Summary
Vitamin B12 deficiency, mostly of maternal origin in newborns, is a well treatable condition but can cause severe neurologic sequelae. In women of childbearing age and pregnant women worldwide vitamin B12 deficiency has been reported with frequencies of 10%–50%. Children with vitamin B12 deficiency are asymptomatic at birth but may develop severe multisystemic symptoms, including irreversible developmental impairment in the second half-year of life. Early detection of vitamin B12 deficiency allows for presymptomatic treatment. This article provides an overview over the function of vitamin B12 and discusses causes and frequency of vitamin B12 deficiency in newborns, infants, and women of childbearing age. It describes novel successful approaches to newborn screening (NBS) for vitamin B12 deficiency and results of a pilot study which performed systematic NBS for vitamin B12 deficiency using so-called second-tier strategies by measuring homocysteine and methylmalonic acid in dried blood spots. Recommendations for diagnostics in mothers of children with vitamin B12 deficiency are described as well as results of systematic work-up in mothers and treatment and follow-up of children with vitamin B12 deficiency detected by NBS. Treatment options of vitamin B12 deficiency are presented including a newly developed standardized supplementation scheme with exclusively oral vitamin B12 supplementation. Recommendations for preventive approaches to vitamin B12 deficiency for children and mothers are stated. Many children worldwide could benefit from systematic inclusion of vitamin B12 deficiency into NBS panels. In addition, preventive approaches to maternal vitamin B12 deficiency should be implemented systematically during maternal care.
Article PDF
Similar content being viewed by others
Avoid common mistakes on your manuscript.
References
Hodgkin DC, Kamper J, Mackay M, et al. Structure of vitamin B12. Nature, 1956,178(4524):64–66
Stabler SP. Vitamin B12 deficiency. N Engl J Med, 2013,368(21):2041–2042
Lindenbaum J, Healton EB, Savage DG, et al. Neuropsychiatric disorders caused by cobalamin deficiency in the absence of anemia or macrocytosis. N Engl J Med, 1988,318(26):1720–1728
Healton EB, Savage DG, Brust JC, et al. Neurologic aspects of cobalamin deficiency. Medicine, 1991,70(4):229–245
Hannibal L, Lysne V, Bjorke-Monsen AL, et al.. Biomarkers and Algorithms for the Diagnosis of Vitamin B12 Deficiency. Front Mol Biosci, 2016,3:27
Stabler SP, Allen RH. Vitamin B12 deficiency as a worldwide problem. Annu Rev Nutr, 2004,24:299–326
Jain R, Singh A, Mittal M, et al. Vitamin B12 deficiency in children: a treatable cause of neurodevelopmental delay. J Child Neurol, 2015,30(5):641–643
Whitehead VM. Acquired and inherited disorders of cobalamin and folate in children. Br J Haematol, 2006,134(2):125–136
Graham SM, Arvela OM, Wise GA, Long-term neurologic consequences of nutritional vitamin B12 deficiency in infants. J Pediatr, 1992,121(5 Pt 1):710–714
Singh G, Le D, Schnabl K, et al. Vitamin B12 Deficiency in Infancy: The Case for Screening. Pediatr Blood Cancer, 2016,63(4):740–742
Scolamiero E, Villani GR, Ingenito L, et al. Maternal vitamin B12 deficiency detected in expanded newborn screening. Clin Biochem, 2014,47(18):312–317
Sukumar N, Rafnsson SB, Kandala NB, et al. Prevalence of vitamin B-12 insufficiency during pregnancy and its effect on offspring birth weight: a systematic review and meta-analysis. Am J Clin Nutr, 2016,103(5):1232–1251
Ray JG, Goodman J, O’mahoney PR, et al. High rate of maternal vitamin B12 deficiency nearly a decade after Canadian folic acid flour fortification. QJM, 2008,101(6):475–477
Jeruszka-Bielak M, Isman C, Schroder TH, et al. South Asian Ethnicity Is Related to the Highest Risk of Vitamin B12 Deficiency in Pregnant Canadian Women. Nutrients 2017,9(4):317
Finkelstein JL, Kurpad AV, Thomas T, et al. Vitamin B12 status in pregnant women and their infants in South India. Eur J Clin Nutr, 2017,71(9):1046–1053
Schroder TH, Sinclair G, Mattman A, et al. Pregnant women of South Asian ethnicity in Canada have substantially lower vitamin B12 status compared with pregnant women of European ethnicity. Br J Nutr, 2017,118(6):454–462
Obeid R, Murphy M, Sole-Navais P, et al. Cobalamin Status from Pregnancy to Early Childhood: Lessons from Global Experience. Adv Nutr, 2017,8(6):971–979
Sukumar N, Venkataraman H, Wilson S, et al. Vitamin B12 Status among Pregnant Women in the UK and Its Association with Obesity and Gestational Diabetes. Nutrients, 2016,8(12):768
Mishra J, Tomar A, Puri M, et al. Trends of folate, vitamin B12, and homocysteine levels in different trimesters of pregnancy and pregnancy outcomes. Am J Hum Biol, 2020,32(5):e23388
Lindner M, Gramer G, Haege G, et al.. Efficacy and outcome of expanded newborn screening for metabolic diseases-report of 10 years from South-West Germany. Orphanet J Rare Dis, 2011,6:44
