Association between early-life antibiotic use and the risk of islet or celiac disease autoimmunity

Kaisa M. Kemppainen; Kendra Vehik; Kristian F. Lynch; Helena Elding Larsson; Ronald J. Canepa; Ville Simell; Sibylle Koletzko; Edwin Liu; Olli G. Simell; Jorma Toppari; Anette G. Ziegler; Marian J. Rewers; Åke Lernmark; William A. Hagopian; Jin-Xiong She; Beena Akolkar; Desmond A. Schatz; Mark A. Atkinson; Martin J. Blaser; Jeffrey P. Krischer; Heikki Hyöty; Daniel Agardh; Eric W. Triplett; Kimberly Bautista; Judith Baxter; Ruth Bedoy; Daniel Felipe-Morales; Kimberly Driscoll; Brigitte I. Frohnert; Patricia Gesualdo; Michelle Hoffman; Rachel Karban; Jill Norris; Adela Samper-Imaz; Andrea Steck; Kathleen Waugh; Hali Wright; Annika Adamsson; Suvi Ahonen; Jorma Ilonen; Sanna Jokipuu; Tiina Kallio; Leena Karlsson; Miia Kähönen; Mikael Knip; Lea Kovanen; Mirva Koreasalo; Kalle Kurppa; Tiina Latva-Aho; Maria Lönnrot; Elina Mäntymäki; Katja Multasuo; Juha Mykkänen; Tiina Niininen; Sari Niinistö; Mia Nyblom; Petra Rajala; Jenna Rautanen; Anne Riikonen; Mika Riikonen; Jenni Rouhiainen; Minna Romo; Tuula Simell; Maija Sjöberg; Aino Stenius; Maria Leppänen; Sini Vainionpää; Eeva Varjonen; Riitta Veijola; Suvi M. Virtanen; Mari Vähä-Mäkilä; Mari Åkerlund; Katri Lindfors; Desmond Schatz; Diane Hopkins; Leigh Steed; Jamie Thomas; Janey Adams; Katherine Silvis; Michael Haller; Melissa Gardiner; Richard A McIndoe; Ashok Kumar Sharma; Joshua William; Gabriela Young; Stephen W. Anderson; Laura Jacobsen; Andreas Beyerlein; Ezio Bonifacio; Michael Hummel; Sandra Hummel; Kristina Foterek; Nicole Janz; Mathilde Kersting; Annette Knopff; Claudia Peplow; Roswith Roth; Marlon Scholz; Joanna Stock; Katharina Warncke; Lorena Wendel; Christiane Winkler; Carin Andrén Aronsson; Maria Ask; Jenny Bremer; Ulla Marie Carlsson; Corrado Cilio; Emelie Ericson-Hallström; Lina Fransson; Thomas Gard; Joanna Gerardsson; Rasmus Bennet; Monica Hansen; Gertie Hansson; Susanne Hyberg; Fredrik Johansen; Berglind Jonsdottir; Marielle Lindström; Markus Lundgren; Maria Månsson-Martinez; Maria Markan; Jessica Melin; Zeliha Mestan; Karin Ottosson; Kobra Rahmati; Anita Ramelius; Falastin Salami; Sara Sibthorpe; Birgitta Sjöberg; Ulrica Swartling; Evelyn Tekum Amboh; Carina Törn; Anne Wallin; Åsa Wimar; Sofie Åberg; Michael Killian; Claire Cowen Crouch; Jennifer Skidmore; Josephine Carson; Maria Dalzell; Kayleen Dunson; Rachel Hervey; Corbin Johnson; Rachel Lyons; Arlene Meyer; Denise Mulenga; Alexander Tarr; Morgan Uland; John Willis; Dorothy Becker; Margaret Franciscus; Mary Ellen Dalmagro Elias Smith; Ashi Daftary; Mary Beth Klein; Chrystal Yates; Michael Abbondondolo; Sarah Austin-Gonzalez; Maryouri Avendano; Sandra Baethke; Rasheedah Brown; Brant Burkhardt; Martha Butterworth; Joanna Clasen; David Cuthbertson; Christopher Eberhard; Steven Fiske; Dena Garcia; Jennifer Garmeson; Veena Gowda; Kathleen Heyman; Francisco Perez Laras; Hye Seung Lee; Shu Liu; Xiang Liu; Kristian Lynch; Jamie Malloy; Cristina McCarthy; Steven Meulemans; Hemang Parikh; Chris Shaffer; Laura Smith; Susan Smith; Noah Sulman; Roy Tamura; Ulla Uusitalo; Ponni Vijayakandipan; Keith Wood; Jimin Yang; Lori Ballard; David Hadley; Wendy McLeod; Kasia Bourcier; Thomas Briese; Suzanne Bennett Johnson; Liping Yu; Dongmei Miao; Polly Bingley; Alistair William's; Kyla Chandler; Saba Rokni; Claire Willia; Rebecca Wyatt; Gifty George; Sian Grace; Niveen Mulholland

doi:10.1001/jamapediatrics.2017.2905

Association between early-life antibiotic use and the risk of islet or celiac disease autoimmunity

