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Maternal Thyroxine Levels During Pregnancy and Outcomes of Cognitive Development in Children

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Abstract

Though there were many studies assessing the relationship between maternal thyroxine levels during pregnancy and cognitive development in children, there was still lack of evidence for the association from a comprehensive assessment of published data. To get a more comprehensive estimate of the influence of low maternal thyroxine levels on cognitive function, a meta-analysis of prospective cohort studies was performed. Two electronic databases, MEDLINE and EMBASE, were searched for relevant prospective cohort studies. Relative risks (RR) with 95 % confidence intervals (95 % CI) were pooled using random-effect model of meta-analysis to assess the risk of delayed cognitive development in children. Seven prospective cohort studies with a total of 8273 mother-child pairs were included into the meta-analysis. There was obvious between-study heterogeneity in the meta-analysis (I 2 = 69.6 %). Meta-analysis of using random-effect model showed that low maternal thyroxine level was significantly associated with a threefold risk of delayed cognitive development in children (random RR = 3.08, 95 % CI 1.83–5.18, P < 0.001). When excluding the study with largest weight, there was no obvious between-study heterogeneity in the left studies (I 2 = 47.6 %), and meta-analysis using random-effect model showed that low maternal thyroxine level was still significantly associated with increased risk of delayed cognitive development in children (random RR = 3.76, 95 % CI 2.14–6.58, P < 0.001). Sensitivity analysis by omitting other studies by turns showed that there was no obvious change in the pooled risk estimates, and all pooled RRs were statistically significant. Therefore, the findings from the meta-analysis provide strong evidence for the association between maternal thyroxine levels during pregnancy and cognitive development in children. Low maternal thyroxine level is significantly associated with a threefold risk of delayed cognitive development in children.

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References

  1. Bryan J, Osendarp S, Hughes D, Calvaresi E, Baghurst K, van Klinken JW (2004) Nutrients for cognitive development in school-aged children. Nutr Rev 62(8):295–306

    Article  PubMed  Google Scholar 

  2. Pavuluri MN, Sweeney JA (2008) Integrating functional brain neuroimaging and developmental cognitive neuroscience in child psychiatry research. J Am Acad Child Adolesc Psychiatry 47(11):1273–1288

    Article  PubMed  PubMed Central  Google Scholar 

  3. Chen R, Clifford A, Lang L, Anstey KJ (2013) Is exposure to secondhand smoke associated with cognitive parameters of children and adolescents?—a systematic literature review. Ann Epidemiol 23(10):652–661

    Article  PubMed  Google Scholar 

  4. Clifford A, Lang L, Chen R (2012) Effects of maternal cigarette smoking during pregnancy on cognitive parameters of children and young adults: a literature review. Neurotoxicol Teratol 34(6):560–570

    Article  CAS  PubMed  Google Scholar 

  5. Jurewicz J, Polanska K, Hanke W (2013) Exposure to widespread environmental toxicants and children’s cognitive development and behavioral problems. Int J Occup Med Environ Health 26(2):185–204

    Article  PubMed  Google Scholar 

  6. Tarabulsy GM, Pearson J, Vaillancourt-Morel MP, Bussieres EL, Madigan S, Lemelin JP, Duchesneau AA, Hatier DE et al (2014) Meta-analytic findings of the relation between maternal prenatal stress and anxiety and child cognitive outcome. J Dev Behav Pediatr 35(1):38–43

    Article  PubMed  Google Scholar 

  7. Rovet JF (2014) The role of thyroid hormones for brain development and cognitive function. Endocr Dev 2626–43

  8. Henrichs J, Ghassabian A, Peeters RP, Tiemeier H (2013) Maternal hypothyroxinemia and effects on cognitive functioning in childhood: how and why? Clin Endocrinol (Oxf) 79(2):152–162

    Article  Google Scholar 

  9. Morreale de Escobar G, Obregon MJ, Escobar del Rey F (2004) Role of thyroid hormone during early brain development. Eur J Endocrinol 151(3U25-37)

  10. Zhang Y, Fan Y, Yu X, Wang X, Bao S, Li J, Fan C, Shan Z et al (2014) Maternal subclinical hypothyroidism impairs neurodevelopment in rat offspring by inhibiting the CREB signaling pathway. Mol Neurobiol

  11. de Escobar GM, Obregon MJ, del Rey FE (2004) Maternal thyroid hormones early in pregnancy and fetal brain development. Best Pract Res Clin Endocrinol Metab 18(2):225–248

    Article  PubMed  Google Scholar 

  12. Pharoah PO, Connolly KJ, Ekins RP, Harding AG (1984) Maternal thyroid hormone levels in pregnancy and the subsequent cognitive and motor performance of the children. Clin Endocrinol (Oxf) 21(3):265–270

    Article  CAS  Google Scholar 

  13. Haddow JE, Palomaki GE, Allan WC, Williams JR, Knight GJ, Gagnon J, O’Heir CE, Mitchell ML et al (1999) Maternal thyroid deficiency during pregnancy and subsequent neuropsychological development of the child. N Engl J Med 341(8):549–555

