Life-threatening Manifestations of Vitamin B12 Deficiency in Infants on a Vegan Diet

Although plant-based diets (pescetarianism, lactoovovegetarianism, lactovegetarianism, ovovegetarianism and veganism) are generally considered as healthy and nutritionally adequate in adults, and may provide health benefits in the prevention and treatment of certain diseases, not all families are aware of the nutritional supplements and other necessary aspects that are required for their infants. A well-balanced plant-based diet (usually lacto-ovo-vegetarian diet) with appropriate supplements and regular medical and dietetic supervision can guarantee normal growth and development (Fewtrell M et al., J Pediatr Gastroenterol Nutr 2017; 64: 119–132). In contrast, a strict vegan diet, excluding all animal food products, generates considerably greater risk for nutritional deficiencies, such as vitamin B12 deficiency, less often then iron, calcium, omega 3 fatty acids, selen or zinc deficiency (Pawlak R. Eur J Clin Nutr 2017; 71: 1259–1262).

It is known that most individuals with vitamin B12 deficiency (mainly ovovegetarians and vegans or exclusively breast-fed infants of mothers on a strict vegetarian/vegan diet) present asymptomatically with an incidental laboratory finding or with the slow development of symptoms, such as failure to thrive, hypotonia, developmental delay, microcephaly, dyskinezia, and cerebral atrophy (Honzik T et al., Eur J Paediatr Neurol 2010; 14: 488–495).

However, in rare cases, life-threatening manifestations may occur, such as serious hematological, metabolic and neurological complications. Whereas vegan diets have shown a rise of the popularity, we mention several previously published cases ([Tab. 1]) demonstrating potentially life-threatening manifestations of this deficiency in infants (Guez S et al., BMC Pediatr 2012; 12: 85; Higginbottom MC et al., N Engl J Med 1978; 299: 317–323; Kühne T et al., Eur J Pediatr 1991; 150: 205–208; Lund AM, Acta Paediatr 2019; 108: 1377–1379; Codazzi D et al., Pediatr Crit Care Med 2005; 6: 483–485; Giannini A et al., Pediatr Crit Care Med 2006; 7: 188). The main symptoms included unconsciousness, seizures and/or metabolic impairments. Notably, all presented patients did not have adequate vitamin B12 supplementation.

Tab. 1 Previously published cases demonstrating potentially life-threatening manifestations of nutritional vitamin B12 deficiency in infants.

Age	Nutritional history	Clinical features	Authors
5 months	Exclusively breastfed vegan mother, vitamin B12 supplementation only during the second and third trimester	Poor weight gain, feeding difficulties, severe pallor, muscle hypotonia and somnolence	Guez S et al.
6 months	Exclusively breastfed vegetarian mother without vitamin B12 supplementation	Coma, severe megaloblastic anemia, methylmalonic aciduria and homocystinuria	Higginbottom MC et al.
9 months	Exclusively breastfed vegetarian mother without vitamin B12 supplementation	Dystrophy, weakness, muscular atrophy, psychomotoric regression and unconsciousness	Kühne T et al.
10 months	Strict vegan without vitamin B12 supplementation	Failure to thrive, peripheral and truncal hypotonia, dyskinetic movements and generalised tonic-clonic seizures	Lund AM
10 months	Exclusively breastfed vegan mother without vitamin B12 supplementation	Coma, respiratory failure, muscular hypotonia, involuntary movements and diffuse cortical-subcortical atrophy	Codazzi D et al.
12 months	Strict vegetarian without vitamin B12 supplementation	Malnutrition, dehydratation, metabolic impairment and severe brain damage	Giannini A et al.

Vitamin B12 (cobalamin) is a water-soluble vitamin, but its main stores are found in liver tissue. Animal products are exclusive natural sources of active vitamin B12. On the other hand, plants (seaweed, mushrooms or fermented products) contain only its inactive form and cannot be considered as a suitable source. It is confirmed, that most of vegans with poor diet composition are at risk of vitamin B12 deficiency (Gilsing AMJ et al., Eur J Clin Nutr 2010; 64: 933–939).

Vitamin B12 plays a major role in human intermediary metabolism and nucleotide synthesis, mainly in hematopoiesis and neuronal function. It is required to convert methylmalonyl-CoA to succinyl-CoA and to ensure the activity of methionine synthase which catalyses the methylation of homocysteine. Vitamin B12 deficiency leads to the accumulation of methylmalonic acid and homocysteine in blood and urine. Homocysteine stimulates the glutamate (NMDA) receptors which increase the influx of calcium ion resulting in oxidative stress, neuronal death and neurological symptomatology (Honzik T et al., Eur J Paediatr Neurol 2010; 14: 488–495).

In differential diagnosis, it is important to rule out an inborn error of vitamin B12 metabolism (with an incidence of 1:5,355 newborns, Gramer G et al., J Pediatr 2020; 216: 165–172), nevertheless nutritional deficiency is more frequent. Diagnosis is based on a detailed clinical and dietary history – especially the lack of regular vitamin B12 supplementation, laboratory markers such as total and active B12 levels, total homocysteine and metabolic screening including methylmalonate (Rizzo G et al., Nutrients 2016; 8: 1–23). Anemization (megaloblastic) is often masked by sufficient folate intake from the vegan diet, therefore it is always necessary to measure the level of active vitamin B12 (holotranscobalamin).

The initial therapy of severe symptomatic patients with vitamin B12 deficiency includes a parenteral (usually intramuscular) injection of synthetic form of vitamin B12 (cyanocobalamin), a dose of 500–1,000 μg once per week until the deficiency is corrected. Although improvements in red blood cell production takes several days, there is no evidence of benefit from using a higher dose. On the other hand, intramuscular method is associated with some disadvantages, such as pain, high cost, or bleeding in patients with coagulation disorders. Regarding the above mentioned, sublingual route is now being considered for cyanocobalamin administration. A significant difference of treating with sublingual versus parenteral vitamin B12 has not been confirmed as well (Tuğba-Kartal A et al., Rev Invest Clin 2020; 216: 165–172). After the initial treatment, regular per oral supplementation in adequate dosage is necessary (adequate daily intake 250–1,000 μg/day depending on the serum levels of vitamin B12). In extremely rare cases of severe deficiency with hemodynamic compromise due to severe anemia, a blood transfusion may be given. In this case, more intensive monitoring is definitely indicated (Rizzo G et al., Nutrients 2016; 8: 1–23).

This article may help to increase awareness of this rare but potentially life-threatening complication of nutritional vitamin B12 deficiency among health professionals in pediatric care and may have some practical consequences. Firstly, a history of a vegan diet could be an important clue in the differential diagnosis in an infant with sudden symptomatology (e. g. unconsciousness, seizures or metabolic impairment). Secondly, all presented patients did not adequately supplement vitamin B12. This emphasizes the role of appropriate and regular medical supervision in infants on a vegan diet. Vitamin B12 supplementation is always necessary, while iron, calcium, omega 3 fatty acids, selen and zinc substitution is recommended only in individual cases.

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Artikel online veröffentlicht:
01. September 2021