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Neurodevelopmental effects of prenatal vitamin D in humans: systematic review and meta-analysis

Abstract

Diverse studies have investigated the impact of prenatal exposure to vitamin D levels on brain development; however, evidence in humans has never been systematically reviewed. This article summarized evidence of the association between 25-hydroxyvitamin D [25(OH)D] levels in maternal blood in pregnancy or newborn blood at birth and neurodevelopmental outcomes, including cognition, psychomotor performance, language development, behavioral difficulties, attention deficit and hyperactivity disorder (ADHD), and autistic traits. PubMed, Web of Science and SCOPUS databases were systematically searched for epidemiologic studies published through May 2018 using keywords. Random-effects meta-analyses were conducted. Of 260 identified articles, 25 were included in the present review. Comparing the highest vs. the lowest category of prenatal 25(OH)D levels, the pooled beta coefficients were 0.95 (95% CI −0.03, 1.93; p = 0.05) for cognition, and 0.88 (95% CI −0.18, 1.93; p = 0.10) for psychomotor development. The pooled relative risk for ADHD was 0.72 (95% CI, 0.59, 0.89; p = 0.002), and the pooled odds ratio for autism-related traits was 0.42 (95% CI, 0.25, 0.71; p = 0.001). There was little evidence for protective effects of high prenatal 25(OH)D for language development and behavior difficulties. This meta-analysis provides supporting evidence that increased prenatal exposure to 25(OH)D levels is associated with improved cognitive development and reduced risk of ADHD and autism-related traits later in life. Associations represent a potentially high public health burden given the current prevalence of vitamin D deficiency and insufficiency among childbearing aging and pregnant women.

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References

  1. 1.

    Bitsko RH, Holbrook JR, Robinson LR, Kaminski JW, Ghandour R, Smith C, et al. Health care, family, and community factors associated with mental, behavioral, and developmental disorders in early childhood—United States, 2011–2012. MMWR Morb Mortal Wkly Rep. 2016;65:221–6.

    PubMed  Google Scholar 

  2. 2.

    Bellanger M, Pichery C, Aerts D, Berglund M, Castaño A, Cejchanová M, et al. Economic benefits of methylmercury exposure control in Europe: monetary value of neurotoxicity prevention. Environ Health. 2013;12:3.

    PubMed  PubMed Central  Google Scholar 

  3. 3.

    Stumpf WE, Sar M, Clark SA, DeLuca HF. Brain target sites for 1,25-dihydroxyvitamin D3. Science. 1982;215:1403–5.

    CAS  PubMed  Google Scholar 

  4. 4.

    Eyles DW, Smith S, Kinobe R, Hewison M, McGrath JJ. Distribution of the vitamin D receptor and 1 alpha-hydroxylase in human brain. J Chem Neuroanat. 2005;29:21–30.

    CAS  PubMed  Google Scholar 

  5. 5.

    Eyles D, Brown J, Mackay-Sim A, McGrath J, Feron F. Vitamin D3 and brain development. Neuroscience. 2003;118:641–53.

    CAS  PubMed  PubMed Central  Google Scholar 

  6. 6.

    Eyles DW, Burne TH, McGrath JJ. Vitamin D, effects on brain development, adult brain function and the links between low levels of vitamin D and neuropsychiatric disease. Front Neuroendocrinol. 2013;34:47–64.

    CAS  PubMed  Google Scholar 

  7. 7.

    Moher D, Liberati A, Tetzlaff J, Altman DG, PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med. 2009;6:e1000097.

    PubMed  PubMed Central  Google Scholar 

  8. 8.

    Wells GA, Shea B, O’Connell D, Peterson J, Welch V, Losos M, et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp

  9. 9.

    Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997;315:629–34.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. 10.

    Viechtbauer W. Conducting meta-analyses in R with the metafor package. J Stat Softw. 2010;36:1–48.

    Google Scholar 

  11. 11.

    Gale CR, Robinson SM, Harvey NC, Javaid MK, Jiang B, Martyn CN, et al. Maternal vitamin D status during pregnancy and child outcomes. Eur J Clin Nutr. 2008;62:68–77.

    CAS  PubMed  Google Scholar 

  12. 12.

