Sage Journals: Discover world-class research

Abstract

Background:

An optimal cobalamin status is necessary for normal neurodevelopment.

Objective:

To give a description of the epidemiology, pathophysiology and diagnostic challenges related to cobalamin insufficiency in neonates and infants in order to prevent its occurence.

Results:

Inadequate cobalamin status is prevalent among neonates and young infants, due to a high prevalence of maternal cobalamin deficiency, exclusive breastfeeding for extended periods and late introduction of animal food. Cobalamin insufficiency is associated with delayed neurodevelopment and subtle clinical symptoms like feeding difficulties, regurgitations and constipation in young infants. Early diagnosis and treatment of impaired cobalamin status is important to prevent neurologic damage.

Conclusion:

Clinical suspicion of cobalamin insufficiency in infants should infer immediate biochemical testing and a plasma total homocysteine > 5.0 µmol/L indicate cobalamin insufficiency in need of intramuscular treatment with hydroxycobalamin, followed by introduction of animal food after 4 months of age.

Plain language title

Vitamin B12 Is Important for Normal Development in Young Children

Plain language summary

Vitamin B12, also called cobalamin, is found only in animal-sourced food. As low-meat, vegetarian, and vegan diets are increasingly popular in Western countries, vitamin B12 deficiency has become common, also in pregnant women and babies. Vitamin B12 status is essential for normal development and adequate levels of this vitamin is particularly important during pregnancy and the first years of life. In pregnancy, vitamin B12 is transferred from the mother to the fetus, so the baby has a store of this vitamin at birth. However, if the mother has vitamin B12 deficiency or the baby is born premature or with a low birth weight, the vitamin store may be insufficient and the baby may develop vitamin B12 deficiency. Maternal vitamin B12 status is important as long as the baby is exclusively breastfed. Breast milk contains vitamin B12, but the concentration decreases after 4 to 6 weeks and may be too low to support the baby until animal-sourced foods are introduced. The vitamin B12 content in formula milk is higher than in breast milk, and vitamin B12 deficiency is more common in exclusively breastfed babies. Vitamin B12 deficiency is associated with diffuse symptoms in small babies and may be difficult to detect, and the diagnosis have a mean delay of 4 months in this age-group. Typical symptoms are regurgitations or spitting up, constipation, problems with feeding and swallowing, and delayed psychomotor development. Suspicion of vitamin B12 insufficiency in babies should prompt immediate biochemical testing. Plasma total homocysteine is a metabolic marker of vitamin B12 status and can be measured in a blood sample from the baby. A level >5.0 µmol/L indicates probable vitamin B12 insufficiency and the baby should receive vitamin B12 supplementation, followed by introduction of animal-sourced foods at 3 to 4 months of age.

Keywords

cobalamin vitamin B12 infants neonates deficiency insufficiency neurodevelopment decision limits

Introduction

An adequate cobalamin (vitamin B12) status is essential for normal neurodevelopment during fetal life and infancy, as demonstrated by inborn errors of cobalamin metabolism and published case reports.^1
-3 Severe cobalamin deficiency in early life can cause permanent neurological deficits, but even moderate cobalamin deficiency is associated with delayed psychomotor development and clinical symptoms, like tremors, regurgitations, feeding difficulties, and constipation in infants.^4
-6 Intervention studies show that cobalamin supplementation improves psychomotor development and symptoms in infants with cobalamin insufficiency,^7,8 confirming the importance of an optimal cobalamin status in infancy. Early treatment is essential to ensure optimal neurodevelopment and prevent irreversible neurologic damage, but the challenge lies in diagnosing the patients.

Factors Determining Cobalamin Status in Neonates and Infants

The cobalamin status of a neonate depends on maternal cobalamin status during pregnancy, placental function, and gestational age at birth.⁴ There is a strong dose–response relation between markers of maternal cobalamin status in pregnancy week 18 and infants at 6 months of age.⁹ A maternal serum cobalamin concentration >275 pmol/L measured by routine laboratory methods at week 18 of pregnancy is reported to secure an optimal infant cobalamin status during the first 6 months of life.^9,10 Maternal cobalamin deficiency, prematurity, and low birth weight are all associated with lower fetal cobalamin stores and risk of deficiency, particularly if the infant is exclusively breastfed.^8,11,12 In recent years, vegetarian and vegan diets have become increasingly popular in Western societies,¹³ particularly among young women,¹⁴ imposing a risk for cobalamin deficiency in the infant, even when supplements are used during pregnancy.^2,15,16

