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

  • Quynh A Duong
    Affiliations
    Department of Community Health, 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

    Department of Pediatrics, Gynecology and 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
    Corresponding author at: Department of Community Health, Faculty of Science and Medicine, University of Fribourg, Fribourg, Route des Arsenaux 41, Fribourg 1700, Switzerland.
    Affiliations
    Department of Community Health, 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, Fribourg, Switzerland
    Search for articles by this author
Open AccessPublished:January 09, 2022DOI:https://doi.org/10.1016/j.jinf.2022.01.005

      Summary

      Background

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

      Methods

      A systematic search using PRISMA guidelines to identify original studies reporting associations between antibiotic exposure and adverse long-term health outcomes in children. Overall pooled estimates of the odds ratios (ORs) were obtained using 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 amongst 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 studies is summarised in Fig. 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 3944, 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 Supplementary Table 2.
      Table 1Summary of studies investigating the effect of antibiotic exposure on health outcomes in children. See Ref.
      • Aghaali M
      • Hashemi-Nazari SS.
      Association between early antibiotic exposure and risk of childhood weight gain and obesity: a systematic review and meta-analysis.
      * calculated from reported data
      1WISC-IV (Wechsler Intelligence Scale for Children-fourth edition), CPT 3 (Conners Continuous Performance Test-third edition), CANTAB (Cambridge Automated Neuropsychological Test Battery), BRIEF (Behavior Rating Inventory of Executive Function), Conners 3, SDQ (Strengths and Difficulties Questionnaire), MASC 2 (Multidimensional Anxiety Scale for Children), CES-DC (Center for Epidemiological Studies for Children)
      AB – antibiotic
      ADHD – attention deficit hyperactivity disorder
      a – adjusted
      ASD – autism spectrum disorders
      ATC – anatomical-therapeutic-chemical
      BASME – Barn, Alleergi, Miljö, Stockhol, Epidemiologi
      BMI – body mass index
      CI – confidence interval
      ECRHS II – European Community Respiratory Health Survey second version
      GP – general practitioner
      HLA – human leucocyte antigen
      HR – hazard ratio
      IBD – inflammatory bowel disease
      ICD-10-CA – international classification of disease, tenth revision, Canadian Edition
      ICD-9-CM – international classification of disease, ninth revision, clinical modification
      ICD-9/10 – international classification of disease, ninth/tenth revision
      IgE – immunoglobulin E
      IRR – incidence rate ratio
      ISAAC – International Study of Allergy and Asthma in Childhood
      JIA – juvenile idiopathic arthritis
      LRTI – lower respiratory tract infections
      m – month
      nr – not reported
      OR – odds ratio
      RP – ratio of proportion
      RR – risk ratio
      RRR – prevalence ratio
      SPT – skin prick test
      w – week
      y – year

