Maternal Iodine Status During Pregnancy Is Not Consistently Associated with Attention-Deficit Hyperactivity Disorder or Autistic Traits in Children

BACKGROUND: Severe iodine deficiency during pregnancy can cause intellectual disability, presumably through inadequate placental transfer of maternal thyroid hormone to the fetus. The association between mild-to-moderate iodine deficiency and child neurodevelopmental problems is not well understood. OBJECTIVES: We investigated the association of maternal iodine status during pregnancy with child attention-deficit hyperactivity disorder (ADHD) and autistic traits. METHODS: This was a collaborative study of 3 population-based birth cohorts: Generation R (n = 1634), INfancia y Medio Ambiente (n = 1293), and the Avon Longitudinal Study of Parents and Children (n = 2619). Exclusion criteria were multiple fetuses, fertility treatment, thyroid-interfering medication use, and pre-existing thyroid disease. The mean age of assessment in the cohorts was between 4.4 and 7.7 y for ADHD symptoms and 4.5 and 7.6 y for autistic traits. We studied the association of the urinary iodine-to-creatinine ratio (UI/Creat) <150 μg/g-in all mother-child pairs, and in those with a urinary-iodine measurement at ≤18 weeks and ≤14 weeks of gestation-with the risk of ADHD or a high autistic-trait score (≥93rd percentile cutoff), using logistic regression. The cohort-specific effect estimates were combined by random-effects meta-analyses. We also investigated whether UI/Creat modified the associations of maternal free thyroxine (FT4) or thyroid-stimulating hormone concentrations with ADHD or autistic traits. RESULTS: UI/Creat <150 μg/g was not associated with ADHD (OR: 1.2; 95% CI: 0.7, 2.2; P = 0.56) or with a high autistic-trait score (OR: 0.8; 95% CI: 0.6, 1.1; P = 0.22). UI/Creat <150 μg/g in early pregnancy (i.e., ≤18 weeks or ≤14 weeks of gestation) was not associated with a higher risk of behavioral problems. The association between a higher FT4 and a greater risk of ADHD (OR: 1.3; 95% CI: 1.0, 1.6; P = 0.017) was not modified by iodine status. CONCLUSIONS: There is no consistent evidence to support an association of mild-to-moderate iodine deficiency during pregnancy with child ADHD or autistic traits

Association of maternal iodine status with child IQ: a meta-analysis of individual-participant data

Dataset, supplement to the article (to be added later

Maternal iodine status during pregnancy is not consistently associated with attention-deficit hyperactivity disorder or autistic traits in the child

Background: Severe iodine deficiency during pregnancy can cause intellectual disability, presumably through inadequate placental transfer of maternal thyroid hormone to the fetus. The association between mild-to-moderate iodine deficiency and child neurodevelopmental problems is not well understood. Objective: We investigated the association of maternal iodine status during pregnancy with child attention-deficit hyperactivity disorder (ADHD) and autistic traits. Methods: Collaborative study of three population-based birth cohorts: Generation R (N=1634), INMA (N=1293), and ALSPAC (N=2619). Exclusion criteria were multiple fetuses, fertility treatment, thyroid-interfering medication use, and pre-existing thyroid disease. The mean age of assessment in the cohorts was between 4.4 – 7.7 years for ADHD symptoms and 4.5 – 7.6 years for autistic traits. We studied the association of the urinary iodine-to-creatinine ratio (UI/Creat) < 150 μg/g – in all mother-child pairs, and in those with a urinary-iodine measurement at ≤ 18 weeks and ≤ 14 weeks of gestation – with the risk of ADHD or a high autistic-trait score (≥ 93rd percentile cut-off), using logistic regression. The cohort-specific effect estimates were combined by random effects meta-analyses. We also investigated whether UI/Creat modified the association of maternal free thyroxine (FT4) or thyroid stimulating hormone (TSH) concentrations with ADHD or autistic traits. Results: UI/Creat <150 μg/g was not associated with ADHD [odds ratio (OR): 1.2; 95% CI: 0.7, 19 2.2; P=0.56] or with a high autistic-trait score (OR: 0.8; 95% CI: 0.6-1.1; P=0.22). UI/Creat <150 20 μg/g in early pregnancy (i.e., ≤ 18 weeks or ≤ 14 weeks of gestation) was not associated with a higher risk of behavioral problems. The association between a higher FT4 and a greater risk of ADHD (OR: 1.3; 95% CI: 1.0, 1.6; P=0.017) was not modified by iodine status. Conclusion: There is no consistent evidence to support an association of mild-to-moderate iodine deficiency during pregnancy with child ADHD or autistic traits