As long as the infant is exclusively breastfed, maternal cobalamin status will continue to have an impact. Total cobalamin concentration in human milk falls progressively during the lactation period,¹⁷ and in exclusively breastfed term infants with adequate birth weight, a biochemical profile indicative of impaired cobalamin status is reported to be common from 4 months.⁴ As formula is supplemented with several B vitamins, deficiency is uncommon in formula-fed infants.¹⁸

Exclusive breastfeeding for extended periods is associated with short- and long-term feeding difficulties,^19,20 which may postpone weaning, thereby increasing the risk of cobalamin deficiency. Approximately 50% of Norwegian infants start with porridge, fruit, and vegetables between 4 and 6 months of age. The introduction of animal-sourced foods is usually postponed until after 6 months and the portions are initially small,²¹ something which increases the risk of cobalamin deficiency during infancy.

Prevalence of Cobalamin Deficiency

Cobalamin deficiency in infants has traditionally been considered to be a problem in countries with endemic cobalamin deficiency,⁴ but expanded newborn screening and infant studies have detected a high prevalence of cobalamin deficiency in both Europe and the United States.^22

-27 Depending on the decision limit used, the prevalence of cobalamin deficiency in newborn screening varies from 1:1989 to 1:17 837²⁷ and in infants from 13% to 66%.^28,29

As serum cobalamin progressively decreases during pregnancy,⁹ prevalence data of cobalamin deficiency in pregnant women depend on which pregnancy week the test was applied. Women with a low intake of animal-sourced foods, malabsorption due to disease or bariatric surgery are particularly at risk.^4,16,30 The prevalence of cobalamin deficiency in pregnancy is reported to be high,^16,31 from 72% in Turkey (serum cobalamin <118 pmol/L)²³ to 5% in Canadian women in early pregnancy (<125 pmol/L).³² Cobalamin deficiency is reported to be prevalent also in lactating mothers. At 5 weeks postpartum (range 0-20 weeks), 41% of German mothers had a serum cobalamin concentration below 160 pmol/L.³³

Clinical Signs of Impaired Cobalamin Status in Infants

The symptoms and signs of cobalamin deficiency in childhood depend on the age of the child and the severity and duration of the deficit.³⁴ Classical signs are delayed neurodevelopment and neurological symptoms,³⁵ but severe cobalamin deficiency may be associated with reduced weight, length, and head circumference,^36,37 as well as macrocytic anemia.^37,38 In contrast, moderate deficiency is associated with normal or even increased weight^39
-41 and normal hematological parameters.^40,42,43 Symptoms may appear as early as the second month of life^35,44 and include feeding difficulties, regurgitations, constipation, apathy, irritability, twitching, tremors, myoclonic jerks, and developmental delay with reduced gross motor development, as well as reduced smiling and babbling.^7,35,38,45

Diagnosing cobalamin insufficiency in young infants may be difficult, as there are large variations in normal psychomotor development⁴⁶ and minor developmental delays may not be considered abnormal in this age-group.⁴⁷ Doctors may be uncertain about the degree of delay that deserves evaluation and may also have concerns about causing parental anxiety.⁴⁷

Subtle symptoms associated with infant cobalamin deficiency, like tremors, regurgitations, and feeding difficulties, are very common in young infants.^48
-50 In a population-based study, 55% of the infants suffered from gastrointestinal symptoms, of which regurgitation was the most common, followed by colic, constipation, failure to thrive, vomiting, and diarrhoea.⁴⁷ Consequently, cobalamin deficiency may be overlooked in the youngest age groups and cobalamin deficiency has a reported median diagnostic delay of 4 months in infants,³⁵ which is particularly concerning during a period of rapid brain growth and development.⁵¹

Biochemical Markers of Cobalamin Status in Children

Cobalamin status undergoes marked changes during infancy and childhood.^43,52 During the first weeks of life, serum cobalamin decreases by approximately 30%, and the lowest cobalamin concentrations are seen in exclusively breastfed infants aged 4 to 6 months.^43,53

-57 After the introduction of animal-sourced foods containing cobalamin, which usually happens around 7 to 8 months,⁵⁸ serum cobalamin increases and peaks at 3 to 7 years and then gradually decreases to levels seen in adolescents and adults.⁴³

As serum folate concentrations are very high in infants and young children, plasma total homocysteine (tHcy) is considered the primary metabolic marker of cobalamin status in this age-group.⁴³ In older children and adults, plasma tHcy becomes more of a metabolic marker of intracellular folate status.

