Vitamin K1 in Infancy and throughout Life



Vitamin K1 is synthesized by plants, and green vegetables provide the primary source of vitamin K to humans through dietary consumption. Vitamin K is important for normal clotting of blood in humans and for maintaining bone strength. Its biological role is to act as a cofactor for a specific carboxylation reaction that transforms selective glutamate (Glu) residues to gamma-carboxyglutamate (Gla) residues.

The liver stores about 10% of vitamin K1. Deficiency of vitamin K or disturbances of liver function, which hampers vitamin K absorption, may lead to deficiencies of blood clotting factors, defective blood clotting and excess bleeding. Vitamin K1 is also needed for bone’s health, deficiency can lead to osteoporosis.

Vitamin K Deficiency bleeding (VKDB) – Infants

In infants up to the age of 6 months, vitamin K deficiency is uncommon, but it represents a significant public health problem throughout the world, particularly in Southeast Asia [1]. The higher incidence in Asia, around 10-fold higher than in Europe suggests there are genetic or environmental factors that predispose Asian populations to VKDB [1]. The deficiency syndrome is termed vitamin K deficiency bleeding (VKDB); it has a high risk of mortality and permanent disability from intracranial haemorrhage [1].

The time of onset of VKDB is unpredictable; three distinct syndromes have been classified as early, classic and late VKDB.

Table 1. Classification of vitamin K deficiency bleeding of the newborn infant

Syndrome Time of presentation Common bleeding sites Comments
Early VKDB 0-24 hours Cephalohaematoma, intracranial, intrathoracic, intraabdominal Maternal drugs are a frequent cause (e.g. warfarin, anti-convulsants)
Classic VKDB 1-7 days Gastrointestinal, skin, nasal, circumcision Mainly idiopathic; maternal drugs are sometimes a cause
Late VKDB 1-12 weeks Intracranial, skin, gastrointestinal Mainly idiopathic, but may be a presenting feature of underlying disease (e.g. cystic fibrosis, alpha-1-antitrypsin deficiency, biliary atresia); some degree of cholestasis often present

 Source: Shearer MJ. Vitamin K metabolism and nutriture. Blood Reviews, 1992, 6:92-104.

Late VKDB, is different to the classic form because it has a high incidence of death or severe and permanent brain damage resulting from intracranial haemorrhage. Over 50% of infants with late VKDB (post 1-week) present with intracranial haemorrhage (ICH) [2]. The underlying cause of late onset VKDB are inadequate plasma concentrations of active coagulation factors II, VII, IX and X.

In the absence of vitamin K prophylaxis, the incidence of late VKDB (per 100 000 births) has been estimated to be 4.4 in United Kingdom, 7.2 in Germany and 4.2-7.8 in Thailand. Like Europe and Thailand, a similarly high incidence of late VKDB without vitamin K prophylaxis has been reported in several countries in Asia including Japan, Vietnam and China. In a study conducted in Vietnam [3], researchers analysed the prevalence of intracranial haemorrhage due to late onset VKDB in Hanoi province, Vietnam. Cases of intracranial haemorrhage in infants aged 1-13 weeks were identified for 5 years (1995-1999) and vitamin K deficiency evidence was collected. The data was then used to compare with those on VKDB in developed countries. The estimated incidence of late onset VKDB in infants who received no prophylaxis was high, with 142 and 81 per 100,000 births in rural and urban areas respectively. Mortality was 9%. Of the surviving infants, 42% were neurologically abnormal when they were discharged from the hospital.

What are the causes of these deadly conditions?  Case studies have shown that maternal dietary depletion can lead to fetal cerebral haemorrhage [4]. However, epidemiological studies identified the two major risk factors for both classic and late VKDB are exclusive human-milk feeding and failure to give vitamin K prophylaxis. The increased risk for infants fed human milk compared to formula milk is most likely related to the relatively low concentrations of Vitamin K1 in breast milk compared to formula milk.