Similarities and differences of dietary and other determinants of iodine status in pregnant women from three European birth cohorts

Purpose As a component of thyroid hormones, adequate iodine intake is essential during pregnancy for fetal neurodevelopment. Across Europe, iodine deficiency is common in pregnancy, but data are lacking on the predictors of iodine status at this life stage. We, therefore, aimed to explore determinants of iodine status during pregnancy in three European populations of differing iodine status. Methods Data were from 6566 pregnant women from three prospective population-based birth cohorts from the United Kingdom (ALSPAC, n = 2852), Spain (INMA, n = 1460), and The Netherlands (Generation R, n = 2254). Urinary iodine-to-creatinine ratio (UI/Creat, µg/g) was measured in spot-urine samples in pregnancy (≤ 18-weeks gestation). Maternal dietary intake, categorised by food groups (g/day), was estimated from food-frequency questionnaires (FFQs). Multivariable regression models used dietary variables (energy-adjusted) and maternal characteristics as predictors of iodine status. Results Median UI/Creat in pregnant women of ALSPAC, INMA, and Generation R was 121, 151, and 210 µg/g, respectively. Maternal age was positively associated with UI/Creat in all cohorts (P ˂ 0.001), while UI/Creat varied by ethnicity only in Generation R (P ˂ 0.05). Of the dietary predictors, intake of milk and dairy products (per 100 g/day) was positively associated with UI/Creat in all cohorts [ALSPAC (B = 3.73, P ˂ 0.0001); INMA (B = 6.92, P = 0.002); Generation R (B = 2.34, P = 0.001)]. Cohort-specific dietary determinants positively associated with UI/Creat included fish and shellfish in ALSPAC and INMA, and eggs and cereal/cereal products in Generation R. Conclusions The cohort-specific dietary determinants probably reflect not only dietary habits but iodine-fortification policies; hence, public-health interventions to improve iodine intake in pregnancy need to be country-specific

Maternal iodine status during pregnancy is not consistently associated with attention-deficit hyperactivity disorder or autistic traits in the child

Background: Severe iodine deficiency during pregnancy can cause intellectual disability, presumably through inadequate placental transfer of maternal thyroid hormone to the fetus. The association between mild-to-moderate iodine deficiency and child neurodevelopmental problems is not well understood. Objective: We investigated the association of maternal iodine status during pregnancy with child attention-deficit hyperactivity disorder (ADHD) and autistic traits. Methods: Collaborative study of three population-based birth cohorts: Generation R (N=1634), INMA (N=1293), and ALSPAC (N=2619). Exclusion criteria were multiple fetuses, fertility treatment, thyroid-interfering medication use, and pre-existing thyroid disease. The mean age of assessment in the cohorts was between 4.4 – 7.7 years for ADHD symptoms and 4.5 – 7.6 years for autistic traits. We studied the association of the urinary iodine-to-creatinine ratio (UI/Creat) < 150 μg/g – in all mother-child pairs, and in those with a urinary-iodine measurement at ≤ 18 weeks and ≤ 14 weeks of gestation – with the risk of ADHD or a high autistic-trait score (≥ 93rd percentile cut-off), using logistic regression. The cohort-specific effect estimates were combined by random effects meta-analyses. We also investigated whether UI/Creat modified the association of maternal free thyroxine (FT4) or thyroid stimulating hormone (TSH) concentrations with ADHD or autistic traits. Results: UI/Creat <150 μg/g was not associated with ADHD [odds ratio (OR): 1.2; 95% CI: 0.7, 19 2.2; P=0.56] or with a high autistic-trait score (OR: 0.8; 95% CI: 0.6-1.1; P=0.22). UI/Creat <150 20 μg/g in early pregnancy (i.e., ≤ 18 weeks or ≤ 14 weeks of gestation) was not associated with a higher risk of behavioral problems. The association between a higher FT4 and a greater risk of ADHD (OR: 1.3; 95% CI: 1.0, 1.6; P=0.017) was not modified by iodine status. Conclusion: There is no consistent evidence to support an association of mild-to-moderate iodine deficiency during pregnancy with child ADHD or autistic traits

