Early-life antibiotic use and risk of attention-deficit hyperactivity disorder and autism spectrum disorder: results of a discordant twin study

Elise M A Slob; Bronwyn K Brew; Susanne J H Vijverberg; Talitha Dijs; Catharina E M Van Beijsterveldt; Gerard H Koppelman; Meike Bartels; Conor V Dolan; Henrik Larsson; Sebastian Lundström; Paul Lichtenstein; Tong Gong; Anke H Maitland-van Der Zee; Aletta D Kraneveld; Catarina Almqvist; Dorret I Boomsma

doi:10.1093/ije/dyaa168

Early-life antibiotic use and risk of attention-deficit hyperactivity disorder and autism spectrum disorder: results of a discordant twin study

Elise M A Slob
, Bronwyn K Brew
, Susanne J H Vijverberg
, Talitha Dijs
, Catharina E M Van Beijsterveldt
, Gerard H Koppelman
, Meike Bartels
, Conor V Dolan
, Henrik Larsson
, Sebastian Lundström
, Paul Lichtenstein
, Tong Gong
, Anke H Maitland-van Der Zee
, Aletta D Kraneveld
, Catarina Almqvist
, Dorret I Boomsma

Research output: Contribution to Journal › Article › Academic › peer-review

Abstract

Background
Development of the gut-brain axis in early life may be disturbed by antibiotic use. It has been hypothesized that this disturbance may contribute to development of neurodevelopmental disorders, including autism spectrum disorder and attention-deficit hyperactivity disorder. We aimed to assess the association between antibiotic use in early life and the risk of developing attention-deficit hyperactivity disorder or autism spectrum disorder, while controlling for shared genetic and environmental factors in a discordant twin design.

Methods
We conducted a cohort study in twins (7–12 years; 25 781 twins) from the Netherlands Twin Register (NTR) and a replication study in the Childhood and Adolescent Twin Study in Sweden (CATSS; 7946 9-year-old twins). Antibiotic use was recorded before age 2 years. Attention-deficit hyperactivity disorder and autism spectrum disorder were parent-reported in the Netherlands Twin Register and register-based in the Childhood and Adolescent Twin Study in Sweden.

Results
Early-life antibiotic use was associated with increased risk of attention-deficit hyperactivity disorder development [pooled odds ratio (OR) 1.10, 95% confidence interval (CI) 1.02-1.17] and autism spectrum disorder (pooled OR 1.15, 95% CI 1.06-1.25) in a case-control design. When restricting to monozygotic twin pairs discordant for the outcome, associations disappeared for both disorders in both cohorts (attention-deficit hyperactivity disorder OR 0.90, 95% CI 0.48-1.69 and OR 0.80, 95% CI 0.37-1.76, and autism spectrum disorder OR 0.66, 95% CI 0.38-1.16 and OR 0.29, 95% CI 0.02-4.50, respectively).

Conclusions
Our findings suggest that the association between early-life antibiotic use and risk of attention-deficit hyperactivity and autism spectrum disorder may be confounded by shared familial environment and genetics.

Original language	English
Pages (from-to)	475-484
Number of pages	10
Journal	International Journal of Epidemiology
Volume	50
Issue number	2
Early online date	12 Nov 2020
DOIs	https://doi.org/10.1093/ije/dyaa168
Publication status	Published - Apr 2021

Funding

This work was supported by the Swedish Research Council framework (grant number 340–2013-5867); grants from the Stockholm County Council (ALF-projects); the Swedish Heart-Lung Foundation (Childhood and Adolescent Twin Study in Sweden); the Netherlands Organization for Scientific Research (NWO) and The Netherlands Organisation for Health Research and Development (ZonMW) grants including OCW-NWO Gravity program (grant number 024.001.003); NWO-Groot (grant number 480–15-001/ 674); Amsterdam Public Health (APH) research institute; KNAW Academy Professor Award (grant number PAH/6635 to D.I.B); Dutch Lung Foundation (grant number 5.1.16.094); AMC Young Talent Fund (to E.M.A.S.); Jo Kolk Studiefonds (to E.M.A.S.) (NTR).

