      • Hirsch T
      • Leupold W
      • Keil U
      • Weiland SK.
      Frequency of infections and risk of asthma, atopy and airway hyperresponsiveness in children.


      Germany

      1999
      Single-centre cross-sectional study (3b)222; 5,006

      168; 3,904

      54; 1,102
      < 3 y

      No

      Medical records
      5-7 ySerum IgE (inhalant allergens) plus SPTExposure to AB in first 3 y of life not associated with increased risk.

      • OR 0.87 (95%CI 0.64-1.19), p=0.40
      calculated from reported data
      946; 5,267

      745; 4,006

      201; 1,261
      9-11 yExposure to AB in first 3 y of life associated with increased risk.

      OR 1.20 (95%CI 1.02-1.43), p=0.03
      calculated from reported data
      Food allergies
      Aversa et al.
      • Aversa Z
      • Atkinson EJ
      • Schafer MJ
      • et al.
      Association of Infant Antibiotic Exposure With Childhood Health Outcomes.


      USA

      2021
      Multicentre prospective cohort study (2b)261; 14,572

      201; 10,220

      60; 4,352
      < 2 y

      Yes

      Medical records
      6-11 yICD-9 and ICD-10 codesExposure to AB in first 2 y of life not associated with increased risk.

      • aHR 1.33 (95%CI 0.99-1.77), p=0.05

      Girls

      • penicillins: HR 0.74 (95%CI 0.47-1.15), p=0.18

      • cephalosporins: HR 2.73 (95%CI 1.74-4.28), p<0.01

      • macrolides: HR 1.00 (95%CI 0.62-1.59), p=0.99

      •sulfonamides: HR 1.27 (95%CI 0.65-2.49), p=0.49

      Boys

      • penicillins: HR 1.06 (95%CI 0.73-1.53), p=0.77

      • cephalosporins: HR 1.96 (95%CI 1.39-2.76), p<0.01

      • macrolides: HR 0.99 (95%CI 0.69-1.41), p=0.94

      •sulfonamides: HR 0.67 (95%CI 0.31-1.43), p=0.30
      Sex, ethnicity, maternal age, maternal education, antibiotic use during pregnancy, birth weight, delivery mode, maternal smoking
      Zou et al.
      • Zou Z
      • Liu W
      • Huang C
      • Sun C
      • Zhang J.
      First-Year Antibiotics Exposure in Relation to Childhood Asthma, Allergies, and Airway Illnesses.


      China

      2020
      Multicentre cross-sectional study (3b)1,938; 12,667

      560; 3,049

      1,378; 9,618
      < 1 y

      No

      Parent questionnaire
      4-6 yQuestionnaire for allergic symptoms (ISAAC)Exposure to AB in first y of life associated with increased risk.

      aOR 1.29 (95%CI 1.13-1.46), p<0.01
      Age, sex, living area, family history of atopy, breastfeeding, home decoration, pet, smoke and home dampness-related exposure
      Levin et al.
      • Levin ME
      • Botha M
      • Basera W
      • et al.
      Environmental factors associated with allergy in urban and rural children from the South African Food Allergy (SAFFA) cohort.


      South-Africa

      2020
      Multicentre prospective cohort study (2b)27; 1,185

      18; 654

      9; 531
      < 1 y

      No

      Parent questionnaire
      12-36 mQuestionnaire for allergic symptoms (based on ISAAC)Exposure to AB in first y of life not associated with increased risk in urban cohort.

      • OR 1.64 (95%CI 0.73-3.68), p=0.23
      calculated from reported data
      2; 398

      2; 347

      0; 51
      Exposure to AB in first y of life not associated with increased risk in rural cohort.

      • OR 0.75 (95%CI 0.04-15.75), p=0.19
      calculated from reported data
      Metzler et al.
      • Metzler S
      • Frei R
      • Schmauser-Hechfellner E
      • et al.
      Association between antibiotic treatment during pregnancy and infancy and the development of allergic diseases.


      Switzerland

      2019
      Multicentre prospective cohort study (2b)75; 1,019

      37; 419

      38; 600
      < 1 y

      No

      Parent questionnaire
      < 6 yQuestionnaire for allergic symptoms (based on ISAAC) plus parent-reported physician's diagnosisExposure to AB in first y of life not associated with increased risk.

      • aOR 1.47 (95%CI 0.73-2.98), p=nr
      Sex, family history of atopy, number of siblings, living area, smoking during pregnancy, pet exposure during pregnancy, delivery mode, duration of breastfeeding, pet exposure
      Gao et al.
      • Gao X
      • Yan Y
      • Zeng G
      • et al.
      Influence of prenatal and early-life exposures on food allergy and eczema in infancy: a birth cohort study.


      China

      2019
      Single-centre prospective cohort study (2b)200; 903

      43; 201

      157; 702
      < 1 y

      No

      Parent questionnaire
      12 mParent-reportedExposure to AB in first y of life not associated with increased risk.

      • OR 0.94 (95%CI 0.65-1.38), p=0.77
      calculated from reported data
      Sex, family history of atopy, antibiotic use during pregnancy, season of birth, egg and milk consumption
      Li et al.
      • Marisen J
      • Hais A
      • Meyer C
      • et al.
      Efficacy of Bifidobacterium longum, B. infantis and Lactobacillus acidophilus probiotics to prevent gut dysbiosis in preterm infants of 28+0-32+6 weeks of gestation: a randomised, placebo-controlled, double-blind, multicentre trial: the PRIMAL Clinical Study protocol.


      USA

      2019
      Multicentre prospective cohort study (2b)14,812; 1,001,294

      9,193; 500,647

      5,619; 500,647
      < 1 y

      No

      Registry
      < 4 yICD-9-CM codesExposure to AB in first y of life associated with increased risk.

      aHR 1.40 (95%CI 1.34-1.45), p=nr
      Day care, living area, prematurity, birth weight, delivery mode, neonatal intensive-care unit admission, State Children's Health Insurance Program, atopy
      Mitre et al.
      • Mitre E
      • Susi A
      • Kropp LE
      • Schwartz DJ
      • Gorman GH
      • Nylund CM.
      Association Between Use of Acid-Suppressive Medications and Antibiotics During Infancy and Allergic Diseases in Early Childhood.


      USA

      2018
      Multicentre retrospective cohort study (2b)24,514; 792,130

      4,753; 131,708

      19,761; 660,422
      < 6 m

      No

      Registry
      1-6 yICD-9-CM codesExposure to AB in first 6 m of life associated with increased risk.

      aHR 1.14 (95%CI 1.10-1.18), p=nr
      Sex, prematurity, delivery mode, medication (incl. anti-reflux medication) use
      Hirsch et al.
      • Hirsch AG
      • Pollak J
      • Glass TA
      • et al.
      Early-life antibiotic use and subsequent diagnosis of food allergy and allergic diseases.


      USA

      2017
      Multicentre case-control study (3b)484; 2,904

      210; 1,074

      274; 1,830
      >1-2 m before diagnosis

      Yes

      Medical records
      < 7 yCow's milk allergy ICD-9 codes plus medical or prescription recordsExposure to AB until 2 m before diagnosis associated with increased risk.

      aOR 1.58 (95%CI 1.24-2.02), p=nr

      • ≤ 2 AB courses: aOR 1.49 (95%CI 1.15-1.96), p=nr

      • ≥ 3 AB courses: aOR 1.78 (95%CI 1.28-2.48), p=nr

      • penicillins: aOR 1.58 (95%CI 1.24-2.02), p=nr

      • cephalosporins: aOR 1.40 (95%CI 1.02-1.93), p=nr

      • macrolides: aOR 1.68 (95%CI 1.19-2.37), p=nr
      Ethnicity, healthcare use
      598; 3,588

      445; 2,496

      153; 1,092
      Non-milk food allergy ICD-9 codes plus medical or prescription recordsExposure to AB until 2 m before diagnosis associated with increased risk.

      aOR 1.49 (95%CI 1.18-1.87), p=nr

      • ≤ 2 AB courses: aOR 1.38 (95%CI 1.08-1.77), p=nr

      • ≥ 3 AB courses: aOR 1.65 (95%CI 1.27-2.14), p=nr

      • penicillins: aOR 1.29 (95%CI 1.04-1.59), p=nr

      • cephalosporins: aOR 1.57 (95%CI 1.29-1.93), p=nr

      • macrolides: aOR 1.58 (95%CI 1.28-1.96), p=nr
      Batool et al.
      • Batool T
      • Reece PL
      • Schulze KM
      • et al.
      Prenatal and early-life predictors of atopy and allergic disease in Canadian children: results of the Family Atherosclerosis Monitoring In earLY life (FAMILY) Study.


