Serum Folate Concentrations in Exclusively Breastfed Preterm Infants Who Received No Supplementary Oral Folic Acid After Discharge: A Prospective Cohort Study

Overview

Journal Nutrients

Date 2024 Dec 17

PMID 39683614

Authors

Isabel Iglesias-Platas

Agata Sobczynska-Malefora

Vennila Ponnusamy

Ajit Mahaveer

Kieran Voong

Amy Nichols

Karen Dockery

Nicky Holland

Shaveta Mulla

Martin J Shearer

David Card

Lindsay J Hall

Dominic J Harrington

Paul Clarke

Affiliations

Soon will be listed here.

Abstract

Adequate folate intake is required in preterm infants for rapid growth and development, but there is little evidence to back recommendations. We aimed to assess folate status in preterm infants at discharge and in early infancy, according to exposure to folate sources, particularly in those exclusively/predominantly breastfed. A prospective, multicenter, observational cohort study was conducted in the UK, involving 45 preterm infants <33 weeks' gestational age (GA) exclusively/predominantly fed human milk when approaching NICU (Neonatal Intensive Care Unit) discharge. Serum folate levels were measured near NICU discharge (T1) and at 2-3 months corrected age (T2). Folate status was categorized per WHO (World Health Organization) guidelines: deficiency (<6.8 nmol/L), possible deficiency (6.8-13.4 nmol/L), normal (13.5-45.3 nmol/L), and elevated (>45.3 nmol/L). Nutritional information on feed and supplements was collected from hospital notes and maternal interviews. Thirty-two infants (71%) received parenteral nutrition. Twelve infants (32%) remained exclusively breastfed at T2. No infant from the whole cohort had a serum folate concentration <13.5 nmol/L at either time point. A proportion of infants had serum folate concentrations >45.3 nmol/L: 14/45 (31%) at T1, 19/37 (42%) at T2, and 7/37 (16%) at both time points. Elevated concentrations were seen particularly in infants who received folic acid supplements or nutrition containing folic acid, such as parenteral nutrition and breastmilk fortifiers. Folate deficiency was not observed in this cohort; folate concentrations were high and in line with those observed in healthy term infants. Further research is needed to assess the high folate concentrations in premature babies and whether they may have any adverse clinical impact.

References

Devalia V, Hamilton M, Molloy A . Guidelines for the diagnosis and treatment of cobalamin and folate disorders. Br J Haematol. 2014; 166(4):496-513. DOI: 10.1111/bjh.12959. View

Sulistyoningrum D, Sullivan T, Skubisz M, Palmer D, Wood S, Ueland P . Maternal serum unmetabolized folic acid concentration following multivitamin and mineral supplementation with or without folic acid after 12 weeks gestation: A randomized controlled trial. Matern Child Nutr. 2024; 20(4):e13668. PMC: 11574634. DOI: 10.1111/mcn.13668. View

Selhub J, Morris M, Jacques P, Rosenberg I . Folate-vitamin B-12 interaction in relation to cognitive impairment, anemia, and biochemical indicators of vitamin B-12 deficiency. Am J Clin Nutr. 2009; 89(2):702S-6S. PMC: 2647758. DOI: 10.3945/ajcn.2008.26947C. View

Allen L . B vitamins in breast milk: relative importance of maternal status and intake, and effects on infant status and function. Adv Nutr. 2012; 3(3):362-9. PMC: 3649471. DOI: 10.3945/an.111.001172. View

Embleton N, Pang N, Cooke R . Postnatal malnutrition and growth retardation: an inevitable consequence of current recommendations in preterm infants?. Pediatrics. 2001; 107(2):270-3. DOI: 10.1542/peds.107.2.270. View

. Transport properties of folate bound to human milk folate-binding protein. Nutr Rev. 1988; 46(6):230-2. DOI: 10.1111/j.1753-4887.1988.tb05439.x. View

