Late Vitamin K Deficiency-related Bleeding in Neonates (VKLB): Comparison of Different Strategies to Prophylaxis (VKLB)

Late Vitamin K Deficiency-related Bleeding in Neonates (VKDB): Comparison of Four Different Strategies to Prophylaxis Measuring Proteins Induced by Vitamin K Absence (PIVKA)

The goal of this multicentric observational study was to compare four vitamin K dosing regimens in exclusively breastfed healthy term newborns. The main questions it aims to answer were:

• comparing protein induced by vitamin K absence (PIVKA) levels in the different prophylaxis protocols at 48 hours, 1 month and 4 months
• to investigate the compliance and safety of oral vitamin K 1 administration Participants received vitamin K prophilaxis according to birth Hospital regimen. A blood sample was taken at 48 hours, 1 month and 3 months of life. Plasmatic PIVKA-II concentretion was be dosed

Researchers compared four groups of Vitamin K dosing regimens:

1. an intramuscolar injection of 1 mg vitamin K at birth
2. an intramuscolar injection of 1 mg vitamin K at birth followed by 50 μg/die orally from the second to the fourteenth week of life.
3. an intramuscolar injection of 1 mg vitamin K at birth followed by 150 μg/die orally from the second to the fourteenth week of life.
4. an oral dose of 2 mg vitamin K at birth, followed by a second dose at 4 weeks, and a third dose at 12 weeks to see if there is PIVKA-II plasmatic concentration differences.

Study Overview

• Status: Completed
• Conditions: Late Vitamin K Deficiency-related Bleeding
• Intervention / Treatment: Dietary supplement: Konakion

Detailed Description

Partecipanting Centers

• Azienda Ospedaliera Universitaria di Parma
• Azienda Ospedaliera Universitaria di Siena
• Ospedale Buon Consiglio Fatebenefratelli, Napoli
• Ospedale Di Venere, Bari

Materials and Methods Term healthy newborn born from March 2019 to June 2021 was enrolled Vitamin K formulation was Konakion 2 mg/0,2 ml MM paediatric, solution for injection or oral administration, Cheplapharm Arzneimittel GMBH

PIVKA level was was measured on blood drops obtained by heel prick at 48 hours of life, 1 month and 3 months, using the PIVKA-II ELISA Kit, MyBiosource, San Diego, CA, USA.

Blood samples (0,5 ml) were collected in Lithium Heparine draw. After centrifugation at 1000 rpm for 15 minutes plasma was frozen and stored at -20°C. The samples were subsequently analyzed in the Laboratorio di Patologia Clinica, Università degli Studi di Siena.

Medication adherence was measured by questionnaires administrated to parents at 1 month and 3 months of life. A protocol violation (lack of vitamin K administration, concomitant use of other drugs except vitamins, ormula milk or mixed milk feeding) led to exclution of patients

Addictional collected data were:

• sex
• gestational age
• mode of delivery
• Apgar score
• antenatal corticosteroids
• antenatal antibiotics or others drugs
• birth weight
• premature rupture of membranes

Statistical analysis:

Statistical analysis was performed using SPSS 23.0 (IBM, Chicago, IL, USA) and MATLAB 8.0 (The MathWorks, Inc., Natick, MA, USA).

Data were tested for normality with the Shapiro-Wilk test, with the results expressed as mean and standard deviation, median and interquartile range, or frequency and percentage. Data were analyzed using Student's t-test or Wilcoxon rank-sum test for continuous data, and chi-square or Fisher's exact test for categorical variables. A two-tailed p-value <0.05 was considered significant. PIVKA levels were analyzed with repeated measures-ANOVA: different administration regimen was inserted as covariate.

• Study Type: Observational
• Enrollment (Actual): 80

Contacts and Locations

Study Locations

• Italy
  • Parma, Italy
    • Pr Serafina Perrone

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 day to 1 day (CHILD)
• Accepts Healthy Volunteers: N/A
• Genders Eligible for Study: All

• Sampling Method: Probability Sample

Study Population

Term healthy newborn born from March 2019 to June 2021

Description

Inclusion Criteria:

• gestational age between 37+ 0/7 and 42+ 0/7 weeks
• exclusive breastfeeding
• Informed consent by at least one parent

Exclusion Criteria:

• gestational age less than 37+ 0/7 weeks or more than 42+0/7 weeks
• neonatal disease
• liver disease
• formula milk or mixed milk feeding
• withdrawal of informed consent

Study Plan

How is the study designed?