      Atopic dermatitis

      Forty studies in 1,602,639 children (183,244 cases with one study not reporting number of cases) investigated the association between antibiotic exposure and the risk of developing atopic dermatitis, evaluated by the International Study of Allergy and Asthma in Childhood (ISAAC) questionnaire, international classification of disease (ICD) codes, parent-reported symptoms or physician's diagnosis, the Criteria by the American Academy of Dermatology, Hanifin and Rajka criteria or William's criteria (Table 1).
      • 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.
      ,
      • Cohet C
      • Cheng S
      • MacDonald C
      • et al.
      Infections, medication use, and the prevalence of symptoms of asthma, rhinitis, and eczema in childhood.
      ,
      • 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.
      ,
      • 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?.
      ,
      • Farooqi IS
      • Hopkin JM.
      Early childhood infection and atopic disorder.
      • Floistrup H
      • Swartz J
      • Bergstrom A
      • et al.
      Allergic disease and sensitization in Steiner school children.
      • 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.
      • 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.
      ,
      • 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.
      ,
      • Ho CL
      • Chang LI
      • Wu WF.
      The prevalence and risk factors of atopic dermatitis in 6-8 year-old first graders in Taipei.
      ,
      • 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.
      ,
      • 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.
      ,
      • 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.
      ,
      • Metzler S
      • Frei R
      • Schmauser-Hechfellner E
      • et al.
      Association between antibiotic treatment during pregnancy and infancy and the development of allergic diseases.
      ,
      • 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.
      ,
      • Mullooly JP
      • Schuler R
      • Barrett M
      • Maher JE.
      Vaccines, antibiotics, and atopy.
      ,
      • 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.
      ,
      • Oosterloo BC
      • van Elburg RM
      • Rutten NB
      • et al.
      Wheezing and infantile colic are associated with neonatal antibiotic treatment.
      ,
      • Purvis DJ
      • Thompson JM
      • Clark PM
      • et al.
      Risk factors for atopic dermatitis in New Zealand children at 3.5 years of age.
      ,
      • Rutter CE
      • Silverwood RJ
      • Williams HC
      • et al.
      Are Environmental Factors for Atopic Eczema in ISAAC Phase Three due to Reverse Causation?.
      ,
      • 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.
      ,
      • Singh S
      • Sharma BB
      • Salvi S
      • et al.
      Allergic rhinitis, rhinoconjunctivitis, and eczema: prevalence and associated factors in children.
      ,
      • Su Y
      • Rothers J
      • Stern DA
      • Halonen M
      • Wright AL.
      Relation of early antibiotic use to childhood asthma: confounding by indication?.
      ,
      • 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.
      ,
      • 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.
      ,
      • 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.
      ,
      • Zou Z
      • Liu W
      • Huang C
      • Sun C
      • Zhang J.
      First-Year Antibiotics Exposure in Relation to Childhood Asthma, Allergies, and Airway Illnesses.
      ,
      • Karimi M
      • Mirzaei M.
      Antibiotic use and symptoms of asthma, allergic rhinitis and eczema in children.
      ,
      • Aversa Z
      • Atkinson EJ
      • Schafer MJ
      • et al.
      Association of Infant Antibiotic Exposure With Childhood Health Outcomes.
      • 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.
      • 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.
      • Loo EX
      • Shek LP
      • Goh A
      • et al.
      Atopic Dermatitis in Early Life: Evidence for at Least Three Phenotypes? Results from the GUSTO Study.
      • 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.
      • 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.
      • Mai XM
      • Kull I
      • Wickman M
      • Bergström A.
      Antibiotic use in early life and development of allergic diseases: respiratory infection as the explanation.
      • McKeever TM
      • Lewis SA
      • Smith C
      • Hubbard R.
      The importance of prenatal exposures on the development of allergic disease: a birth cohort study using the West Midlands General Practice Database.
      • Böhme M
      • Lannerö E
      • Wickman M
      • Nordvall SL
      • Wahlgren CF.
      Atopic dermatitis and concomitant disease patterns in children up to two years of age.
      • 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.
      Of the 40 studies, 38 (95%) investigated the effect of antibiotic exposure in the first five years of life (36 (90%) in the first two years of life).
      • 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.
      ,
      • Cohet C
      • Cheng S
      • MacDonald C
      • et al.
      Infections, medication use, and the prevalence of symptoms of asthma, rhinitis, and eczema in childhood.
      ,
      • 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.
      ,
      • 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?.
      ,
      • Farooqi IS
      • Hopkin JM.
      Early childhood infection and atopic disorder.
      • Floistrup H
      • Swartz J
      • Bergstrom A
      • et al.
      Allergic disease and sensitization in Steiner school children.
      • 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.
      • 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.
      ,
      • 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.
      ,
      • Ho CL
      • Chang LI
      • Wu WF.
      The prevalence and risk factors of atopic dermatitis in 6-8 year-old first graders in Taipei.
      ,
      • 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.
      ,
      • 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.
      ,
      • 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.
      ,
      • Metzler S
      • Frei R
      • Schmauser-Hechfellner E
      • et al.
      Association between antibiotic treatment during pregnancy and infancy and the development of allergic diseases.