Figure 1 is based on published data from 173 newborns aged 4 days⁵⁹ and shows that plasma tHcy progressively changes over what is considered to be a normal cobalamin range (200-500 pmol/L). Plasma tHcy gradually starts to increase when serum cobalamin falls below 700 to 800 pmol/L, with a steeper increase below 300 to 400 pmol/L (Table 1). The same metabolic pattern is seen in older infants and indicates that there is a gradual transition from an optimal to a deficient intracellular cobalamin status below a serum cobalamin concentration of 800 pmol/L.

Figure 1.

Serum cobalamin concentrations in relation plasma total homocysteine (tHcy) in newborns aged 4 days, by generalized additive models (GAM). The values on the y-axes represent the difference from the mean plasma tHcy concentration.

Table 1.

Plasma Total Homocysteine in Relation to Serum Cobalamin in Newborns Aged 4 Days.^a

Parameter	Serum cobalamin, pmol/L					P value^b
Parameter	112-200n = 24	200-300n = 55	300-400n = 32	400-500n = 25	500-1351n = 36	P value^b
Plasma total homocysteine, µmol/L^b	7.3 (5.4-8.2)	5.9 (4.9-7.3)	5.2 (4.3-6.6)	5.0 (4.4-6.0)	4.5 (3.7-5.0)	<.001

^a N = 173.

^b Median, (25th, 75th percentile) compared by Kruskal-Wallis test.

Serum methylmalonic acid (MMA) is inversely related to circulating cobalamin. It is a marker of cobalamin status, but during the first years of life, the MMA concentrations are higher through the whole range of cobalamin concentrations compared to older children and adults.⁴³ The causes of the higher MMA levels in young children are uncertain, but it may be the result of increased intestinal absorption of propionate and MMA precursors produced by intestinal bacteria or degradation of odd-chain fatty acids present in milk.^43,60

Strategies for Classifying Vitamin Status

Many laboratories use reference values for serum cobalamin, of which the lower 2.5 percentile is often considered a marker for deficiency.⁶¹ However, the reference values for micronutrients vary according to the diet of the population on which the reference range is based and do not tell us whether the status is adequate or not. We should preferably define micronutrient decision limits based on a vitamin-replete status.⁶¹

Traditionally, decision limits for micronutrients have been based on clear signs and symptoms of depleted stores, but there is an increasing awareness that also subclinical deficiencies may have a negative impact on development and health.⁶² Decision limits may therefore vary over time depending on the chosen outcome parameter, exemplified by the different decision limits for serum folate published by the World Health Organization (WHO) over the years. In 1968, the decision limit for serum folate was 6.8 nmol/L and based on the presence of megaloblastic anaemia, that is, a severe vitamin deficiency causing clinical disease.⁶³ In 2005, WHO chose a decision limit of 10 nmol/L for folate deficiency based on changes in the metabolic marker tHcy.⁶⁴ In 2015, a decision limit of 25.5 nmol/L in fertile women was chosen for optimal neural tube defects prevention.^65,66 The relation between serum folate and plasma homocysteine in older children and adults resembles the metabolic pattern observed for serum cobalamin and plasma homocysteine in Figure 1. Plasma tHcy starts to increase when serum folate falls below 25 to 27 nmol/L, indicating suboptimal intracellular folate status and increases sharply when serum folate falls below 10 nmol/L, indicating intracellular folate deficiency.⁶⁷

What Decision Limits Should Be Used for Cobalamin Status?

