AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

The more appropriate term for hemorrhagic disease of newborn is vitamin K deficiency bleeding (VKDB). Historically, all bleeding disorders in the newborn were grouped together under the diagnosis of hemorrhagic disease of the newborn (HDN). With methods available today for the accurate diagnosis of other factor deficiency states and immune thrombocytopenias, VKDB can be distinguished from other disorders by exclusion and appropriate analysis of these other factors involved in coagulation.

Vitamin K is a fat-soluble vitamin that can be absorbed from the GI tract in the presence of bile salts. Vitamin K is required for the production of coagulation factors II, VII, IX, and X in the liver. Because of the short half-life of these factors, and the small amounts of vitamin K that can be stored in the body, inadequate intake of vitamin K can result in deficiency in a short period of time. PIVKA, inactive precursor proteins induced in vitamin K's absence, are measurable and can be used as an indicator of vitamin K deficiency.

The 3 forms of vitamin K are as follows:

• K1: Phylloquinone, found in dairy products, green vegetables, and vegetable oils, is an aqueous, colloidal solution of vitamin K1.
• K2: Menaquinone, which 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.

Pathophysiology

Newborns are relatively vitamin K deficient for a variety of reasons. Factors that can contribute to this deficiency include low vitamin K stores at birth, poor placental transfer of vitamin K, low levels of vitamin K in breast milk, and sterility of the gut. Because standard commercial infant formulas contain supplemental vitamin K, VKDB is almost exclusively a problem of breastfed infants. Infants with inadequate intake are at higher risk.

The most common sites of bleeding are the umbilicus, mucous membranes, GI tract, circumcision, and venipunctures. Hematomas at sites of trauma, such as large cephalohematomas and bruising, are also common findings. Intracranial bleeding can occur and is the main cause of mortality and long-term morbidity.

Frequency

United States

In the United States, routine intramuscular administration of vitamin K immediately after birth has made VKDB an uncommon occurrence. The frequency of VKDB is variably reported, from 0.25-1.7% in the first week of life. The frequency in a given US population depends upon the frequency of breastfeeding. Late VKDB (2-12 wk) appears to be prevented with parenteral administration of vitamin K, as well.

International

The frequency of 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 VKDB has fallen from 4.4-7.2/100,000 births to 1.4-6.4/100,000 births in reports from Asia and Europe after regimens for prophylaxis were instituted.

Mortality/Morbidity

Intracranial hemorrhage (ICH) is uncommon in classic VKDB but can be observed in more than 50% of infants with late-onset VKDB. ICH is responsible for nearly all mortality and all long-term sequelae resulting from VKDB.

Race

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

Sex

No apparent sex predilection exists.

Age

VKDB can occur in 3 general time frames.

• Early onset, at less than 24 hours after birth, rarely occurs and is almost always associated with maternal medications that interfere with vitamin K, such as anticonvulsants, anticoagulants, and antibiotics. Postnatal administration of vitamin K has no effect in preventing early-onset disease. Maternal vitamin K supplementation that is administered prenatally may prevent this form of VKDB.
• The classic onset of VKDB is 2-7 days after birth in breastfed infants.
• Late-onset VKDB occurs after 2 weeks of life. In addition to breastfeeding, risk factors include diarrhea, hepatitis, cystic fibrosis (CF), celiac disease, and alpha1-antitrypin deficiency or absence of prophylaxis in otherwise healthy infants. Late-onset VKDB tends to be more severe than early-onset or classic disease and has a high frequency of ICH.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Physical

The findings from the physical examination are normal except for findings at the sites of bleeding.

Causes

Vitamin K deficiency in the newborn, which can be present for a variety of reasons, causes VKDB (see Pathophysiology).

• Maternal medications that interfere with vitamin K stores or function, such as carbamazepine, phenytoin, barbiturates, some cephalosporins, rifampin, isoniazid, and warfarin, can result in VKDB in the infant.
• In addition to breastfeeding, risk factors for late-onset VKDB include the following:
• • Diarrhea
  • Hepatitis
  • Cystic fibrosis
  • Celiac disease
  • Alpha1-antitrypin deficiency

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Maternal isoimmune thrombocytopenia
Alloimmune thrombocytopenia
Hepatobiliary disease
Uncommon coagulopathies

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Include prothrombin time (PT), activated partial thromboplastin time (aPTT), fibrinogen levels, and a platelet count in the initial workup for bleeding in a newborn. A thrombin clotting time (TCT) is optional.
• • A prolonged PT usually is the first laboratory test result to be abnormal in VKDB; however, no laboratory test can confirm the diagnosis of VKDB.
  • Vitamin K direct assay is not useful because levels normally are low in newborns.
  • Levels of protein induced by vitamin K antagonism (PIVKA) II are increased in VKDB, but this test generally is not available outside of research laboratories.
  • Infants with VKDB typically have a prolonged PT with reference range platelet counts and fibrinogen levels. Thrombocytopenia or a prolonged aPTT should prompt workup for other causes of bleeding.
• The diagnosis of VKDB is confirmed if administration of vitamin K brings a halt to the bleeding and reduces the PT value.

