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Effect of vitamin B12 deficiency on neurodevelopment in infants: current knowledge and possible mechanisms

Daphna K Dror, Lindsay H Allen
DOI: http://dx.doi.org/10.1111/j.1753-4887.2008.00031.x 250-255 First published online: 1 May 2008


Severe vitamin B12 deficiency produces a cluster of neurological symptoms in infants, including irritability, failure to thrive, apathy, anorexia, and developmental regression, which respond remarkably rapidly to supplementation. The underlying mechanisms may involve delayed myelination or demyelination of nerves; alteration in the S-adenosylmethionine:S-adenosylhomocysteine ratio; imbalance of neurotrophic and neurotoxic cytokines; and/or accumulation of lactate in brain cells. This review summarizes the current knowledge concerning infantile vitamin B12 deficiency, including a pooled analysis of case studies of infants born to mothers with untreated pernicious anemia or a strict vegetarian lifestyle and a discussion of the mechanisms that may underlie the manifestations of deficiency.

  • deficiency
  • infant
  • neurodevelopment
  • vitamin B12


Vitamin B12 deficiency has long been recognized to result in neurological degeneration in infants.1 The first report of nutritional vitamin B12 deficiency in early life was published in 1962, when Jadhav et al.2 described a syndrome of apathy, developmental regression, involuntary movements, and alterations in skin pigmentation that manifested in the first year of life of Indian infants. Since this report, many other case studies have documented the incidence, symptoms, and outcomes of vitamin B12 deficiency in infants. An improved understanding of the biochemistry of vitamin B12 and its functions has supported the development of several theories regarding the mechanisms underlying the neurological manifestations of deficiency. In this article we review the accumulated information on vitamin B12 deficiency in infancy, provide a pooled analysis of relevant case studies, and summarize what is known about the mechanisms of its effects on neurodevelopment.


Most of the available information on vitamin B12 deficiency in infants comes from case studies, in all of which deficiency was due to maternal depletion of the vitamin. There are two main causes of maternal vitamin B12 deficiency. Nutritional deficiency can occur if animal source food consumption is low, because vitamin B12 is found exclusively in animal products including meat, eggs, fish, and milk. Strict vegetarians are at high risk of nutritional vitamin B12 deficiency, and those who consume lacto-ovo vegetarian diets are at greater risk than omnivores.3 In addition, it is now apparent that in poor regions of the world populations that have limited access to foods of animal origin are at high risk of vitamin B12 depletion. Because the adequacy of maternal intake and absorption of the vitamin during pregnancy and lactation have a stronger influence on infant status than maternal stores, even relatively short-term maternal dietary restriction can result in poor infant vitamin B12 status.4

The second main cause of maternal vitamin B12 deficiency is malabsorption, which may be due to pernicious anemia, achlorhydria, ileal damage, or gastric bypass surgery. Pernicious anemia is caused by lack of intrinsic factor (IF), a glycoprotein secreted by gastric parietal cells that is required for vitamin B12 absorption from the terminal ileum. Lack of IF may be caused by atrophy of the gastric mucosa, autoimmunity against the gastric parietal cells that secrete IF, and/or autoimmunity against IF itself. Most clinical cases of B12 deficiency in infants are due to maternal veganism or pernicious anemia, although several cases have been reported due to maternal gastric bypass surgery.5,6 Inborn errors of cobalamin absorption and transport are rarely the cause of vitamin B12 deficiency in infancy.7

While most adults may tolerate a vitamin B12-deficient diet or malabsorptive disorder for years without developing clinical symptoms of deficiency, newborn infants have limited hepatic reserves (especially if maternal status and intake are poor during pregnancy) and, if predominantly breastfed, can develop vitamin B12 deficiency within months after birth. Even though they are born of normal size with apparently normal neurological development, symptoms in vitamin B12-deficient infants typically appear by 4–10 months of age, but may occur as early as 2 months of age.8 Symptoms include irritability, failure-to-thrive including a falling-off in growth rate, apathy, anorexia, refusal of solid foods, megaloblastic anemia, and developmental regression.


