Vitamin K Deficiency Bleeding

Previously, the term "hemorrhagic disease of the newborn" was used to describe bleeding disorders in neonates associated with a traumatic birth or hemophilia.[1] The current proper diagnostic term that has been adopted is "vitamin K deficiency bleeding" (VKDB), because vitamin K deficiency is not the sole cause of hemorrhagic disorders in preterm and term infants.[2]

Vitamin K represents a group of lipophilic and hydrophobic vitamins. 

Although some controversy surrounds the postnatal timing of the initial hemorrhage, vitamin K deficiency bleeding is usually classified by three distinct time periods after birth, as discussed below.[3]

Early-onset vitamin K deficiency bleeding in the newborn

Early-onset vitamin K deficiency bleeding usually occurs during first 24 hours after birth. It is seen in infants born to mothers taking anticonvulsant (eg, phenytoin, barbiturates, carbamazepine) or antituberculosis medication (eg, rifampin, isoniazid). Serious hemorrhagic complications can occur in this type of hemorrhage.

The mechanisms by which anticonvulsant and antituberculosis medications cause vitamin K deficiency bleeding in neonates is not clearly understood, but limited studies suggest that this disorder is a result of vitamin K deficiency and can be prevented by administration of vitamin K to the mother during the last 2-4 weeks of pregnancy. When vitamin K supplementation is given after the birth for early-onset vitamin K deficiency bleeding, it may be too late to prevent this disease, especially if vitamin K supplementation was not provided during pregnancy.

Numerous other maternal medications and/or exposure to toxins during pregnancy are lalso associated with vitamin K deficiency bleeding in neonates, including but not limited to vitamin K antagonists (eg, warfarin, phenprocoumon).[3]

Classic vitamin K deficiency bleeding in the newborn

Classic vitamin K deficiency bleeding usually occurs after 24 hours after birth but may present as late as the first week of life. It usually occurs from the second day of life to the end of the first week; however, it can occur during first month and sometimes overlaps with late-onset vitamin K deficiency bleeding.

Classic vitamin K deficiency bleeding is observed in infants who have not received prophylactic vitamin K at birth, with an incidence ranging from 0.25 to 1.7 cases per 100 births. Infants who have this disease are often ill, have delayed feeding, or both. Bleeding commonly occurs in the umbilicus, gastrointestinal (GI) tract (ie, melena), skin, nose, surgical sites (ie, circumcision) and, uncommonly, in the brain.[3]

Late-onset vitamin K deficiency bleeding in the newborn

Late-onset vitamin K deficiency bleeding usually occurs between age 2-12 weeks; however, it can be seen as long as 6 months after birth.

This disease is most common in breastfed infants who did not receive vitamin K prophylaxis at birth. Vitamin K content is low in mature human milk, with a range of 1-4 μg/L. Industrial contaminants in breast milk have also been implicated in promoting vitamin K deficiency bleeding.

More than half of these infants present with acute intracranial hemorrhages.[3]

Forms of vitamin K

The following three forms of vitamin K are known:

• K1: Phylloquinone is predominantly found in green leafy vegetables, vegetable oils, and dairy products. The vitamin K given to neonates as a prophylactic agent is an aqueous, colloidal solution of vitamin K1.

• K2: Menaquinone is synthesized by gut flora.

• K3: Menadione is a synthetic, water soluble form that is no longer used medically because of its ability to produce hemolytic anemia.

Vitamin K is an essential cofactor for γ-glutamyl carboxylase enzymatic activity that catalyses the γ-carboxylation of specific glutamic acid residues in a subclass of proteins.[4] These vitamin K–dependent proteins are known as Gla-proteins; the role of Gla proteins is not completely understood.[5]  The image below outlines the vitamin K cycle.

Coagulation factors II, VII, IX, and X as well as other Gla-proteins (eg, protein C, protein S, protein Z) also depend on the presence of vitamin K for their activity. Vitamin K deficiency gives rise to abnormal prothrombin levels; thus, prothrombin does not effectively participate in blood clot formation. As noted above, vitamin K undergoes posttranslational carboxylation of glutamic acid residues on the amino-terminal part of the vitamin K-dependent proteins.

In vitamin K deficiency, des-carboxylated proteins are formed that are functionally defective because they cannot bind calcium and phospholipid. These abnormal coagulation factors are called protein-induced by vitamin K absence (PIVKA). PIVKA-II is a des-carboxylated prothrombin.[6]

The following is a brief history of vitamin K's use in medicine.

