The OK Daily Study is a multi-centred, part-randomised, part blinded, four cohort study. We are exploring daily dietary supplementation with vitamin K2, specifically menaquinone-7 (MK-7), given to breastfed infants or breastfeeding mothers to see whether this improves the incidence of biochemical vitamin K deficiency in the infants at 2 months postnatal age. The overall aims are: * To compare infant MK-7 supplementation with placebo * To compare maternal MK-7 supplementation with placebo * To compare infant MK-7 supplementation and maternal MK-7 supplementation * To compare infant MK-7 supplementation with vitamin K1 supplementation via infant formula milk. Once recruited, mother and infant pairs will be grouped initially based on the families' feeding choice. Breastfed infants will then be randomised 2:1 to the infant supplementation or maternal supplementation group. Within the infant supplementation group, infants will either receive MK-7 with vitamin D or a placebo containing vitamin D. Follow up will occur at 2 months postnatal age (range 2-3 months postnatal age), where bloods and breastmilk samples will be collected to assess the infant and maternal vitamin K status.
The OK Daily Study is a multi-centre study taking place in the Norfolk and Norwich University Hospital, Norwich, UK, and Ashford and St Peters' Hospital, Chertsey, UK. Infants born at ≥37 weeks' gestation will be recruited in the participating site if they meet eligibility criteria and are born within the recruitment window. Recruitment will take place before the mother and infant are discharged from the hospital following birth. The two main arms of this study are breastfeeding and formula feeding. Mother and infant pairs will initially be allocated based on the family's feeding preferences. Infants in the breastfeeding arm will be randomised into group 1 or group 2 in a 2:1 ratio. Group 1 allocation will be blinded; group 2 allocation will be open label. * Group 1 - infant supplementation group. Infants will receive either 45 micrograms/day of MK-7 with 10 micrograms/day vitamin D3 or a placebo consisting of 10 micrograms/day vitamin D3 * Group 2 - maternal supplementation group. Mothers in this group will receive 2 mg/day MK-7. All breastfeeding infants in this group will receive 10 micrograms/day of vitamin D3. Formula fed infants will be in group 3 and will not require any additional supplementation as part of this study. This is because infant formula is already supplemented with adequate amounts of vitamin K1 and vitamin D. All supplements will be started within 7 days of birth. Vitamin D drops are included for breastfed infants as per national UK guidelines. Follow up will be as follows: * 1 month postnatal visit (range 1-1.5 months) - phone call. o Confirmation of eligibility to continue, assessment of compliance with the intervention, and to schedule the in person follow up visit * 2 months postnatal (range 2-3 months) - in person visit. * All babies will have a single blood sample taken. * Mothers who are in group 2 (mothers who have had MK-7 supplementation) and a selection of mothers from group 1 (breastfeeding mothers who are not supplemented with MK-7) will have a single blood sample taken and will be asked to provide a single breastmilk sample * Mothers will be asked about their opinions on practising the supplementation. Blood samples will be analysed for vitamin K status, including Proteins Induced by Vitamin K Absence/antagonism of prothrombin (PIVKA-II) and of osteocalcin (undercarboxylated osteocalcin), dephosphorylated-undercarboxylated matrix gla-protein (dp-ucMGP) and serum vitamin K concentrations (including of vitamin K1 and MK-7). Breastmilk samples will be analysed for vitamin K concentrations (including vitamin K1 and MK-7) Once this in person follow up visit has been completed, the mother and baby pair will have completed the study.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
PREVENTION
Masking
SINGLE
Enrollment
134
6 drops/day providing 45 micrograms/day MK-7 plus 10 micrograms/day of vitamin D3
6 drops/day providing 10 micrograms/day vitamin D3 and no supplementary MK-7.
1 mg capsules of menaquinone-7, with a daily dose of 2 mg (i.e. 2 capsules per day)
Comparison of the proportion of participants who have a PIVKA-II >0.05 AU/mL in the unsupplemented and supplemented infants.
PIVKA-II = protein induced by vitamin K antagonism/absence; clotting protein II. Measured via serum blood sample in arbitrary units/mL. For the primary outcome, this is the comparison between the supplemented and unsupplemented infants.
Time frame: 2 months postnatal age (range 2-3 months).
Comparison of the proportion of participants who have a PIVKA-II >0.05 AU/mL in the various study groups.
PIVKA-II = protein induced by vitamin K antagonism/absence; clotting protein II. Measured via serum blood sample in arbitrary units/mL. For secondary outcome, this is comparison between remaining groups, other than those assessed in the primary outcome measure.
Time frame: 2 months postnatal age (range 2-3 months).
Comparison of serum levels of osteocalcin (undercarboxylated and carboxylated) between the study groups.
Both undercarboxylated and carboxylated levels of osteocalcin will be measured in nanograms/mL.
Time frame: 2 months postnatal age (range 2-3 months).
Comparison of the percentage of undercarboxylated osteocalcin as a proportion of total osteocalcin (%GluOC) between the study groups.
Total osteocalcin calculated by the sum of the undercarboxylated and carboxylated osteocalcin values.
Time frame: 2 months postnatal age (range 2-3 months).
Comparison of serum levels of dephosphorylated undercarboxylated matrix Gla Protein in included participants between the study groups.
Measured in picomol/mL
Time frame: 2 months postnatal age (range 2-3 months).
Comparison of levels of serum K vitamers (including, but no limited to, vitamin K1 and menaquinone-7) between the study groups.
Serum K vitamers will be reported in micrograms/mL.
Time frame: 2 months postnatal age (range 2-3 months).
Comparison of the levels of breastmilk K vitamers (including, but not limited to, vitamin K1 and menaquinone-7) between unsupplemented and supplemented mothers.
Serum K vitamers will be reported in nanograms/mL
Time frame: 2 months postnatal age (range 2-3 months).
Investigation of percentage compliance to study supplementation.
Amount of remaining supplement will be assessed at follow up. This will then be used to calculate percentage compliance by comparing it to the expected volumes.
Time frame: 2 months postnatal age (range 2-3 months).
Investigation regarding families' opinions about infant and maternal vitamin supplementation.
Measured via verbal questioning at follow up.
Time frame: 2 months postnatal age (range 2-3 months).
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