Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Role of zinc in neonatal growth and brain growth: review and scoping review

A Correction to this article was published on 02 March 2021

This article has been updated


This manuscript includes (1) a narrative review of Zinc as an essential nutrient for fetal and neonatal growth and brain growth and development and (2) a scoping review of studies assessing the effects of Zinc supplementation on survival, growth, brain growth, and neurodevelopment in neonates. Very preterm infants and small for gestational age infants are at risk for Zinc deficiency. Zinc deficiency can cause several complications including periorificial lesions, delayed wound healing, hair loss, diarrhea, immune deficiency, growth failure with stunting, and brain atrophy and dysfunction. Zinc is considered essential for oligodendrogenesis, neurogenesis, neuronal differentiation, white matter growth, and multiple biological and physiological roles in neurobiology. Data support the possibility that the critical period of Zinc delivery for brain growth in the mouse starts at 18 days of a 20–21-day pregnancy and extends during lactation and in human may start at 26 weeks of gestation and extend until at least 44 weeks of postmenstrual age. Studies are needed to better elucidate Zinc requirement in extremely low gestational age neonates to minimize morbidity, optimize growth, and brain growth, prevent periventricular leukomalacia and optimize neurodevelopment.


  • Zinc is essential for growth and brain growth and development.

  • In the USA, very preterm small for gestational age infants are at risk for Zinc deficiency.

  • Data support the possibility that the critical period of Zinc delivery for brain growth in the mouse starts at 18 days of a 20–21-day pregnancy and extends during lactation and in human may start at 26 weeks’ gestation and extend until at least 44 weeks of postmenstrual age.

  • Several randomized trials of Zinc supplementation in neonates have shown improvement in growth when using high enough dose, for long duration in patients likely to or proven to have a Zinc deficiency.

  • Studies are needed to better elucidate Zinc requirement in extremely low gestational age neonates to minimize morbidity, optimize growth and brain growth, prevent periventricular leukomalacia and optimize neurodevelopment.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Fig. 1: Zinc role in growth and brain growth and development.
Fig. 2: Flow diagram of the scoping review.

Change history


  1. 1.

    Fenton, T. R. et al. “Extrauterine growth restriction” and “postnatal growth failure” are misnomers for preterm infants. J. Perinatol. 40, 704–714 (2020).

    PubMed  Google Scholar 

  2. 2.

    Cormack, B. E., Harding, J. E., Miller, S. P. & Bloomfield, F. H. The influence of early nutrition on brain growth and neurodevelopment in extremely preterm babies: a narrative review. Nutrients 11, 2029 (2019).

    CAS  PubMed Central  Google Scholar 

  3. 3.

    Valentine, C. J. Nutrition and the developing brain. Pediatr. Res. 87, 190–191 (2020).

    PubMed  Google Scholar 

  4. 4.

    Volpe, J. J. Iron and zinc: nutrients with potential for neurorestoration in premature infants with cerebral white matter injury. J. Neonatal Perinat. Med. 12, 365–368 (2019).

    Google Scholar 

  5. 5.

    Georgieff, M. K., Ramel, S. E. & Cusick, S. E. Nutritional influences on brain development. Acta Paediatr. 107, 1310–1321 (2018).

    PubMed  PubMed Central  Google Scholar 

  6. 6.

    Georgieff, M. K., Brunette, K. E. & Tran, P. V. Early life nutrition and neural plasticity. Dev. Psychopathol. 27, 411–423 (2015).

    PubMed  PubMed Central  Google Scholar 

  7. 7.

    Krebs, N. F. Update on zinc deficiency and excess in clinical pediatric practice. Ann. Nutr. Metab. 62(suppl 1), 19–29 (2013).

    CAS  PubMed  Google Scholar 

  8. 8.

    de Benoist, B., Darnton-Hill, I., Davidsson, L., Fontaine, O. & Hotz, C. Conclusions of the joint WHO/UNICEF/IAEA/IZiNCG interagency meeting on zinc status indicators. Food Nutr. Bull. 28(3 Suppl), S480–S484 (2007).

    PubMed  Google Scholar 

  9. 9.

    Wessells, K. R. & Brown, K. H. Estimating the global prevalence of zinc deficiency: results based on zinc availability in national food supplies and the prevalence of stunting. PLoS ONE 7, e50568 (2012).

    PubMed  PubMed Central  Google Scholar 

  10. 10.

    Golan, Y., Kambe, T. & Assaraf, Y. G. The role of the zinc transporter SLC30A2/ZnT2 in transient neonatal zinc deficiency. Metallomics 9, 1352 (2017).

    CAS  PubMed  Google Scholar 

  11. 11.

    Prasad, A. S. Discovery of human zinc deficiency: its impact on human health and disease. Adv. Nutr. 4, 176–190 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. 12.

    Terrin, G. et al. Zinc in early life: a key element in the fetus and preterm neonate. Nutrients 7, 10427–10446 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. 13.

