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J Clin Endocrinol Metab. 2018 Aug 1;103(8):2967-2979. doi: 10.1210/jc.2018-00224.

Thyroid Function in Early Pregnancy, Child IQ, and Autistic Traits: A Meta-Analysis of Individual Participant Data.

Levie D1,2,3,4,5,6, Korevaar TIM5,6, Bath SC7, Dalmau-Bueno A1,2,3, Murcia M3,8, Espada M3,9, Dineva M7, Ibarluzea JM3,10,11,12, Sunyer J1,2,3,13, Tiemeier H4,14,15, Rebagliato M3,8,16, Rayman MP7, Peeters RP5, Guxens M1,2,3,4.

Author information

Barcelona Institute for Global Health (ISGlobal), Barcelona, Spain.
Pompeu Fabra University, Barcelona, Barcelona, Spain.
Spanish Consortium for Research on Epidemiology and Public Health, Instituto de Salud Carlos III, Madrid, Spain.
Department of Child and Adolescent Psychiatry/Psychology, Erasmus University Medical Centre-Sophia Children's Hospital, Rotterdam, Netherlands.
Department of Internal Medicine, Academic Center for Thyroid Diseases, Erasmus University Medical Centre, Rotterdam, Netherlands.
The Generation R Study Group, Erasmus University Medical Centre, Rotterdam, Netherlands.
Department of Nutritional Sciences, Faculty of Health and Medical Sciences, University of Surrey, Guildford, United Kingdom.
Epidemiology and Environmental Health Joint Research Unit, FISABIO-Universitat Jaume I-Universitat de València, Valencia, Spain.
Clinical Chemistry Unit, Public Health Laboratory of Bilbao, Basque Government, Parque Tecnológico de Bizkaia, Derio, Spain.
Departamento de Sanidad Gobierno Vasco, Subdirección de Salud Pública de Guipúzcoa, Donostia - San Sebastián, Spain.
Biodonostia Health Research Institute, Donostia - San Sebastián, Spain.
Facultad de Psicología, University of the Basque Country UPV/EHU, Donostia - San Sebastián, Spain.
Hospital del Mar Research Institute, Barcelona, Spain.
Department of Social and Behavioral Science, Harvard T. H. Chan School of Public Health, Boston, Massachusetts.
Department of Psychiatry, Erasmus University Medical Centre, Rotterdam, Netherlands.
Departmento de Medicina, Universitat Jaume I, Castelló de la Plana, Spain.



Low maternal free T4 (FT4) has been associated with poor child neurodevelopment in some single-center studies. Evidence remains scarce for the potential adverse effects of high FT4 and whether associations differ in countries with different iodine status.


To assess the association of maternal thyroid function in early pregnancy with child neurodevelopment in countries with a different iodine status.

Design, Setting, and Participants:

Meta-analysis of individual participant data from 9036 mother-child pairs from three prospective population-based birth cohorts: INMA [Infancia y Medio Ambiente (Environment and Childhood project) (Spain)], Generation R (Netherlands), and ALSPAC (Avon Longitudinal Study of Parents and Children, United Kingdom). The exclusion criteria were multiple pregnancies, fertility treatments, thyroid-interfering medication usage, and known thyroid disease.

Main Outcomes:

Child nonverbal IQ at 5 to 8 years of age, verbal IQ at 1.5 to 8 years of age, and autistic traits within the clinical range at 5 to 8 years of age.


FT4 <2.5th percentile was associated with a 3.9-point (95% CI, -5.7 to -2.2) lower nonverbal IQ and a 2.1-point (95% CI, -4.0 to -0.1) lower verbal IQ. A suggestive association of hypothyroxinemia with a greater risk of autistic traits was observed. FT4 >97.5th percentile was associated with a 1.9-fold (95% CI, 1.0 to 3.4) greater risk of autistic traits. No independent associations were found with TSH.


Low maternal FT4 was consistently associated with a lower IQ across the cohorts. Further studies are needed to replicate the findings of autistic traits and investigate the potential modifying role of maternal iodine status. FT4 seems a reliable marker of fetal thyroid state in early pregnancy, regardless of the type of immunoassay.


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