An infant born to a vitamin B12-replete mother has approximately 25 µg of vitamin B12 stored at birth and uses about 0.1–0.4 µg per day for tissue synthesis.9 In addition, exclusively breastfed infants of vitamin B12-replete mothers consume an average of 0.25 µg per day of the vitamin from breast milk in the first 6 months of life. Most of the vitamin B12 in human milk is present as haptocorrin (attached to an R binder) that is stable to proteolytic enzymes in the gastrointestinal tract and can be absorbed intact by infants.10

The endogenous vitamin B12 stores of infants may be much lower at birth if the mother's intake or absorption of vitamin B12 during pregnancy is poor.11 Furthermore, the vitamin B12 concentrations in the breast milk of mothers with poor intake or absorption of the vitamin have been reported in several studies to be substantially lower than those of mothers with adequate B12 status (50–85 ng/L compared with the normal range 180–300 ng/L).12


Case studies of vitamin B12-deficient infants were identified by searching PubMed using the following key words: vitamin B12, cobalamin, deficiency, infant, lactation, and vegan. Further studies were identified by searching for additional reports in the bibliographies of the articles identified in PubMed. A total of 48 useful cases were identified, including 18 studies in which maternal pernicious anemia had been diagnosed (although the method of diagnosis was not always stated), and 28 cases of maternal strict veganism. Two additional studies reported “very low” maternal animal-source food intake. No mothers were reported as being lacto-ovo vegetarian. From these case studies the following data were summarized: type of symptom; reported age when symptoms initially developed; age at which symptoms were diagnosed as being caused by vitamin B12 deficiency (0–8 months after the first symptom appeared, with a median diagnostic delay of 4 months); serum B12 concentration of the infant (reported in all but two cases, although in 10 cases the value was reported as “less than” 45 or 50 pg/mL); serum B12 concentration of the mother (reported in all but 10 cases); breast milk B12 concentration; anemia and megaloblastosis in infant blood; anthropometry; feeding practices, including refusal of complementary food; appetite; and any other data related to infant development (Table 1).942

View this table:
Table 1

Percent of studies reporting clinical symptoms and poor growth in 48 cases of infant B12 deficiency due to maternal pernicious anemia or veganism.

Clinical symptom anthropometryPernicious anemia (n = 18)Veganism (n = 30)
Clinical symptom
 Megaloblastic anemia100100
 Complementary food refusal8353
 Developmental delay5660
 Slow/abnormal EEG5033
 Unable to sit alone3343
 Not smiling1123
 Weight <10th percentile7853
 Height <10th percentile5630
 Head circumference <10th percentile5633
 Cerebral atrophy2837

Recovery from deficiency after treatment was classified as “yes” or “no” based on comments in the case study reports. Assessment of recovery was made with the Bayley Neonatal Assessment Scale in one case, but in others was based on “psychomotor” function (eight cases), neurological function/abnormal reflexes (six cases), speech ability (three cases), and intelligence (four cases, all older children). Most cases described abnormal “functioning” or “development” with little information on the actual assessment tools.

Pooling data from case studies has its limitations, including the fact that it is usually not possible to know whether absence of a symptom was due to its not being measured or because it did not occur. Also, treatment and follow-up varied among studies. However, there is remarkable similarity between the neurological symptoms of infants raised by mothers with pernicious anemia (in which vitamin B12 is the only deficient nutrient) and those whose mothers were vegans or had very low intake of animal-source foods (who may have other nutrient deficiencies, in addition to vitamin B12).

All of the infants identified as being B12 deficient in these case studies were breastfed exclusively. Breastfeeding is likely to increase the risk of deficiency because the concentration of the vitamin in breast milk will be low due to maternal depletion. In addition, exclusive breastfeeding disallows the provision of B12 through complementary foods. Interestingly, the duration of exclusive breastfeeding may be longer in B12-deficient infants; many case studies reported their refusal to consume complementary foods, with acceptance of complementary feeding being rapid once the infants were supplemented with B12. The cause of this behavior is unknown, although hypotonia and difficulty consuming solid foods might be involved.


The typical treatment for infants with hematological and neurological manifestations of vitamin B12 deficiency is 1 mg intramuscular vitamin B12 for 4 days, sometimes followed by large oral doses to replete stores. The pooled analysis revealed that very rapid recovery occurred in all infants, with major improvements documented within days of treatment initiation. Most of the infants experienced rapid reversal of apathy, muscle hypotonia, anorexia, and involuntary movements of the limbs and tongue. Hematological indices and biochemical parameters also returned to normal soon after vitamin B12 repletion. Cerebral atrophy and nerve demyelination reversed within several months, and growth resumed at an accelerated rate. The major recovery within days of starting B12 therapy means that at least some of the clinical symptoms in these infants are likely to be due to abnormalities in rapidly responding chemical, hormonal, or inflammatory processes and cannot be ascribed solely to lack of myelin or other major structural abnormalities.