Kaisa M. Kemppainen, Kendra Vehik, Kristian F. Lynch, Helena Elding Larsson, Ronald J. Canepa, Ville Simell, Sibylle Koletzko, Edwin Liu, Olli G. Simell, Jorma Toppari, Anette G. Ziegler, Marian J. Rewers, Åke Lernmark, William A. Hagopian, Jin-Xiong She, Beena Akolkar, Desmond A. Schatz, Mark A. Atkinson, Martin J. Blaser, Jeffrey P. KrischerHeikki Hyöty, Daniel Agardh, Eric W. Triplett, Kimberly Bautista, Judith Baxter, Ruth Bedoy, Daniel Felipe-Morales, Kimberly Driscoll, Brigitte I. Frohnert, Patricia Gesualdo, Michelle Hoffman, Rachel Karban, Jill Norris, Adela Samper-Imaz, Andrea Steck, Kathleen Waugh, Hali Wright, Annika Adamsson, Suvi Ahonen, Jorma Ilonen, Sanna Jokipuu, Tiina Kallio, Leena Karlsson, Miia Kähönen, Mikael Knip, Lea Kovanen, Mirva Koreasalo, Kalle Kurppa, Tiina Latva-Aho, Maria Lönnrot, Elina Mäntymäki, Katja Multasuo, Juha Mykkänen, Tiina Niininen, Sari Niinistö, Mia Nyblom, Petra Rajala, Jenna Rautanen, Anne Riikonen, Mika Riikonen, Jenni Rouhiainen, Minna Romo, Tuula Simell, Maija Sjöberg, Aino Stenius, Maria Leppänen, Sini Vainionpää, Eeva Varjonen, Riitta Veijola, Suvi M. Virtanen, Mari Vähä-Mäkilä, Mari Åkerlund, Katri Lindfors, Desmond Schatz, Diane Hopkins, Leigh Steed, Jamie Thomas, Janey Adams, Katherine Silvis, Michael Haller, Melissa Gardiner, Richard A McIndoe, Ashok Kumar Sharma, Joshua William, Gabriela Young, Stephen W. Anderson, Laura Jacobsen, Andreas Beyerlein, Ezio Bonifacio, Michael Hummel, Sandra Hummel, Kristina Foterek, Nicole Janz, Mathilde Kersting, Annette Knopff, Claudia Peplow, Roswith Roth, Marlon Scholz, Joanna Stock, Katharina Warncke, Lorena Wendel, Christiane Winkler, Carin Andrén Aronsson, Maria Ask, Jenny Bremer, Ulla Marie Carlsson, Corrado Cilio, Emelie Ericson-Hallström, Lina Fransson, Thomas Gard, Joanna Gerardsson, Rasmus Bennet, Monica Hansen, Gertie Hansson, Susanne Hyberg, Fredrik Johansen, Berglind Jonsdottir, Marielle Lindström, Markus Lundgren, Maria Månsson-Martinez, Maria Markan, Jessica Melin, Zeliha Mestan, Karin Ottosson, Kobra Rahmati, Anita Ramelius, Falastin Salami, Sara Sibthorpe, Birgitta Sjöberg, Ulrica Swartling, Evelyn Tekum Amboh, Carina Törn, Anne Wallin, Åsa Wimar, Sofie Åberg, Michael Killian, Claire Cowen Crouch, Jennifer Skidmore, Josephine Carson, Maria Dalzell, Kayleen Dunson, Rachel Hervey, Corbin Johnson, Rachel Lyons, Arlene Meyer, Denise Mulenga, Alexander Tarr, Morgan Uland, John Willis, Dorothy Becker, Margaret Franciscus, Mary Ellen Dalmagro Elias Smith, Ashi Daftary, Mary Beth Klein, Chrystal Yates, Michael Abbondondolo, Sarah Austin-Gonzalez, Maryouri Avendano, Sandra Baethke, Rasheedah Brown, Brant Burkhardt, Martha Butterworth, Joanna Clasen, David Cuthbertson, Christopher Eberhard, Steven Fiske, Dena Garcia, Jennifer Garmeson, Veena Gowda, Kathleen Heyman, Francisco Perez Laras, Hye Seung Lee, Shu Liu, Xiang Liu, Kristian Lynch, Jamie Malloy, Cristina McCarthy, Steven Meulemans, Hemang Parikh, Chris Shaffer, Laura Smith, Susan Smith, Noah Sulman, Roy Tamura, Ulla Uusitalo, Ponni Vijayakandipan, Keith Wood, Jimin Yang, Lori Ballard, David Hadley, Wendy McLeod, Kasia Bourcier, Thomas Briese, Suzanne Bennett Johnson, Liping Yu, Dongmei Miao, Polly Bingley, Alistair William's, Kyla Chandler, Saba Rokni, Claire Willia, Rebecca Wyatt, Gifty George, Sian Grace, Niveen Mulholland