Maternal iodine status during pregnancy is not consistently associated with attention-deficit hyperactivity disorder or autistic traits in children

Background: Severe iodine deficiency during pregnancy can cause intellectual disability, presumably through inadequate placental transfer of maternal thyroid hormone to the fetus. The association between mild-to-moderate iodine deficiency and child neurodevelopmental problems is not well understood. Objectives: We investigated the association of maternal iodine status during pregnancy with child attention-deficit hyperactivity disorder (ADHD) and autistic traits. Methods: This was a collaborative study of 3 population-based birth cohorts: Generation R (n = 1634), INfancia y Medio Ambiente (n = 1293), and the Avon Longitudinal Study of Parents and Children (n = 2619). Exclusion criteria were multiple fetuses, fertility treatment, thyroid-interfering medication use, and pre-existing thyroid disease. The mean age of assessment in the cohorts was between 4.4 and 7.7 y for ADHD symptoms and 4.5 and 7.6 y for autistic traits. We studied the association of the urinary iodine-to-creatinine ratio (UI/Creat) <150 μg/g-in all mother-child pairs, and in those with a urinary-iodine measurement at ≤18 weeks and ≤14 weeks of gestation-with the risk of ADHD or a high autistic-trait score (≥93rd percentile cutoff), using logistic regression. The cohort-specific effect estimates were combined by random-effects meta-analyses. We also investigated whether UI/Creat modified the associations of maternal free thyroxine (FT4) or thyroid-stimulating hormone concentrations with ADHD or autistic traits. Results: UI/Creat <150 μg/g was not associated with ADHD (OR: 1.2; 95% CI: 0.7, 2.2; P = 0.56) or with a high autistic-trait score (OR: 0.8; 95% CI: 0.6, 1.1; P = 0.22). UI/Creat <150 μg/g in early pregnancy (i.e., ≤18 weeks or ≤14 weeks of gestation) was not associated with a higher risk of behavioral problems. The association between a higher FT4 and a greater risk of ADHD (OR: 1.3; 95% CI: 1.0, 1.6; P = 0.017) was not modified by iodine status. Conclusions: There is no consistent evidence to support an association of mild-to-moderate iodine deficiency during pregnancy with child ADHD or autistic traits.Supported by the European Union's Horizon 2020 research and innovation program under grant agreement 634453 (to DL, MG, SCB, TIMK, MD, MPR, JS, RPP, and HT). The Generation R study is conducted by the Erasmus Medical Center in close collaboration with the Faculty of Social Sciences of the Erasmus University Rotterdam; the Municipal Health Service Rotterdam area, Rotterdam; and the Stichting Trombosedienst & Artsenlaboratorium Rijnmond (STAR-MDC), Rotterdam. The Generation R Study is supported by the Erasmus Medical Center, Rotterdam; the Erasmus University Rotterdam; the Netherlands Organization for Health Research and Development (ZonMw); the Netherlands Organization for Scientific Research; and the Ministry of Health, Welfare and Sport. A grant from the Sophia Children's Hospital Research Funds supports the neurodevelopmental work on thyroid; RPP is supported by a ZonMw VIDI grant, project number 1717331. HT is supported by a ZonMw VICI grant with personal grant number 016.VICI.170.200. The INMA study was funded by UE grants FP7-ENV-2011 cod 282957 and HEALTH.2010.2.4.5-1; Spain: Instituto de Salud Carlos III grants Red INMA G03/176; CB06/02/0041; FIS-FEDER PI041436, PI05/1079, PI06/0867, PI081151, PI09/00090, PI11/01007, PI11/02591, PI11/02038, PI13/1944, PI13/2032, PI14/00891, PI14/01687, and PI16/1288; Miguel Servet-FEDER CP11/00178, CP15/00025, CPII16/00051, and MS13/00054; and Miguel Servet-FSE MS15/0025 and MSII16/0051; the Alicia Koplowitz Foundation 2017; Generalitat Valenciana: FISABIO grants UGP-15-230, UGP-15-244, and UGP-15-249; Generalitat de Catalunya-CIRIT grant 1999SGR 00241; Fundació La marató de TV3 grant 090430; Department of Health of the Basque Government grants 2005111093 and 2009111069; and Provincial Government of Gipuzkoa grants DFG06/004 and DFG08/001. The Avon Longitudinal Study of Parents and Children (ALSPAC) is supported by the UK Medical Research Council and Wellcome Trust grant 102215/2/13/2, and by the University of Bristol who provide core support for ALSPAC. A comprehensive list of grant funding is available on the ALSPAC website (http://www.bristol.ac.uk/alspac/external/documents/grant-acknowledgements.pdf). The existing iodine measurements in ALSPAC were funded from 1) the NUTRIMENTHE project, which received a research grant from the European Community's 7th Framework Programme (FP7/2008–2013) under grant agreement 212652; and 2) a Ph.D. studentship that was funded by Wassen International and the Waterloo Foundation (2009–2012)

