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

Study Overview
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Brief Summary
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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: an intramuscolar injection of 1 mg vitamin K at birth 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. 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. 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.

Detailed Description
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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.

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

Conditions
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Late Vitamin K Deficiency-related Bleeding

Intervention / Treatment
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* Dietary Supplement: Konakion


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 1 Day
Maximum Age: 1 Day

Sexes Eligible for Study
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All

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| intramuscolar injection<br>intramuscolar injection of 1 mg vitamin K at birth | Dietary Supplement: Konakion<br>* Comparing 4 different regimen of Vitamin K administration in newborn<br>|
| intramuscolar injection following by oral low dose<br>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<br>* Comparing 4 different regimen of Vitamin K administration in newborn<br>|
| intramuscolar injection following by oral high dose<br>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<br>* Comparing 4 different regimen of Vitamin K administration in newborn<br>|
| oral administration<br>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<br>* Comparing 4 different regimen of Vitamin K administration in newborn<br>|

What is the study measuring?
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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 |