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

doi:10.1111/jth.15874

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

^*Corresponding author for this work

Microbes, Infections and Microbiomes

Research output: Contribution to journal › Article › peer-review

2 Citations (Scopus)

52 Downloads (Pure)

Abstract

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, multicenter, observational study in preterm infants born <33 weeks' gestation. Blood samples and dietary history were collected before hospital discharge, and after 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 after discharge.

Results: After 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 one (2%) of 45 breastmilk-fed infants was VK insufficient. After discharge, eight (67%) of 12 exclusively breastmilk-fed babies were VK insufficient versus only one (4%) of 25 formula/mixed-fed babies.

Conclusions: Preterm infants who remain exclusively or predominantly human breastmilk-fed after neonatal unit discharge are at high risk of developing subclinical VK deficiency in early infancy. Routine postdischarge VK₁ supplementation of breastfed infants to provide intakes comparable to those from formula milks should prevent this deficiency.

Original language	English
Pages (from-to)	2773-2785
Number of pages	13
Journal	Journal of Thrombosis and Haemostasis
Volume	20
Issue number	12
Early online date	13 Nov 2022
DOIs	https://doi.org/10.1111/jth.15874
Publication status	Published - Dec 2022

Bibliographical note

Funding Information:
The authors thank all the parents who generously allowed their babies to be studied; also, all doctors, advanced neonatal nurse practitioners, and research/clinical nurses who kindly assisted with sample collection. We acknowledge the kind help of Priyadarshan Ambadkar for supporting the study at James Paget University Hospital. P. Clarke sincerely thanks Mark A. Turner for valuable guidance that helped conceive this study, Simon J. Mitchell for his first conception of preterm vitamin K studies, and Rebecca and Xavier Clarke for manuscript proofing. The authors thank the anonymous reviewers for helpful comments on an earlier version of our manuscript.

Publisher Copyright:
© 2022 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis.

Keywords

hemorrhage
infant
nutrition
vitamin K deficiency
vitamin K1

ASJC Scopus subject areas

Hematology

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Clarke, P., Shearer, M. J., Card, D. J., Nichols, A., Ponnusamy, V., Mahaveer, A., Voong, K., Dockery, K., Holland, N., Mulla, S., Hall, L. J., Maassen, C., Lux, P., Schurgers, L. J., & Harrington, D. J. (2022). Exclusively breastmilk-fed preterm infants are at high risk of developing subclinical vitamin K deficiency despite intramuscular prophylaxis at birth. Journal of Thrombosis and Haemostasis, 20(12), 2773-2785. https://doi.org/10.1111/jth.15874

@article{8fbb7d88be164a8ba9d1d40d3a25ee01,

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

abstract = "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, multicenter, observational study in preterm infants born <33 weeks' gestation. Blood samples and dietary history were collected before hospital discharge, and after discharge at 2–3 months{\textquoteright} 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 after discharge. Results: After 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 one (2%) of 45 breastmilk-fed infants was VK insufficient. After discharge, eight (67%) of 12 exclusively breastmilk-fed babies were VK insufficient versus only one (4%) of 25 formula/mixed-fed babies. Conclusions: Preterm infants who remain exclusively or predominantly human breastmilk-fed after neonatal unit discharge are at high risk of developing subclinical VK deficiency in early infancy. Routine postdischarge VK1 supplementation of breastfed infants to provide intakes comparable to those from formula milks should prevent this deficiency.",

keywords = "hemorrhage, infant, nutrition, vitamin K deficiency, vitamin K1",

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

note = "Funding Information: The authors thank all the parents who generously allowed their babies to be studied; also, all doctors, advanced neonatal nurse practitioners, and research/clinical nurses who kindly assisted with sample collection. We acknowledge the kind help of Priyadarshan Ambadkar for supporting the study at James Paget University Hospital. P. Clarke sincerely thanks Mark A. Turner for valuable guidance that helped conceive this study, Simon J. Mitchell for his first conception of preterm vitamin K studies, and Rebecca and Xavier Clarke for manuscript proofing. The authors thank the anonymous reviewers for helpful comments on an earlier version of our manuscript. Publisher Copyright: {\textcopyright} 2022 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis.",

