No CrossRef data available.
Article contents
Comparative efficacies of vitamin D supplementation regimens in infants: a systematic review and network meta-analysis
Published online by Cambridge University Press: 16 September 2024
Abstract
Vitamin D deficiency in infants is widely prevalent. Most paediatric professional associations recommend routine vitamin D prophylaxis for infants. However, the optimal dose and duration of supplementation are still debated. We aimed to compare the efficacy and safety of different vitamin D supplementation regimens in term and late preterm neonates. For this systematic review and network meta-analysis, we searched MEDLINE, the Cochrane Central Register of Controlled Trials and Embase. Randomised and quasi-randomised clinical trials that evaluated any enteral vitamin D supplementation regimen initiated within 6 weeks of life were included. Two researchers independently extracted data on study characteristics and outcomes and assessed quality of included studies. A network meta-analysis with a Bayesian random-effects model was used for data synthesis. Certainty of evidence (CoE) was assessed using GRADE. Primary outcomes were mean serum vitamin D concentrations and the proportion of infants with vitamin D insufficiency (VDI). We included twenty-nine trials that evaluated fourteen different regimens of vitamin D supplementation. While all dosage regimens of ≥400 IU/d increased the mean 25(OH)D levels compared with no treatment, supplementation of ≤250 IU/d and 1400 IU/week did not. The CoE varied from very low to high. Low CoE indicated that 1600 IU/d, compared with lower dosages, reduced the proportion of infants with VDI. However, our results indicated that any dosage of ≥800 IU/d increased the risk of hypervitaminosis D and hypercalcaemia. Data on major clinical outcomes were sparse. Vitamin D supplementation of 400–600 IU/d may be the most effective and safest in infants.
Keywords
- Type
- Systematic Review and Meta-Analysis
- Information
- Copyright
- © The Author(s), 2024. Published by Cambridge University Press on behalf of The Nutrition Society
Footnotes
PROSPERO registration number: CRD42022360454
References
Creo, AL, Thacher, TD, Pettifor, JM, et al. (2017) Nutritional rickets around the world: an update. Paediatr Int Child Health 37, 84–98.Google Scholar
Li, R, Han, A, Hu, Q, et al. (2023) Relationship between vitamin D deficiency and neonatal hypocalcemia: a meta-analysis. J Pediatr Endocrinol Metab 36, 909–916.Google Scholar
Amrein, K, Scherkl, M, Hoffmann, M, et al. (2020) Vitamin D deficiency 2.0: an update on the current status worldwide. Eur J Clin Nutr 74, 1498–1513.Google Scholar
Jiang, Z, Pu, R, Li, N, et al. (2023) High prevalence of vitamin D deficiency in Asia: a systematic review and meta-analysis. Crit Rev Food Sci Nutr 63, 3602–3611.Google Scholar
Mogire, RM, Mutua, A, Kimita, W, et al. (2020) Prevalence of vitamin D deficiency in Africa: a systematic review and meta-analysis. Lancet Glob Health 8, e134–42.Google Scholar
Van der Pligt, P, Willcox, J, Szymlek-Gay, EA, et al. (2018) Associations of maternal vitamin D deficiency with pregnancy and neonatal complications in developing countries: a systematic review. Nutrients 10, 640.Google Scholar
Jan Mohamed, HJ, Rowan, A, Fong, B, et al. (2014) Maternal serum and breast milk vitamin D levels: findings from the Universiti Sains Malaysia pregnancy cohort study. PLOS ONE 9, e100705.Google Scholar
Dawodu, A & Tsang, RC (2012) Maternal vitamin D status: effect on milk vitamin D content and vitamin D status of breastfeeding infants. Adv Nutr 3, 353–361.Google Scholar
Salameh, K, Al-Janahi, NSA, Reedy, AM, et al. (2016) Prevalence and risk factors for low vitamin D status among breastfeeding mother–infant dyads in an environment with abundant sunshine. Int J Womens Health 8, 529–535.Google Scholar
Jain, V, Gupta, N, Kalaivani, M, et al. (2011) Vitamin D deficiency in healthy breastfed term infants at 3 months & their mothers in India: seasonal variation & determinants. na J Med Res 133, 267–273.Google Scholar
Chacham, S, Rajput, S, Gurnurkar, S, et al. (2020) Prevalence of vitamin D deficiency among infants in Northern India: a hospital based prospective study. Cureus 12, e11353.Google Scholar