    Article  CAS  PubMed  Google Scholar 

  14. Pop VJ, Kuijpens JL, van Baar AL, Verkerk G, van Son MM, de Vijlder JJ, Vulsma T, Wiersinga WM et al (1999) Low maternal free thyroxine concentrations during early pregnancy are associated with impaired psychomotor development in infancy. Clin Endocrinol (Oxf) 50(2):149–155

    Article  CAS  Google Scholar 

  15. Pop VJ, Brouwers EP, Vader HL, Vulsma T, van Baar AL, de Vijlder JJ (2003) Maternal hypothyroxinaemia during early pregnancy and subsequent child development: a 3-year follow-up study. Clin Endocrinol (Oxf) 59(3):282–288

    Article  Google Scholar 

  16. Henrichs J, Bongers-Schokking JJ, Schenk JJ, Ghassabian A, Schmidt HG, Visser TJ, Hooijkaas H, de Muinck Keizer-Schrama SM et al (2010) Maternal thyroid function during early pregnancy and cognitive functioning in early childhood: the generation R study. J Clin Endocrinol Metab 95(9):4227–4234

    Article  CAS  PubMed  Google Scholar 

  17. Li Y, Shan Z, Teng W, Yu X, Fan C, Teng X, Guo R, Wang H et al (2010) Abnormalities of maternal thyroid function during pregnancy affect neuropsychological development of their children at 25–30 months. Clin Endocrinol (Oxf) 72(6):825–829

    Article  CAS  Google Scholar 

  18. Craig WY, Allan WC, Kloza EM, Pulkkinen AJ, Waisbren S, Spratt DI, Palomaki GE, Neveux LM et al (2012) Mid-gestational maternal free thyroxine concentration and offspring neurocognitive development at age two years. J Clin Endocrinol Metab 97(1):E22–E28

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Ghassabian A, El Marroun H, Peeters RP, Jaddoe VW, Hofman A, Verhulst FC, Tiemeier H, White T (2014) Downstream effects of maternal hypothyroxinemia in early pregnancy: nonverbal IQ and brain morphology in school-age children. J Clin Endocrinol Metab 99(7):2383–2390

    Article  CAS  PubMed  Google Scholar 

  20. Wells G, Shea B, O’connell D, Peterson J, Welch V, Losos M, Tugwell P (2014) The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. Ottawa Health Research Institute Web site

  21. Higgins JP, Thompson SG, Deeks JJ, Altman DG (2003) Measuring inconsistency in meta-analyses. BMJ 327(7414):557–560

    Article  PubMed  PubMed Central  Google Scholar 

  22. DerSimonian R, Laird N (1986) Meta-analysis in clinical trials. Control Clin Trials 7(3):177–188

    Article  CAS  PubMed  Google Scholar 

  23. Liu H, Momotani N, Noh JY, Ishikawa N, Takebe K, Ito K (1994) Maternal hypothyroidism during early pregnancy and intellectual development of the progeny. Arch Intern Med 154(7):785–787

    Article  CAS  PubMed  Google Scholar 

  24. Smit BJ, Kok JH, Vulsma T, Briet JM, Boer K, Wiersinga WM (2000) Neurologic development of the newborn and young child in relation to maternal thyroid function. Acta Paediatr 89(3):291–295

    Article  CAS  PubMed  Google Scholar 

  25. Klein RZ, Sargent JD, Larsen PR, Waisbren SE, Haddow JE, Mitchell ML (2001) Relation of severity of maternal hypothyroidism to cognitive development of offspring. J Med Screen 8(1):18–20

    Article  CAS  PubMed  Google Scholar 

  26. Wasserman EE, Nelson K, Rose NR, Eaton W, Pillion JP, Seaberg E, Talor MV, Burek L et al (2008) Maternal thyroid autoantibodies during the third trimester and hearing deficits in children: an epidemiologic assessment. Am J Epidemiol 167(6):701–710

    Article  PubMed  Google Scholar 

  27. Oken E, Braverman LE, Platek D, Mitchell ML, Lee SL, Pearce EN (2009) Neonatal thyroxine, maternal thyroid function, and child cognition. J Clin Endocrinol Metab 94(2):497–503

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Behrooz HG, Tohidi M, Mehrabi Y, Behrooz EG, Tehranidoost M, Azizi F (2011) Subclinical hypothyroidism in pregnancy: intellectual development of offspring. Thyroid 21(10):1143–1147

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Murcia M, Rebagliato M, Iniguez C, Lopez-Espinosa MJ, Estarlich M, Plaza B, Barona-Vilar C, Espada M et al (2011) Effect of iodine supplementation during pregnancy on infant neurodevelopment at 1 year of age. Am J Epidemiol 173(7):804–812

    Article  PubMed  Google Scholar 

  30. Su PY, Huang K, Hao JH, Xu YQ, Yan SQ, Li T, Xu YH, Tao FB (2011) Maternal thyroid function in the first twenty weeks of pregnancy and subsequent fetal and infant development: a prospective population-based cohort study in China. J Clin Endocrinol Metab 96(10):3234–3241