Number of groups / cohorts

4

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
intramuscolar injection; intramuscolar injection of 1 mg vitamin K at birth	Dietary supplement: Konakion; Comparing 4 different regimen of Vitamin K administration in newborn
intramuscolar injection following by oral low dose; intramuscolar injection of 1 mg vitamin K at birth followed by 50 μg/die orally from the second to the fourteenth week of life	Dietary supplement: Konakion; Comparing 4 different regimen of Vitamin K administration in newborn
intramuscolar injection following by oral high dose; intramuscolar injection of 1 mg vitamin K at birth followed by 150 μg/die orally from the second to the fourteenth week of life	Dietary supplement: Konakion; Comparing 4 different regimen of Vitamin K administration in newborn
oral administration; oral dose of 2 mg vitamin K at birth, followed by a second dose at 4 weeks, and a third dose at 12 weeks	Dietary supplement: Konakion; Comparing 4 different regimen of Vitamin K administration in newborn

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
comparing protein induced by vitamin K absence (PIVKA) levels in the different prophylaxis protocols at 48 hours, 1 month and 4 months	PIVKA-II level measured by blood samples	48 hours of life
comparing protein induced by vitamin K absence (PIVKA) levels in the different prophylaxis protocols at 48 hours, 1 month and 4 months	PIVKA-II level measured by blood samples	1 month of life
comparing protein induced by vitamin K absence (PIVKA) levels in the different prophylaxis protocols at 48 hours, 1 month and 4 months	PIVKA-II level measured by blood samples	3 months of life

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
to investigate the compliance and safety of oral vitamin K 1 administration	Medication Adherence Questionnaire	48 hours of life
to investigate the compliance and safety of oral vitamin K 1 administration	Medication Adherence Questionnaire	1 month of life, 3 month of life
to investigate the compliance and safety of oral vitamin K 1 administration	Medication Adherence Questionnaire	3 months of life

Collaborators and Investigators

• Sponsor: Azienda Ospedaliero-Universitaria di Parma

Publications and helpful links

General Publications

• Lembo C, Buonocore G, Perrone S. The challenge to define the optimal prophylactic regimen for vitamin K deficiency bleeding in infants. Acta Paediatr. 2021 Apr;110(4):1113-1118. doi: 10.1111/apa.15566. Epub 2020 Oct 6.
• Shearer MJ. Vitamin K deficiency bleeding (VKDB) in early infancy. Blood Rev. 2009 Mar;23(2):49-59. doi: 10.1016/j.blre.2008.06.001. Epub 2008 Sep 19.
• American Academy of Pediatrics Committee on Fetus and Newborn. Controversies concerning vitamin K and the newborn. American Academy of Pediatrics Committee on Fetus and Newborn. Pediatrics. 2003 Jul;112(1 Pt 1):191-2.
• Mihatsch WA, Braegger C, Bronsky J, Campoy C, Domellof M, Fewtrell M, Mis NF, Hojsak I, Hulst J, Indrio F, Lapillonne A, Mlgaard C, Embleton N, van Goudoever J; ESPGHAN Committee on Nutrition. Prevention of Vitamin K Deficiency Bleeding in Newborn Infants: A Position Paper by the ESPGHAN Committee on Nutrition. J Pediatr Gastroenterol Nutr. 2016 Jul;63(1):123-9. doi: 10.1097/MPG.0000000000001232.

Study record dates

Study Major Dates

• Study Start (ACTUAL): March 27, 2020
• Primary Completion (ACTUAL): October 1, 2021
• Study Completion (ACTUAL): January 20, 2023

Study Registration Dates

• First Submitted: January 24, 2023
• First Submitted That Met QC Criteria: February 2, 2023
• First Posted (ACTUAL): February 6, 2023

Study Record Updates

• Last Update Posted (ACTUAL): February 6, 2023
• Last Update Submitted That Met QC Criteria: February 2, 2023
• Last Verified: February 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Metabolic Diseases; Hematologic Diseases; Nutrition Disorders; Hemorrhagic Disorders; Avitaminosis; Deficiency Diseases; Malnutrition; Blood Coagulation Disorders; Water-Electrolyte Imbalance; Hemorrhage; Hypokalemia; Potassium Deficiency; Vitamin K Deficiency; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Fibrin Modulating Agents; Micronutrients; Vitamins; Antifibrinolytic Agents; Hemostatics; Coagulants; Vitamin K 1
• Other Study ID Numbers: 12150

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No