Yadav, B, Gupta, N, Sasidharan, R, et al. (2022) 800 IU versus 400 IU per day of vitamin D3 in term breastfed infants: a randomized controlled trial from an LMIC. Eur J Pediatr 181, 3473–3482.Google Scholar
EFSA Panel on Dietetic Products N, Allergies (NDA) (2016) Dietary reference values for vitamin D. EFSA J 14, e04547.Google Scholar
Institute of Medicine (US) Committee to Review Dietary Reference Intakes for Vitamin D and Calcium (2011) Dietary Reference Intakes for Calcium and Vitamin D. Washington (DC): National Academies Press (US).Google Scholar
Munns, CF, Shaw, N, Kiely, M, et al. (2016) Global consensus recommendations on prevention and management of nutritional rickets. J Clin Endocrinol Metab 101, 394–415.Google Scholar
Wagner, CL, Greer, FR, American Academy of Pediatrics Section on Breastfeeding, et al. (2008) Prevention of rickets and vitamin D deficiency in infants, children, and adolescents. Pediatr 122, 1142–1152.Google Scholar
Misra, M, Pacaud, D, Petryk, A, et al. (2008) Vitamin D deficiency in children and its management: review of current knowledge and recommendations. Pediatr 122, 398–417.Google Scholar
Priyadarshi, M, Sankar, MJ, Gupta, N, et al. (2018) Efficacy of daily supplementation of 800 IU vitamin D on vitamin D status at 6 months of age in term healthy Indian infants. J Perinatol 38, 1566–1572.Google Scholar
Vidailhet, M, Mallet, E, Bocquet, A, et al. (2012) Vitamin D: still a topical matter in children and adolescents. A position paper by the committee on nutrition of the french society of paediatrics. Arch Pédiatrie 19, 316–328.Google Scholar
Gallo, S, Comeau, K, Vanstone, C, et al. (2013) Effect of different dosages of oral vitamin D supplementation on vitamin D status in healthy, breastfed infants: a randomized trial. Jama 309, 1785–1792.Google Scholar
Grant, CC, Stewart, AW, Scragg, R, et al. (2014) Vitamin D during pregnancy and infancy and infant serum 25-hydroxyvitamin D concentration. Pediatr 133, e143–53.Google Scholar
Roth, DE, Morris, SK, Zlotkin, S, et al. (2018) Vitamin D supplementation in pregnancy and lactation and infant growth. N Engl J Med 379, 535–546.Google Scholar
Cooper, C, Harvey, NC, Bishop, NJ, et al. (2016) Maternal gestational vitamin D supplementation and offspring bone health (MAVIDOS): a multicentre, double-blind, randomised placebo-controlled trial. Lancet Diabetes Endocrinol 4, 393–402.Google Scholar
Tan, ML, Abrams, SA & Osborn, DA (2020) Vitamin D supplementation for term breastfed infants to prevent vitamin D deficiency and improve bone health. Cochrane Database Syst Rev 12, CD013046.Google Scholar
Bilbao, NA (2017) Vitamin D toxicity in young breastfed infants: report of 2 cases. Glob Pediatr Health 4, 2333794X17731695.Google Scholar
Brustad, N, Yousef, S, Stokholm, J, et al. (2022) Safety of high-dose vitamin D supplementation among children aged 0–6 years: a systematic review and meta-analysis. JAMA Netw Open 5, e227410–e227410.Google Scholar
Thankaraj, A, Gupta, N, Ramaswamy, VV, et al. (2022) Different strategies of vitamin D supplementation in term, late preterm infants - A systematic review, network meta-analysis PROSPERO 2022 CRD42022360454. https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=360454 (accessed November 2023).Google Scholar
Hutton, B, Salanti, G, Caldwell, DM, et al. (2015) The PRISMA extension statement for reporting of systematic reviews incorporating network meta-analyses of health care interventions: checklist and explanations. Ann Intern Med 162, 777–784.Google Scholar
Holick, MF, Binkley, NC, Bischoff-Ferrari, HA, et al. (2011) Evaluation, treatment, and prevention of vitamin D deficiency: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 96, 1911–1930.Google Scholar
Rayyan (2021) AI Powered Tool for Systematic Literature Reviews. https://www.rayyan.ai/ (accessed September 2023).Google Scholar
Sterne, JA, Savović, J, Page, MJ, et al. (2019) RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ 366, l4898.Google Scholar
R Core Team (2020) R: A Language and Environment for Statistical Computing. Vienna, Austria: R Foundation for Statistical Computing.Google Scholar
Rücker, G & Schwarzer, G (2015) Ranking treatments in frequentist network meta-analysis works without resampling methods. BMC Med Res Methodol 15, 1–9.Google Scholar