      Canada

      2016
      Multicentre prospective cohort study (2b)143; 818

      62; 285

      81; 533
      < 1 y

      No

      Parent questionnaire
      1 yParent-reported food allergies or SPTExposure to AB in first y of life associated with increased risk.

      OR 1.55 (95%CI 1.07-2.24), p=0.02
      calculated from reported data
      Love et al.
      • Love BL
      • Mann JR
      • Hardin JW
      • Lu ZK
      • Cox C
      • Amrol DJ.
      Antibiotic prescription and food allergy in young children.


      USA

      2016
      Multicentre retrospective case-control study (3b)1,504; 7,499

      722; 3,324

      782; 4,175
      < 1 y

      Yes

      Prescription records
      0-3 yICD-9-CM codesExposure to AB in first y of life associated with increased risk.

      aOR 1.21 (95%CI 1.06-1.39), p<0.01

      • penicillins: aOR 1.19 (95%CI 1.04-1.36), p=0.01

      • cephalosporins: aOR 1.50 (95%CI 1.27-1.77), p<0.01

      • macrolides: aOR 1.36 (95%CI 1.13-1.63), p<0.01

      •sulfonamides: aOR 1.54 (95%CI 1.19-2.01), p<0.01
      Maternal age, pre-pregnancy diabetes, living area, smoking during pregnancy, gestational age, delivery mode, atopy, breastfeeding, maternal smoking
      Metsälä et al.
      • Metsala J
      • Lundqvist A
      • Virta LJ
      • Kaila M
      • Gissler M
      • Virtanen SM.
      Mother's and offspring's use of antibiotics and infant allergy to cow's milk.


      Finland

      2013
      Multicentre case-control study (3b)533; 15,672

      162
      calculated from reported data
      ; 3,292

      371
      calculated from reported data
      ; 12,380
      < 1 m before diagnosis

      Yes

      Registry
      1 m-8 yCow's milk allergy ICD-10 codes plus SPT plus serum IgEExposure to AB within 1 m before diagnosis associated with increased risk.

      aOR 1.71 (95%CI 1.59-1.84), p=nr

      • penicillin: aOR 1.97 (95%CI 1.50-2.58), p=nr

      • amoxicillin: aOR 1.39 (95%CI 1.29-1.51), p=nr

      • cephalosporins: aOR 2.43 (95%CI 2.14-2.77), p=nr

      • macrolides: aOR 1.65 (95%CI 1.49-1.82), p=nr

      • trimethoprim/sulfamethoxazole: aOR 1.60 (95%CI 1.27-2.02), p=nr
      Maternal age, maternal parity, smoking during pregnancy, birth weight, delivery mode
      Dowhower Karpa et al.
      • Dowhower Karpa K
      • Paul IM
      • Leckie JA
      • et al.
      A retrospective chart review to identify perinatal factors associated with food allergies.


      USA

      2012
      Single-centre retrospective case-control study (4)99; 291

      16; 40

      83; 251
      < 1 m

      No

      Medical records
      0-18 yICD-9-CM codes plus serum IgE or SPT or physician's diagnosisEarly exposure to AB not associated with increased risk.

      • OR 1.35 (95%CI 0.68-2.68), p=0.39
      Raciborski et al.
      • Raciborski F
      • Tomaszewska A
      • Komorowski J
      • et al.
      The relationship between antibiotic therapy in early childhood and the symptoms of allergy in children aged 6-8 years - the questionnaire study results.


      Poland

      2012
      Multicentre retrospective cohort study (2b)307; 1,330

      211; 820

      96; 510
      < 1 y

      No

      Parent questionnaire
      6-8 yQuestionnaire for allergic symptoms (ISAAC)Exposure to AB in first y of life associated with increased risk.

      OR 1.49 (95%CI 1.14-1.96), p<0.01
      calculated from reported data


      • 1 AB course: OR 1.23 (95%CI nr), p=0.22

      • 2-3 AB courses: OR 1.30 (95%CI nr), p=0.18

      • > 3 AB courses: OR 1.52 (95%CI nr), p=0.05
      307; 1,321

      273; 1,145

      34; 176
      1-3 y

      No

      Parent questionnaire
      Exposure to AB in first to third y of life not associated with increased risk.

      • OR 1.31 (95%CI 0.88-1.95), p=0.19

      • 1-2 AB courses: OR 1.12 (95%CI nr), p=0.62

      • 3-4 AB courses: OR 1.32 (95%CI nr), p=0.23

      • > 4 AB courses: OR 1.32 (95%CI nr), p=0.24
      Mai et al.
      • Mai XM
      • Kull I
      • Wickman M
      • Bergström A.
      Antibiotic use in early life and development of allergic diseases: respiratory infection as the explanation.


      Sweden

      2010
      Single-centre prospective cohort study (2b)354; 3,306

      181; 1,420

      173; 1,886
      < 1 y

      No

      Parent questionnaire
      4 yQuestionnaire for allergic symptoms (BAMSE based on ISAAC)Exposure to AB in first y of life associated with increased risk.

      aOR 1.40 (95%CI 1.10-1.70), p=nr
      Sex, maternal age, family history of atopy, number of siblings, breastfeeding, maternal smoking
      436; 3,306

      206; 1,420

      230; 1,886
      8 yExposure to AB in first y of life not associated with increased risk.

      • aOR 1.20 (95%CI 0.90-1.40), p=nr
      Eggesbo et al.
      • Eggesbo M
      • Botten G
      • Stigum H
      • Nafstad P
      • Magnus P.
      Is delivery by cesarean section a risk factor for food allergy?.


      Norway

      2003
      Single-centre retrospective cohort study (2b)32; 2,759

      12; 963

      20; 1,796
      < 6 m

      No

      Parent questionnaire
      2.5 yParent-reported immediate reaction plus serum IgEExposure to AB in first 6 m of life not associated with increased risk.

      • aOR 1.50 (95% CI, 0.60-3.70), p=0.40
      Maternal age, number of siblings, maternal education, restricted growth in pregnancy, pregnancy complications, gestational age, birth weight, maternal smoking
      Allergic rhinoconjunctivitis
      Aversa et al.
      • Aversa Z
      • Atkinson EJ
      • Schafer MJ
      • et al.
      Association of Infant Antibiotic Exposure With Childhood Health Outcomes.


      USA

      2021
      Multicentre prospective cohort study (2b)971; 14,572

      760; 10,220

      211; 4,352
      < 2 y

      Yes

      Medical records
      6-11 yICD-9 and ICD-10 codesExposure to AB in first 2 y of life associated with increased risk.

      aHR 1.36 (95%CI 1.17-1.59), p<0.01

      Girls

      • penicillins: HR 1.15 (95%CI 0.91-1.46), p=0.25

      • cephalosporins: HR 1.83 (95%CI 1.46-2.30), p<0.01

      • macrolides: HR 1.11 (95%CI 0.88-1.40), p=0.36

      •sulfonamides: HR 1.16 (95%CI 0.81-1.66), p=0.41

      Boys

      • penicillins: HR 1.16 (95%CI 0.95-1.41), p=0.15

      • cephalosporins: HR 1.29 (95%CI 1.07-1.55), p<0.01

      • macrolides: HR 1.39 (95%CI 1.16-1.66), p<0.01

      •sulfonamides: HR 1.10 (95%CI 0.80-1.52), p=0.56
      Sex, ethnicity, maternal age, maternal education, antibiotic use during pregnancy, birth weight, delivery mode, maternal smoking
      Zou et al.
      • Zou Z
      • Liu W
      • Huang C
      • Sun C
      • Zhang J.
      First-Year Antibiotics Exposure in Relation to Childhood Asthma, Allergies, and Airway Illnesses.