There is no clear agreement on what constitutes deficient or optimal cobalamin status in either children or adults.⁴ The lower decision limit for cobalamin deficiency (<148 pmol/L) is based on the presence of clinical deficiency symptoms, decision limits in the range of 200 to 250 pmol/L are based on changes in the metabolic markers tHcy and MMA,⁴ while molecular studies show that serum cobalamin concentrations need to be >300 pmol/L in order to minimize DNA damage.⁶⁸

In newborns aged 4 days, a serum cobalamin cut-point value of 359 (95% CI = 332-391) pmol/L was obtained by segmented regression, with plasma tHcy concentration as the dependent variable (Figure 1). This serum cobalamin concentration might be used as a decision limit for cobalamin deficiency in newborns and infants; however, as the figure shows, plasma tHcy is not stabilized until serum cobalamin is >700 to 800 pmol/L, indicating cobalamin insufficiency and possibly also associated impaired neurodevelopment below these levels.

Plasma tHcy is a suitable marker for cobalamin status in infants. It is possible to reduce tHcy by cobalamin supplementation, implying that high plasma tHcy concentrations in young infants reflect cobalamin insufficiency and not organ immaturity.^7,69 Higher plasma tHcy concentrations are related to impaired neurodevelopment in infants.^5,7,8,53 A dose–response reduction in AIMS score, an observational tool for evaluating gross motor development,⁷⁰ with increasing levels of tHcy and MMA were seen in infants at 6 months⁸ and an increase in Alberta Infant Motor Scale (AIMS) score with decreased tHcy levels have been confirmed in randomized, controlled cobalamin intervention studies in young infants.^7,8

A plasma tHcy concentration of 6.5 µmol/L has been suggested as a decision limit for impaired cobalamin function in infants. This cutoff represented the 97.5th percentile in 4 months old infants given a single intramuscular dose of 400 µg hydroxycobalamin at 6 weeks and was considered a vitamin-optimized value.²⁸ However, the chosen plasma tHcy decision limit might be too high. The infants received a moderately low cobalamin supplement dosage and the plasma tHcy 97.5th percentile more than 2 months later might include infants with deficient cobalamin status. In the cobalamin-treated infants, the median plasma tHcy concentration was 4.6 µmol/L (IQR = 4.0-5.1) µmol/L. The same plasma tHcy range is seen in neonates with serum cobalamin concentrations >500 pmol/L (Table 1). A plasma tHcy concentration below 5.0 µmol/L (the 75th percentile) might be a more appropriate decision limit for securing an adequate cobalamin status in neonates and infants.

When defining decision limits for newborn screening of cobalamin status,²⁷ one has to take into account the expected 30% reduction in serum cobalamin and the increase in plasma tHcy, which appear during the first weeks of life in exclusively breastfed infants.⁴³ If the decision limit for plasma tHcy level is too high, infants at risk of developing a deficiency in the following weeks might escape attention.

How Much Cobalamin Is Needed in Infants?

Adequate cobalamin intake (AI) for infants aged 0 to 6 months is approximately 0.4 μg/day, based on the assumption that breast milk contains sufficient cobalamin for optimal health during this period of life.⁷¹ The AI is calculated based on an average intake of breast milk of ∼800 mL/d and an average cobalamin concentration in breast milk of ∼0.45 μg/L. Whether this amount of cobalamin is enough will depend on infant cobalamin stores, which will be low in premature and low birthweight infants, and in infants born to cobalamin-deficient mothers.

Only 28% of infants at 6 weeks and 34% at 4 months achieve the recommended intake of 0.4 µg cobalamin per day from breast milk.⁹ As cobalamin insufficiency is reported to be common among young infants, the assumption that breast milk contains enough cobalamin for optimal health during the first 6 months of life does not seem to apply to most infants.^{28,40,49,65,67}

The dosage of 400 µg hydroxycobalamin given intramuscularly in intervention studies in infants represents approximately twice the total amount of cobalamin considered necessary for the first year of life (0.4 µg/d for the first 6 months of life and 0.5 µg/d for the next 6 months).⁷¹ The dosage necessary for treatment of cobalamin deficiency in infants must depend on the severity of deficiency, age, and weight of the patient and might be increased to 1 mg hydroxycobalamin. If the infant has deficiency symptoms, cobalamin should be given as an intramuscular injection for rapid cure. Unless the infant has very low stores and is still exclusively breastfed, it is usually not necessary to repeat the intramuscular treatment. It is advisable to control serum cobalamin and plasma tHcy levels to see whether the patient has achieved and maintains an optimal status and if necessary, cobalamin supplementation should be repeated. There are no known adverse effects of excess cobalamin intake.⁷²