Imaging Studies

• Intracranial bleeding is rare and usually associated with other causes of bleeding, particularly the thrombocytopenias; however, ICH has been reported in VKDB and can be fatal. Investigate any neurologic symptoms with a CT scan.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

Prevention of VKDB with intramuscular vitamin K is of primary importance in medical care. A single dose of intramuscular vitamin K after birth effectively prevents classic VKDB. While oral vitamin K prophylaxis improves coagulation tests at 1-7 days, it has not been tested in randomized trials for its effect on either classic or late VKDB.

• Immediately administer vitamin K subcutaneously for any infant in whom VKDB is suggested or who has any sort of bleeding until a diagnosis is established.
• • IM administration can result in a hematoma because of the coagulopathy.
  • IV administration of vitamin K has been associated with anaphylactoid reactions.
• Fresh frozen plasma may be considered for moderate-to-severe bleeding.
• • Life-threatening bleeding may also be treated with prothrombin complex concentrates (PCC).
  • Because the bleeding in classic VKDB usually is not life threatening, a single dose of parenteral vitamin K is sufficient to stop the bleeding and return PT values to 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 database in the United States could not confirm this association. Because this association is weak at best, routine vitamin K prophylaxis is recommended and supported by the American Academy of Pediatrics.
• 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 an oral prevention strategy is effective at preventing early and late VKDB.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Vitamin K is the mainstay of treatment for 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. SC administration is preferred over the IM route in symptomatic infants.

Drug Category: Vitamins

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

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Outpatient Care

• Follow-up interval after discharge depends on the nature and severity of bleeding, hematocrit at discharge, and any neurologic complications. Mild VKDB that has been treated successfully can be monitored at routine newborn visits.

Transfer

• Infants with evidence of intracranial bleeding may require transfer to a level III nursery after stabilization with SC or IV vitamin K.

Deterrence/Prevention

• IM vitamin K prophylaxis at birth is the standard of care in the United States.
• Commercial infant formulas in the United States contain supplemental vitamin K.
• These measures have served to make VKDB a rarity. However, parental refusal of prophylaxis and an increasing frequency of breastfeeding may cause a resurgence of VKDB in developed countries.

Complications

• ICH is the primary serious complication of VKDB.
• Complications of treatment include anaphylactoid reactions to IV vitamin K, hyperbilirubinemia or hemolytic anemia after high-dose vitamin K, and hematomas at the site of injection if administered IM.

Prognosis

• In the absence of ICH, the prognosis for VKDB in an otherwise healthy infant is excellent. Prognosis after ICH depends on the extent and location of the hemorrhage. Long-term sequelae of ICH may include motor and intellectual deficits.

Patient Education

• For excellent patient education resources, visit eMedicine's Children's Health Center.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Most hospital nurseries include vitamin K administration in standing admission orders. A newborn's hospital chart should have a specific place for documentation of dose and administration. Failure to provide vitamin K at birth and subsequent bleeding presents a legal liability for physicians and hospitals. If parents refuse prophylaxis, document the discussion of the risks and benefits along with the parents' refusal in the chart.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

• American Academy of Pediatrics Vitamin K Ad Hoc Task Force. Controversies concerning vitamin K and the newborn. Pediatrics. May 1993;91(5):1001-3. [Medline].
• Christensen RD, ed. Developmental aspects of blood hemostasis and disorders of coagulation and fibrinolysis in the neonatal period. In: Hematologic Problems in the Neonate. Philadelphia, Pa:. WB Saunders Co;2000:239-271.
• Miller CA, Committee on the Fetus and Newborn, American Academy of Pediatrics. Policy Statement: Controversies Concerning Vitamin K and the Newborn. Pediatrics. 2003;112 No. 1 July:191-192.
• Puckett RM, Offringa M. Prophylactic vitamin K for vitamin K deficiency bleeding in neonates (Review). The Cochrane Database of Systematic Reviews. 2000;Issue 4.
• Taeusch HW, Ballard RA, eds. Hemostatic disorders in newborns. In: Avery's Diseases of the Newborn. 7th ed. Philadelphia, Pa:. WB Saunders Co;1998:1045-1079.
• Taketomo CK, Hodding JH, Kraus DM. Pediatric Dosage Handbook. 6th ed. Hudson, Ohio:. Lexi-Comp;1999:725-728.
• Young TE, Mangum OB, eds. Neofax: A Manual of Drugs Used in Neonatal Care. 13th ed. Raleigh, NC:. Acorn, Inc;2000.

Article Last Updated: Jun 16, 2006