Historical information

The following is a brief history of vitamin K's use in medicine.

In 1894, Charles Townsend described a self-limited bleeding condition that usually occurs 1-5 days after birth in patients with nonclassic hemophilia.[4, 7, 8]  The term "vitamin K" originated from the German koagulations-vitamin.[4]  Henrik Dam and Edward Doisy won the 1943 Nobel Prize for the discovery and functions of vitamin K. Subsequent research has provided significant contributions to the current knowledge of vitamin K and its association with coagulation factors, namely the vitamin K–dependent coagulation factors VII, IX, and X.[9]

Clarke and Shearer wrote a brief but excellent history of vitamin K deficiency bleeding in neonates, including discussion of the following[10] :

• Discovery and rediscovery of vitamin K deficiency bleeding by medical science

• Historic toxicology-related issues related to an older vitamin K preparation given to neonates

• Unproven assumption that older preparations of vitamin K were associated with cancer or leukemia in later life (ie, phenol-containing preparations)

• Problems with administering vitamin K to infants with cholestasis

• Use of oral preparations of vitamin K to prevent vitamin K deficiency bleeding in neonates and the residual risk of vitamin K deficiency bleeding thereafter

• Administration of excess intramuscular (IM) vitamin K in very preterm infants (ie, hepatic storage)

• Measurements of vitamin K antagonist II (PIVKA-II) to provide early detection of vitamin K deficiency (ie, uncarboxylated or abnormal coagulation factor II is released into the blood before changes in the prothrombin time [PT])

• Continued occurrence of serious vitamin K deficiency bleeding associated with parental refusal of vitamin K prophylaxis immediately after birth

Newborn infants are at risk of developing vitamin K deficiency, and this coagulation abnormality leads to serious bleeding. Transplacental transfer of vitamin K is very limited during pregnancy, as is the storage of vitamin K in the neonatal liver, all of which makes the newborn infant uniquely vulnerable to hemorrhagic disorders unless exogenous vitamin K is given for the prevention of bleeding immediately after birth.

Once the infantile gut is colonized with bacterial flora, the microbial production of vitamin K results in a lower risk of infantile vitamin K deficiency bleeding (VKDB).[11] A gut-related microbial source of vitamin K is particularly important if dietary phylloquinone (vitamin K1) is restricted.[12]

The most common sites of hemorrhage or bleeding are the umbilicus, mucous membrane, the gastrointestinal (GI) tract, circumcision site, and venipuncture sites. Hematomas frequently occur at the sites of trauma (ie, large cephalohematomas, scalp bruising related to instrumentation used at delivery and, rarely, intracranial hemorrhage). Neonatal mortality and long-term neurologic morbidity are severe consequences of vitamin K deficiency bleeding.

Placental transfer of vitamin K is very limited,[13] and phylloquinone levels in umbilical cord blood is very low.[14] The newborn infant’s intestinal tract is relatively sterile and takes some time to colonize with bacteria, which may have a role in synthesizing vitamin K2 (menaquinone). Because Bacteroides species are among the most common bacteria that inhabit the human intestinal tract, and because strains such as B fragilis synthesize vitamin K, Bacteroides species are more significant in producing human vitamin K in the intestine than Escherichia coli.[15]

As noted earlier, breast milk is a poor source of vitamin K (breast milk levels are 1-4 μ g/L). The recommended dietary intake of vitamin K is 1 μg/kg/day.[16] Exclusively breastfed infants have intestinal colonization with lactobacilli that do not synthesize vitamin K; thus, reduced production of menaquinone increases the neonatal risk of developing a hemorrhagic disorder if not supplemented with vitamin K. Formula-fed infants have higher fecal concentrations of vitamin K1 because of dietary intake, as well as significant quantities of fecal menaquinone, reflecting the gut’s microflora.[17]

Preterm infants who are receiving total parenteral nutrition (TPN) are not at such bleeding risk because they are receiving vitamin K via the multivitamin additive in the TPN. However, special consideration is needed for very low birth weight infants whose intestinal tract bacterial flora is altered because of multiple courses of broad-spectrum antimicrobials. Once preterm infants are weaned off TPN, they may develop vitamin K deficiency if they are exclusively fed breast milk.

Vitamin K deficiency in the newborn can be present for various reasons (see Pathophysiology).