Thyroid function in early pregnancy, child IQ, and autistic traits: a meta-analysis of individual participant data

Context: 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. Objective: 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. Results: 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. Conclusions: 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.EUthyroid Project: European Union’s Horizon 2020 research and innovation programme (grant 634453). INMA, Spain: This study was funded by grants from the European Union (grants FP7-ENV-2011 cod 282957 and HEALTH.2010.2.4.5-1) and Spain: Instituto de Salud Carlos III (grants Red INMA G03/176, CB06/02/0041, FIS-FEDER: PI041436, PI05/1079, PI06/0867, PI081151, FIS- and PS09/00090, PI11/01007, PI11/02591, PI11/02038, PI13/1944, PI13/2032, PI14/00891, PI14/01687, and PI16/1288, Miguel Servet-FEDER CP11/00178, CP15/00025, and CPII16/00051, MS13/00054), Generalitat Valenciana: FISABIO (grants UGP 15-230, UGP-15-244, and UGP-15-249), Generalitat de Catalunya-CIRIT 1999SGR 00241, Fundació La Marató de TV3 (grants 090430), Department of Health of the Basque Government (grants 2005111093 and 2009111069), and the Provincial Government of Gipuzkoa (grants DFG06/004 and DFG08/001)

Thyroid function in early pregnancy, child IQ, and autistic traits: a meta-analysis of individual participant data

Context: 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. Objective: 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. Results: 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. Conclusions: 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.EUthyroid Project: European Union’s Horizon 2020 research and innovation programme (grant 634453). INMA, Spain: This study was funded by grants from the European Union (grants FP7-ENV-2011 cod 282957 and HEALTH.2010.2.4.5-1) and Spain: Instituto de Salud Carlos III (grants Red INMA G03/176, CB06/02/0041, FIS-FEDER: PI041436, PI05/1079, PI06/0867, PI081151, FIS- and PS09/00090, PI11/01007, PI11/02591, PI11/02038, PI13/1944, PI13/2032, PI14/00891, PI14/01687, and PI16/1288, Miguel Servet-FEDER CP11/00178, CP15/00025, and CPII16/00051, MS13/00054), Generalitat Valenciana: FISABIO (grants UGP 15-230, UGP-15-244, and UGP-15-249), Generalitat de Catalunya-CIRIT 1999SGR 00241, Fundació La Marató de TV3 (grants 090430), Department of Health of the Basque Government (grants 2005111093 and 2009111069), and the Provincial Government of Gipuzkoa (grants DFG06/004 and DFG08/001)