Izcovich, A, Chu, DK, Mustafa, RA, et al. (2023) A guide and pragmatic considerations for applying GRADE to network meta-analysis. BMJ 381, e074495.Google Scholar
Ala-Houhala, M (1985) 25-Hydroxyvitamin D levels during breast-feeding with or without maternal or infantile supplementation of vitamin D. J Pediatr Gastroenterol Nutr 4, 220–226.Google Scholar
Alonso, A, Rodríguez, J, Carvajal, I, et al. (2011) Prophylactic vitamin D in healthy infants: assessing the need. Metab 60, 1719–1725.Google Scholar
Atas, E, Karademır, F, Ersen, A, et al. (2013) Comparison between daily supplementation doses of 200 versus 400 IU of vitamin D in infants. Eur J Pediatr 172, 1039–1042.Google Scholar
Chandy, DD, Kare, J, Singh, SN, et al. (2016) Effect of vitamin D supplementation, directly or via breast milk for term infants, on serum 25 hydroxyvitamin D and related biochemistry, and propensity to infection: a randomised placebo-controlled trial. Br J Nutr 116, 52–58.Google Scholar
Feliciano, ES, Ho, ML, Specker, BL, et al. (1994) Seasonal and geographical variations in the growth rate of infants in China receiving increasing dosages of vitamin D supplements. J Trop Pediatr 40, 162–165.Google Scholar
Greer, FR & Marshall, S (1989) Bone mineral content, serum vitamin D metabolite concentrations, and ultraviolet B light exposure in infants fed human milk with and without vitamin D2 supplements. J Pediatr 114, 204–212.Google Scholar
Greer, FR, Searcy, JE, Levin, RS, et al. (1981) Bone mineral content and serum 25-hydroxyvitamin D concentration in breast-fed infants with and without supplemental vitamin D. J Pediatr 98, 696–701.Google Scholar
Greer, FR, Searcy, JE, Levin, RS, et al. (1982) Bone mineral content and serum 25-hydroxyvitamin D concentrations in breast-fed infants with and without supplemental vitamin D: one-year follow-up. J Pediatr 100, 919–922.Google Scholar
Hauta-Alus, HH, Holmlund-Suila, EM, Kajantie, E, et al. (2021) The effects of vitamin D supplementation during infancy on growth during the first 2 years of life. J Clin Endocrinol Metab 106, e1140–55.Google Scholar
Holmlund-Suila, E, Viljakainen, H, Hytinantti, T, et al. (2012) High-dose vitamin D intervention in infants—effects on vitamin D status, calcium homeostasis, and bone strength. J Clin Endocrinol Metab 97, 4139–4147.Google Scholar
Huynh, J, Lu, T, Liew, D, et al. (2017) Vitamin D in newborns. A randomised controlled trial comparing daily and single oral bolus vitamin D in infants. J Paediatr Child Health 53, 163–169.Google Scholar
Kumar, GT, Sachdev, HS, Chellani, H, et al. (2011) Effect of weekly vitamin D supplements on mortality, morbidity, and growth of low birthweight term infants in India up to age 6 months: randomised controlled trial. BMJ 342, d2975.Google Scholar
Lin, C, Lin, C, Sung, Y, et al. (2022) Effect of oral vitamin D
3
supplementation in exclusively breastfed newborns: prospective, randomized, double-blind, placebo-controlled trial. J Bone Miner Res 37, 786–793.Google Scholar
Madar, AA, Klepp, KI & Meyer, HE (2009) Effect of free vitamin D2 drops on serum 25-hydroxyvitamin D in infants with immigrant origin: a cluster randomized controlled trial. Eur J Clin Nutr 63, 478–484.Google Scholar
Moodley, A & Spector, SA (2015) Single high-dose vitamin D at birth corrects vitamin D deficiency in infants in Mexico. Int J Food Sci Nutr 66, 336–341.Google Scholar
Pacheco-Acosta, J & Pizarro, F (2020) Effect of vitamin D supplementation as a single dose on the nutritional status of vitamin D. Rev Chil Pediatr 91, 684–690.Google Scholar
Ponnapakkam, T, Bradford, E & Gensure, R (2010) A treatment trial of vitamin D supplementation in breast-fed infants: universal supplementation is not necessary for rickets prevention in southern Louisiana. Clin Pediatr (Phila) 49, 1053–1060.Google Scholar
Razaghi, M, Gharibeh, N, Vanstone, CA, et al. (2022) Correction of neonatal vitamin D status using 1000 IU vitamin D/d increased lean body mass by 12 months of age compared with 400 IU/d: a randomized controlled trial. Am J Clin Nutr 115, 1612–1625.Google Scholar
Rosendahl, J, Pelkonen, AS, Helve, O, et al. (2019) High-dose vitamin D supplementation does not prevent allergic sensitization of infants. J Pediatr 209, 139–145.Google Scholar