    Rahman, M. T. & Karim, M. M. Metallothionein: a potential link in the regulation of zinc in nutritional immunity. Biol. Trace Elem. Res. 182, 1–13 (2018).

    CAS  PubMed  Google Scholar 

  14. 14.

    Kambe, T., Hashimoto, A. & Fujimoto, S. Current understanding of ZIP and ZnT zinc transporters in human health and diseases. Cell Mol. Life Sci. 71, 3281–3295 (2014).

    CAS  PubMed  Google Scholar 

  15. 15.

    King, J. C. et al. Biomarkers of nutrition for development (BOND)-zinc review. J. Nutr. 146, 858S–885S (2015).

    PubMed  Google Scholar 

  16. 16.

    Nissensohn, M. et al. Effect of zinc intake on serum/plasma zinc status in infants: a meta-analysis. Matern. Child Nutr. 9, 285–298 (2013). [published correction appears in Matern. Child Nutr. 11, 1056 [2015].

  17. 17.

    Simons, T. J. Intracellular free zinc and zinc buffering in human red blood cells. J. Membr. Biol. 123, 63–71 (1991).

    CAS  PubMed  Google Scholar 

  18. 18.

    Ohno, H. et al. A study of zinc distribution in erythrocytes of normal humans. Blut 50, 113–116 (1985).

    CAS  PubMed  Google Scholar 

  19. 19.

    Moynihan, J. B. Relationship between maturity and isoenzymes of erythrocytic carbonic anhydrase in newborn infants. Pediatr. Res. 11, 871–873 (1977).

    CAS  PubMed  Google Scholar 

  20. 20.

    Cousins, R. J. Absorption, transport, and hepatic metabolism of copper and zinc: special reference to metallothionein and ceruloplasmin. Physiol. Rev. 65, 238–309 (1985).

    CAS  PubMed  Google Scholar 

  21. 21.

    Terrin, G. Nutritional intake influences zinc levels in preterm newborns: an observational study. Nutrients 19, E529 (2020).

    Google Scholar 

  22. 22.

    Lowe, N. M. Assessing zinc in humans. Curr. Opin. Clin. Nutr. Metab. Care 19, 321–327 (2016).

    CAS  PubMed  Google Scholar 

  23. 23.

    Jackson, M. J., Jones, D. A. & Edwards, R. H. Tissue zinc levels as an index of body zinc status. Clin. Physiol. 2, 333–343 (1982).

    CAS  PubMed  Google Scholar 

  24. 24.

    Cho., J. M., Kim, J. Y. & Yang, H. R. Effects of oral zinc supplementation on zinc status and catch-up growth during the first 2 years of life in children with non-organic failure to thrive born preterm and at term. Pediatr. Neonatol. 60, 201–209 (2019).

    PubMed  Google Scholar 

  25. 25.

    Bueno, O. et al. Zinc supplementation in infants with asymmetric intra uterine growth retardation; effect on growth, nutritional status and leptin secretion. Nutr. Hosp. 23, 212–219 (2008).

    CAS  PubMed  Google Scholar 

  26. 26.

    Díaz-Gómez, N. M. et al. The effect of zinc supplementation on linear growth, body composition, and growth factors in preterm infants. Pediatrics 111, 1002–1009 (2003).

    PubMed  Google Scholar 

  27. 27.

    El-Farghali, O., Abd El-Wahed, M., Hassan, N. E., Imam, S. & Alian, K. Early zinc supplementation and enhanced growth of the low-birth weight neonate. Open Access Maced. J. Med. Sci. 3, 63–68 (2015).

    PubMed  Google Scholar 

  28. 28.

    Donangelo, C. M. & King, J. C. Maternal zinc intakes and homeostatic adjustments during pregnancy and lactation. Nutrients 4, 782–798 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. 29.

    Hambidge, K. M. et al. Zinc nutritional status during pregnancy: a longitudinal study. Am. J. Clin. Nutr. 37, 429–442 (1983).

    CAS  PubMed  Google Scholar 

  30. 30.

    Razagui, I. B. A. & Ghribi, I. Maternal and neonatal scalp hair concentrations of zinc, copper, cadmium, and lead relationship to some lifestyle factors. Biol. Trace Elem. Res. 106, 1–26 (2005).

    CAS  PubMed  Google Scholar 

  31. 31.

    Kuhnert, P. M. et al. The effect of smoking on placental and fetal zinc status. Am. J. Obstet. Gynecol. 157, 1241–1246 (1987).

    CAS  PubMed  Google Scholar 

  32. 32.

    Hovdenak, N. & Haram, K. Influence of mineral and vitamin supplements on pregnancy outcome. Eur. J. Obstet. Gynecol. Reprod. Biol. 164, 127–132 (2012).

    CAS  PubMed  Google Scholar 

  33. 33.

    Moghimi, M., Ashrafzadeh, S., Rassi, S. & Naseh, A. Maternal zinc deficiency and congenital anomalies in newborns. Pediatr. Int. 59, 443–446 (2017).

    PubMed  Google Scholar 

  34. 34.

