1. Attention Deficit Hyperactivity Disorder and Autism Spectrum Disorder in Children Born to Mothers with Thyroid Dysfunction: a Danish Nationwide Cohort Study Andersen SL, Laurberg P, Wu CS and Olsen J Aalborg University Hospital and Aalborg University, Denmark

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3. Scenario A pregnant woman with hypothyrdoism is concerned after reading about the associations between thyroid disease and autism. She asks: "Is my thyroid problem going to affect my baby?".

4. Background Maternal thyroid hormones are important regulators of fetal brain development. Abnormal maternal thyroid hormone levels might lead to structural changes in fetal brains. Previous studies investigating the relationship between maternal thyroid dysfunction and child neurocognitive development reported inconsistent results.

5. Background How common are Attention Deficit Hyperactivity Disorder (ADHD) and Autism Spectrum Disorder (ASD) in your community?

6. The Clinical Question Do abnormal maternal thyroid hormone levels in pregnancy increase the risk of ADHD and ASD in the child?

7. Description of Research ParticipantsSingletons born in Denmark between 1991-2004, alive and living in Denmark at the age of 3 years. InterventionMaternal thyroid dysfunction (hyper- or hypothyroidism), registered before or after childbirth. ComparisonChildren born to mothers without registered diagnosis of thyroid dysfunction in pregnancy OutcomesDiagnosis of autism spectrum disorder (ASD) Diagnosis of ADHD and/or prescription of ADHD medication DesignPopulation-based cohort study

9. Methods Critically appraise this study using the CASP Checklist for Cohort Studies (http://bit.ly/19nADNW).http://bit.ly/19nADNW

10. Hazard ratio: Diagnosis of ADHD and ASD

11. Hazard ratio: Diagnosis of ADHD in children born to mothers with hyperthyroidism Stratified by time of maternal diagnosis in relation to birth of the child.

12. Hazard ratio: Diagnosis of ASD in children born to mothers with hypothyroidism Stratified by time of maternal diagnosis in relation to birth of the child. Note! Few cases = wide confidence intervals

13. Results What was the association between the timing of diagnosis (before or after childbirth) and the outcomes measured? Can you briefly summarise the results of this study and comment on the effect estimates? How likely is it that the observed associations between thyroid dysfunction, ADHD and ASD are causal (Proc R Soc Med 1965;58:295)?

14. Discussion Which alternative study design(s) would you choose to answer the question in the scenario? Should we screen pregnant women for thyroid dysfunction? Explain your answer(s).

15. Authors’ conclusions Children born to mothers first time diagnosed and treated for thyroid dysfunction after their birth had increased risks of ADHD and ASD. These children may have suffered from the results of untreated maternal thyroid dysfunction during pregnancy. The underlying biological mechanisms explaining the results of this study are to be clarified.

16. Suggested reading Pop VJ, Kuijpens JL, van Baar AL, Verkerk G, van Son MM, de Vijlder JJ, et al. Low maternal free thyroxine concentrations during early pregnancy are associated with impaired psychomotor development in infancy. Clin Endocrinol (Oxf) 1999;50:149-55. Haddow JE, Palomaki GE, Allan WC, Williams JR, Knight GJ, Gagnon J, et al. Maternal thyroid deficiency during pregnancy and subsequent neuropsychological development of the child. N Engl J Med 1999;341:549-55 Lazarus JH, Bestwick JP, Channon S, Paradice R, Maina A, Rees R, Chiusano E, John R, Guaraldo V, George LM, Perona M, Dall'Amico D, Parkes AB, Joomun M, Wald NJ. Antenatal thyroid screening and childhood cognitive function. N Engl J Med. 2012 Feb 9;366(6):493-501. Vila L, Velasco I, González S, Morales F, Sánchez E, Torrejón S, Soldevila B, Stagnaro- Green A, Puig-Domingo M. Controversies in endocrinology: On the need for universal thyroid screening in pregnant women. Eur J Endocrinol. 2013 Nov 29;170(1):R17-30.

17. Authors’ affiliations SL Andersen, P Laurberg and J Olsen Department of Endocrinology, Aalborg University Hospital, 9000 Aalborg, Denmark CS Wu Section for Epidemiology, Department of Public Health, Aarhus University, 8000 Aarhus, Denmark