Rosendahl, J, Valkama, S, Holmlund-Suila, E, et al. (2018) Effect of higher vs standard dosage of vitamin D3 supplementation on bone strength and infection in healthy infants: a randomized clinical trial. JAMA Pediatr 172, 646–654.Google Scholar
Rothberg, AD, Pettifor, JM, Cohen, DF, et al. (1982) Maternal-infant vitamin D relationships during breast-feeding. J Pediatr 101, 500–503.Google Scholar
Ruangkit, C, Suwannachat, S, Wantanakorn, P, et al. (2021) Vitamin D status in full-term exclusively breastfed infants versus full-term breastfed infants receiving vitamin D supplementation in Thailand: a randomized controlled trial. BMC Pediatr 21, 1–10.Google Scholar
Rueter, K, Jones, AP, Siafarikas, A, et al. (2019) Direct infant UV light exposure is associated with eczema and immune development. J Allergy Clin Immunol 143, 1012–1020.Google Scholar
Shakiba, M, Sadr, S, Nefei, Z, et al. (2010) Combination of bolus dose vitamin D with routine vaccination in infants: a randomised trial. Singap Med J 51, 440.Google Scholar
Siafarikas, A, Piazena, H, Feister, U, et al. (2011) Randomised controlled trial analysing supplementation with 250 versus 500 units of vitamin D3, sun exposure and surrounding factors in breastfed infants. Arch Dis Child 96, 91–95.Google Scholar
Specker, BL, Ho, ML, Oestreich, A, et al. (1992) Prospective study of vitamin D supplementation and rickets in China. J Pediatr 120, 733–739.Google Scholar
Trilok-Kumar, G, Arora, H, Rajput, M, et al. (2012) Effect of vitamin D supplementation of low birth weight term Indian infants from birth on cytokine production at 6 months. Eur J Clin Nutr 66, 746–750.Google Scholar
Trilok-Kumar, G, Kaur, M, Rehman, AM, et al. (2015) Effects of vitamin D supplementation in infancy on growth, bone parameters, body composition and gross motor development at age 3–6 years: follow-up of a randomized controlled trial. Int J Epidemiol 44, 894–905.Google Scholar
Tuovinen, S, Räikkönen, K, Holmlund-Suila, E, et al. (2021) Effect of high-dose vs standard-dose vitamin D supplementation on neurodevelopment of healthy term infants: a randomized clinical trial. JAMA Netw Open 4, e2124493.Google Scholar
Weiler, HA, Hazell, TJ, Majnemer, A, et al. (2022) Vitamin D supplementation and gross motor development: a 3-year follow-up of a randomized trial. Early Hum Dev 171, 105615.Google Scholar
Wicklow, B, Gallo, S, Majnemer, A, et al. (2016) Impact of vitamin D supplementation on gross motor development of healthy term infants: a randomized dose-response trial. Phys Occup Ther Pediatr 36, 330–342.Google Scholar
Zeghoud, F, Ben-Mekhbi, H, Djeghri, N, et al. (1994) Vitamin D prophylaxis during infancy: comparison of the long-term effects of three intermittent doses (15, 5, or 2.5 mg) on 25-hydroxyvitamin D concentrations. Am J Clin Nutr 60, 393–396.Google Scholar
Zhou, J, Du, J, Huang, L, et al. (2018) Preventive effects of vitamin D on seasonal influenza A in infants: a multicenter, randomized, open, controlled clinical trial. Pediatr Infect Dis J 37, 749–754.Google Scholar
Ziegler, EE, Nelson, SE & Jeter, JM (2014) Vitamin D supplementation of breastfed infants: a randomized dose–response trial. Pediatr Res 76, 177–183.Google Scholar
Ziegler, EE, Koo, WW, Nelson, SE, et al. (2017) Lack of effect of graded doses of vitamin D on bone metabolism of breastfed infants. J Clin Nutr Metab 1, 105.Google Scholar
Randev, S, Kumar, P & Guglani, V (2018) Vitamin D supplementation in childhood–a review of guidelines. na J Pediatr 85, 194–201.Google Scholar
Giustina, A, Bouillon, R, Binkley, N, et al. (2020) Controversies in vitamin D: a statement from the third international conference. JBMR Plus 4, e10417.Google Scholar
Bouillon, R (2017) Comparative analysis of nutritional guidelines for vitamin D. Nat Rev Endocrinol 13, 466–479.Google Scholar
Zittermann, A, Pilz, S & Berthold, HK (2020) Serum 25-hydroxyvitamin D response to vitamin D supplementation in infants: a systematic review and meta-analysis of clinical intervention trials. Eur J Nutr 59, 359–369.Google Scholar
Beauchesne, AR, Cara, KC, Krobath, DM, et al. (2022) Vitamin D intakes and health outcomes in infants and preschool children: summary of an evidence report. Ann Med 54, 2277–2300.Google Scholar
Abiramalatha et al. supplementary material
Abiramalatha et al. supplementary material
File
5.4 MB