    Tomat, A. L. et al. Morphological and functional effects on cardiac tissue induced by moderate zinc deficiency during prenatal and postnatal life in male and female rats. Am. J. Physiol. Heart Circ. Physiol. 305, H1574–H1583 (2013).

    CAS  PubMed  Google Scholar 

  35. 35.

    Akdas, S., & Yazihan, N. Cord blood zinc status effects on pregnancy outcomes and its relation with maternal serum zinc levels: a systematic review and meta-analysis. World J. Pediatr. (2019).

  36. 36.

    Ota, E. et al. Zinc supplementation for improving pregnancy and infant outcome. Cochrane Database Syst. Rev. 2, CD000230 (2015).

    Google Scholar 

  37. 37.

    Chaffee, B. W. & King, J. C. Effect of zinc supplementation on pregnancy and infant outcomes: a systematic review. Paediatr. Perinat. Epidemiol. 26(Suppl 1), 118–137 (2012).

    PubMed  PubMed Central  Google Scholar 

  38. 38.

    Hess, S. Y. & King, J. C. Effects of maternal zinc supplementation on pregnancy and lactation outcomes. Food Nutr. Bull. 30, S60–S78 (2009).

    PubMed  Google Scholar 

  39. 39.

    Oh, C., Keats, E. C. & Bhutta, Z. A. Vitamin and mineral supplementation during pregnancy on maternal, birth, child health and development outcomes in low- and middle-income countries: a systematic review and meta-analysis. Nutrients 12, 491 (2020).

    CAS  PubMed Central  Google Scholar 

  40. 40.

    Keats, E. C., Haider, B. A., Tam, E. & Bhutta, Z. A. Multiple-micronutrient supplementation for women during pregnancy. Cochrane Database Syst. Rev. 3, CD004905 (2019).

    PubMed  Google Scholar 

  41. 41.

    Bax, C. M. R. & Bloxam, D. L. Two major pathways of zinc(II) acquisition by human placental syncytiotrophoblast. J. Cell. Physiol. 164, 546–554 (1995).

    CAS  PubMed  Google Scholar 

  42. 42.

    Aslam, N. & McArdle, H. J. Mechanism of zinc uptake by microvilli isolated from human term placenta. J. Cell. Physiol. 151, 533–538 (1993).

    Google Scholar 

  43. 43.

    Simmer, K., Dwight, J. S., Brown, I. M., Thompson, R. P. & Young, M. Placental handling of zinc in the guinea pig. Biol. Neonate 48, 114–121 (1985).

    CAS  PubMed  Google Scholar 

  44. 44.

    Beer, W. H. et al. Human placental transfer of zinc: normal characteristics and role of ethanol. Alcohol Clin. Exp. Res. 16, 98–105 (1992).

    CAS  PubMed  Google Scholar 

  45. 45.

    Nandakumaran, M., Dashti, H. M., Al-Saleh, E. & Al-Zaid, N. S. Transport kinetics of zinc, copper, selenium, and iron in perfused human placental lobule in vitro. Mol. Cell Biochem. 252, 91–96 (2003).

    CAS  PubMed  Google Scholar 

  46. 46.

    Mas, A. & Sarkar, B. Binding, uptake and efflux of 65Zn by isolated human trophoblast cells. Biochim. Biophys. Acta 1092, 35–38 (1991).

    CAS  PubMed  Google Scholar 

  47. 47.

    Osada, H. et al. Profile of trace element concentrations in the feto-placental unit in relation to fetal growth. Acta Obstet. Gynecol. Scand. 81, 931–937 (2002).

    PubMed  Google Scholar 

  48. 48.

    Zapata, C. L., Melo, M. R. & Donangelo, C. M. Maternal, placental and cord zinc components in healthy women with different levels of serum zinc. Biol. Neonate 72, 84–93 (1997).

    CAS  PubMed  Google Scholar 

  49. 49.

    Matsusaka, N. et al. Whole-body retention and fetal uptake of 65Zn in pregnant mice fed a Zn-deficient diet. J. Radiat. Res. 36, 196–202 (1995).

    CAS  PubMed  Google Scholar 

  50. 50.

    Asano, N. et al. Expression profiles of zinc transporters in rodent placental models. Toxicol. Lett. 154, 45–53 (2004).

    CAS  PubMed  Google Scholar 

  51. 51.

    Ford, D. Intestinal and placental zinc transport pathways. Proc. Nutr. Soc. 63, 21–29 (2004).

    CAS  PubMed  Google Scholar 

  52. 52.

    Jobarteh, M. L. et al. mRNA levels of placental iron and zinc transporter genes are upregulated in gambian women with low iron and zinc status. J. Nutr. 147, 1401–1409 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. 53.

    Ronco., A. M., Arguello, G., Suazo, M. & Llanos, M. N. Increased levels of metallothionein in placenta of smokers. Toxicology 208, 133–139 (2005).

    CAS  PubMed  Google Scholar 

  54. 54.