      ,
      • 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.
      ,
      • Mullooly JP
      • Schuler R
      • Barrett M
      • Maher JE.
      Vaccines, antibiotics, and atopy.
      ,
      • 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.
      ,
      • Oosterloo BC
      • van Elburg RM
      • Rutten NB
      • et al.
      Wheezing and infantile colic are associated with neonatal antibiotic treatment.
      ,
      • Purvis DJ
      • Thompson JM
      • Clark PM
      • et al.
      Risk factors for atopic dermatitis in New Zealand children at 3.5 years of age.
      ,
      • Rutter CE
      • Silverwood RJ
      • Williams HC
      • et al.
      Are Environmental Factors for Atopic Eczema in ISAAC Phase Three due to Reverse Causation?.
      ,
      • 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.
      ,
      • Singh S
      • Sharma BB
      • Salvi S
      • et al.
      Allergic rhinitis, rhinoconjunctivitis, and eczema: prevalence and associated factors in children.
      ,
      • Su Y
      • Rothers J
      • Stern DA
      • Halonen M
      • Wright AL.
      Relation of early antibiotic use to childhood asthma: confounding by indication?.
      ,
      • 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.
      ,
      • 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?.
      ,
      • 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.
      ,
      • Zou Z
      • Liu W
      • Huang C
      • Sun C
      • Zhang J.
      First-Year Antibiotics Exposure in Relation to Childhood Asthma, Allergies, and Airway Illnesses.
      ,
      • Karimi M
      • Mirzaei M.
      Antibiotic use and symptoms of asthma, allergic rhinitis and eczema in children.
      ,
      • Aversa Z
      • Atkinson EJ
      • Schafer MJ
      • et al.
      Association of Infant Antibiotic Exposure With Childhood Health Outcomes.
      • 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.
      • 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.
      • Loo EX
      • Shek LP
      • Goh A
      • et al.
      Atopic Dermatitis in Early Life: Evidence for at Least Three Phenotypes? Results from the GUSTO Study.
      • 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.
      • 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.
      • Mai XM
      • Kull I
      • Wickman M
      • Bergström A.
      Antibiotic use in early life and development of allergic diseases: respiratory infection as the explanation.
      • McKeever TM
      • Lewis SA
      • Smith C
      • Hubbard R.
      The importance of prenatal exposures on the development of allergic disease: a birth cohort study using the West Midlands General Practice Database.
      • Böhme M
      • Lannerö E
      • Wickman M
      • Nordvall SL
      • Wahlgren CF.
      Atopic dermatitis and concomitant disease patterns in children up to two years of age.
      • 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.
      Overall, 26 (65%) studies reported a significantly increased incidence of atopic dermatitis in children who were exposed to antibiotics
      • Cohet C
      • Cheng S
      • MacDonald C
      • et al.
      Infections, medication use, and the prevalence of symptoms of asthma, rhinitis, and eczema in childhood.
      ,
      • 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.
      ,
      • Farooqi IS
      • Hopkin JM.
      Early childhood infection and atopic disorder.
      • Floistrup H
      • Swartz J
      • Bergstrom A
      • et al.
      Allergic disease and sensitization in Steiner school children.
      • 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.
      • 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.
      ,
      • 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.
      ,
      • Ho CL
      • Chang LI
      • Wu WF.
      The prevalence and risk factors of atopic dermatitis in 6-8 year-old first graders in Taipei.
      ,
      • 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.
      ,
      • Metzler S
      • Frei R
      • Schmauser-Hechfellner E
      • et al.
      Association between antibiotic treatment during pregnancy and infancy and the development of allergic diseases.
      ,
      • 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.
      ,
      • 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.
      ,
      • Rutter CE
      • Silverwood RJ
      • Williams HC
      • et al.
      Are Environmental Factors for Atopic Eczema in ISAAC Phase Three due to Reverse Causation?.
      ,
      • 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.
      ,
      • Singh S
      • Sharma BB
      • Salvi S
      • et al.
      Allergic rhinitis, rhinoconjunctivitis, and eczema: prevalence and associated factors 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.
      ,
      • 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?.
      ,
      • 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.
      ,
      • Zou Z
      • Liu W
      • Huang C
      • Sun C
      • Zhang J.
      First-Year Antibiotics Exposure in Relation to Childhood Asthma, Allergies, and Airway Illnesses.
      ,
      • Aversa Z
      • Atkinson EJ
      • Schafer MJ
      • et al.
      Association of Infant Antibiotic Exposure With Childhood Health Outcomes.
      ,
      • 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.
      ,
      • Loo EX
      • Shek LP
      • Goh A
      • et al.
      Atopic Dermatitis in Early Life: Evidence for at Least Three Phenotypes? Results from the GUSTO Study.
      ,
      • 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.
      ,
      • McKeever TM
      • Lewis SA
      • Smith C
      • Hubbard R.
      The importance of prenatal exposures on the development of allergic disease: a birth cohort study using the West Midlands General Practice Database.
      • Böhme M
      • Lannerö E
      • Wickman M
      • Nordvall SL
      • Wahlgren CF.
      Atopic dermatitis and concomitant disease patterns in children up to two years of age.
      • 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.
      ; However, in two studies the incidence atopic dermatitis was higher only if exposed to two or more courses of antibiotics.
      • 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.
      ,
      • Böhme M
      • Lannerö E
      • Wickman M
      • Nordvall SL
      • Wahlgren CF.