Implementation of animal-sourced foods should start as soon as possible. Introduction of solid food at age 3 months in breastfed infants do not affect the growth or the duration of breast-feeding and may also reduce food allergy.^73,74

Conclusion

Cobalamin deficiency is prevalent among young infants due to low maternal cobalamin status, exclusive breastfeeding for extended periods and late introduction of animal food. Optimal cobalamin status is essential for normal neurodevelopment, and early diagnosis and treatment of cobalamin insufficiency are vital to prevent irreversible neurologic damage. Clinical diagnosis of cobalamin deficiency is difficult in young infants, and suspicion of cobalamin insufficiency should prompt immediate biochemical testing. A plasma tHcy >5.0 µmol/L indicates cobalamin insufficiency in need of cobalamin supplementation. In infants with clinical symptoms of cobalamin deficiency, an intramuscular injection of 0.4 to 1 mg of hydroxycobalamin, adjusted for deficiency severity, age, and weight, should be promptly given. Decision limits for cobalamin status used in newborn-screening programs must take into account the expected 30% reduction in cobalamin status which occurs during the first weeks of life.

Supplemental Material

Supplemental Material, sj-pdf-1-fnb-10.1177_03795721241227782 - Defining Optimal Cobalamin Status for Neonates and Infants

Supplemental Material, sj-pdf-1-fnb-10.1177_03795721241227782 for Defining Optimal Cobalamin Status for Neonates and Infants by Anne-Lise Bjørke-Monsen in Food and Nutrition Bulletin

Footnotes

Acknowledgments

The author thank Paul Kjetil Soldal Lillemoen at Department of Medical Biochemistry and Pharmacology, Haukeland University Hospital, Bergen, Norway, for help preparing the figure.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iD

Anne-Lise Bjørke-Monsen

References

Goraya

Kaur

Mehra

. Neurology of nutritional vitamin B12 deficiency in infants: case series from India and literature review. J Child Neurol. 2015;30(13):1831–1837.

Guez

Chiarelli

Menni

Salera

Principi

Esposito

. Severe vitamin B12 deficiency in an exclusively breastfed 5-month-old Italian infant born to a mother receiving multivitamin supplementation during pregnancy. BMC Pediatr. 2012;12:85.

Whitehead

. Acquired and inherited disorders of cobalamin and folate in children. Br J Haematol. 2006;134(2):125–136.

Green

Allen

Bjørke-Monsen

, et al. Correction: vitamin B12 deficiency. Nat Rev Dis Primers. 2017;3:17054.

Ljungblad

Astrup

Morkrid

, et al. Breastfed infants with spells, tremor, or irritability: rule out vitamin B12 deficiency. Pediatr Neurol. 2022;131:4–12.

Black

. Effects of vitamin B12 and folate deficiency on brain development in children. Food Nutr Bull. 2008;29(2 Suppl):S126–S131.

Torsvik

Ueland

Markestad

Bjorke-Monsen

. Cobalamin supplementation improves motor development and regurgitations in infants: results from a randomized intervention study. Am J Clin Nutr. 2013;98(5):1233–1240.

Torsvik

Ueland

Markestad

Midttun

Bjorke Monsen

. Motor development related to duration of exclusive breastfeeding, B vitamin status and B12 supplementation in infants with a birth weight between 2000-3000g, results from a randomized intervention trial. BMC Pediatr. 2015;15:218.

Varsi

Ueland

Torsvik

Bjorke-Monsen

. Maternal serum cobalamin at 18 weeks of pregnancy predicts infant cobalamin status at 6 months—a prospective, observational study. J Nutr. 2018;148(5):738–745.

10.

Bjorke-Monsen

. Assessment of cobalamin status [Article in English, Norwegian]. Tidsskr Nor Laegeforen. 2020;140(9).

11.

Baker

Thind

Frank

DeAngelis

Caterini

Louria

. Vitamin levels in low-birth-weight newborn infants and their mothers. Am J Obstet Gynecol. 1977;129(5):521–524.

12.

Pathak

Godwin

. Vitamin B12 and folic acid values in premature infants. Pediatrics. 1972;50(4):584–589.