    Holm, M. B. et al. Uptake and release of amino acids in the fetal-placental unit in human pregnancies. PLoS ONE 12, e0185760 (2017).

    PubMed  PubMed Central  Google Scholar 

  55. 55.

    Al-Saleh, E., Nandakumaran, M., Al-Shammari, M., Al-Falah, F. & Al-Harouny, A. Assessment of maternal-fetal status of some essential trace elements in pregnant women in late gestation: relationship with birth weight and placental weight. J. Matern. Fetal Neonatal Med. 16, 9–14 (2004).

    CAS  PubMed  Google Scholar 

  56. 56.

    Katz, O. et al. Severe pre-eclampsia is associated with abnormal trace elements concentrations in maternal and fetal blood. J. Matern. Fetal Neonatal Med. 25, 1127–1130 (2012).

    CAS  PubMed  Google Scholar 

  57. 57.

    Lazer, T. et al. Trace elements′ concentrations in maternal and umbilical cord plasma at term gestation: a comparison between active labor and elective cesarean delivery. J. Matern. Fetal Neonatal Med. 25, 286–289 (2012).

    CAS  PubMed  Google Scholar 

  58. 58.

    Al-Saleh, E., Nandakumaran, M., Al-Shammari, M. & Al-Harouny, A. Maternal-fetal status of copper, iron, molybdenum, selenium and zinc in patients with gestational diabetes. J. Matern. Fetal Neonatal Med. 16, 15–21 (2004).

    CAS  PubMed  Google Scholar 

  59. 59.

    Al-Saleh, E. et al. Maternal-fetal status of copper, iron, molybdenum, selenium and zinc in insulin-dependent diabetic pregnancies. Arch. Gynecol. Obstet. 271, 212–217 (2005).

    CAS  PubMed  Google Scholar 

  60. 60.

    Krachler, M., Rossipal, E. & Micetic-Turk, D. Trace element transfer from the mother to the newborn investigations on triplets of colostrum, maternal and umbilical cord sera. Eur. J. Clin. Nutr. 53, 486–494 (1999).

    CAS  PubMed  Google Scholar 

  61. 61.

    Galinier, A. et al. Reference range for micronutrients and nutritional marker proteins in cord blood of neonates appropriated for gestational ages. Early Hum. Dev. 81, 583–593 (2005).

    CAS  PubMed  Google Scholar 

  62. 62.

    Kojima, C. et al. Association of zinc and copper with clinical parameters in the preterm newborn. Pediatr. Int. 59, 1165–1168 (2017).

    CAS  PubMed  Google Scholar 

  63. 63.

    Shaw, J. C. Trace elements in the fetus and young infant. I. Zinc. Am. J. Dis. Child. 133, 1260–1268 (1979).

    CAS  PubMed  Google Scholar 

  64. 64.

    Klein, D., Scholz, P., Drasch, G. A., Müller-Höcker, J. & Summer, K. H. Metallothionein, copper and zinc in fetal and neonatal human liver: changes during development. Toxicol. Lett. 56, 61–67 (1991).

    CAS  PubMed  Google Scholar 

  65. 65.

    Klein, C. J. Nutrient requirements for preterm infant formulas. J. Nutr. 132(Suppl. 1), 1395S–1577S (2002). 6.

    CAS  PubMed  Google Scholar 

  66. 66.

    Casey, C. E. & Robinson, M. F. Copper, manganese, zinc, nickel, cadmium and lead in human foetal tissues. Br. J. Nutr. 39, 639–646 (1978).

    CAS  PubMed  Google Scholar 

  67. 67.

    Chaube, S., Nishimura, H. & Swinyard, C. A. Zinc and cadmium in normal human embryos and fetuses: analyses by atomic absorption spectrophotometry. Arch. Environ. Health 26, 237–240 (1973).

    CAS  PubMed  Google Scholar 

  68. 68.

    Zlotkin, S. H. & Cherian, M. G. Hepatic metallothionein as a source of zinc and cysteine during the first year of life. Pediatr. Res. 24, 326–329 (1988).

    CAS  PubMed  Google Scholar 

  69. 69.

    Rosenthal, M. D., Albrecht, E. D. & Pepe, G. J. Estrogen modulates developmentally regulated gene expression in the fetal baboon liver. Endocrine 23, 219–228 (2004).

    CAS  PubMed  Google Scholar 

  70. 70.

    Dorea, J. G., Brito, M. & Araujo, M. O. Concentration of copper and zinc in liver of fetuses and infants. J. Am. Coll. Nutr. 6, 491–495 (1987).

    CAS  PubMed  Google Scholar 

  71. 71.

    Bilde, K. et al. Reduced hepatic metallothionein expression in first trimester fetuses in response to intrauterine smoking exposure: a consequence of low maternal zinc levels? Hum. Reprod. 34, 2129–2143 (2019).

    CAS  PubMed  Google Scholar 

  72. 72.

    Griffin, I. J., Domellöf, M., Bhatia, J., Anderson, D. M. & Kler, N. Zinc and copper requirements in preterm infants: an examination of the current literature. Early Hum. Dev. 89, S29–S34 (2013).

