Relation between infant microbiota and autism? - Results from a national cohort sibling-design study

Paul Bryde Axelsson; Tine Dalsgaard Clausen; Anne Helby Petersen; Ida Hageman; Anja Pinborg; Lars Vedel Kessing; Thomas Bergholt; Steen Christian Rasmussen; Niels Keiding; Ellen Christine Leth Løkkegaard

doi:10.1097/EDE.0000000000000928

Relation between infant microbiota and autism? - Results from a national cohort sibling-design study

Paul Bryde Axelsson, Tine Dalsgaard Clausen, Anne Helby Petersen, Ida Hageman, Anja Pinborg, Lars Vedel Kessing, Thomas Bergholt, Steen Christian Rasmussen, Niels Keiding, Ellen Christine Leth Løkkegaard

Section of Biostatistics

12 Citations (Scopus)

Abstract

Background: Hypotheses concerning adverse effects of changes in microbiota have received much recent attention, but unobserved confounding makes them difficult to test. We investigated whether surrogate markers for potential adverse microbiota change in infancy affected autism risk, addressing unobserved confounding using a sibling study design. Methods: This is a population-based, prospective cohort study including all singleton live births in Denmark from 1997 to 2010. The exposure variables were cesarean delivery and antibiotic use in the first 2 years of life. The outcome was a subsequent autism diagnosis. We used the between- and within-sibling model and compared it with sibling-stratified Cox models and simpler standard Cox models that ignored sibship. Results: Of our study population including 671,606 children, who were followed for up to 15 years (7,341,133 person-years), 72% received antibiotics, 17.5% were delivered by cesarean, and 1.2% (8,267) developed autism. The standard Cox models predicted that both cesarean (compared with vaginal) delivery and antibiotics increased the risk of autism. In the sibling-stratified Cox model, only broader spectrum antibiotics were associated with increased risk of autism: hazard ratio (HR) = 1.16 (95% confidence interval = 1.01, 1.36). The between-within model estimated no exposure effects: intrapartum cesarean HR = 1.06 (0.89, 1.26); prelabor cesarean HR = 0.97 (0.83, 1.15); exclusively penicillin HR = 1.05 (0.93, 1.18); and broader spectrum antibiotics HR = 1.05 (0.95, 1.16). Conclusions: The between-within model rendered more precise estimates than sibling-stratified Cox models, and we believe that it also provided more valid estimates. Results from these preferred models do not support a causal relation between antibiotic treatment during infancy, cesarean delivery, and autism. See video abstract at, http://links.lww.com/EDE/B432.

Original language	English
Journal	Epidemiology (Cambridge, Mass.)
Volume	30
Issue number	1
Pages (from-to)	52-60
Number of pages	9
ISSN	1044-3983
DOIs	https://doi.org/10.1097/EDE.0000000000000928
Publication status	Published - 1 Jan 2019

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title = "Relation between infant microbiota and autism? - Results from a national cohort sibling-design study",

abstract = "Background: Hypotheses concerning adverse effects of changes in microbiota have received much recent attention, but unobserved confounding makes them difficult to test. We investigated whether surrogate markers for potential adverse microbiota change in infancy affected autism risk, addressing unobserved confounding using a sibling study design. Methods: This is a population-based, prospective cohort study including all singleton live births in Denmark from 1997 to 2010. The exposure variables were cesarean delivery and antibiotic use in the first 2 years of life. The outcome was a subsequent autism diagnosis. We used the between- and within-sibling model and compared it with sibling-stratified Cox models and simpler standard Cox models that ignored sibship. Results: Of our study population including 671,606 children, who were followed for up to 15 years (7,341,133 person-years), 72% received antibiotics, 17.5% were delivered by cesarean, and 1.2% (8,267) developed autism. The standard Cox models predicted that both cesarean (compared with vaginal) delivery and antibiotics increased the risk of autism. In the sibling-stratified Cox model, only broader spectrum antibiotics were associated with increased risk of autism: hazard ratio (HR) = 1.16 (95% confidence interval = 1.01, 1.36). The between-within model estimated no exposure effects: intrapartum cesarean HR = 1.06 (0.89, 1.26); prelabor cesarean HR = 0.97 (0.83, 1.15); exclusively penicillin HR = 1.05 (0.93, 1.18); and broader spectrum antibiotics HR = 1.05 (0.95, 1.16). Conclusions: The between-within model rendered more precise estimates than sibling-stratified Cox models, and we believe that it also provided more valid estimates. Results from these preferred models do not support a causal relation between antibiotic treatment during infancy, cesarean delivery, and autism. See video abstract at, http://links.lww.com/EDE/B432.",

author = "Axelsson, {Paul Bryde} and Clausen, {Tine Dalsgaard} and Petersen, {Anne Helby} and Ida Hageman and Anja Pinborg and Kessing, {Lars Vedel} and Thomas Bergholt and Rasmussen, {Steen Christian} and Niels Keiding and L{\o}kkegaard, {Ellen Christine Leth}",

year = "2019",

month = jan,

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doi = "10.1097/EDE.0000000000000928",

language = "English",

volume = "30",

pages = "52--60",

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T1 - Relation between infant microbiota and autism? - Results from a national cohort sibling-design study