      China

      2020
      Multicentre cross-sectional study (3b)1,579; 12,667

      479; 3,049

      1,100; 9,618
      < 1 y

      No

      Parent questionnaire
      4-6 yQuestionnaire for allergic rhinitis symptoms (ISAAC)Exposure to AB in first y of life associated with increased risk.

      aOR 1.23 (95%CI 1.07-1.41), p<0.01
      Age, sex, living area, family history of atopy, breastfeeding, home decoration, pet, smoke and home dampness-related exposure
      Levin et al.
      • Levin ME
      • Botha M
      • Basera W
      • et al.
      Environmental factors associated with allergy in urban and rural children from the South African Food Allergy (SAFFA) cohort.


      South-Africa

      2020
      Multicentre prospective cohort study (2b)295; 1,185

      187; 654

      108; 531
      < 1 y

      No

      Parent questionnaire
      12-36 mQuestionnaire for allergic rhinitis symptoms (based on ISAAC)Exposure to AB in first y of life associated with increased risk in urban cohort.

      OR 1.57 (95%CI 1.20-2.06), p<0.01
      calculated from reported data
      13; 398

      12; 347

      1; 51
      Exposure to AB in first y of life not associated with increased risk in rural cohort.

      • OR 1.79 (95%CI 0.23-14.07), p=0.58
      calculated from reported data
      Chinratanapisit et al.
      • Chinratanapisit S
      • Suratannon N
      • Pacharn P
      • Sritipsukho P
      • Vichyanond P.
      Prevalence and risk factors of allergic rhinitis in children in Bangkok area.


      Thailand

      2019
      Multicentre cross-sectional study (3b)462; 3,074

      237; 1,138

      225; 1,936
      < 1 y

      No

      Parent questionnaire
      6-7 yQuestionnaire for allergic rhinitis symptoms (ISAAC)Exposure to AB in first y of life associated with increased risk.

      OR 2.00 (95%CI 1.64-2.44), p<0.01
      calculated from reported data
      Age, sex, family history of atopy, number of siblings, migration, birth weight, BMI, medication use, parental smoking, diet, pet, farm animal, air pollution, cooking fuels, and traffic exposure
      Ni et al.
      • Ni J
      • Friedman H
      • Boyd BC
      • et al.
      Early antibiotic exposure and development of asthma and allergic rhinitis in childhood.


      USA

      2019
      Single-centre retrospective cohort study (4)233; 2,398

      130
      calculated from reported data
      ; 1,060

      103
      calculated from reported data
      ; 1,338
      < 1 y

      Yes

      Medical records
      1-10 yICD-9 and ICD-10 codesExposure to AB in first y of life not associated with increased risk.

      • aOR 1.41 (95%CI 0.48-4.14), p=0.53

      Results according to antibiotic class nr
      Age, sex, ethnicity, socioeconomic status, prematurity, birth weight, delivery mode, neonatal intensive-care unit admission
      215; 2,398

      198
      calculated from reported data
      ; 1,755

      17
      calculated from reported data
      ; 643
      < 10 y

      Yes

      Medical records
      Exposure to AB in first 10 y of life associated with increased risk.

      aOR 2.43 (95%CI 1.43-4.11), p<0.01

      Results according to antibiotic class nr
      Norbäck et al.
      • Norback D
      • Lu C
      • Zhang Y
      • et al.
      Sources of indoor particulate matter (PM) and outdoor air pollution in China in relation to asthma, wheeze, rhinitis and eczema among pre-school children: Synergistic effects between antibiotics use and PM10and second hand smoke.


      China

      2019
      Multicentre retrospective cohort study (2b)3,463; 39,782

      3,000; 29,303

      463; 10,479
      < 1 y

      No

      Parent questionnaire
      3-6 yParent-reported physician's diagnosisExposure to AB in first y of life associated with increased risk.

      aOR 1.77 (95%CI 1.54-2.03), p<0.01

      • 1 AB course: aOR 1.19 (95%CI 1.06-1.34), p<0.01

      • > 1 AB courses: aOR 1.51 (95%CI 1.36-1.68), p<0.01
      Living city, time spend outdoors, air pollution, temperature in each city
      Metzler et al.
      • Metzler S
      • Frei R
      • Schmauser-Hechfellner E
      • et al.
      Association between antibiotic treatment during pregnancy and infancy and the development of allergic diseases.


      Switzerland

      2019
      Multicentre prospective cohort study (2b)59; 1,019

      21; 419

      38; 600
      < 1 y

      No

      Parent questionnaire
      < 6 yQuestionnaire for allergic symptoms (based on ISAAC) plus parent-reported physician's diagnosisExposure to AB in first y of life not associated with increased risk.

      • aOR 0.70 (95%CI 0.33-1.51), p=nr
      Sex, family history of atopy, number of siblings, living area, smoking during pregnancy, pet exposure during pregnancy, delivery mode, duration of breastfeeding, pet exposure
      Mitre et al.
      • Mitre E
      • Susi A
      • Kropp LE
      • Schwartz DJ
      • Gorman GH
      • Nylund CM.
      Association Between Use of Acid-Suppressive Medications and Antibiotics During Infancy and Allergic Diseases in Early Childhood.


      USA

      2018
      Multicentre retrospective cohort study (2b)24,585; 792,130

      5,047; 131,708

      19,538; 660,422
      < 6 m

      No

      Registry
      1-6 yAllergic conjunctivitis

      ICD-9-CM codes
      Exposure to AB in first 6 m of life associated with increased risk.

      aHR 1.42 (95%CI 1.34-1.50), p=nr
      Sex, prematurity, delivery mode, medication (incl. anti-reflux medication) use
      248,232; 792,130

      52,135; 131,708

      196,097; 660,422
      Allergic rhinitis

      ICD-9-CM codes
      Exposure to AB in first 6 m of life associated with increased risk.

      aHR 1.75 (95%CI 1.72-1.78), p=nr
      Singh et al.
      • Singh S
      • Sharma BB
      • Salvi S
      • et al.
      Allergic rhinitis, rhinoconjunctivitis, and eczema: prevalence and associated factors in children.


      India

      2018
      Multicentre cross-sectional study (3b)1,753; 44,928

      nr; nr

      nr; nr
      < 1 y

      No

      Parent questionnaire
      6-7 yQuestionnaire for allergic rhinoconjunctivitis symptoms (ISAAC)Exposure to AB in first y of life associated with increased risk.

      OR 1.90 (95%CI 1.70-2.20), p<0.01
      5,100; 44,928

      nr; nr

      nr; nr
      Questionnaire for allergic rhinitis symptoms (ISAAC)Exposure to AB in first y of life associated with increased risk.



      OR 1.90 (95%CI 1.70-2.00), p<0.01
      Han et al.
      • Han YY
      • Forno E
      • Badellino HA
      • Celedon JC.
      Antibiotic Use in Early Life, Rural Residence, and Allergic Diseases in Argentinean Children.


      Argentina

      2017
      Multicentre cross-sectional study (3b)207; 1,517

      155; 921

      52; 596
      < 1 y

      No

      Parent questionnaire
      6-7 yQuestionnaire for allergic rhinoconjunctivitis symptoms (ISAAC)Exposure to AB in first y of life associated with increased risk.

      aOR 1.90 (95%CI 1.30-2.70), p<0.01
      Number of LRTIs, medication use
      Yamamoto-Hanada et al.
      • Yamamoto-Hanada K
      • Yang L
      • Narita M
      • Saito H
      • Ohya Y
      Influence of antibiotic use in early childhood on asthma and allergic diseases at age 5.