Maternal medications that interfere with vitamin K stores or function (eg, carbamazepine, phenytoin, barbiturates, some cephalosporins, rifampin, isoniazid, warfarin or warfarinlike drugs) can result in vitamin K deficiency bleeding (VKDB) in the infant.

In addition to breastfeeding, clinical states that are risk factors for late-onset vitamin K deficiency bleeding include the following:

• Diarrhea

• Hepatitis

• Cystic fibrosis

• Celiac disease

• Alpha1-antitrypsin deficiency

• Short bowel syndrome

• Intestinal bacterial overgrowth

• Chronic exposure to broad spectrum antimicrobial agents

United States data

In the United States, routine intramuscular (IM) administration of vitamin K immediately after birth has made vitamin K deficiency bleeding (VKDB) an uncommon occurrence. The frequency of vitamin K deficiency bleeding varies from 0.25% to 1.7% in the first week of life in infants not receiving vitamin K prophylaxis. The risk of such bleeding is 1,700 per 100,000 infants (1 of 59) if vitamin K is not given; when IM vitamin K is provided, the risk of vitamin K deficiency bleeding falls to 1 per 100,000 infants.[18] Late vitamin K deficiency bleeding (2-12 weeks after birth) appears to be reduced or prevented with parenteral administration of vitamin K at birth.

International data

The frequency of vitamin K deficiency bleeding (VKDB) in countries outside the United States varies with the use of vitamin K prophylaxis, the efficacy of prophylaxis programs, frequency of breastfeeding, and the vitamin K content of locally available formulas. 

Late vitamin K deficiency bleeding has fallen from 4.4-7.2 cases per 100,000 births to 1.4-6.4 cases per 100,000 births in reports from Asia and Europe after regimens for prophylaxis were instituted.[19, 20, 21]  Interest is growing for requiring mandatory vitamin K prophylaxis in India and China, as well as in other countries with a high burden of neonatal deaths, to reduce the long-term morbidity and mortality related to vitamin K deficiency bleeding.[22]

Race-, sex-, and age-related demographics

No racial predilection is noted, but breastfeeding practices can result in apparent racial disparities.

No predilection to vitamin K deficiency bleeding based on sex is apparent.

Vitamin K deficiency bleeding is primarily a disease of the newborn, but such hemorrhage can occur beyond the neonatal period, especially if conditions such as short gut syndrome, intestinal bacterial overgrowth, and certain genetic conditions are present.

Prognosis is based on the amount of blood loss, bleeding site, and gestational age of the newborn. It can range form mild to severe complications, and even death can occur.

In the absence of intracranial hemorrhage, the prognosis for vitamin K deficiency bleeding (VKDB) in an otherwise healthy infant is excellent. Prognosis after intracranial hemorrhage depends on the extent and location of the hemorrhage. Long-term sequelae of intracranial hemorrhage may include motor and intellectual deficits.

Complications

Intracranial hemorrhage is the primary serious complication of vitamin K deficiency bleeding. Intracranial hemorrhage is uncommon in classic vitamin K deficiency bleeding, but it can be observed in more than 50% of infants with late-onset vitamin K deficiency bleeding. Intracranial hemorrhage is responsible for nearly all mortality and long-term sequelae due to vitamin K deficiency bleeding.

Hepatic or adrenal gland bleeding may also be a complication.[23]

Complications of treatment include anaphylactoidlike reactions during intravenous vitamin K administration, hyperbilirubinemia or hemolytic anemia after high doses of vitamin K, and hematomas at the site of injection, if administered intramuscularly.

In the era of internet and social media widespread information regarding vitamin K deficiency bleeding (VKDB) is available—but such information may not be accurate, peer-reviewed, and scientifically evaluated. It is highly advisable that clinicians address this issue during visits in the antenatal period. By providing parents with factual information and education, acceptance of Vitamin K has been shown to increased.[18, 24, 25]

The following may be useful resources from various governments and educational organizations:

• American Academy of Pediatrics policy statement on vitamin K (2003; most recent, as of December 2017)

• Australian government publication on vitamin K (2010; most recent, as of December 2017)

• Canadian Pediatric Society statement on vitamin K (1997; reaffirmed 2016)

• European Society for Paediatric Gastroenterology Hepatology and Nutrition position paper (2016)

• Vitamin K prophylaxis guidelines from Stanford University (2006; most recent, as of December 2017)

History

The maternal history is very important when assessing vitamin K deficiency bleeding (VKDB) in neonates and infants, especially the medications used during pregnancy, the presence of medical conditions such as short gut syndrome, and unusual dietary intakes.