Wilcken B, Haas M, Joy P, et al. Expanded newborn screening: outcome in screened and unscreened patients at age 6 years. Pediatrics, 2009,124(2):e241–248
Gramer G, Hoffmann GF, Nennstiel-Ratzel U. Das erweiterte Neugeborenenscreening — Erfolge und neue Herausforderungen. 2015, Springer Essentials, Springer Wiesbaden, ISBN 978-3-658-10492-4
Wilson JMG, Jungner G. Principles and Practice of Screening for Disease. World Health Organization, Geneva, 1968
Hinton CF, Ojodu JA, Fernhoff PM, et al. Maternal and neonatal vitamin B12 deficiency detected through expanded newborn screening—United States, 2003–2007. J Pediatr, 2010,157(1):162–163
Sarafoglou K, Rodgers J, Hietala A, et al. Expanded newborn screening for detection of vitamin B12 deficiency. JAMA, 2011,305(12):1198–1200
Campbell CD, Ganesh J, Ficicioglu C. Two newborns with nutritional vitamin B12 deficiency: challenges in newborn screening for vitamin B12 deficiency. Haematologica, 2005,90(12 Suppl):ECR45
Franssen M, Maroske W, Langlitz J. Vitamin-B12-Mangel veganer Mütter und ihrer Säuglinge — voll im Trend? (English title: Vitamin B12 Deficiency in Vegan Mothers and Their Neonates: The New “It” Disease?). Monatsschr Kinderheilkd (German), 2007, 165:794–799
Gramer G, Fang-Hoffmann J, Feyh P, et al. High incidence of maternal vitamin B12 deficiency detected by newborn screening: first results from a study for the evaluation of 26 additional target disorders for the German newborn screening panel. World J Pediatr, 2018,14(5):470–481
Gramer G, Fang-Hoffmann J, Feyh P, et al.. Newborn Screening for Vitamin B12 Deficiency in Germany-Strategies, Results, and Public Health Implications. J Pediatr, 2020,216:165–172.e4
Gramer G, Abdoh G, Ben-Omran T, et al. Newborn screening for remethylation disorders and vitamin B12 deficiency—evaluation of new strategies in cohorts from Qatar and Germany. World J Pediatr, 2017,13(2):136–143
Röschinger W, Sonnenschein S, Schuhmann E, et al.. Neue Zielerkrankungen im Neugeborenenscreening — Empfehlungen aus einem Pilotprojekt. (English title: New target diseases in newborn screening. Recommendations derived from a pilot study). Monatsschr Kinderheilkd (German), 2015,163:142–149
Baumgartner MR, Hörster F, Dionisi-Vici C, et al.. Proposed guidelines for the diagnosis and management of methylmalonic and propionic acidemia. Orphanet J Rare Dis, 2014,9:130
La Marca G, Malvagia S, Pasquini E, et al. Rapid 2nd-tier test for measurement of 3-OH-propionic and methylmalonic acids on dried blood spots: reducing the false-positive rate for propionylcarnitine during expanded newborn screening by liquid chromatography-tandem mass spectrometry. Clin Chem, 2007,53(7):1364–1369
Matern D, Tortorelli S, Oglesbee D, et al. Reduction of the false-positive rate in newborn screening by implementation of MS/MS-based second-tier tests: the Mayo Clinic experience (2004–2007). J Inherit Metab Dis, 2007,30(4):585–592
Monostori P, Klinke G, Richter S, et al. Simultaneous determination of 3-hydroxypropionic acid, methylmalonic acid and methylcitric acid in dried blood spots: Second-tier LC-MS/MS assay for newborn screening of propionic acidemia, methylmalonic acidemias and combined remethylation disorders. PLoS One, 2007, 12(9):e0184897
Okun JG, Gan-Schreier H, Ben-Omran T, et al.. Newborn Screening for Vitamin B6 Non-responsive Classical Homocystinuria: Systematical Evaluation of a Two-Tier Strategy. JIMD Rep, 2017,32:87–94
Huemer M, Kozich V, Rinaldo P, et al. Newborn screening for homocystinurias and methylation disorders: systematic review and proposed guidelines. J Inherit Metab Dis 2015,38(6):1007–1019
Gan-Schreier H, Kebbewar M, Fang-Hoffmann J, et al. Newborn population screening for classic homocystinuria by determination of total homocysteine from Guthrie cards. J Pediatr, 2010,156(3):427–432
Gramer G, Nennstiel-Ratzel U, Hoffmann GF. 50 Jahre Neugeborenenscreening in Deutschland (English title: 50 years of newborn screening in Germany. Achievements and future challenges). Monatsschr Kinderheilkd (German), 2018,166:987–993
Reinson K, Künnapas K, Kriisa A, et al.. High incidence of low vitamin B12 in Estonian newborns. Mol Genet Metab Rep, 2018,15:1–5
Hawthorne S, Levy HL. Can Newborn Screening for Vitamin B12 Deficiency be Incorporated into All Newborn Screening Programs? J Pediatr, 2020,216:9–11.e1
Koletzko B, Cremer M, Flothkotter M, et al.. Diet and Lifestyle Before and During Pregnancy—Practical Recommendations of the Germany-wide Healthy Start —Young Family Network. Geburtshilfe und Frauenheilkunde, 2018,78:1262–1282
Thamm M, Mensink GB, Thierfelder W. Folic acid intake of women in childbearing age. Gesundheitswesen (German), 1999,61(Spec No):S207–212
Anonymous, Schweizerische Eidgenossenschaft. Bericht des Bundesrats 2015 zur Gesundheit von Müttern und Kindern mit Migrationshintergrund, Bern, 2015.