      Japan

      2017
      Multicentre prospective cohort study (2b)96; 902

      59; 436

      37; 466
      < 2 y

      Yes

      Parent questionnaire
      5 yQuestionnaire for allergic rhinitis (ISAAC) symptoms plus medical recordsExposure to AB in first 2 y of life associated with increased risk.

      aOR 1.65 (95%CI 1.05-2.58), p=0.03

      • penicillins: aOR 0.58 (95%CI 0.22-1.51), p=0.26

      • cephem: aOR 1.82 (95%CI 1.12-2.93), p=0.02

      • macrolides: aOR 1.50 (95%CI 0.902.49), p=0.12
      Sex, maternal age, maternal parity, maternal BMI, maternal history of atopy, day care, maternal education, smoking during pregnancy, gestational age, delivery mode, number of LRTIs
      Wang et al.
      • Wang X
      • Liu W
      • Hu Y
      • Zou Z
      • Shen L
      • Huang C.
      Home environment, lifestyles behaviors, and rhinitis in childhood.


      China

      2016
      Multicentre cross-sectional study (3b)1,624; 13,335

      nr; nr

      nr; nr
      < 1 y

      No

      Parent questionnaire
      4-6 yQuestionnaire for allergic rhinitis (ISAAC)Exposure to AB in first y of life associated with increased risk.

      aOR 1.23 (95%CI 1.09–1.40), p=nr
      Age, sex, family history of atopy
      Yang et al.
      • Yang SI
      • Lee E
      • Jung YH
      • et al.
      Effect of antibiotic use and mold exposure in infancy on allergic rhinitis in susceptible adolescents.


      Korea

      2014
      Multicentre cross-sectional study (3b)1,768; 6,435

      1,258; 1,947

      2,629; 4,488
      < 1 y

      No

      Parent questionnaire
      15 yQuestionnaire for allergic rhinitis symptoms (ISAAC)Exposure to AB in first y of life associated with increased risk.

      aOR 1.25 (95%CI 1.04-1.50), p=0.02
      Age, sex, study centre, family history of atopy, income, BMI
      Alm et al.
      • Alm B
      • Goksor E
      • Pettersson R
      • et al.
      Antibiotics in the first week of life is a risk factor for allergic rhinitis at school age.


      Sweden

      2014
      Multicentre prospective cohort study (2b)564; 4,051

      40
      calculated from reported data
      ; 187

      524
      calculated from reported data
      ; 3,864
      < 1 w

      No

      Parent questionnaire
      8 yQuestionnaire for allergic rhinitis symptoms (ISAAC and BAMSE)Exposure to AB in first w of life associated with increased risk.

      aOR 1.75 (95%CI 1.03-2.97), p=nr
      Sex, maternal age, family history of atopy, living area, paternal education, maternal medication during pregnancy, weight for gestational age, atopy, diet, pacifier use, time spend outdoors, pet exposure
      Tamay et al.
      • Tamay Z
      • Akçay A
      • Ergin A
      • Güler N.
      Prevalence of allergic rhinitis and risk factors in 6- to 7-yearold children in İstanbul, Turkey.


      Turkey

      2014
      Multicentre prospective cohort study (2b)803; 9,875

      nr; nr

      nr; nr
      < 1 y

      No

      Parent questionnaire
      6-7 yQuestionnaire for allergic rhinitis symptoms (ISAAC)Exposure to AB in first y of life associated with increased risk.

      aOR 1.41 (95%CI 1.15-1.73), p<0.05
      Number of LRTIs, perianal redness, adenotonsillectomy, medication use, pet exposure, environmental factors
      Hoskin-Parr et al.
      • Hoskin-Parr L
      • Teyhan A
      • Blocker A
      • Henderson AJ.
      Antibiotic exposure in the first two years of life and development of asthma and other allergic diseases by 7.5 yr: a dose-dependent relationship.


      UK

      2013
      Single-centre prospective cohort study (2b)503; 5,780

      260
      calculated from reported data
      ; 2,659

      243
      calculated from reported data
      ; 3,121
      < 2 y

      No

      Parent questionnaire
      7.5 y (mean)Parents-reported physician's diagnosisExposure to AB in first 2 y of life associated with increased risk.

      aOR 1.28 (95%CI 1.03-1.60), p=nr

      • 1 AB course: aOR 1.17 (95%CI 0.88-1.54), p=nr

      • 2 AB courses: aOR 1.21 (95%CI 0.90-1.61), p=nr

      • 3 AB courses: aOR 1.18 (95%CI 0.86-1.61), p=nr

      • ≥ 4 AB courses: aOR 1.60 (95%CI 1.21-2.10), p=nr
      Age, sex, maternal age, parental marital status, home ownership status, degree of difficulty in paying for food, maternal education, smoking during pregnancy, disinfectant use during pregnancy, gestational age, birth weight, delivery mode, age of child at outcome measurement, breastfeeding, time spend outdoors, pet exposure
      Muc et al.
      • Muc M
      • Padez C
      • Pinto AM.
      Exposure to paracetamol and antibiotics in early life and elevated risk of asthma in childhood.


      Portugal

      2013
      Multicentre cross-sectional study (3b)14; 1,037

      5
      calculated from reported data
      ; 237

      9
      calculated from reported data
      ; 800
      < 1 y

      No

      Parent questionnaire
      6-9 yQuestionnaire for allergic rhinitis symptoms (ISAAC)Exposure to AB in first y of life associated with increased risk.

      aOR 1.84 (95%CI 1.30-2.59), p<0.01
      Age, sex, prematurity, atopy
      Wang et al.
      • Wang JY
      • Liu LF
      • Chen CY
      • Huang YW
      • Hsiung CA
      • Tsai HJ.
      Acetaminophen and/or antibiotic use in early life and the development of childhood allergic diseases.


      Taiwan

      2013
      Multicentre prospective cohort study (2b)82,292; 263,620

      nr; 15,663

      nr; 247,957
      < 1 y

      Yes

      Medical records
      2-6 yICD-9-CM codesExposure to AB in first y of life associated with increased risk.

      aHR 1.41 (95%CI 1.35-1.47), p<0.05

      Results according to antibiotic class nr
      Sex, living area, socioeconomic status, healthcare use
      Kim et al.
      • Kim WK
      • Kwon JW
      • Seo JH
      • et al.
      Interaction between IL13 genotype and environmental factors in the risk for allergic rhinitis in Korean children.


      Korea

      2012
      Multicentre cross-sectional study (3b)1,550; 4,436

      748
      calculated from reported data
      ; 1,528

      802
      calculated from reported data
      ; 2,908
      < 1 y

      No

      Parent questionnaire
      9.5 y (mean)Questionnaire for allergic rhinitis symptoms (ISAAC)Exposure to AB in first y of life associated with increased risk.

      aOR 1.95 (95%CI 1.61-2.36), p<0.01

      Strongest risk of children with atopic parents

      aOR 6.00 (95%CI 4.63-7.80), p=nr
      Age, sex, study centre, family history of atopy, maternal education, BMI, smoke exposure
      Peñaranda et al.
      • Penaranda A
      • Aristizabal G
      • Garcia E
      • Vasquez C
      • Rodriguez-Martinez CE
      • Satizabal CL.
      Allergic rhinitis and associated factors in schoolchildren from Bogota, Colombia.


      Colombia

      2012
      Multicentre cross-sectional study (3b)588; 3,256

      401; nr

      163; nr
      < 1 y

      No

      Parent questionnaire
      6-7 yQuestionnaire for allergic rhinitis symptoms (ISAAC)Exposure to AB in first y of life associated with increased risk.

      aOR 1.30 (1.10-1.70), p=0.01
      Maternal education, delivery mode, atopy, medication use, household smoking
      687; 3,830

      nr; nr

      nr; nr
      13-14 yExposure to AB in first y of life not associated with increased risk.
      Sandini et al.
      • Sandini U
      • Kukkonen AK
      • Poussa T
      • Sandini L
      • Savilahti E
      • Kuitunen M.
      Protective and risk factors for allergic diseases in high-risk children at the ages of two and five years.


      Finland

      2011
      Single-centre prospective cohort study (2b)177; 891

      nr; nr

      nr; nr
      < 6 m

      No

      Parent questionnaire
      5 yParent-reported allergic rhinitis symptomsExposure to AB in first 6 m of life not associated with increased risk.

      • OR 0.92 (95%CI 0.54-1.56), p=0.75
      Mai et al.
      • Mai XM
      • Kull I
      • Wickman M
      • Bergström A.
      Antibiotic use in early life and development of allergic diseases: respiratory infection as the explanation.