      Atopic dermatitis and concomitant disease patterns in children up to two years of age.
      In contrast, two studies (5%) reported a decreased incidence in children who were exposed to antibiotics.
      • 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.
      ,
      • 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.
      Five studies reported that the risk of atopic dermatitis increased with the number of antibiotic courses.
      • 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.
      ,
      • Metzler S
      • Frei R
      • Schmauser-Hechfellner E
      • et al.
      Association between antibiotic treatment during pregnancy and infancy and the development of allergic diseases.
      ,
      • 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.
      ,
      • 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.
      ,
      • 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.
      One study, however, did not find an association between the number of antibiotic courses and the risk of atopic dermatitis.
      • 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.
      Four studies compared the effect of different antibiotic classes.
      • 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.
      ,
      • 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.
      ,
      • Aversa Z
      • Atkinson EJ
      • Schafer MJ
      • et al.
      Association of Infant Antibiotic Exposure With Childhood Health Outcomes.
      ,
      • 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.
      One study reported that the risk of atopic dermatitis increased after exposure to cephalosporins and macrolides, but not after exposure to penicillins
      • 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.
      ; one study after amoxicillin but not penicillin, amoxicillin/clavulanic acid, macrolides or cephalosporins,
      • 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.
      one study after macrolides
      • 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.
      and the last study reported an increased risk in girls after exposure to cephalosporins but a decreased risk after exposure to macrolides.
      • Aversa Z
      • Atkinson EJ
      • Schafer MJ
      • et al.
      Association of Infant Antibiotic Exposure With Childhood Health Outcomes.
      Of the 40 studies, 32 (80%) provided sufficient data to be included in the meta-analysis (supplementary Fig. 1).
      • 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.
      ,
      • Cohet C
      • Cheng S
      • MacDonald C
      • et al.
      Infections, medication use, and the prevalence of symptoms of asthma, rhinitis, and eczema in childhood.
      ,
      • 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.
      ,
      • 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?.
      ,
      • Farooqi IS
      • Hopkin JM.
      Early childhood infection and atopic disorder.
      ,
      • Floistrup H
      • Swartz J
      • Bergstrom A
      • et al.
      Allergic disease and sensitization in Steiner school children.
      ,
      • 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.
      ,
      • 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.
      ,
      • Ho CL
      • Chang LI
      • Wu WF.
      The prevalence and risk factors of atopic dermatitis in 6-8 year-old first graders in Taipei.
      ,
      • 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.
      ,
      • 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.
      ,
      • 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.
      ,
      • Metzler S
      • Frei R
      • Schmauser-Hechfellner E
      • et al.
      Association between antibiotic treatment during pregnancy and infancy and the development of allergic diseases.
      ,
      • 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.
      ,
      • 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.
      ,
      • Oosterloo BC
      • van Elburg RM
      • Rutten NB
      • et al.
      Wheezing and infantile colic are associated with neonatal antibiotic treatment.
      ,
      • Purvis DJ
      • Thompson JM
      • Clark PM
      • et al.
      Risk factors for atopic dermatitis in New Zealand children at 3.5 years of age.
      ,
      • Rutter CE
      • Silverwood RJ
      • Williams HC
      • et al.
      Are Environmental Factors for Atopic Eczema in ISAAC Phase Three due to Reverse Causation?.
      ,
      • 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.
      ,
      • Su Y
      • Rothers J
      • Stern DA
      • Halonen M
      • Wright AL.
      Relation of early antibiotic use to childhood asthma: confounding by indication?.
      ,
      • 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.
      ,
      • 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.
      ,
      • Zou Z
      • Liu W
      • Huang C
      • Sun C
      • Zhang J.
      First-Year Antibiotics Exposure in Relation to Childhood Asthma, Allergies, and Airway Illnesses.
      ,
      • Karimi M
      • Mirzaei M.
      Antibiotic use and symptoms of asthma, allergic rhinitis and eczema in children.
      ,
      • Aversa Z
      • Atkinson EJ
      • Schafer MJ
      • et al.
      Association of Infant Antibiotic Exposure With Childhood Health Outcomes.
      • 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.
      • 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.
      ,
      • 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.
      ,
      • Mai XM
      • Kull I
      • Wickman M
      • Bergström A.
      Antibiotic use in early life and development of allergic diseases: respiratory infection as the explanation.
      ,
      • Böhme M
      • Lannerö E
      • Wickman M
      • Nordvall SL
      • Wahlgren CF.
      Atopic dermatitis and concomitant disease patterns in children up to two years of age.
      ,
      • 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.
      Of the 309,828 children exposed to antibiotics 51,543 (17%) developed atopic dermatitis compared to 105,587 (14%) of 766,331 children not exposed to antibiotics. The overall odds ratio (OR) for developing atopic dermatitis after antibiotic exposure was 1.40, 95% confidence interval (CI) 1.30 to 1.52, p < 0.01 (Fig. 2).
      Fig 2
      Fig. 2Comparison of incidence of adverse health outcomes in children exposed and not exposed to antibiotics (number of studies in brackets).