13.

Leitzmann

. Vegetarian nutrition: past, present, future. Am J Clin Nutr. 2014;(100 Suppl 1):496S–502S.

14.

Alles

Baudry

Mejean

, et al. Comparison of sociodemographic and nutritional characteristics between self-reported vegetarians, vegans, and meat-eaters from the NutriNet-Sante study. Nutrients. 2017;9(9):1023.

15.

Green

. Vitamin B(12) deficiency from the perspective of a practicing hematologist. Blood. 2017;129(19):2603–2611.

16.

Obeid

Murphy

Sole-Navais

Yajnik

. Cobalamin status from pregnancy to early childhood: lessons from global experience. Adv Nutr. 2017;8(6):971–979.

17.

Dror

Allen

. Vitamin B-12 in human milk: a systematic review. Adv Nutr. 2018;9(suppl_1):358S–366S.

18.

Fokkema

Woltil

van Beusekom

Schaafsma

Dijck-Brouwer

Muskiet

. Plasma total homocysteine increases from day 20 to 40 in breastfed but not formula-fed low-birthweight infants. Acta Paediatr. 2002;91(5):507–511.

19.

Northstone

Emmett

Nethersole

. The effect of age of introduction to lumpy solids on foods eaten and reported feeding difficulties at 6 and 15 months. J Hum Nutr Diet. 2001;14(1):43–54.

20.

Coulthard

Harris

Emmett

. Delayed introduction of lumpy foods to children during the complementary feeding period affects child’s food acceptance and feeding at 7 years of age. Matern Child Nutr. 2009;5(1):75–85.

21.

Lande

Andersen

Baerug

, et al. Infant feeding practices and associated factors in the first six months of life: the Norwegian infant nutrition survey. Acta Paediatr. 2003;92(2):152–161.

22.

Gramer

Abdoh

Ben-Omran

, 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.

23.

Koc

Kocyigit

Soran

, et al. High frequency of maternal vitamin B12 deficiency as an important cause of infantile vitamin B12 deficiency in Sanliurfa province of Turkey. Eur J Nutr. 2006;45(5):291–297.

24.

Pajares

Arranz

Ormazabal

, et al. Implementation of second-tier tests in newborn screening for the detection of vitamin B12 related acquired and genetic disorders: results on 258,637 newborns. Orphanet J Rare Dis. 2021;16(1):195.

25.

Hinton

Ojodu

Fernhoff

Rasmussen

Scanlon

Hannon

. Maternal and neonatal vitamin B12 deficiency detected through expanded newborn screening—United States, 2003-2007. J Pediatr. 2010;157(1):162–163.

26.

Rozmaric

Mitulovic

Konstantopoulou

, et al. Elevated homocysteine after elevated propionylcarnitine or low methionine in newborn screening is highly predictive for low vitamin B12 and holo-transcobalamin levels in newborns. Diagnostics (Basel). 2020;10(9):626.

27.

Tangeraas

Ljungblad

Lutvica

, et al. Vitamin B12 deficiency (Un-)detected using newborn screening in Norway. Int J Neonatal Screen. 2023;9(1):3.

28.

Bjørke-Monsen

Torsvik

Saetran

Markestad

Ueland

. Common metabolic profile in infants indicating impaired cobalamin status responds to cobalamin supplementation. Pediatrics. 2008;122(1):83–91.

29.

Casterline

Allen

Ruel

. Vitamin B-12 deficiency is very prevalent in lactating Guatemalan women and their infants at three months postpartum. J Nutr. 1997;127(10):1966–1972.

30.

Mead

Sakkatos

Sakellaropoulos

Adonakis

Alexandrides

Kalfarentzos

. Pregnancy outcomes and nutritional indices after 3 types of bariatric surgery performed at a single institution. Surg Obes Relat Dis. 2014;10(6):1166–1173.

31.

Rashid

Meier

Patrick

. Review of vitamin B12 deficiency in pregnancy: a diagnosis not to miss as veganism and vegetarianism become more prevalent. Eur J Haematol. 2021;106(4):450–455.

32.

Ray

Goodman

O’Mahoney

Mamdani

Jiang

. High rate of maternal vitamin B12 deficiency nearly a decade after Canadian folic acid flour fortification. QJM. 2008;101(6):475–477.