Sjostrom E, Ohlund I, Ahlsson F, Domellof M . Intakes of Micronutrients Are Associated With Early Growth in Extremely Preterm Infants. J Pediatr Gastroenterol Nutr. 2015; 62(6):885-92. DOI: 10.1097/MPG.0000000000001085. View

Obeid R, Warnke I, Bendik I, Troesch B, Schoop R, Chenal E . Infants' Folate Markers and Postnatal Growth in the First 4 Months of Life in Relation to Breastmilk and Maternal Plasma Folate. Nutrients. 2023; 15(6). PMC: 10051157. DOI: 10.3390/nu15061495. View

. Prevention of neural tube defects: results of the Medical Research Council Vitamin Study. MRC Vitamin Study Research Group. Lancet. 1991; 338(8760):131-7. View

10.

Hibbard E, OBST D, Kenna A . Plasma and erythrocyte folate levels in low-birth-weight infants. J Pediatr. 1974; 84(5):750-3. DOI: 10.1016/s0022-3476(74)80025-9. View

11.

Clarke P, Shearer M, Card D, Nichols A, Ponnusamy V, Mahaveer A . Exclusively breastmilk-fed preterm infants are at high risk of developing subclinical vitamin K deficiency despite intramuscular prophylaxis at birth. J Thromb Haemost. 2022; 20(12):2773-2785. PMC: 9828794. DOI: 10.1111/jth.15874. View

12.

Pathak A, Godwin H . Vitamin B 12 and folic acid values in premature infants. Pediatrics. 1972; 50(4):584-9. View

13.

Godbole K, Gayathri P, Ghule S, Sasirekha B, Kanitkar-Damle A, Memane N . Maternal one-carbon metabolism, MTHFR and TCN2 genotypes and neural tube defects in India. Birth Defects Res A Clin Mol Teratol. 2011; 91(9):848-56. DOI: 10.1002/bdra.20841. View

14.

Rycyna K, Bacich D, OKeefe D . Divergence between dietary folate intake and concentrations in the serum and red blood cells of aging males in the United States. Clin Nutr. 2015; 35(4):928-34. PMC: 4713383. DOI: 10.1016/j.clnu.2015.07.002. View

15.

Roberts P, Arrowsmith D, Rau S, Monk-Jones M . Folate state of premature infants. Arch Dis Child. 1969; 44(237):637-42. PMC: 2020087. DOI: 10.1136/adc.44.237.637. View

16.

G Bjorkevoll S, Konijnenberg C, Kvestad I, McCann A, Ueland P, Naess Sleire S . Vitamin B12 and Folate Status in Pregnant Females and Their Infants in Norway: Secondary Analysis from the Mommy's Food Study. J Nutr. 2023; 153(12):3543-3554. PMC: 10739771. DOI: 10.1016/j.tjnut.2023.10.013. View

17.

Ek J, Behncke L, Halvorsen K, Magnus E . Plasma and red cell folate values and folate requirements in formula-fed premature infants. Eur J Pediatr. 1984; 142(2):78-82. DOI: 10.1007/BF00445582. View

18.

Vasu V, Mulla S, Pandya A, Card D, Shearer M, Clarke P . Late-onset vitamin K deficiency bleeding in an extremely preterm infant fed an exclusively human milk-based diet. J Thromb Haemost. 2023; 22(2):466-469. DOI: 10.1016/j.jtha.2023.10.029. View

19.

Houghton L, Yang J, OConnor D . Unmetabolized folic acid and total folate concentrations in breast milk are unaffected by low-dose folate supplements. Am J Clin Nutr. 2008; 89(1):216-20. DOI: 10.3945/ajcn.2008.26564. View

20.

Embleton N, Moltu S, Lapillonne A, van den Akker C, Carnielli V, Fusch C . Enteral Nutrition in Preterm Infants (2022): A Position Paper From the ESPGHAN Committee on Nutrition and Invited Experts. J Pediatr Gastroenterol Nutr. 2023; 76(2):248-268. DOI: 10.1097/MPG.0000000000003642. View