PEDIATRICS Vol. 108 No. 1 July 2001, pp. 217-217

Folate and Vitamin B12 Supplementation in Very Low Birth Weight Infants Treated With Erythropoietin: A Cautionary Note

To the Editor.

Although iron supplementation is reported in detail in all studies of erythropoietin in very low birth weight infants, the dosages for folate and vitamin B12 are often not clearly mentioned, despite their considerable role in the prevention of anemia of prematurity.¹ Vitamin B12 appears to be even more important than folate in this context.¹ Vitamin B12 deficiency reduces the endogenous erythropoietin response to anemia,² and thus could create a bias in favor of the treatment group in studies comparing erythropoietin to placebo.

A wide range of dosages has been used for folate supplementation in preterm infants, most authors recommending 50-100 µg/day.^13-5 Excessive plasma folate levels were found in preterm infants immediately after introduction of an oral daily dose of 1 mg.⁵

In their study on erythropoietin in very low birth weight infants, Donato et al⁶ did not report on vitamin B12 supplementation, and administered folate at an oral dose of 2 mg/day, exceeding the range of previously recommended dosages by a factor of 10 to 40. High folate intake (1 mg/day) has been shown to adversely affect zinc status in preterm infants,⁷ and inadequate zinc intake has been linked to impaired growth and neurodevelopment in very low birth weight infants.⁸ An overdosage of folate beyond a certain limit may only increase undesirable side effects, without further promoting erythropoiesis. Thus, data on plasma folate and zinc levels are required to confirm the safety of a high-dose folate supplementation as used by Donato et al.⁶

Peter Raupp, MD
Department of Paediatrics
Tawam Hospital
Al Ain, United Arab Emirates

REFERENCES

1. Worthington-White DA, Behnke M, Gross S Premature infants require additional folate and vitamin B-12 to reduce the severity of the anemia of prematurity. Am J Clin Nutr. 1994; 60:930-935 [Abstract/Free Full Text]
2. Ross MP, Christensen RD, Rothstein G, A randomized trial to develop criteria for administering erythrocyte transfusions to anaemic preterm infants from 1 to 3 months of age. J Perinatol. 1989; 9:246-253 [Medline]
3. Fewtrell M, Lucas A. Nutritional physiology: dietary requirements of term and preterm infants. In: Rennie JM, Roberton NRC, eds. Textbook of Neonatology. Edinburgh, Scotland: Churchill-Livingstone; 1999:322
4. Letsky EA. Anaemia in the newborn. In: Rennie JM, Roberton NRC, eds. Textbook of Neonatology. Edinburgh, Scotland: Churchill-Livingstone; 1999:813
5. Fuller NJ, Bates CJ, Cole TJ, Plasma folate levels in preterm infants, with and without a 1 mg folate supplement. Eur J Pediatr. 1992; 151:48-50 [CrossRef][Medline]
6. Donato H, Vain N, Rendo P, Effect of early versus late administration of human recombinant erythropoietin on transfusion requirements in premature infants: results of a randomized, placebo-controlled, multicenter trial. Pediatrics. 2000; 105:1066-1072 [Abstract/Free Full Text]
7. Fuller NJ, Bates CJ, Evans PH, High folate intakes related to zinc status in preterm infants. Eur J Pediatr. 1992; 151:51-53 [CrossRef][Medline]
8. Friel JK, Andrews WL, Matthew JD, Zinc supplementation in very-low-birth-weight infants. J Pediatr Gastroenterol Nutr. 1993; 17:97-104 [Medline]

In Reply.

As Dr Raupp noted, we did not administer vitamin B12 supplementation to very low birth weight (VLBW) infants in our study¹; moreover, no trial concerning the treatment of anemia of prematurity (AP) with erythropoietin (rHuEPO) reported on vitamin B12 supplementation. Although some studies have suggested that vitamin B12 seems to play a role in the treatment and prevention of AP,^2,3 its routine administration to VLBW infants is not yet established. We agree with Dr Raupp's opinion about the need for further investigation on vitamin B12 in forthcoming studies of rHuEPO in AP.

The recommended dosage for folate supplementation in healthy preterm infants is 0.05 to 0.2 mg/day.^34-6 For several reasons, this was not the case for patients in our trial. The rate of erythropoiesis in severe hemolytic anemias is increased several-fold compared with normal, and high requirements of folic acid supplementation are needed to sustain an adequate erythropoiesis, at any age. We believe that the same is true for the markedly increased erythropoiesis induced by the rHuEPO treatment in premature infants. After supplementation with oral folic acid, Emmerson et al demonstrated a significantly increased concentration (more than 50% higher) of red cell folate incorporated into the newly formed red cells in VLBW infants treated with rHuEPO compared with the placebo group.⁷ No recommendation regarding adequate doses of folic acid supplementation in VLBW infants receiving rHuEPO has been reported. In newborn infants with severe immune hemolytic disease, the supplementation with 1 mg of folic acid daily was associated with a significant improvement in growth.⁸ Fuller et al⁵ reported that, in premature infants receiving the same doses, plasma folate levels decreased progressively after the introduction of the supplement, despite continuing daily supplementation; this decrease could be explained by gradual dilution of the folate into a larger pool, induced by the continuous increase in body size. When we designed our trial, we speculated that a population of rapidly growing infants with a very high rate of erythropoiesis should require a folate supplementation largely in excess of the normal dosage. For such a reason, we decided to use such a large dose (2 mg/day) of folic acid.