33.

Reischl-Hajiabadi

Garbade

Feyh

, et al. Maternal vitamin B(12) deficiency detected by newborn screening-evaluation of causes and characteristics. Nutrients. 2022;14(18):3767.

34.

Bjorke-Monsen

Ueland

. Cobalamin status in children. J Inherit Metab Dis. 2011;34(1):111–119.

35.

Dror

Allen

. Effect of vitamin B12 deficiency on neurodevelopment in infants: current knowledge and possible mechanisms. Nutr Rev. 2008;66(5):250–255.

36.

Ganesan

Thanawala

Hussain

. Vitamin B12 deficiency: a treatable cause of developmental delay in infancy. J Paediatr Child Health. 2013;49(4): E348–E349.

37.

Strand

Taneja

Kumar

, et al. Vitamin B-12, folic acid, and growth in 6- to 30-month-old children: a randomized controlled trial. Pediatrics. 2015;135(4):e918–e926.

38.

Zengin

Sarper

Caki Kilic

. Clinical manifestations of infants with nutritional vitamin B deficiency due to maternal dietary deficiency. Acta Paediatr. 2009;98(1):98–102.

39.

Hussein

Abdel Aziz

Tapouzada

Boehles

. Serum vitamin B(12) concentrations among mothers and newborns and follow-up study to assess implication on the growth velocity and the urinary methylmalonic acid excretion. Int J Vitam Nutr Res. 2009;79(5-6):297–307.

40.

Jenssen

Torsvik

Ueland

Midttun

Bjorke-Monsen

. Biochemical signs of impaired cobalamin function do not affect hematological parameters in young infants: results from a double-blind randomized controlled trial. Pediatr Res. 2013;74(3):327–32.

41.

Wighton

Manson

Speed

Robertson

Chapman

. Brain damage in infancy and dietary vitamin B12 deficiency. Med J Austr. 1979;2(1):1–3.

42.

Honzik

Adamovicova

Smolka

Magner

Hruba

Zeman

. 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):488–95.

43.

Monsen

Refsum

Markestad

Ueland

. Cobalamin status and its biochemical markers methylmalonic acid and homocysteine in different age groups from 4 days to 19 years. Clin Chem. 2003;49(12):2067–2075.

44.

Michaud

Lemieux

Ogier

Lambert

. Nutritional vitamin-B12 deficiency—two cases detected by routine newborn urinary screening. Eur J Pediatr. 1992;151(3):218–220.

45.

Cetinkaya

Yildirmak

Kutluk

Erdem

. Nutritional vitamin B12 deficiency in hospitalized young children. Pediatr Hematol Oncol. 2007;24(1):15–21.

46.

Rydz

Shevell

Majnemer

Oskoui

. Developmental screening. J Child Neurol. 2005;20(1):4–21.

47.

King

Glascoe

. Developmental surveillance of infants and young children in pediatric primary care. Curr Opin Pediatr. 2003;15(6):624–629.

48.

Biggs

Dery

. Evaluation and treatment of constipation in infants and children. Am Fam Physician. 2006;73(3):469–477.

49.

Borowitz

. Feeding problems in infants and children: assessment and etiology. Pediatr Clin North Am. 2018;65(1):59–72.

50.

Uddin

Rodnitzky

. Tremor in children. Semin Pediatr Neurol. 2003;10(1):26–34.

51.

Holland

Chang

Ernst

, et al. Structural growth trajectories and rates of change in the first 3 months of infant brain development. JAMA Neurol. 2014;71(10):1266–1274.

52.

Bjørke-Monsen

Ueland

. Cobalamin status in children. J Inherit Metab Dis. 2011;34(1):111–119.

53.

Ljungblad

Paulsen

Morkrid

, et al. The prevalence and clinical relevance of hyperhomocysteinemia suggesting vitamin B12 deficiency in presumed healthy infants. Eur J Paediatr Neurol. 2021;35:137–146.

54.

Specker

Brazerol

Norman

. Urinary methylmalonic acid excretion in infants fed formula or human milk. Am J Clin Nutr. 1990;51(2):209–211.

55.