Vitamin K contents of breast milk and formula milk

The average concentrations of Vitamin K1 in colostrum and mature human milk is around 2mcg/l and 1mcg/l, respectively [5]. These vitamin K1 levels are substantially lower than cows milk, which contains 60mcg/l and formula fed infants whose intakes average is approximately 50mcg/d.

Table 2. Comparison of average dietary intakes and plasma levels of phylloquinone (vitamin K1) in breast fed and formula fed infants

Age (weeks) Phylloquinone intake (mcg/day) Plasma phylloquinon (mcg/l)
Breast-fed Formula fed Breast fed Formula fed
6 0.55 45.4 0.13 6.0
12 0.74 55.5 0.20 5.6
26 0.56 52.2 0.24 4.4

 Source: Greer FR et al. Vitamin K status of lactating mothers, human milk and breastfeeding infants. Pediatrics, 1991, 88: 751-756.

For classic VKDB, studies on subclinical vitamin K deficiency have suggested that it is the low cumulative intake of human milk in the first week of life that lead to the problem [6].

It is  observed that severe Vitamin K deficiency was associated with an extremely small amount of breast milk ingested, and babies who received more than 500mL of total breast milk during the first 3 days of life showed Vitamin K deficiency [7].

For late VKDB, other factors appear to be more important because the deficiency syndrome occurs when breastfeeding has been established and mothers of affected infants seem to have normal levels of vitamin K in their milk. In some cases, infants who develop late haemorrhagic disease are found to have abnormalities in liver functionality that could affect their bile acid production and result in a degree of malabsorption of vitamin K. The degree of cholestasis may be mild and its course may be transient and self correcting, however infants that are affected will have an increased requirement for vitamin K because of reduced absorption efficiency.

Can Vitamin K be boosted up by supplementation during Pregnancy and Lactation?

Vitamin K placental transport from mother to infant is very poor and it is present in very low levels in breast milk [8]. In a different clinical trial [9] it was shown that lactating mothers who received phylloquinone orally had only small rises of Vitamin K in plasma and breast milk concentrations. Researchers observed that plasma phylloquinone concentrations in infants fed human milk remained very low (mean less than 0.25ng/ml) throughout the first 6 months of life compared to formula fed infants (4.39 to 5.99 ng/ml). Breastfed infants do not receive the recommended vitamin K intake via human milk, it is necessary to administer vitamin K prophylaxis to prevent vitamin K deficiency in the newborn [8].

However in more recent studies, researchers have found that prophylaxis at birth to infants alone may not be enough if mother’s daily dietary intake of Vitamin K is inadequate. Based on the dietary recalls analysis, breastfed infants may benefit from increased maternal Vitamin K intake (>1mcg/kg/day) during pregnancy and breastfeeding [10]. While infants less than 35 weeks’ gestation age are susceptible to periventricular-intraventricular hemorrhage (PIVH) (partially attributed to low concentration of Vitamin K- dependent coagulation factors), a study shows that admistration of Vitamin K1 to mums may result in improved coagulation and may reduce the incidence as well as severity of PIVH[11].

In conclusion, in the absence of further evidence, it is urged that:

  • All pregnant and breastfeeding women to maintain adequate vitamin K level intake (>1mcg/kg/day); and
  • Mothers to alternate between breastfeeding and formula feeding their baby to ensure their baby obtains adequate vitamin K levels, in cases breast milk levels are not sufficient; and
  • Vitamin K prophylaxis to be given to all newborns or to those whose mothers intend to only breast feed them

Vitamin K prophylaxis is not routinely administered at birth in many developing countries. The amounting body of evidence shows that without vitamin K prophylaxis, infants have a small but real risk of dying from, or suffering from permanent brain damage by vitamin K deficiency in the first 6 months of life.

Vitamin K and Bone Health

Vitamin K helps maintain bone strength and mounting evidence suggest that poor vitamin K status may be an independent risk factor for postmenopausal bone loss [12]. Vitamin K functions as a cofactor in the posttranslational carboxylation of a number of bone proteins, the most abundant is osteocalcin (ucOC) [12]. Circulating ucOC is a sensitive marker that can be measured to reflect vitamin K status. Several researchers have demonstrated that low serum concentrations of either vitamin K or ucOC are associated with low bone mineral density (BMD) as a result there is an elevated risk for osteoporotic hip fractures.