    Morales E, Guxens M, Llop S, Rodríguez-Bernal CL, Tardón A, Riaño I, et al. Circulating25-hydroxyvitamin D3 in pregnancy and infant neuropsychological development. Pediatrics. 2012;130:e913–920.

    PubMed  Google Scholar 

  13. 13.

    Whitehouse AJ, Holt BJ, Serralha M, Holt PG, Kusel MM, Hart PH. Maternal serum vitamin D levels during pregnancy and offspring neurocognitive development. Pediatrics. 2012;129:485–93.

    PubMed  Google Scholar 

  14. 14.

    Whitehouse AJ, Holt BJ, Serralha M, Holt PG, Hart PH, Kusel MM. Maternal vitamin D levels and the autism phenotype among offspring. J Autism Dev Disord. 2013;43:1495–504.

    PubMed  Google Scholar 

  15. 15.

    Hanieh S, Ha TT, Simpson JA, Thuy TT, Khuong NC, Thoang DD, et al. Maternal vitamin D status and infant outcomes in rural Vietnam: a prospective cohort study. PLoS One. 2014;9:e99005.

    PubMed  PubMed Central  Google Scholar 

  16. 16.

    Keim SA, Bodnar LM, Klebanoff MA. Maternal and cord blood 25(OH)-vitamin D concentrations in relation to child development and behaviour. Paediatr Perinat Epidemiol. 2014;28:434–44.

    PubMed  PubMed Central  Google Scholar 

  17. 17.

    Strøm M, Halldorsson TI, Hansen S, Granström C, Maslova E, Petersen SB, et al. Vitamin D measured in maternal serum and offspring neurodevelopmental outcomes: a prospective study with long-term follow-up. Ann Nutr Metab. 2014;64:254–61.

    PubMed  Google Scholar 

  18. 18.

    Fernell E, Bejerot S, Westerlund J, Miniscalco C, Simila H, Eyles D, et al. Autism spectrum disorder and low vitamin D at birth: a sibling control study. Mol Autism. 2015;6:3.

    PubMed  PubMed Central  Google Scholar 

  19. 19.

    Gustafsson P, Rylander L, Lindh CH, Jönsson BA, Ode A, Olofsson P, et al. Vitamin D status at birth and future risk of attention deficit/hyperactivity disorder (ADHD). PLoS One. 2015;10:e0140164.

    PubMed  PubMed Central  Google Scholar 

  20. 20.

    Morales E, Julvez J, Torrent M, Ballester F, Rodríguez-Bernal CL, Andiarena A, et al. Vitamin D in pregnancy and attention deficit hyperactivity disorder-like symptoms in childhood. Epidemiology. 2015;26:458–65.

    PubMed  Google Scholar 

  21. 21.

    Tylavsky FA, Kocak M, Murphy LE, Graff JC, Palmer FB, Völgyi E, et al. Gestational vitamin 25(OH)D status as a risk factor for receptive language development: a 24-month, longitudinal, observational study. Nutrients. 2015;7:9918–30.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. 22.

    Zhu P, Tong SL, Hao JH, Tao RX, Huang K, Hu WB, et al. Cord blood vitamin D and neurocognitive development are nonlinearly related in toddlers. J Nutr. 2015;145:1232–8.

    CAS  PubMed  Google Scholar 

  23. 23.

    Chen J, Xin K, Wei J, Zhang K, Xiao H. Lower maternal serum 25(OH) D in first trimester associated with higher autism risk in Chinese offspring. J Psychosom Res. 2016;89:98–101.

    PubMed  Google Scholar 

  24. 24.

    Magnusson C, Lundberg M, Lee BK, Rai D, Karlsson H, Gardner R, et al. Maternal vitamin D deficiency and the risk of autism spectrum disorders: population-based study. BJPsych Open. 2016;2:170–2.

    PubMed  PubMed Central  Google Scholar 

  25. 25.

    Stubbs G, Henley K, Green J. Autism: will vitamin D supplementation during pregnancy and early childhood reduce the recurrence rate of autism in newborn siblings? Med Hypotheses. 2016;88:74–78.

    CAS  PubMed  Google Scholar 

  26. 26.

    Chawla D, Fuemmeler B, Benjamin-Neelon SE, Hoyo C, Murphy S, Daniels JL. Early prenatal vitamin D concentrations and social-emotional development in infants. J Matern Fetal Neonatal Med 2017; e-pubmed ahead of print 4 December 2017; https://doi.org/10.1080/14767058.2017.1408065.