The potentially toxic effect of an overdosage of folic acid supplementation is controversial, considering that there is no linear relationship between the amount of folate ingested and its plasma or erythrocyte levels. Moreover, a direct correlation between the amount of folic acid ingested and its excretion has been demonstrated. When a normal adult receives daily doses of <200 µg, little or none is lost in urine, but at higher doses urinary loss is considerable: 6% of a 1-mg dose, 10% of 2 mg, 50% of 5 mg, and 80% of 15 mg.^9,10 The interrelationship between folic acid intake and zinc status is not clear, because evidence both for and against such relationship has been reported.^11-15 The hypothesis that a high folate intake adversely affects zinc status in preterm infants is based on an interesting observation reported in an uncontrolled study: Fuller et al⁶ reported a significant inverse relationship between the maximum attained serum folate level and the minimum attained serum zinc level. However, the same authors recognized that plasma zinc concentrations do not necessarily reflect zinc status and the correlation reported is not unequivocal evidence for causation.⁶ Moreover, these results have not subsequently been confirmed by other trials.

In conclusion, VLBW infants enrolled in our trial have been controlled during, at least, 12 months. All of them present normal growth and neurodevelopment appropriate to their gestational age.

Hugo Donato, MD
Nestor Vain, MD
Pablo Rendo, MD
Clinical Research Area, Bio Sidus S.A.
Department of Pediatrics, Sanatorio de la Trinidad
Tarija 4243-1254 Buenos Aires, Argentina

REFERENCES

1. Donato H, Vain N, Rendo P, Effect of early versus late administration of human recombinant erythropoietin on transfusion requirements in premature infants: results of a randomized, placebo-controlled, multicenter trial. Pediatrics. 2000; 105:1066-1072
2. Ross MP, Christensen RD, Rothstein G, A randomized trial to develop criteria for administering erythrocyte transfusions to anaemic preterm infants from 1 to 3 months of age. J Perinatol. 1989; 9:246-253
3. Worthington-White DA, Behnke M, Gross S Premature infants require additional folate and vitamin B-12 to reduce the severity of the anemia of prematurity. Am J Clin Nutr. 1994; 60:930-935
4. Ek J, Behncke L, Halvorsen KS, Magnus E Plasma and red cell folate values and folate requirements in formula-fed premature infants. Eur J Pediatr. 1984; 142:78-82 [CrossRef][Medline]
5. Fuller NJ, Bates CJ, Cole TJ, Lucas A Plasma folate levels in preterm infants, with and without a 1 mg daily folate supplement. Eur J Pediatr. 1992; 151:48-50
6. Fuller NJ, Bates CJ, Evans PH, Lucas A High folate intakes related to zinc status in preterm infants. Eur J Pediatr. 1992; 151:51-53
7. Emmerson AJ, Coles HJ, Stern CM, Pearson TC Double blind trial of recombinant human erythropoietin in preterm infants. Arch Dis Child. 1993; 68:291-296 [Abstract/Free Full Text]
8. Gandy G, Jacobson W Influence of folic acid on birth-weight and growth of the erythroblastotic infant. Arch Dis Child. 1977; 52:16-21 [Abstract/Free Full Text]
9. Clark SL Oral folic acid tolerance test in normal human subjects and patients with pernicious anemia. Proc Soc Exp Biol Med. 1958; 82:25-27
10. Chanarin I. The megaloblastic anemias. London, United Kingdom; Blackwell Scientific; 1979:35
11. Milne DB, Canfield WK, Mahalko JR, Sandstead HH Effect of oral folic acid supplements on zinc, copper, and iron absorption and excretion. Am J Clin Nutr. 1984; 39:535-539 [Abstract/Free Full Text]
12. Ghisan FK, Said HM, Wilson PC, Intestinal transport of zinc and folic acid: a mutual inhibitory effect. Am J Clin Nutr. 1986; 43:258-262 [Abstract/Free Full Text]
13. Simmer K, Iles CA, James C, Thompson RPH Are iron-folate supplements harmful? Am J Clin Nutr. 1987; 45:122-125 [Abstract/Free Full Text]
14. Keating JN, Wada L, Stokstad ELR, King JL Folic acid: effect on zinc absorption in humans and in the rat. Am J Clin Nutr. 1987; 46:835-839 [Abstract/Free Full Text]
15. Butterworth CE, Hatch K, Cole P, Zinc concentration in plasma and erythrocytes of subjects receiving folic acid supplementation. Am J Clin Nutr. 1988; 47:484-486 [Abstract/Free Full Text]