      Sweden

      2010
      Single-centre prospective cohort study (2b)369; 3,306

      176; 1,420

      193; 1,886
      < 1 y

      No

      Parent questionnaire
      4 yQuestionnaire for allergic rhinitis symptoms (BAMSE based on ISAAC)Exposure to AB in first y of life not associated with increased risk.

      • aOR 1.20 (95%CI 0.90-1.50), p=nr
      Sex, maternal age, family history of atopy, number of siblings, breastfeeding, maternal smoking
      447; 3,306

      202; 1,420

      245; 1,886
      8 yExposure to AB in first y of life not associated with increased risk.

      • aOR 1.10 (95%CI 0.90-1.30), p=nr
      Sultesz et al.
      • Sultész M
      • Katona G
      • Hirschberg A
      • Gálffy G.
      Prevalence and risk factors for allergic rhinitis in primary schoolchildren in Budapest.


      Hungary

      2010
      Single-centre case-control study (3b)883; 3,322

      473; 1,495

      410; 1,827
      < 1 y

      No

      Parent questionnaire
      6-12 yQuestionnaire for allergic rhinitis symptoms (based on ISAAC)Exposure to AB in first y of life associated with increased risk.

      OR 1.60 (95%CI 1.37-1.87), p<0.01
      Foliaki et al.
      • Foliaki S
      • Pearce N
      • Bjorksten B
      • et al.
      Antibiotic use in infancy and symptoms of asthma, rhinoconjunctivitis, and eczema in children 6 and 7 years old: International Study of Asthma and Allergies in Childhood Phase III.


      Sweden

      2009
      Multicentre retrospective cross-sectional study (3b)nr; 193,412

      nr; 135,775

      nr; 57,637
      < 1 y

      No

      Parent questionnaire
      6-7 yQuestionnaire for rhinoconjunctivitis (ISAAC)Exposure to AB in first y of life associated with increased risk.



      aOR 1.56 (95%CI 1.46-1.66), p=nr
      Sex, language, living area, income
      Karimi et al.
      • Karimi M
      • Mirzaei M.
      Antibiotic use and symptoms of asthma, allergic rhinitis and eczema in children.


      Iran

      2009
      Multicentre cross-sectional study (3b)195; 1,476

      134; 958
      calculated from reported data


      61; 518
      calculated from reported data
      < 1 y

      No

      nr
      6-7 yQuestionnaire for allergic rhinitis symptoms (ISAAC)Exposure to AB in first y of life not associated with increased risk.

      • OR 1.22 (95%CI 0.87-1.72), p=0.20
      Harris et al.
      • Harris JM
      • Mills P
      • White C
      • Moffat S
      • Newman Taylor AJ
      • Cullinan P
      Recorded infections and antibiotics in early life: associations with allergy in UK children and their parents.


      UK

      2007
      Single-centre prospective cohort study (2b)124; 523

      43; nr

      81; nr
      < 5 y

      No

      Medical records
      8 yQuestionnaire for allergic rhinitis symptoms (ISAAC)Exposure to AB in first 5 y of life associated with increased risk.

      aOR 1.06 (95%CI 1.03-1.09), p<0.01
      Family history of atopy, birth order, smoke exposure
      Mullooly et al.
      • Mullooly JP
      • Schuler R
      • Barrett M
      • Maher JE.
      Vaccines, antibiotics, and atopy.


      USA

      2007
      Single-centre case-control study (3b)660; 844

      nr; nr

      nr; nr
      < 2 y

      No

      Medical records
      10.3 y (mean)Parent-reported physician's diagnosisExposure to AB in first 2 y of life not associated with increased risk.

      • aOR 1.03 (95%CI 0.99-1.08), p=nr
      Sex, ethnicity, maternal age, birth weight, age of child at time of outcome, breastfeeding, household smoking
      Tamay et al.
      • Tamay Z
      • Akcay A
      • Ones U
      • Guler N
      • Kilic G
      • Zencir M.
      Prevalence and risk factors for allergic rhinitis in primary school children.


      Turkey

      2007
      Multicentre prospective cohort study (2b)671; 2,500

      430; nr

      241; nr
      < 1 y

      No

      Parent questionnaire
      6-12 yQuestionnaire for allergic rhinitis symptoms (ISAAC)Exposure to AB in first y of life associated with increased risk.

      aOR 1.26 (1.01-1.57), p=nr
      Family history of atopy, number of LRTIs and sinusitis, atopy, adenotonsillectomy, perianal redness, medication use, pet, home-dampness and diesel trucks exposure
      Floistrup et al.
      • Floistrup H
      • Swartz J
      • Bergstrom A
      • et al.
      Allergic disease and sensitization in Steiner school children.


      Netherlands, Austria, Germany, Sweden, Switzerland

      2006
      Multicentre cross-sectional study (3b)216; 4,606

      67
      calculated from reported data
      ; 788

      149
      calculated from reported data
      ; 3,818
      < 1 y

      No

      Parent questionnaire
      7-11 yParent-reported physician's diagnosisExposure to AB in first y of life associated with increased risk.

      aOR 1.97 (95%CI 1.26-3.08), p=nr
      Age, sex, family history of atopy, number of siblings, living country, parental education, measles infection, vaccination status, medication use, smoking during pregnancy, diet, household smoking, pet exposure
      Thomsen et al.
      • Thomsen SF
      • Ulrik CS
      • Porsbjerg C
      • Backer V.
      Early life exposures and risk of atopy among Danish children.


      Denmark

      2006
      Single-centre case-control study (4)44; 470

      12
      calculated from reported data
      ; 152

      32
      calculated from reported data
      ; 318
      < 2 y

      No

      Parent questionnaire
      7-17 yParent-reported physician's diagnosisExposure to AB in first 2 y of life not associated with increased risk.

      • OR 0.77 (95%CI 0.38-1.53), p=0.45
      calculated from reported data
      Cohet et al.
      • Cohet C
      • Cheng S
      • MacDonald C
      • et al.
      Infections, medication use, and the prevalence of symptoms of asthma, rhinitis, and eczema in childhood.


      New Zealand

      2004
      Single-centre case-control study (3b)699; 3,927

      534; 2,684

      165; 1,243
      < 1 y

      No

      Parent questionnaire
      6-7 yQuestionnaire for allergic rhinitis symptoms (ISAAC)Exposure to AB in first y of life associated with increased risk.

      OR 1.52 (95%CI 1.25-1.85), p=nr
      Bremner et al.
      • Bremner SA
      • Carey IM
      • DeWilde S
      • et al.
      Early-life exposure to antibacterials and the subsequent development of hayfever in childhood in the UK: case-control studies using the General Practice Research Database and the Doctors' Independent Network.


      UK

      2003
      Multicentre nested case-control study (3b)2,902; 40,183

      nr; nr

      nr; nr
      < 3 y

      Yes

      Medical records
      5.1 y (mean)Read codesExposure to AB in first 3 y of life associated with increased risk.

      • AB first y: OR 1.15 (95%CI, 1.03-1.29), p=0.02

      • AB in second y: OR 1.29 (95%CI, 1.15-1.46), p<0.01

      • AB in third y: OR 1.32 (95%CI, 1.17-1.48), p<0.01

      Results according to antibiotic class nr
      4,196; 76,310

      nr; nr

      nr; nr
      < 1 y

      Yes

      Medical records
      4.6 y (mean)Oxford Medical Information System (OXMIS) or Read codesExposure to AB in first y of life not associated with increased risk.

      • AB first y: OR 1.08 (95%CI, 0.98-1.20), p=0.13

      • 1 AB course: aOR 1.11 (95%CI 1.02-1.22), p=0.02

      • 2 AB courses: aOR 1.26 (95%CI 1.14-1.41), p<0.01

      • ≥ 3 AB courses: aOR 1.36 (95%CI 1.23-1.50), p<0.01

      • penicillins: aOR 0.97 (95%CI 0.92-1.03), p=0.35

      • cephalosporins: aOR 0.95 (95%CI 0.86-1.06), p=0.34

      • macrolides: aOR 0.97 (95%CI 0.91-1.04), p=0.46

      • trimethoprim/sulfamethoxazole: aOR 0.92 (95%CI 0.82-1.02), p=0.12
      1-2 y

      Yes

      Medical records
      Exposure to AB in second y of life associated with increased risk.