Research output: Contribution to journal › Article › peer-review

65 Scopus citations

Abstract

IMPORTANCE: Evidence is lacking regarding the consequences of antibiotic use in early life and the risk of certain autoimmune diseases. OBJECTIVE: To test the association between early-life antibiotic use and islet or celiac disease (CD) autoimmunity in genetically at-risk children prospectively followed up for type 1 diabetes (T1D) or CD. DESIGN, SETTING, AND PARTICIPANTS: HLA-genotyped newborns from Finland, Germany, Sweden, and the United States were enrolled in the prospective birth cohort of The Environmental Determinants of Diabetes in the Young (TEDDY) study between November 20, 2004, and July 8, 2010. The dates of analysis were November 20, 2004, to August 31, 2014. Individuals from the general population and those having a first-degree relative with T1D were enrolled if they had 1 of 9 HLA genotypes associated with a risk for T1D. EXPOSURES: Parental reports of the most common antibiotics (cephalosporins, penicillins, and macrolides) used between age 3 months and age 4 years were recorded prospectively. MAIN OUTCOMES AND MEASURES: Islet autoimmunity and CD autoimmunitywere defined as being positive for islet or tissue transglutaminase autoantibodies at 2 consecutive clinic visits at least 3 months apart. Hazard ratios and 95%CIs calculated from Cox proportional hazards regression models were used to assess the relationship between antibiotic use in early life before seroconversion and the development of autoimmunity. RESULTS: Participants were 8495 children (49.0% female) and 6558 children (48.7% female) enrolled in the TEDDY study who were tested for islet and tissue transglutaminase autoantibodies, respectively. Exposure to and frequency of use of any antibiotic assessed in this study in early life or before seroconversion did not influence the risk of developing islet autoimmunity or CD autoimmunity. Cumulative use of any antibiotic during the first 4 years of life was not associated with the appearance of any autoantibody (hazard ratio [HR], 0.98; 95% CI, 0.95-1.01), multiple islet autoantibodies (HR, 0.99; 95% CI, 0.95-1.03), or the transglutaminase autoantibody (HR, 1.00; 95% CI, 0.98-1.02). CONCLUSIONS AND RELEVANCE: The use of the most prescribed antibiotics during the first 4 years of life, regardless of geographic region, was not associated with the development of autoimmunity for T1D or CD. These results suggest that a risk of islet or tissue transglutaminase autoimmunity need not influence the recommendations for clinical use of antibiotics in young children at risk for T1D or CD.

Original language	English (US)
Pages (from-to)	1217-1225
Number of pages	9
Journal	JAMA Pediatrics
Volume	171
Issue number	12
DOIs	https://doi.org/10.1001/jamapediatrics.2017.2905
State	Published - Dec 2017

ASJC Scopus subject areas

Pediatrics, Perinatology, and Child Health

Access to Document

10.1001/jamapediatrics.2017.2905

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Kemppainen, K. M., Vehik, K., Lynch, K. F., Larsson, H. E., Canepa, R. J., Simell, V., Koletzko, S., Liu, E., Simell, O. G., Toppari, J., Ziegler, A. G., Rewers, M. J., Lernmark, Å., Hagopian, W. A., She, J-X., Akolkar, B., Schatz, D. A., Atkinson, M. A., Blaser, M. J., ... Mulholland, N. (2017). Association between early-life antibiotic use and the risk of islet or celiac disease autoimmunity. JAMA Pediatrics, 171(12), 1217-1225. https://doi.org/10.1001/jamapediatrics.2017.2905