    CAS  PubMed  Google Scholar 

  73. 73.

    Hambidge, K. M., Krebs, N. F., Westcott, J. E. & Miller, L. V. Changes in zinc absorption during development. J. Pediatr. 149, S64–S68 (2006).

    CAS  PubMed  Google Scholar 

  74. 74.

    Djurović, D. et al. Zinc concentrations in human milk and infant serum during the first six months of lactation. J. Trace Elem. Med. Biol. 41, 75–78 (2017).

    PubMed  Google Scholar 

  75. 75.

    Young, B. E. et al. Effect of pooling practices and time postpartum of milk donations on the energy, macronutrient, and zinc concentrations of resultant donor human milk pools. J. Pediatr. 214, 54–59 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. 76.

    Casey, C. E., Neville, M. C. & Hambidge, K. M. Studies in human lactation: secretion of zinc, copper, and manganese in human milk. Am. J. Clin. Nutr. 49, 773–785 (1989).

    CAS  PubMed  Google Scholar 

  77. 77.

    Finch, C. W. Review of trace mineral requirements for preterm infants: what are the current recommendations for clinical practice?. Nutr. Clin. Pr. 30, 44–58 (2015).

    Google Scholar 

  78. 78.

    Gupta, N., Bansal, S., Gupta, M. & Nadda, A. A comparative study of serum zinc levels in small for gestational age babies and appropriate for gestational age babies in a Tertiary Hospital, Punjab. J. Fam. Med. Prim. Care 9, 933–937 (2020).

    Google Scholar 

  79. 79.

    Brion, L. P. et al. Zinc deficiency limiting head growth to discharge in extremely low gestational age infants with insufficient linear growth: a cohort study [published online ahead of print, 2020 Aug 12]. J. Perinatol. (2020)

  80. 80.

    Kienas, A., Roth, B., Bossier, C., Jojabri., C. & Hoeger, P. H. Zinc-deficiency dermatitis in breast-fed infants. Eur. J. Pediatr. 166, 189–194 (2007).

    Google Scholar 

  81. 81.

    Itsumura, N. et al. Compound heterozygous mutations in SLC30A2/ZnT2 results in low milk zinc concentrations: a novel mechanism for zinc deficiency in a breast-fed infant. PLoS ONE 8, e64045 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. 82.

    Qian, L., Wang, B., Tang, N., Zhang, W. & Cai, W. Polymorphisms of SLC30A2 and selected perinatal factors associated with low milk zinc in Chinese breastfeeding women. Early Hum. Dev. 88, 663–668 (2012).

    CAS  PubMed  Google Scholar 

  83. 83.

    Vashist, S., Rana, A. & Mahajan, V. K. Transient symptomatic zinc deficiency in a breastfed infant associated with low zinc levels in maternal serum and breast milk improving after zinc supplementation: an uncommon phenotype? Indian Dermatol. Online J. 11, 623–626 (2020).

    PubMed  PubMed Central  Google Scholar 

  84. 84.

    Terrin, G. et al. Zinc supplementation reduces morbidity and mortality in very-low birth-weight preterm neonates: a hospital-based randomized, placebo-controlled trial in an industrialized country. Am. J. Clin. Nutr. 98, 1468–1474 (2013).

    CAS  PubMed  Google Scholar 

  85. 85.

    Sjöström, E. S., Öhlund, I., Ahlsson, F. & Domellöf, M. Intakes of micronutrients are associated with early growth in extremely preterm infants. J. Pediatr. Gastroenterol. Nutr. 62, 885–892 (2016).

    PubMed  Google Scholar 

  86. 86.

    Harris, T., Gardner, F., Podany, A., Kelleher, S. L. & Doheny, K. K. Increased early enteral zinc intake improves weight gain in hospitalised preterm infants. Acta Paediatr. 108, 1978–1984 (2019).

    CAS  PubMed  Google Scholar 

  87. 87.

    Haase, H. & Rink, L. Functional significance of zinc-related signaling pathways in immune cells. Annu. Rev. Nutr. 29, 133–152 (2009).

    CAS  PubMed  Google Scholar 

  88. 88.

    Abdollahi, M., Abdollahi, Z., Fozouni, F. & Bondarianzadeh, D. Oral zinc supplementation positively affects linear growth, but not weight, in children 6-24 months of age. Int. J. Prev. Med. 5, 280–286 (2014).

    PubMed  PubMed Central  Google Scholar 

  89. 89.

    Sauer, A. K. & Grabrucker, A. M. Zinc deficiency during pregnancy leads to altered microbiome and elevated inflammatory markers in mice. Front. Neurosci. 13, 1295 (2019).

    PubMed  PubMed Central  Google Scholar 

  90. 90.

    Friel, J. K., Gibson, R. S., Balassa, R. & Watts, J. L. A comparison of the zinc, copper and manganese status of very low birth weight pre-term and full-term infants during the first twelve months. Acta Paediatr. Scand. 73, 596–601 (1984).