      OR 1.40 (95%CI, 1.26-1.56), p<0.01

      Results according to antibiotic class nr
      2-3 y

      Yes

      Medical records
      Exposure to AB in third y of life associated with increased risk.

      OR 1.59 (95%CI, 1.44-1.75), p<0.01

      Results according to antibiotic class nr
      Celedon et al.
      • Celedon JC
      • Litonjua AA
      • Ryan L
      • Weiss ST
      • Gold DR.
      Lack of association between antibiotic use in the first year of life and asthma, allergic rhinitis, or eczema at age 5 years.


      USA

      2002
      Multicentre prospective cohort study (2b)45; 448

      30; 302

      15; 146
      < 1 y

      No

      Parent questionnaire
      5 yParent-reported physician's diagnosisExposure to AB in first y of life not associated with increased risk.

      • OR 0.96 (95%CI 0.50-1.85), p=0.91
      calculated from reported data


      • 1 AB course: aOR 0.90 (95%CI 0.40-2.20), p=nr

      • ≥ 2 AB courses: aOR 0.70 (95%CI 0.30-1.50), p=nr
      Sex, family history of atopy, income
      McKeever et al.
      • McKeever TM
      • Lewis SA
      • Smith C
      • et al.
      Early exposure to infections and antibiotics and the incidence of allergic disease: a birth cohort study with the West Midlands General Practice Research Database.


      UK

      2002
      Single-centre prospective cohort study (2b)2,948; 23,604

      nr; 15,775

      nr; 7,829
      < 1 y

      Yes

      Medical records
      < 11 y

      3.5 (mean)
      Oxford Medical Information System (OXMIS), ICD-8 or Read codesExposure to AB in first y of life not associated with increased risk.

      • 1 AB course: aHR 1.14 (95%CI 0.94-1.38), p=nr

      • 2 AB courses: aHR 1.13 (95%CI 0.92-1.40), p=nr

      • 3 AB courses: aHR 0.95 (95%CI 0.74-1.22), p=nr

      • 4 AB courses: aHR 1.29 (95%CI 0.99-1.69), p=nr

      • > 4 AB courses: aHR 1.14 (95%CI 0.88-1.47), p=nr

      • penicillin: aHR 1.05 (95%CI 0.87-1.26), p=nr

      • amoxicillin: aHR 1.05 (95%CI 0.91-1.21), p=nr

      • amoxicillin/clavulanic acid: aHR 0.94 (95%CI 0.67-1.32) p=nr

      • cephalosporins: aHR 1.01 (95%CI 0.81-1.26), p=nr

      • macrolides: aHR 1.09 (95%CI 0.94-1.27), p=nr
      Number of GP visits
      Wjst et al.
      • Wjst M
      • Hoelscher B
      • Frye C
      • Wichmann HE
      • Dold S
      • Heinrich J.
      Early antibiotic treatment and later asthma.


      Germany

      2001
      Multicentre cross-sectional study (3b)180; 2,512

      nr; 2,025

      nr; 487
      < 5-14 y

      No

      Medical records
      5-14 yQuestionnaire for allergic rhinitis symptoms (ISAAC)Exposure to AB in first y of life not associated with increased risk.

      • aOR 2.30 (95%CI 0.80-6.50), p=0.13
      Age, sex, family history of atopy, season, parental education
      Droste et al.
      • Droste JH
      • Wieringa MH
      • Weyler JJ
      • Nelen VJ
      • Vermeire PA
      • Van Bever HP.
      Does the use of antibiotics in early childhood increase the risk of asthma and allergic disease?.


      Belgium

      2000
      Multicentre cross-sectional study (3b)67; 1,180

      34; 375

      33; 805
      < 1 y

      No

      Parent questionnaire
      7-8 yQuestionnaire for allergic rhinitis symptoms (ISAAC)Exposure to AB in first y of life associated with increased risk in high-risk children.

      aOR 2.30 (95%CI 1.30-3.80) p<0.01
      Sex, family history of atopy, number of siblings, living area, smoking during pregnancy, smoke exposure
      Ponsonby et al.
      • Ponsonby AL
      • Couper D
      • Dwyer T
      • Carmichael A
      • Kemp A.
      Relationship between early life respiratory illness, family size over time, and the development of asthma and hay fever: a seven year follow up study.


      Australia

      1999
      Multicentre prospective cohort study (2b)162; 864

      24; 117

      138; 747
      < 1 m

      No

      Parent questionnaire
      2.1 y (mean)Questionnaire for allergic rhinitis symptoms (ISAAC)Exposure to AB in first m of life not associated with increased risk.

      • aRR 0.95 (95%CI 0.62-1.44), p=nr
      Age, prematurity, birth weight, smoking family history of atopy, breastfeeding, household size, gas heater in living room
      Von Mutius et al.
      • von Mutius E
      • Illi S
      • Hirsch T
      • Leupold W
      • Keil U
      • Weiland SK.
      Frequency of infections and risk of asthma, atopy and airway hyperresponsiveness in children.


      Germany

      1999
      Single-centre cross-sectional study (3b)222; 5,006

      179; 3,904

      43; 1,102
      < 3 y

      No

      Medical records
      5-7 yQuestionnaire for allergic rhinitis symptoms (ISAAC)Exposure to AB in first 3 y of life not associated with increased risk.

      • OR 1.18 (95%CI 0.84-1.66), p=0.33
      calculated from reported data
      487; 5,267

      403; 4,006

      84; 1,261
      9-11 yExposure to AB in first 3 y of life associated with increased risk.

      OR 1.57 (95%CI 1.23-2.00), p<0.01
      calculated from reported data
      Wickens et al.
      • Wickens K
      • Pearce N
      • Crane J
      • Beasley R.
      Antibiotic use in early childhood and the development of asthma.


      New Zealand

      1999
      Multicentre retrospective cross-sectional study (3b)81; 447

      70; 334

      11; 113
      < 10 y

      No

      Parent questionnaire
      5-10 yQuestionnaire for allergic rhinitis symptoms (ISAAC)Exposure to AB in first 10 y of life not associated with increased risk.

      • aOR 1.99 (95%CI 0.93-4.26), p=nr
      Age, sex, ethnicity, family history of atopy, household size, parental smoking
      Farooqi et al.
      • Farooqi IS
      • Hopkin JM.
      Early childhood infection and atopic disorder.


      UK

      1998
      Single-centre retrospective cohort study (2b)484; 1,855

      374
      calculated from reported data
      ; 1,237

      110
      calculated from reported data
      ; 618
      < 2 y

      Yes

      Medical records
      6-12 yPhysician's diagnosis of seasonal nasal or ocular irritationExposure to AB in first 2 y of life associated with increased risk.

      OR 2.04 (95%CI 1.59-2.62), p<0.01

      Results according to antibiotic class nr
      Wheezing
      Zou et al.
      • Zou Z
      • Liu W
      • Huang C
      • Sun C
      • Zhang J.
      First-Year Antibiotics Exposure in Relation to Childhood Asthma, Allergies, and Airway Illnesses.


      China

      2020
      Multicentre cross-sectional study (3b)3,584; 12,667

      1,082; 3,049

      2,502; 9,618
      < 1 y

      No

      Parent questionnaire
      4-6 yQuestionnaire for wheezing symptoms (ISAAC)Exposure to AB in first y of life associated with increased risk.

      aOR 1.44 (95%CI 1.30-1.60), p<0.01
      Age, sex, living area, family history of atopy, breastfeeding, home decoration, pet, smoke and home dampness-related exposure
      Norbäck et al.
      • Norback D
      • Lu C
      • Zhang Y
      • et al.
      Sources of indoor particulate matter (PM) and outdoor air pollution in China in relation to asthma, wheeze, rhinitis and eczema among pre-school children: Synergistic effects between antibiotics use and PM10and second hand smoke.