Kemppainen, KM, Vehik, K, Lynch, KF, Larsson, HE, Canepa, RJ, Simell, V, Koletzko, S, Liu, E, Simell, OG, Toppari, J, Ziegler, AG, Rewers, MJ, Lernmark, Å, Hagopian, WA, She, J-X, Akolkar, B, Schatz, DA, Atkinson, MA, Blaser, MJ, Krischer, JP, Hyöty, H, Agardh, D, Triplett, EW, Bautista, K, Baxter, J, Bedoy, R, Felipe-Morales, D, Driscoll, K, Frohnert, BI, Gesualdo, P, Hoffman, M, Karban, R, Norris, J, Samper-Imaz, A, Steck, A, Waugh, K, Wright, H, Adamsson, A, Ahonen, S, Ilonen, J, Jokipuu, S, Kallio, T, Karlsson, L, Kähönen, M, Knip, M, Kovanen, L, Koreasalo, M, Kurppa, K, Latva-Aho, T, Lönnrot, M, Mäntymäki, E, Multasuo, K, Mykkänen, J, Niininen, T, Niinistö, S, Nyblom, M, Rajala, P, Rautanen, J, Riikonen, A, Riikonen, M, Rouhiainen, J, Romo, M, Simell, T, Sjöberg, M, Stenius, A, Leppänen, M, Vainionpää, S, Varjonen, E, Veijola, R, Virtanen, SM, Vähä-Mäkilä, M, Åkerlund, M, Lindfors, K, Schatz, D, Hopkins, D, Steed, L, Thomas, J, Adams, J, Silvis, K, Haller, M, Gardiner, M, McIndoe, RA , Sharma, AK, William, J, Young, G, Anderson, SW, Jacobsen, L, Beyerlein, A, Bonifacio, E, Hummel, M, Hummel, S, Foterek, K, Janz, N, Kersting, M, Knopff, A, Peplow, C, Roth, R, Scholz, M, Stock, J, Warncke, K, Wendel, L, Winkler, C, Aronsson, CA, Ask, M, Bremer, J, Carlsson, UM, Cilio, C, Ericson-Hallström, E, Fransson, L, Gard, T, Gerardsson, J, Bennet, R, Hansen, M, Hansson, G, Hyberg, S, Johansen, F, Jonsdottir, B, Lindström, M, Lundgren, M, Månsson-Martinez, M, Markan, M, Melin, J, Mestan, Z, Ottosson, K, Rahmati, K, Ramelius, A, Salami, F, Sibthorpe, S, Sjöberg, B, Swartling, U, Amboh, ET, Törn, C, Wallin, A, Wimar, Å, Åberg, S, Killian, M, Crouch, CC, Skidmore, J, Carson, J, Dalzell, M, Dunson, K, Hervey, R, Johnson, C, Lyons, R, Meyer, A, Mulenga, D, Tarr, A, Uland, M, Willis, J, Becker, D, Franciscus, M, Smith, MEDE, Daftary, A, Klein, MB, Yates, C, Abbondondolo, M, Austin-Gonzalez, S, Avendano, M, Baethke, S, Brown, R, Burkhardt, B, Butterworth, M, Clasen, J, Cuthbertson, D, Eberhard, C, Fiske, S, Garcia, D, Garmeson, J, Gowda, V, Heyman, K, Laras, FP, Lee, HS, Liu, S, Liu, X, Lynch, K, Malloy, J, McCarthy, C, Meulemans, S, Parikh, H, Shaffer, C, Smith, L, Smith, S, Sulman, N, Tamura, R, Uusitalo, U, Vijayakandipan, P, Wood, K, Yang, J, Ballard, L, Hadley, D, McLeod, W, Bourcier, K, Briese, T, Johnson, SB, Yu, L, Miao, D, Bingley, P, William's, A, Chandler, K, Rokni, S, Willia, C, Wyatt, R, George, G, Grace, S & Mulholland, N 2017, 'Association between early-life antibiotic use and the risk of islet or celiac disease autoimmunity', JAMA Pediatrics, vol. 171, no. 12, pp. 1217-1225. https://doi.org/10.1001/jamapediatrics.2017.2905

@article{5f94478344da4f96bf624b7283bff42c,

title = "Association between early-life antibiotic use and the risk of islet or celiac disease autoimmunity",

abstract = "IMPORTANCE: Evidence is lacking regarding the consequences of antibiotic use in early life and the risk of certain autoimmune diseases. OBJECTIVE: To test the association between early-life antibiotic use and islet or celiac disease (CD) autoimmunity in genetically at-risk children prospectively followed up for type 1 diabetes (T1D) or CD. DESIGN, SETTING, AND PARTICIPANTS: HLA-genotyped newborns from Finland, Germany, Sweden, and the United States were enrolled in the prospective birth cohort of The Environmental Determinants of Diabetes in the Young (TEDDY) study between November 20, 2004, and July 8, 2010. The dates of analysis were November 20, 2004, to August 31, 2014. Individuals from the general population and those having a first-degree relative with T1D were enrolled if they had 1 of 9 HLA genotypes associated with a risk for T1D. EXPOSURES: Parental reports of the most common antibiotics (cephalosporins, penicillins, and macrolides) used between age 3 months and age 4 years were recorded prospectively. MAIN OUTCOMES AND MEASURES: Islet autoimmunity and CD autoimmunitywere defined as being positive for islet or tissue transglutaminase autoantibodies at 2 consecutive clinic visits at least 3 months apart. Hazard ratios and 95%CIs calculated from Cox proportional hazards regression models were used to assess the relationship between antibiotic use in early life before seroconversion and the development of autoimmunity. RESULTS: Participants were 8495 children (49.0% female) and 6558 children (48.7% female) enrolled in the TEDDY study who were tested for islet and tissue transglutaminase autoantibodies, respectively. Exposure to and frequency of use of any antibiotic assessed in this study in early life or before seroconversion did not influence the risk of developing islet autoimmunity or CD autoimmunity. Cumulative use of any antibiotic during the first 4 years of life was not associated with the appearance of any autoantibody (hazard ratio [HR], 0.98; 95% CI, 0.95-1.01), multiple islet autoantibodies (HR, 0.99; 95% CI, 0.95-1.03), or the transglutaminase autoantibody (HR, 1.00; 95% CI, 0.98-1.02). CONCLUSIONS AND RELEVANCE: The use of the most prescribed antibiotics during the first 4 years of life, regardless of geographic region, was not associated with the development of autoimmunity for T1D or CD. These results suggest that a risk of islet or tissue transglutaminase autoimmunity need not influence the recommendations for clinical use of antibiotics in young children at risk for T1D or CD.",