  27. 27.

    Darling AL, Rayman MP, Steer CD, Golding J, Lanham-New SA, Bath SC. Association between maternal vitamin D status in pregnancy and neurodevelopmental outcomes in childhood: results from the Avon Longitudinal Study of Parents and Children (ALSPAC). Br J Nutr. 2017;117:1682–92.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. 28.

    Gould JF, Anderson AJ, Yelland LN, Smithers LG, Skeaff CM, Zhou SJ, et al. Association of cord blood vitamin D with early childhood growth and neurodevelopment. J Paediatr Child Health. 2017;53:75–83.

    PubMed  Google Scholar 

  29. 29.

    Laird E, Thurston SW, van Wijngaarden E, Shamlaye CF, Myers GJ, Davidson PW, et al. Maternal Vitamin D status and the relationship with neonatal anthropometric and childhood neurodevelopmental outcomes: results from the Seychelles Child Development Nutrition Study. Nutrients. 2017;9:pii: E1235.

    Google Scholar 

  30. 30.

    Mossin MH, Aaby JB, Dalgård C, Lykkedegn S, Christesen HT, Bilenberg N. Inverse associations between cord vitamin D and attention deficit hyperactivity disorder symptoms: a child cohort study. Aust N Z J Psychiatry. 2017;51:703–10.

    PubMed  Google Scholar 

  31. 31.

    Veena SR, Krishnaveni GV, Srinivasan K, Thajna KP, Hegde BG, Gale CR, et al. Association between maternal vitamin D status during pregnancy and offspring cognitive function during childhood and adolescence. Asia Pac J Clin Nutr. 2017;26:438–49.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. 32.

    Vinkhuyzen AAE, Eyles DW, Burne THJ, Blanken LME, Kruithof CJ, Verhulst F, et al. Gestational vitamin D deficiency and autism spectrum disorder. BJPsych Open. 2017;3:85–90.

    PubMed  PubMed Central  Google Scholar 

  33. 33.

    Daraki V, Roumeliotaki T, Koutra K, Chalkiadaki G, Katrinaki M, Kyriklaki A, et al. High maternal vitamin D levels in early pregnancy may protect against behavioral difficulties at preschool age: the Rhea mother-child cohort, Crete, Greece. Eur Child Adolesc Psychiatry. 2018;27:79–88.

    PubMed  Google Scholar 

  34. 34.

    Vinkhuyzen AAE, Eyles DW, Burne THJ, Blanken LME, Kruithof CJ, Verhulst F, et al. Gestational vitamin D deficiency and autism-related traits: the Generation R Study. Mol Psychiatry. 2018;23:240–6.

    CAS  PubMed  Google Scholar 

  35. 35.

    Wang H, Yu XD, Huang LS, Chen Q, Ouyang FX, Wang X, et al. Fetal vitamin D concentration and growth, adiposity and neurodevelopment during infancy. Eur J Clin Nutr. 2018. https://doi.org/10.1038/s41430-017-0075-9.

    Article  PubMed  PubMed Central  Google Scholar 

  36. 36.

    Rodriguez A, Santa Marina L, Jimenez AM, Esplugues A, Ballester F, Espada M, et al. Vitamin D status in pregnancy and determinants in a Southern European Cohort Study. Paediatr Perinat Epidemiol. 2016;30:217–28.

    PubMed  Google Scholar 

  37. 37.

    Larqué E, Morales E, Leis R, Blanco-Carnero JE. Maternal and foetal health implications of vitamin D status during pregnancy. Ann Nutr Metab. 2018;72:179–92.

    PubMed  Google Scholar 

  38. 38.

    Cannell JJ. Autism and vitamin D. Med Hypotheses. 2008;70:750–9.

    CAS  PubMed  Google Scholar 

  39. 39.

    Cannell JJ, Grant WB. What is the role of vitamin D in autism? Dermatoendocrinol. 2013;5:199–204.

    PubMed  PubMed Central  Google Scholar 

  40. 40.

    Cannell JJ. Vitamin D and autism, what's new? Rev Endocr Metab Disord. 2017;18:183–93.

    CAS  PubMed  Google Scholar 

  41. 41.