Better surveillance during pregnancy and careful medical evaluation of neonate after delivery are essential.

Physical examination

Most newborn infants are healthy upon examination, even if early onset bleeding is present; however, intracranial hemorrhage can occur during the birthing process and can lead to severe complications. Signs of intracranial hemorrhage include apnea with or without seizures and a shocklike syndrome.

Internal hemorrhage of organs other than the brain (eg, liver, adrenal glands) may be difficult to detect; however, if they are suspected, careful physical monitoring and serial imaging after birth are indicated.

Soft-tissue hemorrhage is easier to recognize, but sequential measurements of the bleeding into soft tissues or muscle are mandatory.

A full coagulopathy work-up and hematology consultation are required if clinical and laboratory findings are suggestive of non–vitamin K deficiency bleeding.

If liver disease is suspected, a work-up that includes functional tests and imaging are mandatory.

Hereditary defects in the coagulation system must always be considered among the differential diagnosis.

If the cause of bleeding is not straightforward, clinicians may need to perform other procedures like endoscopic retrograde cholangiopancreatography (ERCP) to rule out hepatobiliary diseases.

If liver biopsy is indicated, histopathology with and without special stains or biochemical analyses may be helpful to rule out hepatitis, biliary atresia,[27, 28]  tumors, and inherited metabolic diseases of the liver.

Coagulations studies

A prothrombin time (PT), activated partial thromboplastin time (aPTT), fibrinogen levels, and a platelet count should be included in the initial workup for vitamin K deficiency bleeding (VKDB) in a newborn. A thrombin clotting time (TCT) is optional.

Note the following:

• A prolonged PT is usually the first laboratory test result to be abnormal in vitamin K deficiency bleeding; however, no laboratory test result can confirm the diagnosis of vitamin K deficiency bleeding.

• A direct blood measurement of vitamin K is not useful, because its levels normally are low in newborns.

• Levels of protein induced by vitamin K antagonism (PIVKA II) are increased in vitamin K deficiency bleeding, but this study is generally not available outside of research laboratories.

• Infants with vitamin K deficiency bleeding typically have a prolonged PT with platelet counts and fibrinogen levels within the normal range for newborns. The presence of thrombocytopenia or a prolonged aPTT should prompt workup for other causes of bleeding during the neonatal period. For example, maternal transfer of antiplatelet antibodies in mothers with immune thrombocytopenia via breastfeeding may be associated with persistent neonatal thrombocytopenia.[29]

The diagnosis of vitamin K deficiency bleeding is confirmed if administration of vitamin K halts the bleeding and reduces the PT value.

There appears to be a significant association between median platelet count and platelet mass with intracranial hemorrhage in neonates at days 1, 2, and 3 after diagnosis of gram-negative sepsis.[30]

Intracranial bleeding is rare and usually associated with other causes of bleeding, particularly thrombocytopenia; however, intracranial hemorrhage has been reported in vitamin K deficiency bleeding (VKDB) and can be fatal.

Neonatal sepsis due to gram-negative bacteria (eg, Enterobacter species) is also a cause of intracranial bleeding.[30]

Investigate any neurologic symptoms with imaging. Magnetic resonance imaging (MRI) does not expose the neonate to radiation, and this imaging modality is becoming the preferred way to study the brain because tissue damage can be better defined.

In general, infants with vitamin K deficiency bleeding (VKDB) do not require surgical care, but in rare cases, an infant may need neurosurgical evaluation and treatment.

Other conditions, such as those associated with short bowel syndrome and hepatobiliary disease may require surgical evaluation.

Consultations

Vitamin K deficiency bleeding usually warrants consultation with a pediatric hematologist to rule out other causes of hemorrhagic disease of the newborn. In such instances, close follow-up is needed after discharge from the hospital.

Pediatric surgery and pediatric neurosurgery consultation should be obtained when they are deemed necessary.

A pediatric hematologist may also be beneficial as a consultant.