Funders	Funder number
Stockholms Läns Landsting
OCW-NWO
Stichting Jo Kolk Studiefonds
ZonMw
Hjärt-Lungfonden
Swedish Research Council framework	340–2013-5867
???publication-publication-funding-organisation-not-added???	024.001.003
Amsterdam Public Health	PAH/6635
NWO-Groot	480–15-001/ 674
Lung Foundation Netherlands	5.1.16.094

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Access to Document

10.1093/ije/dyaa168

https://academic.oup.com/ije/advance-article/doi/10.1093/ije/dyaa168/5975019

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Cite this

Slob, E. M. A., Brew, B. K., Vijverberg, S. J. H., Dijs, T., Van Beijsterveldt, C. E. M., Koppelman, G. H., Bartels, M., Dolan, C. V., Larsson, H., Lundström, S., Lichtenstein, P., Gong, T., Maitland-van Der Zee, A. H., Kraneveld, A. D., Almqvist, C., & Boomsma, D. I. (2021). Early-life antibiotic use and risk of attention-deficit hyperactivity disorder and autism spectrum disorder: results of a discordant twin study. International Journal of Epidemiology, 50(2), 475-484. https://doi.org/10.1093/ije/dyaa168

@article{f2d605723e1347e0b7d0193d4847a2aa,

title = "Early-life antibiotic use and risk of attention-deficit hyperactivity disorder and autism spectrum disorder: results of a discordant twin study",

abstract = "Background Development of the gut-brain axis in early life may be disturbed by antibiotic use. It has been hypothesized that this disturbance may contribute to development of neurodevelopmental disorders, including autism spectrum disorder and attention-deficit hyperactivity disorder. We aimed to assess the association between antibiotic use in early life and the risk of developing attention-deficit hyperactivity disorder or autism spectrum disorder, while controlling for shared genetic and environmental factors in a discordant twin design. Methods We conducted a cohort study in twins (7–12 years; 25 781 twins) from the Netherlands Twin Register (NTR) and a replication study in the Childhood and Adolescent Twin Study in Sweden (CATSS; 7946 9-year-old twins). Antibiotic use was recorded before age 2 years. Attention-deficit hyperactivity disorder and autism spectrum disorder were parent-reported in the Netherlands Twin Register and register-based in the Childhood and Adolescent Twin Study in Sweden. Results Early-life antibiotic use was associated with increased risk of attention-deficit hyperactivity disorder development [pooled odds ratio (OR) 1.10, 95\% confidence interval (CI) 1.02-1.17] and autism spectrum disorder (pooled OR 1.15, 95\% CI 1.06-1.25) in a case-control design. When restricting to monozygotic twin pairs discordant for the outcome, associations disappeared for both disorders in both cohorts (attention-deficit hyperactivity disorder OR 0.90, 95\% CI 0.48-1.69 and OR 0.80, 95\% CI 0.37-1.76, and autism spectrum disorder OR 0.66, 95\% CI 0.38-1.16 and OR 0.29, 95\% CI 0.02-4.50, respectively). Conclusions Our findings suggest that the association between early-life antibiotic use and risk of attention-deficit hyperactivity and autism spectrum disorder may be confounded by shared familial environment and genetics.",

author = "Slob, \{Elise M A\} and Brew, \{Bronwyn K\} and Vijverberg, \{Susanne J H\} and Talitha Dijs and \{Van Beijsterveldt\}, \{Catharina E M\} and Koppelman, \{Gerard H\} and Meike Bartels and Dolan, \{Conor V\} and Henrik Larsson and Sebastian Lundstr{\"o}m and Paul Lichtenstein and Tong Gong and \{Maitland-van Der Zee\}, \{Anke H\} and Kraneveld, \{Aletta D\} and Catarina Almqvist and Boomsma, \{Dorret I\}",

year = "2021",

month = apr,

doi = "10.1093/ije/dyaa168",

language = "English",

volume = "50",

pages = "475--484",

journal = "International Journal of Epidemiology",

issn = "0300-5771",

publisher = "Oxford University Press",

number = "2",

}

Slob, EMA, Brew, BK, Vijverberg, SJH, Dijs, T, Van Beijsterveldt, CEM, Koppelman, GH, Bartels, M , Dolan, CV, Larsson, H, Lundström, S, Lichtenstein, P, Gong, T, Maitland-van Der Zee, AH, Kraneveld, AD, Almqvist, C & Boomsma, DI 2021, 'Early-life antibiotic use and risk of attention-deficit hyperactivity disorder and autism spectrum disorder: results of a discordant twin study', International Journal of Epidemiology, vol. 50, no. 2, pp. 475-484. https://doi.org/10.1093/ije/dyaa168

Early-life antibiotic use and risk of attention-deficit hyperactivity disorder and autism spectrum disorder: results of a discordant twin study. / Slob, Elise M A; Brew, Bronwyn K; Vijverberg, Susanne J H et al.
In: International Journal of Epidemiology, Vol. 50, No. 2, 04.2021, p. 475-484.