Association of maternal iodine status with child IQ: a meta-analysis of individual participant data

Context: Although the consequences of severe iodine deficiency are beyond doubt, the effects of mild to moderate iodine deficiency in pregnancy on child neurodevelopment are less well established. Objective: To study the association between maternal iodine status during pregnancy and child IQ and identify vulnerable time windows of exposure to suboptimal iodine availability. Design: Meta-analysis of individual participant data from three prospective population-based birth cohorts: Generation R (Netherlands), INMA (Spain), and ALSPAC (United Kingdom); pregnant women were enrolled between 2002 and 2006, 2003 and 2008, and 1990 and 1992, respectively. Setting: General community. Participants: 6180 mother-child pairs with measures of urinary iodine and creatinine concentrations in pregnancy and child IQ. Exclusion criteria were multiple pregnancies, fertility treatment, medication affecting the thyroid, and preexisting thyroid disease. Main Outcome Measure: Child nonverbal and verbal IQ assessed at 1.5 to 8 years of age. Results: There was a positive curvilinear association of urinary iodine/creatinine ratio (UI/Creat) with mean verbal IQ only. UI/Creat <150 µg/g was not associated with lower nonverbal IQ (−0.6 point; 95% CI: −1.7 to 0.4 points; P = 0.246) or lower verbal IQ (−0.6 point; 95% CI: −1.3 to 0.1 points; P = 0.082). Stratified analyses showed that the association of UI/Creat with verbal IQ was only present up to 14 weeks of gestation. Conclusions: Fetal brain development is vulnerable to mild to moderate iodine deficiency, particularly in the first trimester. Our results show that potential randomized controlled trials investigating the effect of iodine supplementation in women with mild to moderate iodine deficiency on child neurodevelopment should begin supplementation not later than the first trimester.The INMA study, Spain, was funded by grants from UE (FP7-ENV-2011 cod 282957 and HEALTH.2010.2.4.5-1) and Spain: Instituto de Salud Carlos III (Red INMA G03/176; CB06/02/0041; FIS-FEDER: PI041436, PI05/1079, PI06/0867, PI081151, FIS-and PS09/00090, PI11/01007, PI11/02591, PI11/02038, PI13/1944, PI13/2032, PI14/00891, PI14/01687, and PI16/1288; Miguel Servet-FEDER CP11/00178, CP15/00025, and CPII16/00051, MS13/00054), Generalitat Valenciana: FISABIO (UGP 15-230, UGP-15-244, and UGP-15-249), Generalitat de Catalunya-CIRIT 1999SGR 00241, Fundació La marató de TV3 (090430), Department of Health of the Basque Government (2005111093 and 2009111069), and the Provincial Government of Gipuzkoa (DFG06/004 and DFG08/001). The ALSPAC study, United Kingdom, is supported by the UK Medical Research Council and Wellcome (Grant ref: 102215/2/13/2) and the University of Bristol, which provides core support for the ALSPAC. We are extremely grateful to all the families who took part in this study, the midwives for their help in recruiting them, and the whole ALSPAC team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists, and nurses. A comprehensive list of grants funding is available on the ALSPAC website (www.bristol.ac.uk/alspac/external/documents/grant-acknowledgements.pdf). The existing iodine measurements in ALSPAC were funded from (i) the NUTRIMENTHE project, which received a research grant from the European Community’s 7th Framework Programme (FP7/2008–2013) under grant agreement 212652; and (ii) a PhD studentship that was funded by Wassen International and the Waterloo Foundation (2009 to 2012)