    CAS  PubMed  Google Scholar 

  91. 91.

    Levenson, C. W. & Morris, D. Zinc and neurogenesis: making new neurons from development to adulthood. Adv. Nutr. 2, 96–100 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. 92.

    Al-Naama, N., Mackeh, R. & Kino, T. C2H2-type zinc finger proteins in brain development, neurodevelopmental, and other neuropsychiatric disorders: systematic literature-based analysis. Front. Neurol. 11, 32 (2020).

    PubMed  PubMed Central  Google Scholar 

  93. 93.

    Bourassa, D. et al. Chromis-1, a ratiometric fluorescent probe optimized for two-photon microscopy reveals dynamic changes in labile Zn(II) in differentiating oligodendrocytes. A. C. S. Sens. 3, 458–467 (2018).

    CAS  Google Scholar 

  94. 94.

    Zhang, Y. et al. An RNA-sequencing transcriptome and splicing database of glia, neurons, and vascular cells of the cerebral cortex [published correction appears in J Neurosci 34, 11929–11947 (2014)]. J. Neurosci. 35, 846 (2015).

  95. 95.

    Nolte, C. et al. ZnT-1 expression in astroglial cells protects against zinc toxicity and slows the accumulation of intracellular zinc. Glia 48, 145–155 (2004).

    PubMed  Google Scholar 

  96. 96.

    Law, W., Kelland, E. E., Sharp, P. & Toms, N. J. Characterisation of zinc uptake into rat cultured cerebrocortical oligodendrocyte progenitor cells. Neurosci. Lett. 352, 113–116 (2003).

    CAS  PubMed  Google Scholar 

  97. 97.

    Wang, S. Z. et al. An oligodendrocyte-specific zinc-finger transcription regulator cooperates with Olig2 to promote oligodendrocyte differentiation. Development 133, 3389–3398 (2006).

    CAS  PubMed  Google Scholar 

  98. 98.

    Adamo, A. M. & Oteiza, P. I. Zinc deficiency and neurodevelopment: the case of neuron. Biofactors 36, 117–124 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. 99.

    Chowanadisai, W., Kelleher, S. L. & Lönnerdal, B. Maternal zinc deficiency reduces NMDA receptor expression in neonatal rat brain, which persists into early adulthood. J. Neurochem. 94, 510–519 (2005).

    CAS  PubMed  Google Scholar 

  100. 100.

    Liu, H., Oteiza, P. I., Gerswhin, M. E., Golub, M. S. & Keen, C. L. Effects of maternal marginal zinc deficiency on myelin protein profiles in the suckling rat and infant rhesus monkey. Biol. Trace Elem. Res. 34, 55–66 (1992).

    CAS  PubMed  Google Scholar 

  101. 101.

    Gower-Winter, S. D., Corniola, R. S., Morgan, T. J. Jr. & Levenson, C. W. Zinc deficiency regulates hippocampal gene expression and impairs neuronal differentiation. Nutr. Neurosci. 16, 174–182 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. 102.

    Pfaender, S. et al. Cellular zinc homeostasis contributes to neuronal differentiation in human induced pluripotent stem cells. Neural Plast. 2016, 3760702 (2016).

    PubMed  PubMed Central  Google Scholar 

  103. 103.

    Ohlsson, A. Acrodermatitis enteropathica. Reversibility of cerebral atrophy with zinc therapy. Acta Paediatr. 70, 269–273 (1981).

    CAS  Google Scholar 

  104. 104.

    Penkowa, M., Nielsen, H., Hidalgo, J., Bernth, N. & Moos, T. Distribution of metallothionein I + II and vesicular zinc in the developing central nervous system: correlative study in the rat. J. Comp. Neurol. 412, 303–318 (1999).

    CAS  PubMed  Google Scholar 

  105. 105.

    Prohaska, J. R., Luecke, R. W. & Jasinski, R. Effect of zinc deficiency from day 18 of gestation and/or during lactation on the development of some rat brain enzymes. J. Nutr. 11, 1525–1531 (1974).

    Google Scholar 

  106. 106.

    Azman, M. S., Wan Saudi, W. S., Ilhami, M., Mutalib, M. S. & Rahman, M. T. Zinc intake during pregnancy increases the proliferation at ventricular zone of the newborn brain. Nutr. Neurosci. 12, 9–12 (2009).

    CAS  PubMed  Google Scholar 

  107. 107.

    Cozzi, B. et al. Ontogenesis and migration of metallothionein I/II-containing glial cells in the human telencephalon during the second trimester. Brain Res. 1327, 16–23 (2010).

    CAS  PubMed  Google Scholar 

  108. 108.

    Suzuki, K., Nakajiama, K., Otaki, N. & Kimura, M. Metallothionein in developing human brain. Biol. Signals 3, 188–192 (1994).

    CAS  PubMed  Google Scholar 

  109. 109.

