Maternal diabetes and risk of attention-deficit/hyperactivity disorder in offspring in a multinational cohort of 3.6 million mother-child pairs

Adrienne Y. L. Chan; Le Gao; Miyuki Hsing-Chun Hsieh; Lars J. Kjerpeseth; Raquel Avelar; Tobias Banaschewski; Amy Hai Yan Chan; David Coghill; Jacqueline M. Cohen; Mika Gissler; Jeff Harrison; Patrick Ip; Øystein Karlstad; Wallis C. Y. Lau; Maarit K. Leinonen; Wing Cheong Leung; Tzu-Chi Liao; Johan Reutfors; Shih-Chieh Shao; Emily Simonoff; Kathryn Choon Beng Tan; Katja Taxis; Andrew Tomlin; Carolyn E. Cesta; Edward Chia-Cheng Lai; Helga Zoega; Kenneth K. C. Man; Ian C. K. Wong

doi:10.1038/s41591-024-02917-8

Maternal diabetes and risk of attention-deficit/hyperactivity disorder in offspring in a multinational cohort of 3.6 million mother-child pairs

Adrienne Y. L. Chan, Le Gao, Miyuki Hsing-Chun Hsieh, Lars J. Kjerpeseth, Raquel Avelar, Tobias Banaschewski, Amy Hai Yan Chan, David Coghill, Jacqueline M. Cohen, Mika Gissler, Jeff Harrison, Patrick Ip, Øystein Karlstad, Wallis C. Y. Lau, Maarit K. Leinonen, Wing Cheong Leung, Tzu-Chi Liao, Johan Reutfors, Shih-Chieh Shao, Emily SimonoffKathryn Choon Beng Tan, Katja Taxis, Andrew Tomlin, Carolyn E. Cesta, Edward Chia-Cheng Lai, Helga Zoega, Kenneth K. C. Man, Ian C. K. Wong

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Abstract

Previous studies report an association between maternal diabetes mellitus (MDM) and attention-deficit/hyperactivity disorder (ADHD), often overlooking unmeasured confounders such as shared genetics and environmental factors. We therefore conducted a multinational cohort study with linked mother-child pairs data in Hong Kong, New Zealand, Taiwan, Finland, Iceland, Norway and Sweden to evaluate associations between different MDM (any MDM, gestational diabetes mellitus (GDM) and pregestational diabetes mellitus (PGDM)) and ADHD using Cox proportional hazards regression. We included over 3.6 million mother-child pairs between 2001 and 2014 with follow-up until 2020. Children who were born to mothers with any type of diabetes during pregnancy had a higher risk of ADHD than unexposed children (pooled hazard ratio (HR) = 1.16, 95% confidence interval (CI) = 1.08-1.24). Higher risks of ADHD were also observed for both GDM (pooled HR = 1.10, 95% CI = 1.04-1.17) and PGDM (pooled HR = 1.39, 95% CI = 1.25-1.55). However, siblings with discordant exposure to GDM in pregnancy had similar risks of ADHD (pooled HR = 1.05, 95% CI = 0.94-1.17), suggesting potential confounding by unmeasured, shared familial factors. Our findings indicate that there is a small-to-moderate association between MDM and ADHD, whereas the association between GDM and ADHD is unlikely to be causal. This finding contrast with previous studies, which reported substantially higher risk estimates, and underscores the need to reevaluate the precise roles of hyperglycemia and genetic factors in the relationship between MDM and ADHD.

Original language	English
Journal	Nature medicine
Early online date	8 Apr 2024
DOIs	https://doi.org/10.1038/s41591-024-02917-8
Publication status	E-pub ahead of print - 8 Apr 2024

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This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit https://creativecommons.org/licenses/by/4.0/.

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AYL Chan et al_Maternal diabetes and risk of ADHD in offspring in a multinational cohort of 3.6 million mother-child pairs
This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit https://creativecommons.org/licenses/by/4.0/.
Final published version, 3.4 MBLicence: CC BY 4.0

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Chan, A. Y. L., Gao, L., Hsieh, M. H.-C., Kjerpeseth, L. J., Avelar, R., Banaschewski, T., Chan, A. H. Y., Coghill, D., Cohen, J. M., Gissler, M., Harrison, J., Ip, P., Karlstad, Ø., Lau, W. C. Y., Leinonen, M. K., Leung, W. C., Liao, T.-C., Reutfors, J., Shao, S.-C., ... Wong, I. C. K. (2024). Maternal diabetes and risk of attention-deficit/hyperactivity disorder in offspring in a multinational cohort of 3.6 million mother-child pairs. Nature medicine. Advance online publication. https://doi.org/10.1038/s41591-024-02917-8