Prevention of vitamin K deficiency bleeding (VKDB) with administration of intramuscular (IM) vitamin K is of primary importance in the medical care of neonates. A single dose of IM vitamin K after birth effectively prevents classic vitamin K deficiency bleeding. Conversely, oral (PO) vitamin K prophylaxis improves coagulation test results at 1-7 days, but vitamin K administered by this route has not been tested in randomized trials for its efficacy in preventing either classic or late vitamin K deficiency bleeding.[19, 20]

In their policy statements, The American Academy of Pediatrics (AAP) has endorsed the universal supplementation of vitamin K using the IM injection, because no vitamin K preparation is licensed for oral use in the United States.[31, 32, 33]

Immediately administer vitamin K subcutaneously (hold pressure on the site) for any infant in whom vitamin K deficiency bleeding is suspected or who has serious, unexplained neonatal bleeding.

Note the following:

• IM administration can result in a hematoma because of the coagulopathy.

• Intravenous (IV) administration of vitamin K has been associated with anaphylactoidlike reactions.

• Fresh frozen plasma may be considered for moderate to severe bleeding.

• Life-threatening bleeding may also be treated with prothrombin complex concentrates (PCCs). Note that despite the increasing off-label use of PCCs for neonates and infants with severe bleeding or a risk of severe bleeding, a systematic review and meta-analysis indicates there remains insufficient evidence to make a definitive recommendation for administering these products in this population.[34]

• Because the bleeding in classic vitamin K deficiency bleeding usually is not life threatening, a single dose of parenteral vitamin K is generally sufficient to stop the bleeding and return prothrombin time (PT) values to within the reference range.

• In the early 1990s, an association between parenteral vitamin K and the later occurrence of childhood cancer was reported; however, a large cohort study and a large retrospective analysis of a US database could not confirm this association. Because this association is weak at best, the AAP supports and recommends routine vitamin K prophylaxis.

• Oral vitamin K has been studied as an alternative and can improve clotting studies and vitamin K levels, but it has not been studied in large randomized controlled trials to determine if this strategy effectively prevents early and late vitamin K deficiency bleeding.

Studies from different countries have reported evidence of a rise in vitamin K prophylaxis being refused or neglected by parents.[25, 35, 36]  For example, a Canadian study found that of 282,378 children born in Alberta between 2006 and 2012, neonatal prophylaxis was declined in 0.3% of cases, with the incidence of vitamin K refusal being higher in midwife-assisted births than in physician-attended deliveries.[37] In an Israeli study, in which questionnaires were answered by 217 expectant parents, 22.5% of participants were unaware of recommendations regarding neonatal vitamin K prophylaxis.[38]

A more recent US study based on 2011-2013 data in the state of Tennessee found that the parents of 3.0% of infants at hospitals refused injectable vitamin K for their newborns in 2013 (higher frequency than in years 2011 and 2012); in the same year, parents of 31% of infants at birthing centers refused vitamin K prophylaxis.[25]  The most common reasons for parental refusal were a belief the injection was unnecessary (53%) and a desire for a natural birthing process (36%).

Transfer

Infants with evidence of intracranial bleeding may require transfer to a level III nursery after stabilization with subcutaneous vitamin K and other aspects of supportive care.

Discharge planning

In patients with vitamin K deficiency bleeding, follow-up for continued bleeding after vitamin K administration is indicated because other causes may be present. In addition, hematocrit levels should be obtained serially and before discharge

Ensure neurologic complications are stable or resolved before discharge.

Mild vitamin K deficiency bleeding that has been treated successfully can be monitored on an outpatient basis.

The postdischarge follow-up interval depends on the nature and severity of bleeding, the hematocrit level at discharge, and any neurologic abnormalities that could recur.

Diet

The best sources of vitamin K are green leafy vegetables, legumes, soybean, and olive oils.

Breastfed infants should receive vitamin K supplementation; if mothers refuse this prophylaxis, they should be counseled.[27] Because breast milk is not a good source of vitamin K, infants of mothers who refuse prophylaxis and who exclusively breastfeed should receive oral supplementation of vitamin K.[39]

Recommendations

Recommendations on vitamin K supplementation continue to evolve.[40] A relatively recent recommendation for oral (PO) vitamin K supplementation in term infants suggests weekly administration of 1 mg until age 12 weeks or 2 mg at birth and then repeated at age 1 week and age 4 weeks,[41]  but this recommendation emphasizes a lack of information related to the dosing of oral vitamin K in preterm infants. An additional oral dose of 2 mg at age 8 weeks has also been suggested.[42]

A more recent recommendation from the European Society for Paediatric Gastroenterology Hepatology and Nutrition (ESPGHAN) Committee on Nutrition indicates the following for vitamin K administration to healthy newborns[27] :

• One dose of 1 mg vitamin K1 given intramuscularly (IM) at birth, or

• Three doses of 2 mg vitamin K1 PO at birth, at age 4-6 days, and at age 4-6 weeks, or

• One dose of 2 mg vitamin K1 PO at birth, followed by a weekly dose of 1 mg PO for 3 months

• For infants who vomit/regurgitate the formulation within 1 hour of receiving PO vitamin K, it may be appropriate to repeat the dose.