year = "2022",

month = dec,

doi = "10.1111/jth.15874",

language = "English",

volume = "20",

pages = "2773--2785",

journal = "Journal of Thrombosis and Haemostasis",

issn = "1538-7933",

publisher = "Wiley",

number = "12",

}

Clarke, P, Shearer, MJ, Card, DJ, Nichols, A, Ponnusamy, V, Mahaveer, A, Voong, K, Dockery, K, Holland, N, Mulla, S, Hall, LJ, Maassen, C, Lux, P, Schurgers, LJ & Harrington, DJ 2022, 'Exclusively breastmilk-fed preterm infants are at high risk of developing subclinical vitamin K deficiency despite intramuscular prophylaxis at birth', Journal of Thrombosis and Haemostasis, vol. 20, no. 12, pp. 2773-2785. https://doi.org/10.1111/jth.15874

TY - JOUR

T1 - Exclusively breastmilk-fed preterm infants are at high risk of developing subclinical vitamin K deficiency despite intramuscular prophylaxis at birth

AU - Clarke, Paul

AU - Shearer, Martin J.

AU - Card, David J.

AU - Nichols, Amy

AU - Ponnusamy, Vennila

AU - Mahaveer, Ajit

AU - Voong, Kieran

AU - Dockery, Karen

AU - Holland, Nicky

AU - Mulla, Shaveta

AU - Hall, Lindsay J.

AU - Maassen, Cecile

AU - Lux, Petra

AU - Schurgers, Leon J.

AU - Harrington, Dominic J.

N1 - Funding Information: The authors thank all the parents who generously allowed their babies to be studied; also, all doctors, advanced neonatal nurse practitioners, and research/clinical nurses who kindly assisted with sample collection. We acknowledge the kind help of Priyadarshan Ambadkar for supporting the study at James Paget University Hospital. P. Clarke sincerely thanks Mark A. Turner for valuable guidance that helped conceive this study, Simon J. Mitchell for his first conception of preterm vitamin K studies, and Rebecca and Xavier Clarke for manuscript proofing. The authors thank the anonymous reviewers for helpful comments on an earlier version of our manuscript. Publisher Copyright: © 2022 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis.

PY - 2022/12

Y1 - 2022/12

N2 - 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, multicenter, observational study in preterm infants born <33 weeks' gestation. Blood samples and dietary history were collected before hospital discharge, and after 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 after discharge. Results: After 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 one (2%) of 45 breastmilk-fed infants was VK insufficient. After discharge, eight (67%) of 12 exclusively breastmilk-fed babies were VK insufficient versus only one (4%) of 25 formula/mixed-fed babies. Conclusions: Preterm infants who remain exclusively or predominantly human breastmilk-fed after neonatal unit discharge are at high risk of developing subclinical VK deficiency in early infancy. Routine postdischarge VK1 supplementation of breastfed infants to provide intakes comparable to those from formula milks should prevent this deficiency.

AB - 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, multicenter, observational study in preterm infants born <33 weeks' gestation. Blood samples and dietary history were collected before hospital discharge, and after 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 after discharge. Results: After 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 one (2%) of 45 breastmilk-fed infants was VK insufficient. After discharge, eight (67%) of 12 exclusively breastmilk-fed babies were VK insufficient versus only one (4%) of 25 formula/mixed-fed babies. Conclusions: Preterm infants who remain exclusively or predominantly human breastmilk-fed after neonatal unit discharge are at high risk of developing subclinical VK deficiency in early infancy. Routine postdischarge VK1 supplementation of breastfed infants to provide intakes comparable to those from formula milks should prevent this deficiency.

KW - hemorrhage

KW - infant

KW - nutrition

KW - vitamin K deficiency

KW - vitamin K1

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U2 - 10.1111/jth.15874

DO - 10.1111/jth.15874

M3 - Article

C2 - 36087073

AN - SCOPUS:85139262970

SN - 1538-7933

VL - 20

SP - 2773

EP - 2785

JO - Journal of Thrombosis and Haemostasis

JF - Journal of Thrombosis and Haemostasis

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ER -

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

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

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