Despite dramatic clinical and radiological improvement, however, infants treated for vitamin B12 deficiency often suffer long-term cognitive and developmental retardation.21 It is probable that the long-term prognosis depends on the severity and duration of the deficiency.40In the pooled analysis of cases of vitamin B12 deficiency in infants, 30% of infants whose mothers suffered from pernicious anemia and 33% of infants whose mothers were vegans recovered from developmental delay with treatment, while 38% and 50%, respectively, had long-term developmental impairment. However, there was considerable variability in the methods used to assess recovery, age and time after treatment, and assays for plasma B12.

In some infants, a temporary movement disorder consisting of tremor and myoclonus of the face, tongue, and pharynx appears as a response to B12 therapy and resolves independently after several weeks of treatment.22 One proposed explanation for this movement disorder is that the sudden availability of vitamin B12 after a period of severe shortage results in intense stimulation of cobalamin and folate pathways, causing local deficiencies and excesses of metabolic intermediates.22 Another possible explanation is that the tremors and myoclonus result from recovery from myelin degradation with an imbalance of excitatory versus inhibitory fiber tracts.39


Several theories have been proposed regarding the mechanisms by which vitamin B12 deficiency affects neural function in general, and neurodevelopment in infancy.

Delayed myelination or demyelination

It is well-documented that long-term deficiency of vitamin B12 causes impaired myelination or demyelination of the spinal cord and brain.4345 Myelin surrounds and protects the nerve cell and facilitates communication, so loss of myelin integrity alters neural function. Furthermore, initial damage to the myelin sheath is followed by subsequent axonal degeneration. Myelination of the brain is most active in the first 6 months of life.33

Vitamin B12, in the form of adenosylcobalamin and methylcobalamin, is a cofactor in two enzymatic reactions, either or both of which may impact myelin formation. Adenosylcobalamin is required for the conversion of methylmalonyl CoA to succinyl CoA, and inappropriate conversion results in an excess of the precursor proprionyl CoA, which leads to odd chain fatty acid synthesis. Subsequent incorporation of large amounts of unusual C15 and C17 fatty acids into the nerve sheaths synthesized by glial cells results in altered myelin, with reduced amounts of ethanolamine, phospholipids, and sphingomyelin.39

Methylcobalamin is a cofactor in the conversion of homocysteine to methionine, which is subsequently converted into S-adenosylmethionine (SAM), the methyl donor for the conversion of phosphatidylethanolamine to phosphatidylcholine. These lipids account for about 14% and 11%, respectively, of central nervous system myelin.46 Phosphatidylcholine is believed to improve neurotransmission by increasing the microviscosity of cell membranes,47 and inefficient conversion of phosphatidylethanolamine to phosphatidylcholine may impair myelination or cause demyelination.22 Using proton magnetic resonance spectroscopy, Horstmann et al.27 demonstrated reduced intracerebral levels of choline-containing compounds in a 6-month-old infant with nutritional vitamin B12 deficiency.

In one case study, magnetic resonance imaging (MRI) of the brain of a 4-month-old infant with neurological and hematological manifestations of vitamin B12 deficiency showed retarded myelination, most markedly in the frontal and temporal lobes of the brain, but also in the brainstem, cerebellum, internal capsule and posterior areas of the hemispheres. A follow-up MRI, performed 5 months after initiation of vitamin B12 therapy, revealed progressive myelination and significant regression of brain atrophy.33 Cranial MRI of a 10-month-old infant who displayed signs of developmental regression from the age of 8 months also revealed delayed myelination, with amounts similar to those in the brain of a normal 4-month-old infant.22

While abnormal neural myelination or demyelination is associated with severe nutritional vitamin B12 deficiency, it is improbable that the rapid improvement upon initiation of vitamin B12 therapy is the result of morphological changes. Symptoms that resolve within days of therapy include apathy, muscle hypotonia, anorexia, and involuntary movements of the limbs and tongue.1539