      Allergic sensitisation

      Twenty-three studies in 34,806 children (8952 cases) investigated the association between antibiotic exposure and the risk of developing allergic sensitisation diagnosed by skin prick test or serum immunoglobulin (Ig) E levels (Table 1).
      • Azad MB
      • Konya T
      • Guttman DS
      • et al.
      Infant gut microbiota and food sensitization: associations in the first year of life.
      ,
      • 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.
      ,
      • 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?.
      ,
      • Floistrup H
      • Swartz J
      • Bergstrom A
      • et al.
      Allergic disease and sensitization in Steiner school children.
      ,
      • 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.
      ,
      • Johnson CC
      • Ownby DR
      • Alford SH
      • et al.
      Antibiotic exposure in early infancy and risk for childhood atopy.
      ,
      • 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.
      ,
      • 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.
      ,
      • 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.
      ,
      • 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.
      ,
      • Metzler S
      • Frei R
      • Schmauser-Hechfellner E
      • et al.
      Association between antibiotic treatment during pregnancy and infancy and the development of allergic diseases.
      ,
      • Oosterloo BC
      • van Elburg RM
      • Rutten NB
      • et al.
      Wheezing and infantile colic are associated with neonatal antibiotic treatment.
      ,
      • 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.
      ,
      • 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.
      ,
      • Su Y
      • Rothers J
      • Stern DA
      • Halonen M
      • Wright AL.
      Relation of early antibiotic use to childhood asthma: confounding by indication?.
      ,
      • 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?.
      ,
      • Loo EX
      • Shek LP
      • Goh A
      • et al.
      Atopic Dermatitis in Early Life: Evidence for at Least Three Phenotypes? Results from the GUSTO Study.
      • 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.
      • 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.
      • Mai XM
      • Kull I
      • Wickman M
      • Bergström A.
      Antibiotic use in early life and development of allergic diseases: respiratory infection as the explanation.
      ,
      • 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.
      ,
      • 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.
      ,
      • Dubakiene R
      • Rudzeviciene O
      • Butiene I
      • et al.
      Studies on early allergic sensitization in the Lithuanian birth cohort.
      Of the studies, 21 (91%) investigated the effect of antibiotic exposure in the first five years of life (18 (78%) in the first two years of life).
      • Azad MB
      • Konya T
      • Guttman DS
      • et al.
      Infant gut microbiota and food sensitization: associations in the first year of life.
      ,
      • 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.
      ,
      • 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?.
      ,
      • Floistrup H
      • Swartz J
      • Bergstrom A
      • et al.
      Allergic disease and sensitization in Steiner school children.
      ,
      • 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.
      ,