    Back, S. A., Luo, N. L., Borenstein, N. S., Volpe, J. J. & Kinney, H. C. Arrested oligodendrocyte lineage progression during human cerebral white matter development: Dissociation between the timing of progenitor differentiation and myelinogenesis. J. Neuropathol. Exp. Neurol. 61, 197–211 (2002).

    PubMed  Google Scholar 

  110. 110.

    Back, S. A. et al. Late oligodendrocyte progenitors coincide with the developmental window of vulnerability for human perinatal white matter injury. J. Neurosci. 21, 1302–1312 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. 111.

    Vahter, M. et al. Concentrations of copper, zinc and selenium in brain and kidney of second trimester fetuses and infants. J. Trace Elem. Med. Biol. 11, 215–222 (1997).

    CAS  PubMed  Google Scholar 

  112. 112.

    Höck, A., Demmel, U., Shicka, H., Kasperek, K. & Feinendegen, L. E. Trace element concentration in human brain. Activation analysis of cobalt, iron, rubidium, selenium, zinc, chromium, silver, cesium, antimonium and scandium. Brain 98, 49–64 (1975).

    PubMed  Google Scholar 

  113. 113.

    Gélinas, Y., Lafond, J. & Schmidt, J. P. Multielemental analysis of human fetal tissues using inductively coupled plasma-mass spectrometry. Biol. Trace Elem. Res. 59, 63–74 (1997).

    PubMed  Google Scholar 

  114. 114.

    Aruga, J. & Millen, K. J. ZIC1 function in normal cerebellar development and human developmental pathology. Adv. Exp. Med. Biol. 1046, 249–268 (2018).

    CAS  PubMed  Google Scholar 

  115. 115.

    Grinberg, I. et al. Heterozygous deletion of the linked genes ZIC1 and ZIC4 is involved in Dandy-Walker malformation. Nat. Genet. 36, 1053–1055 (2004).

    CAS  PubMed  Google Scholar 

  116. 116.

    Frederickson, C. J., Koh, J. Y. & Bush, A. I. The neurobiology of zinc in health and disease. Nat. Rev. Neurosci. 6, 449–462 (2005).

    CAS  PubMed  Google Scholar 

  117. 117.

    Qi, Z. & Liu, K. J. The interaction of zinc and the blood-brain barrier under physiological and ischemic conditions. Toxicol. Appl. Pharm. 364, 114 (2019).

    CAS  Google Scholar 

  118. 118.

    Zhang, Y., Aizenman, E., DeFranco, D. B. & Rosenberg, P. A. Intra-cellular zinc release, 12-lipoxygenase activation and MAPK dependent neuronal and oligodendroglial death. Mol. Med. 13, 350–355 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. 119.

    Domercq, M. et al. Zn2+-induced ERK activation mediates PARP-1-dependent ischemic-reoxygenation damage to oligodendrocytes. Glia 61, 383–393 (2013).

    PubMed  Google Scholar 

  120. 120.

    Mato, S., Sanchez-Gomez, M. V., Bernal-Chico, A. & Matute, C. Cytosolic zinc accumulation contributes to excitotoxic oligodendroglial death. Glia 61, 750–764 (2013).

    PubMed  Google Scholar 

  121. 121.

    Buser, J. R. et al. Arrested preoligodendrocyte maturation contributes to myelination failure in premature infants. Ann. Neurol. 71, 93–109 (2012).

    PubMed  PubMed Central  Google Scholar 

  122. 122.

    Segovia, K. N. et al. Arrested oligodendrocyte lineage maturation in chronic perinatal white matter injury. Ann. Neurol. 63, 520–530 (2008).

    PubMed  PubMed Central  Google Scholar 

  123. 123.

    Hirayama, A. et al. Myelin transcription factor 1 (MyT1) immunoreactivity in infants with periventricular leukomalacia. Brain Res. Dev. Brain Res. 140, 85–92 (2003).

    CAS  PubMed  Google Scholar 

  124. 124.

    Vela, G. et al. Zinc in gut-brain interaction in autism and neurological disorders. Neural Plast. 2015, 972791 (2015).

    PubMed  PubMed Central  Google Scholar 

  125. 125.

    El Mashad, G. M., El Sayed, H. M. & Elghorab, A. M. S. Effect of zinc supplementation on growth of preterm infants. Menoufia Med. J. 29, 1112–1115 (2016).

    Google Scholar 

  126. 126.

    Shaikhkhalil, A. K., Curtiss, J., Puthoff, T. D. & Valentinem, C. J. Enteral zinc supplementation and growth in extremely-low-birth-weight infants with chronic lung disease. J. Pediatr. Gastroenterol. Nutr. 58, 183–187 (2014).

    PubMed  PubMed Central  Google Scholar 

  127. 127.

    Castillo-Durán, C., Rodríguez, A., Venegas, G., Alvarez, P. & Icaza, G. Zinc supplementation and growth of infants born small for gestational age. J. Pediatr. 127, 206–211 (1995).

    PubMed  Google Scholar 

  128. 128.