Altered S-adenosylmethionine: S-adenosylhomocysteine ratio

Another mechanism that may explain the adverse effects of vitamin B12 deficiency on neurodevelopment is an altered S-adenosylmethionine:S-adenosylhomocysteine (SAM:SAH) ratio. Methylcobalamin is a cofactor in the conversion of homocysteine to methionine by the enzyme methionine synthase. The reaction involves the transfer of a methyl group from 5-methyl-tetrahydrofolate to homocysteine to form tetrahydrofolate (THF) and methionine. Methionine is converted to SAM, which is converted to SAH upon donation of its methyl group. Homocysteine is regenerated when SAH is hydrolyzed. In vitamin B12 deficiency, folate becomes “trapped” as tetrahydrofolate, SAH and homocysteine levels are elevated, and SAM levels are depressed.

The resulting decreased SAM:SAH ratio may impair methylation reactions essential for synthesis of proteins, lipids, and neurotransmitters in the central nervous system.48,49 Furthermore, elevation of homocysteine has been linked with neurodegenerative diseases, possibly as a result of the neurotoxic effect of overstimulation of N-methyl-D-aspartate receptors.50 A decrease in the SAM:SAH ratio also implies inhibition of DNA synthesis and cell division as folate cannot be recycled in the absence of cobalamin.51

Tumor necrosis factor-α and epidermal growth factor imbalance

A novel theory of the pathophysiology of vitamin B12 deficiency has been proposed by Scalabrino.52 The glial cells of the central nervous system (CNS) synthesize various cytokines and growth factors. Some cytokines, such as tumor necrosis factor-α (TNF-α) act as neurotoxins in CNS diseases characterized by demyelination, while others such as epidermal growth factor (EGF) are neurotrophic. Adult patients with vitamin B12 deficiency have higher serum concentrations of TNF-α and lower concentrations of EGF, an imbalance that is rectified by vitamin B12 therapy.53 The same cytokine imbalance presents in the cerebrospinal fluid of adult patients with subacute combined degeneration, the neurological consequence of pernicious anemia.54

In vitamin B12 deficiency, the reduced availability of SAM due to impaired methionine synthase activity may increase TNF-α synthesis in the CNS,55 based on the observation that SAM lowers serum TNF-α in rats stimulated with lipopolysaccharide and reduces gene expression of TNF-α in lipopolysaccharide-treated murine macrophages.56 Cytokine imbalance has not been evaluated in vitamin B12-deficient infants, nor has it been causally linked with the neurological derangements associated with vitamin B12 deficiency. However, since increased TNF-α and decreased EGF are associated with the hematological and neurological manifestations of vitamin B12 deficiency, this could contribute to the loss of neural integrity that compromises brain development in infants.

Accumulation of lactate

In one case study of a 6-month-old infant with nutritional vitamin B12 deficiency, proton magnetic resonance spectroscopy of the white and gray matter of the brain revealed an accumulation of lactate, reflecting a disturbance of oxidative energy metabolism in brain cells. This could be due to an increase in anaerobic glycolysis, although the mechanism is not understood. The rapid improvement in clinical symptoms of vitamin B12 deficiency after treatment may be the result of restored cerebral aerobic energy metabolism.27


The neurological manifestations of vitamin B12 deficiency in infancy are well characterized through case studies. However, the biological basis for the observed symptoms of infantile vitamin B12 deficiency remains in question. Several mechanisms have been proposed, including delayed myelination or demyelination of nerves, alteration in the SAM:SAH ratio, imbalance of neurotrophic and neurotoxic cytokines, and accumulation of lactate in brain cells. While evidence exists to support each of these mechanisms, the rapid reversal of many of the neurological symptoms of deficiency upon treatment with high-dose vitamin B12 raises doubt about the contribution of processes that require time to reverse. It is likely that multiple mechanisms contribute simultaneously to the outcome, as developmental and cognitive delay is a common long-lasting effect of early vitamin B12 deficiency. There is a need for systematic documentation of symptoms and recovery, with inclusion of measures that could support or refute the mechanisms discussed in this review. As more research is dedicated towards elucidating the role of vitamin B12 in neurodevelopment, the ability to recognize and treat infants at an early stage of deficiency will likely improve the long-term outcome.


We would like to thank Janet M. Peerson, senior statistician in the Department of Nutrition at UC Davis, for her statistical assistance with the pooled analysis of case studies of vitamin B12 deficient infants.


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