HEMORRHAGIC DISEASE OF NEWBORN

Hemorrhagic Disease of Newborn
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.

Pathophysiology (hemorrhagic disease of newborn): 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 (hemorrhagic disease of newborn):
• In the US: The frequency of VKDB is variably reported from 0.25-1.7%. The frequency in a given US population depends upon the frequency of breastfeeding.

• Internationally: 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 content of locally available formulas.

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. Late-onset VKDB tends to be more severe than early-onset or classic disease and has a high frequency of ICH.

Physical (hemorrhagic disease of newborn): The findings from the physical examination are normal except for findings at the sites of bleeding.

Causes (hemorrhagic disease of newborn): Vitamin K deficiency in the newborn, which can be present for a variety of reasons, causes VKDB.

• 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:
o Diarrhea
o Hepatitis
o Cystic fibrosis
o Celiac disease
o Alpha1-antitrypin deficiency

Lab Studies (hemorrhagic disease of newborn):
• 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.
o 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.
o Vitamin K direct assay is not useful because levels normally are low in newborns.
o 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.
o 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 (hemorrhagic disease of newborn):
• 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.

Medical Care (hemorrhagic disease of newborn):
• Immediately administer a vitamin K SC dose for any infant in whom VKDB is suggested or with any sort of bleeding.
o IM administration can result in a hematoma because of the coagulopathy.
o IV administration of vitamin K has been associated with anaphylactoid reactions.

• Fresh frozen plasma may be considered for moderate-to-severe bleeding.
o Life-threatening bleeding may also be treated with prothrombin complex concentrates (PCC).
o 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.

Medication (hemorrhagic disease of newborn):
Vitamin K is essential in the treatment of VKDB. Other coagulation factors rarely are needed. Severe bleeding may warrant the use of fresh frozen plasma. No other drugs or treatments are acceptable substitutes for prompt vitamin K dosing. Drug Category: Vitamins -- Vitamin K is required to correct the deficiency that defines VKDB.