Research output: Contribution to Journal › Article › Academic › peer-review

TY - JOUR

T1 - Early-life antibiotic use and risk of attention-deficit hyperactivity disorder and autism spectrum disorder: results of a discordant twin study

AU - Slob, Elise M A

AU - Brew, Bronwyn K

AU - Vijverberg, Susanne J H

AU - Dijs, Talitha

AU - Van Beijsterveldt, Catharina E M

AU - Koppelman, Gerard H

AU - Bartels, Meike

AU - Dolan, Conor V

AU - Larsson, Henrik

AU - Lundström, Sebastian

AU - Lichtenstein, Paul

AU - Gong, Tong

AU - Maitland-van Der Zee, Anke H

AU - Kraneveld, Aletta D

AU - Almqvist, Catarina

AU - Boomsma, Dorret I

PY - 2021/4

Y1 - 2021/4

N2 - Background Development of the gut-brain axis in early life may be disturbed by antibiotic use. It has been hypothesized that this disturbance may contribute to development of neurodevelopmental disorders, including autism spectrum disorder and attention-deficit hyperactivity disorder. We aimed to assess the association between antibiotic use in early life and the risk of developing attention-deficit hyperactivity disorder or autism spectrum disorder, while controlling for shared genetic and environmental factors in a discordant twin design. Methods We conducted a cohort study in twins (7–12 years; 25 781 twins) from the Netherlands Twin Register (NTR) and a replication study in the Childhood and Adolescent Twin Study in Sweden (CATSS; 7946 9-year-old twins). Antibiotic use was recorded before age 2 years. Attention-deficit hyperactivity disorder and autism spectrum disorder were parent-reported in the Netherlands Twin Register and register-based in the Childhood and Adolescent Twin Study in Sweden. Results Early-life antibiotic use was associated with increased risk of attention-deficit hyperactivity disorder development [pooled odds ratio (OR) 1.10, 95% confidence interval (CI) 1.02-1.17] and autism spectrum disorder (pooled OR 1.15, 95% CI 1.06-1.25) in a case-control design. When restricting to monozygotic twin pairs discordant for the outcome, associations disappeared for both disorders in both cohorts (attention-deficit hyperactivity disorder OR 0.90, 95% CI 0.48-1.69 and OR 0.80, 95% CI 0.37-1.76, and autism spectrum disorder OR 0.66, 95% CI 0.38-1.16 and OR 0.29, 95% CI 0.02-4.50, respectively). Conclusions Our findings suggest that the association between early-life antibiotic use and risk of attention-deficit hyperactivity and autism spectrum disorder may be confounded by shared familial environment and genetics.

AB - Background Development of the gut-brain axis in early life may be disturbed by antibiotic use. It has been hypothesized that this disturbance may contribute to development of neurodevelopmental disorders, including autism spectrum disorder and attention-deficit hyperactivity disorder. We aimed to assess the association between antibiotic use in early life and the risk of developing attention-deficit hyperactivity disorder or autism spectrum disorder, while controlling for shared genetic and environmental factors in a discordant twin design. Methods We conducted a cohort study in twins (7–12 years; 25 781 twins) from the Netherlands Twin Register (NTR) and a replication study in the Childhood and Adolescent Twin Study in Sweden (CATSS; 7946 9-year-old twins). Antibiotic use was recorded before age 2 years. Attention-deficit hyperactivity disorder and autism spectrum disorder were parent-reported in the Netherlands Twin Register and register-based in the Childhood and Adolescent Twin Study in Sweden. Results Early-life antibiotic use was associated with increased risk of attention-deficit hyperactivity disorder development [pooled odds ratio (OR) 1.10, 95% confidence interval (CI) 1.02-1.17] and autism spectrum disorder (pooled OR 1.15, 95% CI 1.06-1.25) in a case-control design. When restricting to monozygotic twin pairs discordant for the outcome, associations disappeared for both disorders in both cohorts (attention-deficit hyperactivity disorder OR 0.90, 95% CI 0.48-1.69 and OR 0.80, 95% CI 0.37-1.76, and autism spectrum disorder OR 0.66, 95% CI 0.38-1.16 and OR 0.29, 95% CI 0.02-4.50, respectively). Conclusions Our findings suggest that the association between early-life antibiotic use and risk of attention-deficit hyperactivity and autism spectrum disorder may be confounded by shared familial environment and genetics.

U2 - 10.1093/ije/dyaa168

DO - 10.1093/ije/dyaa168

M3 - Article

SN - 0300-5771

VL - 50

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EP - 484

JO - International Journal of Epidemiology

JF - International Journal of Epidemiology

IS - 2

ER -