    Article  CAS  PubMed  Google Scholar 

  31. Suarez-Rodriguez M, Azcona-San Julian C, Alzina de Aguilar V (2012) Hypothyroxinemia during pregnancy: the effect on neurodevelopment in the child. Int J Dev Neurosci 30(6):435–438

    Article  CAS  PubMed  Google Scholar 

  32. Wasserman EE, Pillion JP, Duggan A, Nelson K, Rohde C, Seaberg EC, Talor MV, Yolken RH et al (2012) Childhood IQ, hearing loss, and maternal thyroid autoimmunity in the Baltimore Collaborative Perinatal Project. Pediatr Res 72(5):525–530

    Article  PubMed  Google Scholar 

  33. Williams F, Watson J, Ogston S, Hume R, Willatts P, Visser T (2012) Mild maternal thyroid dysfunction at delivery of infants born </=34 weeks and neurodevelopmental outcome at 5.5 years. J Clin Endocrinol Metab 97(6):1977–1985

    Article  CAS  PubMed  Google Scholar 

  34. Finken MJ, van Eijsden M, Loomans EM, Vrijkotte TG, Rotteveel J (2013) Maternal hypothyroxinemia in early pregnancy predicts reduced performance in reaction time tests in 5- to 6-year-old offspring. J Clin Endocrinol Metab 98(4):1417–1426

    Article  CAS  PubMed  Google Scholar 

  35. Julvez J, Alvarez-Pedrerol M, Rebagliato M, Murcia M, Forns J, Garcia-Esteban R, Lertxundi N, Espada M et al (2013) Thyroxine levels during pregnancy in healthy women and early child neurodevelopment. Epidemiology 24(1):150–157

    Article  PubMed  Google Scholar 

  36. Williams FL, Watson J, Ogston SA, Visser TJ, Hume R, Willatts P (2013) Maternal and umbilical cord levels of T4, FT4, TSH, TPOAb, and TgAb in term infants and neurodevelopmental outcome at 5.5 years. J Clin Endocrinol Metab 98(2):829–838

    Article  CAS  PubMed  Google Scholar 

  37. Chan S, Kachilele S, McCabe CJ, Tannahill LA, Boelaert K, Gittoes NJ, Visser TJ, Franklyn JA et al (2002) Early expression of thyroid hormone deiodinases and receptors in human fetal cerebral cortex. Brain Res Dev Brain Res 138(2):109–116

    Article  CAS  PubMed  Google Scholar 

  38. Evans IM, Pickard MR, Sinha AK, Leonard AJ, Sampson DC, Ekins RP (2002) Influence of maternal hyperthyroidism in the rat on the expression of neuronal and astrocytic cytoskeletal proteins in fetal brain. J Endocrinol 175(3):597–604

    Article  CAS  PubMed  Google Scholar 

  39. Wang Y, Wei W, Song B, Dong J, Min H, Chen J (2014) Developmental hypothyroxinemia caused by mild iodine deficiency leads to HFS-induced LTD in rat hippocampal CA1 region: involvement of AMPA receptor. Mol Neurobiol 50(2):348–357

    Article  CAS  PubMed  Google Scholar 

  40. Reid SM, Middleton P, Cossich MC, Crowther CA, Bain E (2013) Interventions for clinical and subclinical hypothyroidism pre-pregnancy and during pregnancy. Cochrane Database Syst Rev 5CD007752

  41. Simmonds MC, Higgins JP, Stewart LA, Tierney JF, Clarke MJ, Thompson SG (2005) Meta-analysis of individual patient data from randomized trials: a review of methods used in practice. Clin Trials 2(3):209–217

    Article  PubMed  Google Scholar 

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Conflicts of Interest

We declare that we have no conflicts of interest.

Compliance with Ethical Standards

There was no funding for the study. The present study was a meta-analysis, which did not involve human participants and/or animals. In addition, no informed consent was needed in the meta-analysis.

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    Authors and Affiliations

    1. Obstetrical Department, Maternal and Children Health’s Hospital, Weifang, 261011, China

      Pingping Wang, Yong Guo & Zengfang Wang

    2. Department of Paediatrics, Maternal and Children Health’s Hospital, Weifang, 261011, China

      Jian Gao

    3. Department of Endocrinology, Affiliated Hospital of Qingdao University, Qingdao, 266003, China

      Shihua Zhao

    4. Department of Gynaecology and Obstetrics, Maternal and Children Health’s Hospital, Weifang, 261011, China

      Feng Qi

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    1. Pingping Wang
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    4. Yong Guo
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    5. Zengfang Wang
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    Correspondence to Pingping Wang or Feng Qi.

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    Pingping Wang, Jian Gao and Shihua Zhao contributed equally to this work.

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    Wang, P., Gao, J., Zhao, S. et al. Maternal Thyroxine Levels During Pregnancy and Outcomes of Cognitive Development in Children. Mol Neurobiol 53, 2241–2248 (2016). https://doi.org/10.1007/s12035-015-9189-z

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    • DOI: https://doi.org/10.1007/s12035-015-9189-z

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