Similarly, The French Society of Neonatology recommends the following for vitamin K prophylaxis[23] :

• For term infants: Three doses of 2 mg vitamin K1 PO at birth, at discharge from the maternity ward, and at age 1 month

• For premature infants (birth weight >1500 g): Weekly dose of 2 mg up to the term-equivalent age

• For premature infants (birth weight < 1500 g): Weekly dose of 1 mg up to 1500 g body weight; then, a weekly dose of 2 mg up to the term-equivalent age

• For infants unable to take the PO formulation: Use an IM or intravenous (IV) route with a 50% reduction in dosing

The Canadian Paediatric Society and the College of Family Physicians of Canada also recommend routine IM administration of a single dose vitamin K (0.5 mg to 1.0 mg) to all newborns. Newborns whose parents refuse IM vitamin K should receive an oral dose of 2 mg at birth, repeated at 2-4 and 6-8 weeks of age. This recommendation also notes a lack of information related to the dosing of oral vitamin K in preterm infants.[43]

Note that oral vitamin K prophylaxis may not be sufficient for infants with gastrointestinal tract–related issues, including biliary atresia and cholestasis,[27, 28] for infants too ill to receive PO vitamin K1, or for those whose mothers have taken medications that interfere with vitamin K metabolism.[27]

Activity

During acute bleeding, the infant with vitamin K deficiency bleeding should be handled with caution until the coagulation profile returns to normal after vitamin K supplementation.

Intramuscular (IM) vitamin K prophylaxis at birth is the standard of care in the United States.[26]  This prophylaxis is required even for healthy newborns who don't have bleeding risk factors.[18]

In the United States, commercial infant formulas and maternal supplements during pregnancy/lactation contain supplemental vitamin K, but these preparations are not as effective as parenteral vitamin K.[18, 27]

These measures have served to make vitamin K deficiency bleeding (VKDB) a rarity in the United States. However, parental refusal of prophylaxis and an increasing frequency of breastfeeding may cause a resurgence of vitamin K deficiency bleeding in developed countries.[26, 44]

Vitamin K1 should be given to all newborns as a single IM dose of 0.5 to 1 mg.[27, 31]  Healthcare professionals should promote awareness among families of the risks of late vitamin K deficiency bleeding associated with inadequate vitamin K prophylaxis from current oral dosage regimens, particularly for newborns who are breastfed exclusively.

Vitamin K is the mainstay for prevention of and treatment of vitamin K deficiency bleeding (VKDB). Other coagulation factors are rarely needed. Severe bleeding may warrant the use of fresh frozen plasma. No other drugs or treatments are acceptable substitutes for prompt vitamin K dosing. Subcutaneous administration of vitamin K is preferred over the intramuscular (IM) route in symptomatic infants.

Class Summary

Vitamin K is required to correct the deficiency that defines vitamin K deficiency bleeding. Prophylaxis with IM vitamin K at birth is an effective means of preventing vitamin K deficiency bleeding in the newborn.

Vitamin K1 (phytonadione)

Fat-soluble vitamin that promotes the hepatic synthesis of the following clotting factors: prothrombin (factor II), proconvertin (factor VII), plasma thromboplastin component (factor IX), and Stuart factor (factor X). May not be effective when liver disease is severe. Coagulation factors should increase in 6-12 h after PO dosing and in 1-2 h after parenteral administration. Monitor effectiveness by measuring prothrombin time.

Increased incidence of VKDB observed in countries that have switched to PO prophylaxis. IM preferred route for newborns and is recommended by the American Academy of Pediatrics.

Available as a 2-mg/mL emulsion in 0.5 mL ampul and 10-mg/mL emulsion in 1 mL ampul; also contains dextrose and benzyl alcohol (9 mg/mL). No approved oral formulation in US for infants.