There is evidence that vitamin K has a positive influence on calcium balance in humans.  In a clinical trial [13], humans on a diet rich in vitamin K were observed to have lower excretion of calcium (i.e. increased calcium retention). Co-administration of Vitamin D and Vitamin K1 could greatly contribute to reducing postmenopausal bone loss at the site of the femoral neck [12].  In the same study [12] the addition of Vitamin K to Vitamin D reduced bone loss of femoral neck by 1.3% more than supplementation without Vitamin K.

Vitamin K1 is present in PM NextG Cal and PM Kiddiecal, 2 bone formulas which are suitable for people of all ages, especially for pregnant and breastfeeding women and young children.

References
[1]A. Chuansumrit, T. Plueksacheeva, S. Hanpinitsak, S. Sangwarn, S. Chatvutinun, U. Suthutvoravut, Y. Herabutya, M.J. Shearer, Prevalence of subclinical vitamin K deficiency in Thai newborns: relationship to maternal phylloquinone intakes and delivery risk. Arch Dis Child Fetal Neonatal Ed 95 (2010) F104-108.
[2]P.M. Loughnan, P.N. McDougall, Epidemiology of late onset haemorrhagic disease: a pooled data analysis. J Paediatr Child Health 29 (1993) 177-181.
[3]N. Danielsson, D.P. Hoa, N.V. Thang, T. Vos, P.M. Loughnan, Intracranial haemorrhage due to late onset vitamin K deficiency bleeding in Hanoi province, Vietnam. Arch Dis Child Fetal Neonatal Ed 89 (2004) F546-550.
[4]H. Minami, M. Furuhashi, K. Minami, K. Miyazaki, K. Yoshida, K. Ishikawa, Fetal intraventricular bleeding possibly due to maternal vitamin K deficiency. Fetal Diagn Ther 24 (2008) 357-360.
[5]R. von Kries, M. Shearer, P.T. McCarthy, M. Haug, G. Harzer, U. Gobel, Vitamin K1 content of maternal milk: influence of the stage of lactation, lipid composition, and vitamin K1 supplements given to the mother. Pediatr Res 22 (1987) 513-517.
[6]M.J. Shearer, Vitamin K deficiency bleeding (VKDB) in early infancy. Blood Rev 23 (2009) 49-59.
[7]K. Motohara, I. Matsukane, F. Endo, Y. Kiyota, I. Matsuda, Relationship of milk intake and vitamin K supplementation to vitamin K status in newborns. Pediatrics 84 (1989) 90-93.
[8]F.R. Greer, Vitamin K status of lactating mothers and their infants. Acta Paediatr Suppl 88 (1999) 95-103.
[9]F.R. Greer, S. Marshall, J. Cherry, J.W. Suttie, Vitamin K status of lactating mothers, human milk, and breast-feeding infants. Pediatrics 88 (1991) 751-756.
[10]F.R. Greer, Are breast-fed infants vitamin K deficient? Adv Exp Med Biol 501 (2001) 391-395.
[11]J. Liu, Q. Wang, F. Gao, J.W. He, J.H. Zhao, Maternal antenatal administration of vitamin K1 results in increasing the activities of vitamin K-dependent coagulation factors in umbilical blood and in decreasing the incidence rate of periventricular-intraventricular hemorrhage in premature infants. J Perinat Med 34 (2006) 173-176.
[12]L.A. Braam, M.H. Knapen, P. Geusens, F. Brouns, K. Hamulyak, M.J. Gerichhausen, C. Vermeer, Vitamin K1 supplementation retards bone loss in postmenopausal women between 50 and 60 years of age. Calcif Tissue Int 73 (2003) 21-26.
[13]N. Sakamoto, T. Nishiike, H. Iguchi, K. Sakamoto, The effect of diet on blood vitamin K status and urinary mineral excretion assessed by a food questionnaire. Nutr Health 13 (1999) 1-10.