Exclusively breastmilk-fed preterm infants are at high risk of developing subclinical vitamin K deficiency despite intramuscular prophylaxis at birth

Paul Clarke, Martin J. Shearer, David J. Card, Amy Nichols, Vennila Ponnusamy, Ajit Mahaveer, Kieran Voong, Karen Dockery, Nicky Holland, Shaveta Mulla, Lindsay J. Hall, Cecile Maassen, Petra Lux, Leon J. Schurgers, Dominic J. Harrington

Research output: Contribution to journalArticlepeer-review

5 Citations (Scopus)
9 Downloads (Pure)


Background: There is near-global consensus that all newborns be given parenteral vitamin K1 (VK1) at birth as prophylaxis against VK deficiency bleeding (VKDB). Breastmilk has a low VK content and cases of late VKDB are reported in exclusively breastmilk-fed preterm infants despite VK prophylaxis at birth.

Objectives: To assess the prevalence of functional VK insufficiency in preterm infants based on elevated under-γ-carboxylated (Glu) species of Gla-proteins, factor II (PIVKA-II) and osteocalcin (GluOC), synthesized by liver and bone respectively.

Patients/Methods: Prospective, multi-center, observational study in preterm infants born <33 weeks’ gestation. Blood samples and dietary history were collected before hospital discharge, and post discharge at 2-3 months corrected age. Outcome measures were serum VK1, PIVKA-II, and %GluOC (GluOC as a percentage of the sum of GluOC plus GlaOC) compared between exclusively breastmilk-fed and formula/mixed-fed infants post-discharge.

Results: Post discharge, breastmilk-fed babies had significantly lower serum VK1 (0.15 vs. 1.81 μg/L), higher PIVKA-II (0.10 vs. 0.02 AU/mL) and higher %GluOC (63.6% vs. 8.1%) than those receiving a formula/mixed-feed diet. Pre-discharge (based on elevated PIVKA-II), only 1 (2%) of 45 breastmilk-fed infants was VK insufficient. Post-discharge, 8 (67%) of 12 exclusively breastmilk-fed babies were VK insufficient versus only 1 (4%) of 25 formula/mixed-fed babies.

Conclusions: Preterm infants who remain exclusively or predominantly human breastmilk-fed post neonatal unit discharge are at high risk of developing subclinical VK deficiency in early infancy. Routine post-discharge VK1 supplementation of breastfed infants to provide intakes comparable to those from formula milks should prevent this deficiency.
Original languageEnglish
Pages (from-to)2773-2785
Number of pages13
JournalJournal of Thrombosis and Haemostasis
Issue number12
Early online date10 Sep 2022
Publication statusPublished - Dec 2022


  • hemorrhage
  • infant
  • nutrition
  • vitamin K deficiency
  • vitamin K1

Cite this