    Ashworth, A., Morris, S. S., Lira, P. I. & Grantham-McGregor, S. M. Zinc supplementation, mental development and behaviour in low birth weight term infants in northeast Brazil. Eur. J. Clin. Nutr. 52, 223–227 (1998).

    CAS  PubMed  Google Scholar 

  129. 129.

    Lira, P. I., Ashworth, A. & Morris, S. S. Effect of zinc supplementation on the morbidity, immune function, and growth of low-birth-weight, full-term infants in northeast Brazil. Am. J. Clin. Nutr. 68(2 Suppl), 418S–424S (1998).

    CAS  PubMed  Google Scholar 

  130. 130.

    Sazawal, S. et al. Zinc supplementation in infants born small for gestational age reduces mortality: a prospective, randomized, controlled trial. Pediatrics 108, 1280–1286 (2001).

    CAS  PubMed  Google Scholar 

  131. 131.

    Taneja, S. et al. Effect of zinc supplementation on morbidity and growth in hospital-born, low-birth-weight infants. Am. J. Clin. Nutr. 90, 385–391 (2009).

    CAS  PubMed  Google Scholar 

  132. 132.

    Sur, D. et al. Impact of zinc supplementation on diarrheal morbidity and growth pattern of low birth weight infants in kolkata, India: a randomized, double-blind, placebo-controlled, community-based study. Pediatrics 112, 1327–1332 (2003).

    PubMed  Google Scholar 

  133. 133.

    Friel, J. K. et al. Zinc supplementation in very-low-birth-weight infants. J. Pediatr. Gastroenterol. Nutr. 17, 97–104 (1993).

    CAS  PubMed  Google Scholar 

  134. 134.

    Islam, M. N. et al. Effect of oral zinc supplementation on the growth of preterm infants. Indian J. Pediatr. 47, 845–849 (2010).

    CAS  Google Scholar 

  135. 135.

    Aminisani, N., Barak, M. & Shamshirgaran, S. M. Effect of zinc supplementation on growth of low birth weight infants aged 1-6 mo in Ardabil, Iran. Indian J. Pediatr. 78, 1239–1243 (2011).

    PubMed  Google Scholar 

  136. 136.

    Kumar, T. V. R. & Ramji, S. Effect of zinc supplementation on growth in very low birth weight infants. J. Trop. Pediatr. 58, 50–54 (2012).

    Google Scholar 

  137. 137.

    Mahtur, N. B. & Agarwal, D. K. Zinc supplementation in preterm neonates and neurological development: a randomized controlled trial. Indian Pediatr. 52, 951–955 (2015).

    Google Scholar 

  138. 138.

    Mehta, K., Bhatta, N. K., Majhi, S., Shrivastava, M. K. & Singh, R. R. Oral zinc supplementation for reducing mortality in probable neonatal sepsis: a double-blind randomized placebo-controlled trial. Indian Pediatr. 50, 390–393 (2013).

    CAS  PubMed  Google Scholar 

  139. 139.

    Newton, B., Bhat, B. V., Dhas, B. B., Mondal, N. & Gopalakrishna, S. M. Effect of zinc supplementation on early outcome of neonatal sepsis-a randomized controlled trial. Indian J. Pediatr. 83, 289–293 (2016).

    PubMed  Google Scholar 

  140. 140.

    Banupriya, N. et al. Short-term oral zinc supplementation among babies with neonatal sepsis for reducing mortality and improving outcome—a double-blind randomized controlled trial. Indian J. Pediatr. 85, 5–9 (2018).

    PubMed  Google Scholar 

  141. 141.

    Castillo-Durán, C. et al. Effect of zinc supplementation on development and growth of Chilean infants. J. Pediatr. 138, 229–235 (2001).

    PubMed  Google Scholar 

  142. 142.

    Souza, R. T. et al. Metabolomics applied to maternal and perinatal health: a review of new frontiers with a translation potential. Clinics 74, e894 (2019).

    PubMed  PubMed Central  Google Scholar 

  143. 143.

    Gracie, S. et al. An integrated systems biology approach to the study of preterm birth using "-omic" technology-a guideline for research. B. M. C. Pregnancy Childbirth 11, 71 (2011).

    Google Scholar 

  144. 144.

    Liu, J., Chen, X. X., Li, X. W., Fu, W. & Zhang, W. Q. Metabolomic research on newborn infants with intrauterine growth restriction. Medicine 95, e3564 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

Download references


This study was funded by the Children’s Health, Dallas: Senior Investigator Research Award (CCRAC)–New Direction (L.P.B.).

Author information




L.P.B. wrote the first draft of the manuscript, critically reviewed the revisions, and approved the final manuscript as submitted. R.H. and C.S.L. critically reviewed the revisions and approved the final manuscript as submitted.

Corresponding author

Correspondence to Luc P. Brion.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Brion, L.P., Heyne, R. & Lair, C.S. Role of zinc in neonatal growth and brain growth: review and scoping review. Pediatr Res 89, 1627–1640 (2021).

Download citation

Further reading


Quick links