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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.

  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.

  3. 3.

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

  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.

  5. 5.

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

  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.

  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.

  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.

  10. 10.

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

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  38. 38.

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

  39. 39.

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

  40. 40.

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

  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.

  42. 42.

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

  43. 43.

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

  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.

  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.

  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.

  47. 47.

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

  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.

  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.

  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.

  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.

  52. 52.

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

  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.

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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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The authors declare that they have no conflict of interest.

Correspondence to Eva Morales.

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