Masih SP, Plumptre L, Ly A, et al. Pregnant Canadian Women Achieve Recommended Intakes of One-Carbon Nutrients through Prenatal Supplementation but the Supplement Composition, Including Choline, Requires Reconsideration. J Nutr, 2015,145(8):1824–1834
Herrmann W, Obeid R. Causes and early diagnosis of vitamin B12 deficiency. Dtsch Arztebl Int, 2008,105(40):680–685
Karaoglu L, Pehlivan E, Egri M, et al.. The prevalence of nutritional anemia in pregnancy in an east Anatolian province, Turkey. BMC Public Health, 2010,10:329
Richter M, Beoing H, Grünewald-Funk D, et al.. Vegan Diet. Position of the German Nutrition Society (DGE). Ernahrungs Umschau, 2016,63:92–102
Honzik T, Adamovicova M, Smolka V, et al. Clinical presentation and metabolic consequences in 40 breastfed infants with nutritional vitamin B12 deficiency—what have we learned? Eur J Paediatr Neurol, 2010,14(6):488–495
Huemer M, Baumgartner MR. The clinical presentation of cobalamin-related disorders: From acquired deficiencies to inborn errors of absorption and intracellular pathways. J Inherit Metab Dis, 2019,42(4):686–705
Bahadir A, Reis PG, Erduran E Oral vitamin B12 treatment is effective for children with nutritional vitamin B12 deficiency. J Paediatr Child Health, 2014, 50(9):721–725
Jungert A, Quack Lotscher K, Rohrmann S Vitamin Substitution Beyond Childhood-Requirements and Risks. Dtsch Arztebl Int, 2020,117(1-2):14–22
Wang H, Li L, Qin LL, et al. Oral vitamin B12 versus intramuscular vitamin B12 for vitamin B12 deficiency. Cochrane Database Syst Rev, 2018,3(3):CD004655
Koletzko B, Bauer CP, Cierpka M, et al.. Ernährung und Bewegung von Säuglingen und stillenden Frauen. Aktualisierte Handlungsempfehlungen von “Gesund ins Leben — Netzwerk Junge Familie”, eine Initiative von IN FORM (English title: Nutrition and physical activity of infants and breastfeeding women. Updated recommendations by “Healthy Start — Young Family Network” an initiative from IN FORM, Monatsschr Kinderheilkd (German), 2016,164:S433–S457
Anonymous, From the Centers for Disease Control and Prevention. Neurologic impairment in children associated with maternal dietary deficiency of cobalamin—Georgia, 2001. JAMA, 2003,289(8):979–980
Karall D, Nindl G, Zittera I, et al.. Stillen und Stillberatung — Was Pädiater/-innen über Stillen und Laktation wissen und kommunizieren sollten (English title: Breastfeeding and lactation counselling. What pediatricians should know and communicate about breastfeeding and lactation). Monatsschr Kinderheilkd (German), 2020,168:547–560
Author information
Authors and Affiliations
Corresponding author
Additional information
The study “Newborn Screening 2020” at the Heidelberg Newborn Screening Center is generously supported by the Dietmar Hopp Foundation, St. Leon-Rot, Germany.
Conflict of Interest Statement
The authors have no conflicts of interest relevant to this article to disclose.
Rights and permissions
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License https://creativecommons.org/licenses/by/4.0/), which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless
About this article
Cite this article
Gramer, G., Hoffmann, G.F. Vitamin B12 Deficiency in Newborns and their Mothers—Novel Approaches to Early Detection, Treatment and Prevention of a Global Health Issue. CURR MED SCI 40, 801–809 (2020). https://doi.org/10.1007/s11596-020-2260-7
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11596-020-2260-7