    Ali A, Cui X, Eyles D. Developmental vitamin D deficiency and autism: putative pathogenic mechanisms. J Steroid Biochem Mol Biol. 2018;175:108–18.

    CAS  PubMed  Google Scholar 

  42. 42.

    Lesch KP, Waider J. Serotonin in the modulation of neural plasticity and networks: implications for neurodevelopmental disorders. Neuron. 2012;76:175–91.

    CAS  PubMed  Google Scholar 

  43. 43.

    Patrick RP, Ames BN. Vitamin D Hormone regulates serotonin synthesis. Part 1: relevance for autism. FASEB J. 2014;28:2398–413.

    CAS  PubMed  Google Scholar 

  44. 44.

    Patrick RP, Ames BN. Vitamin D and the omega-3 fatty acids control serotonin synthesis and action, part 2: relevance for ADHD, bipolar disorder, schizophrenia, and impulsive behavior. FASEB J. 2015;29:2207–22.

    CAS  PubMed  Google Scholar 

  45. 45.

    Cui X, Pertile R, Liu P, Eyles DW. Vitamin D regulates tyrosine hydroxylase expression: N-cadherin a possible mediator. Neuroscience. 2015;304:90–100.

    CAS  PubMed  Google Scholar 

  46. 46.

    Kubinyi E, Vas J, Hejjas K, Ronai Z, Brúder I, Turcsán B, et al. Polymorphism in the tyrosine hydroxylase (TH) gene is associated with activity-impulsivity in German Shepherd Dogs. PLoS One. 2012;7:e30271.

    CAS  PubMed  PubMed Central  Google Scholar 

  47. 47.

    Pertile RA, Cui X, Eyles DW. Vitamin D signaling and the differentiation of developing dopamine systems. Neuroscience. 2016;333:193–203.

    CAS  PubMed  Google Scholar 

  48. 48.

    Rice D, Barone S Jr. Critical periods of vulnerability for the developing nervous system: evidence from humans and animal models. Environ Health Perspect. 2000;108:511–33.

    PubMed  PubMed Central  Google Scholar 

  49. 49.

    van Batenburg-Eddes T, de Groot L, Steegers EA, et al. Fetal programming of infant neuromotor development: the generation R study. Pediatr Res. 2010;67:132–7.

    PubMed  Google Scholar 

  50. 50.

    Bodnar LM, Simhan HN, Powers RW, Frank MP, Cooperstein E, Roberts JM. High prevalence of vitamin D insufficiency in black and white pregnant women residing in the northern United States and their neonates. J Nutr. 2007;137:447–52.

    CAS  PubMed  PubMed Central  Google Scholar 

  51. 51.

    Fernández-Alonso AM, Dionis-Sánchez EC, Chedraui P, González-Salmerón MD, Pérez-López FR, Spanish Vitamin D and Women's Health Research Group. First-trimester maternal serum 25-hydroxyvitamin D3 status and pregnancy outcome. Int J Gynaecol Obstet. 2012;116:6–9.

    PubMed  Google Scholar 

  52. 52.

    Liu NQ, Hewison M. Vitamin D, the placenta and pregnancy. Arch Biochem Biophys. 2012;523:37–47.

    CAS  PubMed  Google Scholar 

  53. 53.

    Dietary reference intakes for calcium and vitamin D. Ross AC, Taylor CL, Yaktine AL and Del Valle HB (eds). Washington, DC: Institute of Medicine, National Academies Press; 2011.

  54. 54.

    Rice D, Barone S Jr. Critical periods of vulnerability for the developing nervous system: evidence from humans and animal models. Environ Health Perspect. 2000;108(Suppl 3):511–33.

    PubMed  PubMed Central  Google Scholar 

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Acknowledgements

AMG-S was funded by a predoctoral contract (FI17/00086) and EM was funded by a Miguel Servet Grant Fellowship (MS14/00046) both awarded by the Spanish Instituto de Salud Carlos III (ISCIII), Ministry of Economy and Competitiveness, and Fondos FEDER.

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Correspondence to Eva Morales.

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García-Serna, A.M., Morales, E. Neurodevelopmental effects of prenatal vitamin D in humans: systematic review and meta-analysis. Mol Psychiatry 25, 2468–2481 (2020). https://doi.org/10.1038/s41380-019-0357-9

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