author = "Kemppainen, {Kaisa M.} and Kendra Vehik and Lynch, {Kristian F.} and Larsson, {Helena Elding} and Canepa, {Ronald J.} and Ville Simell and Sibylle Koletzko and Edwin Liu and Simell, {Olli G.} and Jorma Toppari and Ziegler, {Anette G.} and Rewers, {Marian J.} and {\AA}ke Lernmark and Hagopian, {William A.} and Jin-Xiong She and Beena Akolkar and Schatz, {Desmond A.} and Atkinson, {Mark A.} and Blaser, {Martin J.} and Krischer, {Jeffrey P.} and Heikki Hy{\"o}ty and Daniel Agardh and Triplett, {Eric W.} and Kimberly Bautista and Judith Baxter and Ruth Bedoy and Daniel Felipe-Morales and Kimberly Driscoll and Frohnert, {Brigitte I.} and Patricia Gesualdo and Michelle Hoffman and Rachel Karban and Jill Norris and Adela Samper-Imaz and Andrea Steck and Kathleen Waugh and Hali Wright and Annika Adamsson and Suvi Ahonen and Jorma Ilonen and Sanna Jokipuu and Tiina Kallio and Leena Karlsson and Miia K{\"a}h{\"o}nen and Mikael Knip and Lea Kovanen and Mirva Koreasalo and Kalle Kurppa and Tiina Latva-Aho and Maria L{\"o}nnrot and Elina M{\"a}ntym{\"a}ki and Katja Multasuo and Juha Mykk{\"a}nen and Tiina Niininen and Sari Niinist{\"o} and Mia Nyblom and Petra Rajala and Jenna Rautanen and Anne Riikonen and Mika Riikonen and Jenni Rouhiainen and Minna Romo and Tuula Simell and Maija Sj{\"o}berg and Aino Stenius and Maria Lepp{\"a}nen and Sini Vainionp{\"a}{\"a} and Eeva Varjonen and Riitta Veijola and Virtanen, {Suvi M.} and Mari V{\"a}h{\"a}-M{\"a}kil{\"a} and Mari {\AA}kerlund and Katri Lindfors and Desmond Schatz and Diane Hopkins and Leigh Steed and Jamie Thomas and Janey Adams and Katherine Silvis and Michael Haller and Melissa Gardiner and McIndoe, {Richard A} and Sharma, {Ashok Kumar} and Joshua William and Gabriela Young and Anderson, {Stephen W.} and Laura Jacobsen and Andreas Beyerlein and Ezio Bonifacio and Michael Hummel and Sandra Hummel and Kristina Foterek and Nicole Janz and Mathilde Kersting and Annette Knopff and Claudia Peplow and Roswith Roth and Marlon Scholz and Joanna Stock and Katharina Warncke and Lorena Wendel and Christiane Winkler and Aronsson, {Carin Andr{\'e}n} and Maria Ask and Jenny Bremer and Carlsson, {Ulla Marie} and Corrado Cilio and Emelie Ericson-Hallstr{\"o}m and Lina Fransson and Thomas Gard and Joanna Gerardsson and Rasmus Bennet and Monica Hansen and Gertie Hansson and Susanne Hyberg and Fredrik Johansen and Berglind Jonsdottir and Marielle Lindstr{\"o}m and Markus Lundgren and Maria M{\aa}nsson-Martinez and Maria Markan and Jessica Melin and Zeliha Mestan and Karin Ottosson and Kobra Rahmati and Anita Ramelius and Falastin Salami and Sara Sibthorpe and Birgitta Sj{\"o}berg and Ulrica Swartling and Amboh, {Evelyn Tekum} and Carina T{\"o}rn and Anne Wallin and {\AA}sa Wimar and Sofie {\AA}berg and Michael Killian and Crouch, {Claire Cowen} and Jennifer Skidmore and Josephine Carson and Maria Dalzell and Kayleen Dunson and Rachel Hervey and Corbin Johnson and Rachel Lyons and Arlene Meyer and Denise Mulenga and Alexander Tarr and Morgan Uland and John Willis and Dorothy Becker and Margaret Franciscus and Smith, {Mary Ellen Dalmagro Elias} and Ashi Daftary and Klein, {Mary Beth} and Chrystal Yates and Michael Abbondondolo and Sarah Austin-Gonzalez and Maryouri Avendano and Sandra Baethke and Rasheedah Brown and Brant Burkhardt and Martha Butterworth and Joanna Clasen and David Cuthbertson and Christopher Eberhard and Steven Fiske and Dena Garcia and Jennifer Garmeson and Veena Gowda and Kathleen Heyman and Laras, {Francisco Perez} and Lee, {Hye Seung} and Shu Liu and Xiang Liu and Kristian Lynch and Jamie Malloy and Cristina McCarthy and Steven Meulemans and Hemang Parikh and Chris Shaffer and Laura Smith and Susan Smith and Noah Sulman and Roy Tamura and Ulla Uusitalo and Ponni Vijayakandipan and Keith Wood and Jimin Yang and Lori Ballard and David Hadley and Wendy McLeod and Kasia Bourcier and Thomas Briese and Johnson, {Suzanne Bennett} and Liping Yu and Dongmei Miao and Polly Bingley and Alistair William's and Kyla Chandler and Saba Rokni and Claire Willia and Rebecca Wyatt and Gifty George and Sian Grace and Niveen Mulholland",

