Vitamin K Deficiency in neonates Mahta-Fatemeh BASSIR MD, Pediatrician Neonatologist, SBMU, Tehran-Iran

Definition Vitamin K is a cofactor for the synthesis of factor II,VII,IX,X, and protein C and protein S by carboxylation of specific glutamate residues

Presentation (1) Phytonadione, Phytomenadione, or phylloquinone also known as vitamin K1, is a vitamin found in food a naturally obtained compound of vitamin K.

Presentation (2) Bacteriods and some other bacterias that colonize the human’s gut synthetize vitamin K2 or menaquinone, considered for about 10% adult requirement of vitamin. We have also three synthetic forms of vitamin K : K3 (used in pet food industry) , K4 and K5 (inhibition of fungal growth). A water soluble preparation of vitamin K3 or menadione is also available for adult use.

VITAMIN K DEFICIENCY Vitamin K deficiency bleeding (VKDB) is classified as early, classical, or late: Early onset VKDB (6%) is due to cross-placental transfer of compounds that interfere with vitamin K metabolism. Classical VKDB (2%) is due to a physiologic deficiency in vitamin K at birth combined with either a lack of vitamin K in breast milk or inadequate feeding. Late onset VKDB is again due to inadequate vitamin K content in breast milk and is thus found almost universally in exclusively breastfed infants.

Journal of Perinatology. 36 (Supplement 1):S29-S34, May 2016 burden of late VKDB was 35 (10.5 to 80) per 100 000 live births in infants who had not received prophylaxis at birth the burden was much higher in low- and middle-income countries as compared with high-income countries-80 (72 to 80) vs 8.8 (5.8 to 17.8) per 100 000 live births Journal of Perinatology. 36 (Supplement 1):S29-S34, May 2016

late VKDB high risk of mortality and adverse neurodevelopmental outcomes in the survivors—22 and 25% to 67%, respectively, in one study from Thailand

Prophylaxis A large study published in The Lancet in the 1940s showed a fivefold reduction in death from hemorrhage in infants who were given 1 mg of vitamin K3 (menadione) at delivery. The results generated a huge interest in routine vitamin K prophylaxis. AAP : 1961 However, the strategy of routine prophylaxis is not free of any pitfalls. The usual prophylactic dose (1 mg) is about 1000 times more than the daily requirement.

childhood cancers Concerns about the vitamin K shot and leukemia risk stem from a relatively small case-control study (fewer than 800 children) in 1992 which has never been replicated since. The year after it was published, two much larger studies (one with nearly 1.4 million children and another with more than 50,000 children) found no link between vitamin K and cancer or any other conditions. Neither another eight studies done later. There is no mechanism that could physiologically explain how an essential vitamin could cause leukemia, and none of the other ingredients in the shot have been linked to the blood cancer.

1 Mg IM at birth: one trial reported a significant reduction in the incidence of any bleeding (relative risk (RR) 0.73, 95% confidence interval (CI) 0.56 to 0.96) and moderate to severe bleeding (RR 0.19, 0.08 to 0.46; number needed to treat (NNT) 74, (47 to 177), the other trial demonstrated a significant reduction in the risk of secondary bleeding after circumcision in male neonates (RR 0.18, CI 0.08 to 0.42; NNT 9, 6 to 15). 

The relative risk of a bleeding in breastfed compared with formula-fed infants was: 77.5 for 25 microg of daily oral prophylaxis, 7.2 for 1 mg of weekly oral prophylaxis, 9.3 for 2 mg of intramuscular prophylaxis at birth. A vitamin K prophylactic regimen of 1 mg of vitamin K orally at birth followed by a daily oral dosage of either 25 or 150 µg fails to prevent VKDB in breastfed infants. The data support 2 mg vitamin K IM at birth as prophylaxis against VKDB (Pediatrics. 2016;137(5):e20154222 - October 01, 2016)

Lab evaluation 1. Prolonged PT (> 4 times )and INR 2. In severe cases PTT may be affected Levels of vitamin K and PIVKA-II (protein induced in vitamin k absence) are essentially used to monitor patients with disease predisposition.

PREVENTION American association of Pediatrics recommends a single intramuscular administration of 0.5-1 mg vitamin K1 at birth and supplementation of infant formula. UK department of health recommended single IM or Oral dose of 400 mcg/kg (<2.5 kg) or 1 mg ( >2.5 kg). Recent studies demonstrate inefficacity of a single Oral dose of vitamin K for long term protection, specially in exclusively breastfed infants.

Vitamin K deficiency bleeding and early infant male circumcision in Africa. Plank RM Obstet Gynecol. 2013 Aug;122(2 Pt 2):503-5. Early infant (1-60 days of life) male circumcision is being trialed in Africa as a human immunodeficiency virus prevention strategy. Post-circumcision bleeding is particularly concerning where most infants are breastfed, and thus these infants are at increased risk of vitamin K deficiency bleeding.

SIDE EFFECTS EXCESS Vitamin K toxicity is rare. Vitamin K3 (menadione) can cause hemolytic anemia, hyperbilirubinemia and kernicterus in infant specially in G6PD deficient neonates. ANAPHYLACTIC SHOCK Few cases of prophylactic shock after intra muscular injection of vitamin K in prophylaxis of hemorrhagic disease of the newborn have been reported.

TREATMENT Slow intra-venous perfusion (1-2 mg) or subcutaneous injection of vitamin K1 if no venous access is possible is recommended. Fresh frozen plasma is indicated for all infants who bleeding. The Prothrombin Complex Concentrate (PCC) should be considered in presence of severe form of disease.

Further studies needed: To determine adequate preventive dose for term and preterm newborns To determine best route of administration