AU - Axelsson, Paul Bryde

AU - Clausen, Tine Dalsgaard

AU - Petersen, Anne Helby

AU - Hageman, Ida

AU - Pinborg, Anja

AU - Kessing, Lars Vedel

AU - Bergholt, Thomas

AU - Rasmussen, Steen Christian

AU - Keiding, Niels

AU - Løkkegaard, Ellen Christine Leth

PY - 2019/1/1

Y1 - 2019/1/1

N2 - Background: Hypotheses concerning adverse effects of changes in microbiota have received much recent attention, but unobserved confounding makes them difficult to test. We investigated whether surrogate markers for potential adverse microbiota change in infancy affected autism risk, addressing unobserved confounding using a sibling study design. Methods: This is a population-based, prospective cohort study including all singleton live births in Denmark from 1997 to 2010. The exposure variables were cesarean delivery and antibiotic use in the first 2 years of life. The outcome was a subsequent autism diagnosis. We used the between- and within-sibling model and compared it with sibling-stratified Cox models and simpler standard Cox models that ignored sibship. Results: Of our study population including 671,606 children, who were followed for up to 15 years (7,341,133 person-years), 72% received antibiotics, 17.5% were delivered by cesarean, and 1.2% (8,267) developed autism. The standard Cox models predicted that both cesarean (compared with vaginal) delivery and antibiotics increased the risk of autism. In the sibling-stratified Cox model, only broader spectrum antibiotics were associated with increased risk of autism: hazard ratio (HR) = 1.16 (95% confidence interval = 1.01, 1.36). The between-within model estimated no exposure effects: intrapartum cesarean HR = 1.06 (0.89, 1.26); prelabor cesarean HR = 0.97 (0.83, 1.15); exclusively penicillin HR = 1.05 (0.93, 1.18); and broader spectrum antibiotics HR = 1.05 (0.95, 1.16). Conclusions: The between-within model rendered more precise estimates than sibling-stratified Cox models, and we believe that it also provided more valid estimates. Results from these preferred models do not support a causal relation between antibiotic treatment during infancy, cesarean delivery, and autism. See video abstract at, http://links.lww.com/EDE/B432.

AB - Background: Hypotheses concerning adverse effects of changes in microbiota have received much recent attention, but unobserved confounding makes them difficult to test. We investigated whether surrogate markers for potential adverse microbiota change in infancy affected autism risk, addressing unobserved confounding using a sibling study design. Methods: This is a population-based, prospective cohort study including all singleton live births in Denmark from 1997 to 2010. The exposure variables were cesarean delivery and antibiotic use in the first 2 years of life. The outcome was a subsequent autism diagnosis. We used the between- and within-sibling model and compared it with sibling-stratified Cox models and simpler standard Cox models that ignored sibship. Results: Of our study population including 671,606 children, who were followed for up to 15 years (7,341,133 person-years), 72% received antibiotics, 17.5% were delivered by cesarean, and 1.2% (8,267) developed autism. The standard Cox models predicted that both cesarean (compared with vaginal) delivery and antibiotics increased the risk of autism. In the sibling-stratified Cox model, only broader spectrum antibiotics were associated with increased risk of autism: hazard ratio (HR) = 1.16 (95% confidence interval = 1.01, 1.36). The between-within model estimated no exposure effects: intrapartum cesarean HR = 1.06 (0.89, 1.26); prelabor cesarean HR = 0.97 (0.83, 1.15); exclusively penicillin HR = 1.05 (0.93, 1.18); and broader spectrum antibiotics HR = 1.05 (0.95, 1.16). Conclusions: The between-within model rendered more precise estimates than sibling-stratified Cox models, and we believe that it also provided more valid estimates. Results from these preferred models do not support a causal relation between antibiotic treatment during infancy, cesarean delivery, and autism. See video abstract at, http://links.lww.com/EDE/B432.

U2 - 10.1097/EDE.0000000000000928

DO - 10.1097/EDE.0000000000000928

M3 - Journal article

C2 - 30273187

SN - 1044-3983

VL - 30

SP - 52

EP - 60

JO - Epidemiology

JF - Epidemiology

IS - 1

ER -

Relation between infant microbiota and autism? - Results from a national cohort sibling-design study

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