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abstract = "Previous studies report an association between maternal diabetes mellitus (MDM) and attention-deficit/hyperactivity disorder (ADHD), often overlooking unmeasured confounders such as shared genetics and environmental factors. We therefore conducted a multinational cohort study with linked mother-child pairs data in Hong Kong, New Zealand, Taiwan, Finland, Iceland, Norway and Sweden to evaluate associations between different MDM (any MDM, gestational diabetes mellitus (GDM) and pregestational diabetes mellitus (PGDM)) and ADHD using Cox proportional hazards regression. We included over 3.6 million mother-child pairs between 2001 and 2014 with follow-up until 2020. Children who were born to mothers with any type of diabetes during pregnancy had a higher risk of ADHD than unexposed children (pooled hazard ratio (HR) = 1.16, 95% confidence interval (CI) = 1.08-1.24). Higher risks of ADHD were also observed for both GDM (pooled HR = 1.10, 95% CI = 1.04-1.17) and PGDM (pooled HR = 1.39, 95% CI = 1.25-1.55). However, siblings with discordant exposure to GDM in pregnancy had similar risks of ADHD (pooled HR = 1.05, 95% CI = 0.94-1.17), suggesting potential confounding by unmeasured, shared familial factors. Our findings indicate that there is a small-to-moderate association between MDM and ADHD, whereas the association between GDM and ADHD is unlikely to be causal. This finding contrast with previous studies, which reported substantially higher risk estimates, and underscores the need to reevaluate the precise roles of hyperglycemia and genetic factors in the relationship between MDM and ADHD.",

author = "Chan, {Adrienne Y. L.} and Le Gao and Hsieh, {Miyuki Hsing-Chun} and Kjerpeseth, {Lars J.} and Raquel Avelar and Tobias Banaschewski and Chan, {Amy Hai Yan} and David Coghill and Cohen, {Jacqueline M.} and Mika Gissler and Jeff Harrison and Patrick Ip and {\O}ystein Karlstad and Lau, {Wallis C. Y.} and Leinonen, {Maarit K.} and Leung, {Wing Cheong} and Tzu-Chi Liao and Johan Reutfors and Shih-Chieh Shao and Emily Simonoff and Tan, {Kathryn Choon Beng} and Katja Taxis and Andrew Tomlin and Cesta, {Carolyn E.} and Lai, {Edward Chia-Cheng} and Helga Zoega and Man, {Kenneth K. C.} and Wong, {Ian C. K.}",

note = "This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article{\textquoteright}s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article{\textquoteright}s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit https://creativecommons.org/licenses/by/4.0/.",

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Chan, AYL, Gao, L, Hsieh, MH-C, Kjerpeseth, LJ, Avelar, R, Banaschewski, T, Chan, AHY, Coghill, D, Cohen, JM, Gissler, M, Harrison, J, Ip, P, Karlstad, Ø, Lau, WCY, Leinonen, MK, Leung, WC, Liao, T-C, Reutfors, J, Shao, S-C, Simonoff, E, Tan, KCB, Taxis, K, Tomlin, A, Cesta, CE, Lai, EC-C, Zoega, H, Man, KKC & Wong, ICK 2024, 'Maternal diabetes and risk of attention-deficit/hyperactivity disorder in offspring in a multinational cohort of 3.6 million mother-child pairs', Nature medicine. https://doi.org/10.1038/s41591-024-02917-8

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AU - Chan, Adrienne Y. L.

AU - Gao, Le

AU - Hsieh, Miyuki Hsing-Chun

AU - Kjerpeseth, Lars J.

AU - Avelar, Raquel

AU - Banaschewski, Tobias

AU - Chan, Amy Hai Yan

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AU - Cohen, Jacqueline M.

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AU - Karlstad, Øystein

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AU - Leinonen, Maarit K.

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AU - Liao, Tzu-Chi

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AU - Shao, Shih-Chieh

AU - Simonoff, Emily

AU - Tan, Kathryn Choon Beng

AU - Taxis, Katja

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AU - Lai, Edward Chia-Cheng

AU - Zoega, Helga

AU - Man, Kenneth K. C.

AU - Wong, Ian C. K.

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PY - 2024/4/8

Y1 - 2024/4/8

N2 - Previous studies report an association between maternal diabetes mellitus (MDM) and attention-deficit/hyperactivity disorder (ADHD), often overlooking unmeasured confounders such as shared genetics and environmental factors. We therefore conducted a multinational cohort study with linked mother-child pairs data in Hong Kong, New Zealand, Taiwan, Finland, Iceland, Norway and Sweden to evaluate associations between different MDM (any MDM, gestational diabetes mellitus (GDM) and pregestational diabetes mellitus (PGDM)) and ADHD using Cox proportional hazards regression. We included over 3.6 million mother-child pairs between 2001 and 2014 with follow-up until 2020. Children who were born to mothers with any type of diabetes during pregnancy had a higher risk of ADHD than unexposed children (pooled hazard ratio (HR) = 1.16, 95% confidence interval (CI) = 1.08-1.24). Higher risks of ADHD were also observed for both GDM (pooled HR = 1.10, 95% CI = 1.04-1.17) and PGDM (pooled HR = 1.39, 95% CI = 1.25-1.55). However, siblings with discordant exposure to GDM in pregnancy had similar risks of ADHD (pooled HR = 1.05, 95% CI = 0.94-1.17), suggesting potential confounding by unmeasured, shared familial factors. Our findings indicate that there is a small-to-moderate association between MDM and ADHD, whereas the association between GDM and ADHD is unlikely to be causal. This finding contrast with previous studies, which reported substantially higher risk estimates, and underscores the need to reevaluate the precise roles of hyperglycemia and genetic factors in the relationship between MDM and ADHD.

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Maternal diabetes and risk of attention-deficit/hyperactivity disorder in offspring in a multinational cohort of 3.6 million mother-child pairs

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