      China

      2019
      Multicentre retrospective cohort study (2b)7,831; 39,782

      6,442; 29,303

      1,389; 10,479
      < 1 y

      No

      Parent questionnaire
      3-6 yParent-reported physician's diagnosisExposure to AB in first y of life associated with increased risk.

      aOR 1.66 (95%CI 1.52-1.82), p<0.01

      • 1 AB course: aOR 1.24 (95%CI 1.14-1.34), p<0.01

      • > 1 AB courses: aOR 1.57 (95%CI 1.46-1.69), p<0.01
      Living city, time spend outdoors, air pollution, temperature in each city
      Oosterloo et al.
      • Oosterloo BC
      • van Elburg RM
      • Rutten NB
      • et al.
      Wheezing and infantile colic are associated with neonatal antibiotic treatment.


      Netherlands

      2018
      Multicentre prospective cohort study (2b)149; 436

      62; 151

      87; 285
      < 1 w

      No

      Parent questionnaire
      0-1 yParent-reported wheezingExposure to AB in first w of life not associated with increased risk.

      • aOR 1.56 (95%CI 0.99-2.46), p=0.06
      Family history of atopy, parental education, day care, number of siblings, smoking during pregnancy, delivery mode, duration of breastfeeding, household smoking
      Yamamoto-Hanada et al.
      • Yamamoto-Hanada K
      • Yang L
      • Narita M
      • Saito H
      • Ohya Y
      Influence of antibiotic use in early childhood on asthma and allergic diseases at age 5.


      Japan

      2017
      Multicentre prospective cohort study (2b)148; 902

      81; 436

      67; 466
      < 2 y

      Yes

      Parent questionnaire
      5 yQuestionnaire for wheezing symptoms (ISAAC) plus medical recordsExposure to AB in first 2 y of life not associated with increased risk.

      • aOR 1.24 (95%CI 0.86-1.78), p=0.26

      • penicillins: aOR 1.16 (95%CI 0.61-2.18), p=0.65

      • cephem: aOR 1.39 (95%CI 0.92-2.09), p=0.12

      • macrolides: aOR 1.04 (95%CI 0.66-1.64), p=0.86
      Sex, maternal age, maternal parity, maternal BMI, maternal history of atopy, day care, maternal education, smoking during pregnancy, gestational age, delivery mode, number of LRTIs
      Han et al.
      • Han YY
      • Forno E
      • Badellino HA
      • Celedon JC.
      Antibiotic Use in Early Life, Rural Residence, and Allergic Diseases in Argentinean Children.


      Argentina

      2017
      Multicentre cross-sectional study (3b)224; 1,517

      175; 921

      49; 596
      < 1 y

      No

      Parent questionnaire
      6-7 yQuestionnaire for wheezing symptoms (ISAAC)Exposure to AB in first y of life associated with increased risk.

      aOR 1.80 (95%CI 1.30-2.60), p<0.01
      Number of LRTIs, paracetamol use
      Eldeirawi et al.
      • Eldeirawi KM
      • Kunzweiler C
      • Atek A
      • Persky VW.
      Antibiotic use in infancy and the risk of asthma in Mexican American children.


      USA

      2015
      Multicentre cross-sectional study (3b)107; 1,789

      63; 803

      44; 986
      < 1 y

      No

      Parent questionnaire
      1 yQuestionnaire for wheezing (ISAAC)Exposure to AB in first y of life associated with increased risk.

      aOR 1.64 (95% CI, 1.53-3.55), p=0.04

      • 1-2 AB courses: aOR 1.24 (95%CI 0.73-2.12), p=42

      • ≥ 3 AB courses: aOR 2.47 (95%CI 1.39-4.38), p<0.01
      Age, sex, country of birth, family history of atopy, having a regular doctor or clinic, number of ear infections
      Sun et al.
      • Sun W
      • Svendsen ER
      • Karmaus WJ
      • Kuehr J
      • Forster J.
      Early-life antibiotic use is associated with wheezing among children with high atopic risk: a prospective European study.


      China

      2015
      Multicentre prospective cohort study (2b)29; 606

      nr; 142

      nr; 464
      < 3 y

      Yes

      Parent questionnaire
      6 m-3 yQuestionnaire for wheezing symptoms (ISAAC)Exposure to AB in first 3 y of life associated with increased risk in children with high atopic risk factors.

      aRR 1.09 (95%CI 1.05-1.13), p<0.05

      • penicillin: aRR 1.00 (95%CI 0.94-1.05), p=nr

      • ampicillin: aRR 0.99 (95%CI 0.94-1.03), p=nr

      • cephalosporins: aRR 1.02 (95%CI 1.00-1.05), p=nr

      macrolides: aRR 1.09 (95%CI 1.05-1.13), p<0.05

      • trimethoprim: aRR 0.98 (95%CI 0.88-1.09), p=nr

      • broad-spectrum AB: aRR 1.02 (95%CI 0.98-1.06), p=nr
      Family history of atopy, living country, maternal education, birth order
      Lapin et al.
      • Lapin B
      • Piorkowski J
      • Ownby D
      • et al.
      The relationship of early-life antibiotic use with asthma in at-risk children.


      USA

      2014
      Multicentre prospective cohort study (2b)65; 295

      nr; 162

      nr; 133
      < 1 y

      No

      nr
      2-3 yParent-reported wheezingExposure to AB in first y of life associated with increased risk in high-risk children.

      aOR 1.29 (95%CI 1.07-1.55), p=nr
      Ethnicity, smoking during pregnancy, antibiotic and medication use during pregnancy, maternal asthma, birth weight, breastfeeding, household smoking
      Ong et al.
      • Ong MS
      • Umetsu DT
      • Mandl KD.
      Consequences of antibiotics and infections in infancy: bugs, drugs, and wheezing.


      Australia

      2014
      Multicentre retrospective cohort study (2b)5,460; 62,576

      3,190
      calculated from reported data
      26,693

      2,270
      calculated from reported data
      ; 35,883
      < 1 y

      No

      Registry
      < 3 yICD-9 codesExposure to AB in first y of life associated with increased risk.

      OR 2.00 (95%CI 1.90-2.20), p<0.01
      Semic-Jusufagic et al.
      • Semic-Jusufagic A
      • Belgrave D
      • Pickles A
      • et al.
      Assessing the association of early life antibiotic prescription with asthma exacerbations, impaired antiviral immunity, and genetic variants in 17q21: a population-based birth cohort study.


      UK

      2014
      Multicentre prospective cohort study (2b)199; 684

      nr; nr

      nr; nr
      < 1 y

      No

      Parent questionnaire
      1-11 yParent-reported plus medical recordsExposure to AB in first y of life associated with increased risk.

      OR 1.91 (95%CI, 1.29-2.83), p<0.01
      Muc et al.
      • Muc M
      • Padez C
      • Pinto AM.
      Exposure to paracetamol and antibiotics in early life and elevated risk of asthma in childhood.


      Portugal

      2013
      Multicentre cross-sectional study (3b)357; 1,037

      117
      calculated from reported data
      ; 237

      240
      calculated from reported data
      ; 800
      < 1 y

      No

      Parent questionnaire
      6-9 yQuestionnaire for wheezing symptoms (ISAAC)Exposure to AB in first y of life associated with increased risk.

      aOR 2.33 (95%CI 1.70-3.18), p<0.01
      Age, sex, prematurity, atopy
      Raciborski et al.
      • Raciborski F
      • Tomaszewska A
      • Komorowski J
      • et al.
      The relationship between antibiotic therapy in early childhood and the symptoms of allergy in children aged 6-8 years - the questionnaire study results.


      Poland

      2012
      Multicentre retrospective cohort study (2b)197; 1,330

      150; 820

      47; 510
      < 1 y

      No

      Parent questionnaire
      6-8 yQuestionnaire for wheezing symptoms (ISAAC and ECRHS II)Exposure to AB in first y of life associated with increased risk.

      OR 2.21 (95%CI 1.56-3.12), p<0.01
      calculated from reported data


      • 1 AB course: OR 1.12 (95%CI nr), p=0.61

      • 2-3 AB courses: OR 1.93 (95%CI nr), p<0.01

      • > 3 AB courses: OR 4.68 (95%CI 2.60-12.01), p<0.01
      197; 1,321

      185; 1,145

      12; 176
      1-3 y

      No

      Parent questionnaire
      Exposure to AB in first to third y of life associated with increased risk.