Hay

Johnston

Whitelaw

Trygg

Refsum

. Folate and cobalamin status in relation to breastfeeding and weaning in healthy infants. Am J Clin Nutr. 2008;88(1):105–114.

56.

Minet

Bisse

Aebischer

Beil

Wieland

Lutschg

. Assessment of vitamin B-12, folate, and vitamin B-6 status and relation to sulfur amino acid metabolism in neonates. Am J Clin Nutr. 2000;72(3):751–757.

57.

Greibe

Lildballe

Streym

, et al. Cobalamin and haptocorrin in human milk and cobalamin-related variables in mother and child: a 9-mo longitudinal study. Am J Clin Nutr. 2013;98(2):389–395.

58.

Fox

Pac

Devaney

Jankowski

. Feeding infants and toddlers study: what foods are infants and toddlers eating? J Am Diet Assoc. 2004;104(1 Suppl 1):s22–s30.

59.

Bjørke Monsen

Ueland

Vollset

, et al. Determinants of cobalamin status in newborns. Pediatrics. 2001;108(3):624–630.

60.

Molloy

Kirke

Brody

Scott

Mills

. Effects of folate and vitamin B12 deficiencies during pregnancy on fetal, infant, and child development. Food Nutr Bull. 2008;29(2 Suppl):S101–11; discussion S112-5.

61.

Lillemoen

PKS

Bjorke-Monsen

. Nutritional status of vitamins and trace elements. Tidsskr Nor Laegeforen. 2020;140(5).

62.

Houston

. The role of cellular micronutrient analysis, nutraceuticals, vitamins, antioxidants and minerals in the prevention and treatment of hypertension and cardiovascular disease. Ther Adv Cardiovasc Dis. 2010;4(3):165–183.

63.

Nutritional Anaemias. Report of a WHO scientific group. World Health Organ Tech Rep Ser. 1968;405:5–37.

64.

de Benoist

. Conclusions of a WHO technical consultation on folate and vitamin B12 deficiencies. Food Nutr Bull. 2008;29(2 Suppl):S238–S244.

65.

Cordero

Crider

Rogers

Cannon

Berry

. Optimal serum and red blood cell folate concentrations in women of reproductive age for prevention of neural tube defects: World Health Organization guidelines. MMWR Morb Mortal Wkly Rep. 2015;64(15):421–423.

66.

Chen

Rose

, et al. Defining the plasma folate concentration associated with the red blood cell folate concentration threshold for optimal neural tube defects prevention: a population-based, randomized trial of folic acid supplementation. Am J Clin Nutr. 2019;109(5):1452–1461.

67.

Bjorke-Monsen

Renstrom

. What is optimal folate status? Tidsskr Nor Laegeforen. 2020;140(7).

68.

Fenech

. Folate (vitamin B9) and vitamin B12 and their function in the maintenance of nuclear and mitochondrial genome integrity. Mutat Res. 2012;733(1-2):21–33.

69.

Bjorke-Monsen

Torsvik

Saetran

Markestad

Ueland

. Common metabolic profile in infants indicating impaired cobalamin status responds to cobalamin supplementation. Pediatrics. 2008;122(1):83–91.

70.

Darrah

Piper

Watt

. Assessment of gross motor skills of at-risk infants: predictive validity of the Alberta infant motor scale. Dev Med Child Neurol. 1998;40(7):485–491.

71.

Bjørke-Monsen

Lysne

. Vitamin B12 - a scoping review for Nordic Nutrition Recommendations 2023. Food Nutr Res. 2023 Nov 8;67.

72.

SCF. Opinion of the Scientific Committee on Food on the Tolerable Upper Intake Level of Vitamin B12. 2000. Accessed March 4, 2023. https://ec.eu-ropa.eu/food/sites/food/files/safety/docs/sci-com_scf_out80d_en.pdf

73.

Perkin

Logan

Marrs

, et al. Enquiring About Tolerance (EAT) study: feasibility of an early allergenic food introduction regimen. J Allergy Clin Immunol. 2016;137(5):1477–1486.e8.

74.

Perkin

Logan

Tseng

, et al. Randomized trial of introduction of allergenic foods in breast-fed infants. N Engl J Med. 2016;374(18):1733–1743.

Supplementary Material

Please find the following supplemental material available below.

For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.

For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.

0.00 MB

0.46 MB