note = "Funding Information: Funding/Support: This study was funded by grants U01 DK63829, U01 6 DK63861, U01 DK63821, U01 DK63865, U01 DK63863, U01 DK63836, 7 U01 DK63790, UC4 DK63829, UC4 DK63861, UC4 DK63821, UC4 8 DK63865, UC4 DK63863, UC4 DK63836, UC4 DK95300, UC4 DK100238, and UC4 DK106955 and by contract HHSN267200700014C from the National Institute of Diabetes and Digestive and Kidney Diseases. The TEDDY study is also funded by grants from the National Institute of Allergy and Infectious Diseases, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Institute of Environmental Health Sciences, the Juvenile Diabetes Research Foundation, and the Centers for Disease Control and Prevention. Publisher Copyright: {\textcopyright} 2017 American Medical Association. All rights reserved.",

year = "2017",

month = dec,

doi = "10.1001/jamapediatrics.2017.2905",

language = "English (US)",

volume = "171",

pages = "1217--1225",

journal = "A.M.A. American journal of diseases of children",

issn = "2168-6203",

publisher = "American Medical Association",

number = "12",

}

TY - JOUR

T1 - Association between early-life antibiotic use and the risk of islet or celiac disease autoimmunity

AU - Kemppainen, Kaisa M.

AU - Vehik, Kendra

AU - Lynch, Kristian F.

AU - Larsson, Helena Elding

AU - Canepa, Ronald J.

AU - Simell, Ville

AU - Koletzko, Sibylle

AU - Liu, Edwin

AU - Simell, Olli G.

AU - Toppari, Jorma

AU - Ziegler, Anette G.

AU - Rewers, Marian J.

AU - Lernmark, Åke

AU - Hagopian, William A.

AU - She, Jin-Xiong

AU - Akolkar, Beena

AU - Schatz, Desmond A.

AU - Atkinson, Mark A.

AU - Blaser, Martin J.

AU - Krischer, Jeffrey P.

AU - Hyöty, Heikki

AU - Agardh, Daniel

AU - Triplett, Eric W.

AU - Bautista, Kimberly

AU - Baxter, Judith

AU - Bedoy, Ruth

AU - Felipe-Morales, Daniel

AU - Driscoll, Kimberly

AU - Frohnert, Brigitte I.

AU - Gesualdo, Patricia

AU - Hoffman, Michelle

AU - Karban, Rachel

AU - Norris, Jill

AU - Samper-Imaz, Adela

AU - Steck, Andrea

AU - Waugh, Kathleen

AU - Wright, Hali

AU - Adamsson, Annika

AU - Ahonen, Suvi

AU - Ilonen, Jorma

AU - Jokipuu, Sanna

AU - Kallio, Tiina

AU - Karlsson, Leena

AU - Kähönen, Miia

AU - Knip, Mikael

AU - Kovanen, Lea

AU - Koreasalo, Mirva

AU - Kurppa, Kalle

AU - Latva-Aho, Tiina

AU - Lönnrot, Maria

AU - Mäntymäki, Elina

AU - Multasuo, Katja

AU - Mykkänen, Juha

AU - Niininen, Tiina

AU - Niinistö, Sari

AU - Nyblom, Mia

AU - Rajala, Petra

AU - Rautanen, Jenna

AU - Riikonen, Anne

AU - Riikonen, Mika

AU - Rouhiainen, Jenni

AU - Romo, Minna

AU - Simell, Tuula

AU - Sjöberg, Maija

AU - Stenius, Aino

AU - Leppänen, Maria

AU - Vainionpää, Sini

AU - Varjonen, Eeva

AU - Veijola, Riitta

AU - Virtanen, Suvi M.

AU - Vähä-Mäkilä, Mari

AU - Åkerlund, Mari

AU - Lindfors, Katri

AU - Schatz, Desmond

AU - Hopkins, Diane

AU - Steed, Leigh

AU - Thomas, Jamie

AU - Adams, Janey

AU - Silvis, Katherine

AU - Haller, Michael

AU - Gardiner, Melissa

AU - McIndoe, Richard A

AU - Sharma, Ashok Kumar

AU - William, Joshua

AU - Young, Gabriela

AU - Anderson, Stephen W.