      OR 2.63 (95%CI 1.44-4.83), p<0.01
      calculated from reported data


      • 1-2 AB courses: OR 1.41 (95%CI nr), p=0.31

      • 3-4 AB courses: OR 1.89 (95%CI nr), p=0.06

      • > 4 AB courses: OR 4.73 (95%CI 1.41-15.90), p<0.01
      Kwon et al.
      • Kwon JW
      • Kim BJ
      • Song Y
      • et al.
      Changes in the prevalence of childhood asthma in seoul from 1995 to 2008 and its risk factors.


      Korea

      2011
      Multicentre cross-sectional study (3b)442; 3,765

      nr; nr

      nr; nr
      < 1 y

      No

      Parent questionnaire
      9.5 y (mean)Questionnaire for wheezing (ISAAC)Exposure to AB in first y of life associated with increased risk.

      aOR 1.88 (95%CI 1.35-2.62), p<0.01
      Age, sex, parental asthma, maternal education, BMI, smoke exposure
      Rusconi et al.
      • Rusconi F
      • Gagliardi L
      • Galassi C
      • et al.
      Paracetamol and antibiotics in childhood and subsequent development of wheezing/asthma: association or causation?.


      Italy

      2011
      Multicentre cross-sectional study (3b)1,598; 16,933

      1,114; 5,863

      484; 11,070
      < 1 y

      No

      Parent questionnaire
      < 2 yEarly transient wheezing Questionnaire for wheezing (ISAAC)Exposure to AB in first y of life associated with increased risk.

      aOR 3.76 (95%CI 3.31-4.27), p=nr
      Age, sex, study centre, person who completed the questionnaire, maternal age, family history of atopy, day care, number of siblings, sharing a bedroom, parental education, smoking during pregnancy, prematurity, season, breastfeeding, dampness-related exposure
      910; 16,933

      596; 5,345

      314; 11,588
      < 4-5 yPersistent wheezing Questionnaire for wheezing (ISAAC)Exposure to AB in first y of life associated with increased risk.

      aOR 3.06 (95%CI 2.60-3.60), p=nr
      1,011; 16,933

      412; 5,161

      599; 11,772
      4-5 until 6-7 yLate-onset wheezing

      Questionnaire for wheezing (ISAAC)
      Exposure to AB in first y of life associated with increased risk.

      aOR 1.18 (95%CI 1.02-1.38), p=nr
      Goksor et al.
      • Goksor E
      • Alm B
      • Thengilsdottir H
      • Pettersson R
      • Aberg N
      • Wennergren G.
      Preschool wheeze - impact of early fish introduction and neonatal antibiotics.


      Sweden

      2011
      Multicentre prospective cohort study (2b)245; 4,495

      26; 203

      219; 4,292
      < 1 w

      No

      Parent questionnaire
      4.5 yQuestionnaire for wheezing symptoms (ISAAC and BAMSE)Exposure to AB in first w of life associated with increased risk.

      aOR 2.20 (95%CI 1.30-3.80), p<0.05
      Prematurity, delivery mode
      Dom et al.
      • Dom S
      • Droste JH
      • Sariachvili MA
      • et al.
      Pre- and post-natal exposure to antibiotics and the development of eczema, recurrent wheezing and atopic sensitization in children up to the age of 4 years.


      Belgium

      2010
      Multicentre prospective cohort study (2b)235; 667

      210; 586

      25; 81
      < 4 y

      No

      Parent questionnaire
      6 m-4 yQuestionnaire for wheezing symptoms (ISAAC)Exposure to AB before first y of life not associated with increased risk.

      • OR 1.25 (95%CI 0.76-2.06), p=0.38
      calculated from reported data
      Sex, maternal age, family history of atopy, day care, number of siblings, parental education, smoking during pregnancy, pet exposure during pregnancy, birth weight, number of LRTIs, breastfeeding, household smoking, pet exposure
      Mai et al.
      • Mai XM
      • Kull I
      • Wickman M
      • Bergström A.
      Antibiotic use in early life and development of allergic diseases: respiratory infection as the explanation.


      Sweden

      2010
      Single-centre prospective cohort study (2b)482; 3,306

      254; 1,420

      228; 1,886
      < 1 y

      No

      Parent questionnaire
      4 yQuestionnaire for wheezing symptoms (BAMSE based on ISAAC)Exposure to AB in first y of life associated with increased risk.

      aOR 1.40 (95%CI 1.20-1.80), p=nr

      • ≥ 2 AB courses: aOR 1.60 (95%CI 1.10-2.20), p<0.01
      Sex, maternal age, family history of atopy, number of siblings, breastfeeding, maternal smoking
      330; 3,306

      170; 1,420

      160; 1,886
      8 yExposure to AB in first y of life associated with increased risk.

      aOR 1.40 (95%CI 1.10-1.70), p=nr
      Karimi et al.
      • Karimi M
      • Mirzaei M.
      Antibiotic use and symptoms of asthma, allergic rhinitis and eczema in children.


      Iran

      2009
      Multicentre cross-sectional study (3b)141; 1,476

      95; 953
      calculated from reported data


      46; 523
      calculated from reported data
      < 1 y

      No

      nr
      6-7 yQuestionnaire for wheezing symptoms (ISAAC)Exposure to AB in first y of life not associated with increased risk.

      • OR 1.13 (95%CI 0.77-1.67), p=0.50
      Mitchell et al.
      • Mitchell EA
      • Stewart AW
      • Clayton T
      • et al.
      Cross-sectional survey of risk factors for asthma in 6-7-year-old children in New Zealand: International Study of Asthma and Allergy in Childhood Phase Three.


      New Zealand

      2009
      Multicentre cross-sectional study (3b)2,315; 10,423

      1,764; 6,476

      551; 3,947
      < 1 y

      No

      Parent questionnaire
      6-7 yQuestionnaire for wheezing symptoms (ISAAC)Exposure to AB in first y of life associated with increased risk.

      aOR 1.78 (95%CI 1.56-2.04), p<0.01
      Sex, ethnicity, country of birth, number of siblings, socioeconomic status, medication use, maternal smoking
      Alm et al.
      • Alm B
      • Erdes L
      • Mollborg P
      • et al.
      Neonatal antibiotic treatment is a risk factor for early wheezing.


      Sweden

      2008
      Multicentre prospective cohort study (2b)994, 4,921

      67; 219

      927; 4,702
      < 1 m

      No

      Parent questionnaire
      1 yQuestionnaire for wheezing (BAMSE study)Exposure to AB in first m of life associated with increased risk.

      aOR 1.60 (95%CI 1.00–2.50), p=0.04
      Sex, prematurity, neonatal intensive-care unit admission, smoking during pregnancy, family history of atopy, light sleep at 12 months, breastfeeding, pacifier use
      Kusel et al.
      • Kusel MM
      • de Klerk N
      • Holt PG
      • Sly PD.
      Antibiotic use in the first year of life and risk of atopic disease in early childhood.


      Australia

      2008
      Multicentre prospective cohort study (2b)56; 198

      34
      calculated from reported data
      ; 107

      22
      calculated from reported data
      ; 91
      < 1 y

      Yes

      Parent questionnaire
      0-5 yParent-reported current wheezeExposure to AB in first y of life not associated with increased risk.

      • aOR 1.00 (95%CI 0.50-2.20), p=nr

      Results according to antibiotic class nr
      Sex, day care, number of GP visits, pet exposure
      Simon et al.
      • Simon MR
      • Havstad SL
      • Wegienka GR
      • Ownby DR
      • Johnson CC.
      Risk factors associated with transient wheezing in young children.


      USA

      2008
      Multicentre prospective cohort study (2b)117; 239

      67; 142

      50; 97
      < 6 m

      No

      Medical records
      1-4 yParent-reportedExposure to AB in first 6 m of life associated with increased risk.

      aRR 1.60 (95%CI 1.00-2.60), p=0.05
      Sex, family history of atopy, day care, birth order, fever, breastfeeding, pet exposure
      Verhulst et al.