AU - Jacobsen, Laura

AU - Beyerlein, Andreas

AU - Bonifacio, Ezio

AU - Hummel, Michael

AU - Hummel, Sandra

AU - Foterek, Kristina

AU - Janz, Nicole

AU - Kersting, Mathilde

AU - Knopff, Annette

AU - Peplow, Claudia

AU - Roth, Roswith

AU - Scholz, Marlon

AU - Stock, Joanna

AU - Warncke, Katharina

AU - Wendel, Lorena

AU - Winkler, Christiane

AU - Aronsson, Carin Andrén

AU - Ask, Maria

AU - Bremer, Jenny

AU - Carlsson, Ulla Marie

AU - Cilio, Corrado

AU - Ericson-Hallström, Emelie

AU - Fransson, Lina

AU - Gard, Thomas

AU - Gerardsson, Joanna

AU - Bennet, Rasmus

AU - Hansen, Monica

AU - Hansson, Gertie

AU - Hyberg, Susanne

AU - Johansen, Fredrik

AU - Jonsdottir, Berglind

AU - Lindström, Marielle

AU - Lundgren, Markus

AU - Månsson-Martinez, Maria

AU - Markan, Maria

AU - Melin, Jessica

AU - Mestan, Zeliha

AU - Ottosson, Karin

AU - Rahmati, Kobra

AU - Ramelius, Anita

AU - Salami, Falastin

AU - Sibthorpe, Sara

AU - Sjöberg, Birgitta

AU - Swartling, Ulrica

AU - Amboh, Evelyn Tekum

AU - Törn, Carina

AU - Wallin, Anne

AU - Wimar, Åsa

AU - Åberg, Sofie

AU - Killian, Michael

AU - Crouch, Claire Cowen

AU - Skidmore, Jennifer

AU - Carson, Josephine

AU - Dalzell, Maria

AU - Dunson, Kayleen

AU - Hervey, Rachel

AU - Johnson, Corbin

AU - Lyons, Rachel

AU - Meyer, Arlene

AU - Mulenga, Denise

AU - Tarr, Alexander

AU - Uland, Morgan

AU - Willis, John

AU - Becker, Dorothy

AU - Franciscus, Margaret

AU - Smith, Mary Ellen Dalmagro Elias

AU - Daftary, Ashi

AU - Klein, Mary Beth

AU - Yates, Chrystal

AU - Abbondondolo, Michael

AU - Austin-Gonzalez, Sarah

AU - Avendano, Maryouri

AU - Baethke, Sandra

AU - Brown, Rasheedah

AU - Burkhardt, Brant

AU - Butterworth, Martha

AU - Clasen, Joanna

AU - Cuthbertson, David

AU - Eberhard, Christopher

AU - Fiske, Steven

AU - Garcia, Dena

AU - Garmeson, Jennifer

AU - Gowda, Veena

AU - Heyman, Kathleen

AU - Laras, Francisco Perez

AU - Lee, Hye Seung

AU - Liu, Shu

AU - Liu, Xiang

AU - Lynch, Kristian

AU - Malloy, Jamie

AU - McCarthy, Cristina

AU - Meulemans, Steven

AU - Parikh, Hemang

AU - Shaffer, Chris

AU - Smith, Laura

AU - Smith, Susan

AU - Sulman, Noah

AU - Tamura, Roy

AU - Uusitalo, Ulla

AU - Vijayakandipan, Ponni

AU - Wood, Keith

AU - Yang, Jimin

AU - Ballard, Lori

AU - Hadley, David

AU - McLeod, Wendy

AU - Bourcier, Kasia

AU - Briese, Thomas

AU - Johnson, Suzanne Bennett

AU - Yu, Liping

AU - Miao, Dongmei

AU - Bingley, Polly

AU - William's, Alistair

AU - Chandler, Kyla

AU - Rokni, Saba

AU - Willia, Claire

AU - Wyatt, Rebecca

AU - George, Gifty

AU - Grace, Sian

AU - Mulholland, Niveen

N1 - Funding Information: Funding/Support: This study was funded by grants U01 DK63829, U01 6 DK63861, U01 DK63821, U01 DK63865, U01 DK63863, U01 DK63836, 7 U01 DK63790, UC4 DK63829, UC4 DK63861, UC4 DK63821, UC4 8 DK63865, UC4 DK63863, UC4 DK63836, UC4 DK95300, UC4 DK100238, and UC4 DK106955 and by contract HHSN267200700014C from the National Institute of Diabetes and Digestive and Kidney Diseases. The TEDDY study is also funded by grants from the National Institute of Allergy and Infectious Diseases, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Institute of Environmental Health Sciences, the Juvenile Diabetes Research Foundation, and the Centers for Disease Control and Prevention. Publisher Copyright: © 2017 American Medical Association. All rights reserved.

PY - 2017/12

Y1 - 2017/12

N2 - IMPORTANCE: Evidence is lacking regarding the consequences of antibiotic use in early life and the risk of certain autoimmune diseases. OBJECTIVE: To test the association between early-life antibiotic use and islet or celiac disease (CD) autoimmunity in genetically at-risk children prospectively followed up for type 1 diabetes (T1D) or CD. DESIGN, SETTING, AND PARTICIPANTS: HLA-genotyped newborns from Finland, Germany, Sweden, and the United States were enrolled in the prospective birth cohort of The Environmental Determinants of Diabetes in the Young (TEDDY) study between November 20, 2004, and July 8, 2010. The dates of analysis were November 20, 2004, to August 31, 2014. Individuals from the general population and those having a first-degree relative with T1D were enrolled if they had 1 of 9 HLA genotypes associated with a risk for T1D. EXPOSURES: Parental reports of the most common antibiotics (cephalosporins, penicillins, and macrolides) used between age 3 months and age 4 years were recorded prospectively. MAIN OUTCOMES AND MEASURES: Islet autoimmunity and CD autoimmunitywere defined as being positive for islet or tissue transglutaminase autoantibodies at 2 consecutive clinic visits at least 3 months apart. Hazard ratios and 95%CIs calculated from Cox proportional hazards regression models were used to assess the relationship between antibiotic use in early life before seroconversion and the development of autoimmunity. RESULTS: Participants were 8495 children (49.0% female) and 6558 children (48.7% female) enrolled in the TEDDY study who were tested for islet and tissue transglutaminase autoantibodies, respectively. Exposure to and frequency of use of any antibiotic assessed in this study in early life or before seroconversion did not influence the risk of developing islet autoimmunity or CD autoimmunity. Cumulative use of any antibiotic during the first 4 years of life was not associated with the appearance of any autoantibody (hazard ratio [HR], 0.98; 95% CI, 0.95-1.01), multiple islet autoantibodies (HR, 0.99; 95% CI, 0.95-1.03), or the transglutaminase autoantibody (HR, 1.00; 95% CI, 0.98-1.02). CONCLUSIONS AND RELEVANCE: The use of the most prescribed antibiotics during the first 4 years of life, regardless of geographic region, was not associated with the development of autoimmunity for T1D or CD. These results suggest that a risk of islet or tissue transglutaminase autoimmunity need not influence the recommendations for clinical use of antibiotics in young children at risk for T1D or CD.

AB - IMPORTANCE: Evidence is lacking regarding the consequences of antibiotic use in early life and the risk of certain autoimmune diseases. OBJECTIVE: To test the association between early-life antibiotic use and islet or celiac disease (CD) autoimmunity in genetically at-risk children prospectively followed up for type 1 diabetes (T1D) or CD. DESIGN, SETTING, AND PARTICIPANTS: HLA-genotyped newborns from Finland, Germany, Sweden, and the United States were enrolled in the prospective birth cohort of The Environmental Determinants of Diabetes in the Young (TEDDY) study between November 20, 2004, and July 8, 2010. The dates of analysis were November 20, 2004, to August 31, 2014. Individuals from the general population and those having a first-degree relative with T1D were enrolled if they had 1 of 9 HLA genotypes associated with a risk for T1D. EXPOSURES: Parental reports of the most common antibiotics (cephalosporins, penicillins, and macrolides) used between age 3 months and age 4 years were recorded prospectively. MAIN OUTCOMES AND MEASURES: Islet autoimmunity and CD autoimmunitywere defined as being positive for islet or tissue transglutaminase autoantibodies at 2 consecutive clinic visits at least 3 months apart. Hazard ratios and 95%CIs calculated from Cox proportional hazards regression models were used to assess the relationship between antibiotic use in early life before seroconversion and the development of autoimmunity. RESULTS: Participants were 8495 children (49.0% female) and 6558 children (48.7% female) enrolled in the TEDDY study who were tested for islet and tissue transglutaminase autoantibodies, respectively. Exposure to and frequency of use of any antibiotic assessed in this study in early life or before seroconversion did not influence the risk of developing islet autoimmunity or CD autoimmunity. Cumulative use of any antibiotic during the first 4 years of life was not associated with the appearance of any autoantibody (hazard ratio [HR], 0.98; 95% CI, 0.95-1.01), multiple islet autoantibodies (HR, 0.99; 95% CI, 0.95-1.03), or the transglutaminase autoantibody (HR, 1.00; 95% CI, 0.98-1.02). CONCLUSIONS AND RELEVANCE: The use of the most prescribed antibiotics during the first 4 years of life, regardless of geographic region, was not associated with the development of autoimmunity for T1D or CD. These results suggest that a risk of islet or tissue transglutaminase autoimmunity need not influence the recommendations for clinical use of antibiotics in young children at risk for T1D or CD.

UR - http://www.scopus.com/inward/record.url?scp=85038220552&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85038220552&partnerID=8YFLogxK

U2 - 10.1001/jamapediatrics.2017.2905

DO - 10.1001/jamapediatrics.2017.2905

M3 - Article

C2 - 29052687

AN - SCOPUS:85038220552

SN - 2168-6203

VL - 171

SP - 1217

EP - 1225

JO - A.M.A. American journal of diseases of children

JF - A.M.A. American journal of diseases of children

IS - 12

ER -

Association between early-life antibiotic use and the risk of islet or celiac disease autoimmunity

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