Hemorrhagic Disease of Newborn

Author: Dharmendra J Nimavat, MD, FAAP.

BACKGROUND
Vitamin K represents a group of lipophilic and hydrophobic vitamins. The following is a
brief history of vitamin K's use in medicine.
In 1894, Townsend described a self-limited bleeding condition that usually occurs 1-5 days
after birth in patients with nonclassic hemophilia.
[1, 2, 3]
The term vitamin K originated
from koagulations-vitamin in German.
[3]
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 current knowledge of vitamin K and its association with
coagulation factors, namely the vitamin Kdependent coagulation factors VII, IX, and X.
[4]

Clarke and Shearer wrote a brief but excellent history of vitamin K deficiency bleeding
(VKDB) in neonates.
[5]
That article discusses the following:
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 of 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 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
In the past, the term hemorrhagic disease of the newborn was used to describe bleeding
disorders in neonates associated with a traumatic birth or hemophilia.
[6]
The proper diagnostic
term that has been adopted is currently vitamin K deficiency bleeding because vitamin K
deficiency is not the sole cause of hemorrhagic disorders in preterm and term infants.
[7]

Although some controversy surrounds postnatal timing of the initial hemorrhage, vitamin K
deficiency bleeding is usually classified by 3 distinct time periods after birth, as follows:
[8]

Early-onset vitamin K deficiency bleeding in the newborn
o Early-onset vitamin K deficiency bleeding usually occurs during first 24 hours after birth.
o It is seen in infants born to mothers taking anticonvulsant or antituberculosis medication.
o Serious hemorrhagic complications can occur in this type of hemorrhage.
o The mechanisms by which anticonvulsant and antituberculosis medications cause vitamin
K deficiency bleeding in neonates is not clearly understood, but limited studies suggest
that vitamin K deficiency bleeding 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. Vitamin K supplementation given after the birth for early onset vitamin K
deficiency bleeding may be too late to prevent this disease, especially if vitamin K
supplementation was not provided during pregnancy.
o Numerous maternal medications and/or exposure to toxins during pregnancy are
associated with vitamin K deficiency bleeding in neonates (eg, anticonvulsants [eg,
phenytoin, barbiturates, carbamazepine], antitubercular drugs [eg, rifampin, isoniazid],
vitamin K antagonists [eg, warfarin, phenprocoumon]).
[8]

Classic vitamin K deficiency bleeding in the newborn
o Classic vitamin K deficiency bleeding usually occurs after 24 hours and as late as the first
week of life.
o Classic vitamin K deficiency bleeding is observed in infants who have not received
prophylactic vitamin K at birth.
o The incidence of classic vitamin K deficiency bleeding ranges from 0.25-1.7 cases per
100 births.
o Usually the disease 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.
o Infants who have classic vitamin K deficiency bleeding are often ill, have delayed
feeding, or both.
o Bleeding commonly occurs in the umbilicus, GI tract (ie, melena), skin, nose, surgical
sites (ie, circumcision), and, uncommonly, in the brain.
[8]

Late-onset vitamin K deficiency bleeding in the newborn
o This usually occurs between age 2-12 weeks; however, late-onset vitamin K deficiency
bleeding can be seen as long as 6 months after birth.
o This disease is most common in breastfed infants who did not receive vitamin K
prophylaxis at birth.
o Vitamin K content is low in mature human milk and ranges from 1-4 mcg/L.
o Industrial contaminants in breast milk have been implicated in promoting vitamin K
deficiency bleeding.
o More than half of these infants present with acute intracranial hemorrhages.
[8]

Currently, the following 3 forms of vitamin K are known:
K
1
: Phylloquinone is predominantly found in green leafy vegetables, vegetable oils, and
dairy products. Vitamin K given to neonates as a prophylactic agent is an aqueous, colloidal
solution of vitamin K
1
.
K
2
: Menaquinone is synthesized by gut flora.
K
3
: 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 -glutamyl carboxylase enzymatic activity that
catalyses the -carboxylation of specific glutamic acid residues in a subclass of
proteins.
[3]
These vitamin Kdependent proteins are known as Gla-proteins. The image below
outlines the vitamin K cycle.

Vitamin K cycle.

Coagulation factors II, VII, IX, and X and other Gla-proteins (eg, protein C, protein S,
protein Z) also depend on the presence of vitamin K for their activity. The role of Gla
proteins is not completely understood.
[9]
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 resides 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 can not bind calcium and phospholipid. These abnormal coagulation factors are
called protein-induced by vitamin K absence (PIVKA). PIVKA-II is des-carboxylated
prothrombin.
[10]

PATHOPHYSIOLOGY
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, and the storage of vitamin K in neonatal liver is also limited. This makes
the newborn infant uniquely vulnerable to hemorrhagic disorders unless exogenous vitamin K
is given for 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.
[11]
A gut-related microbial
source of vitamin K is particularly important if dietary phylloquinone is restricted.
[12]

The most common sites of hemorrhage or bleeding are the umbilicus, mucus membrane, the
GI tract, circumcision, 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 (vitamin K
1
) levels in
umbilical cord blood is very low.
[14]
The newborn infants intestinal tract is relatively sterile
and takes some time to colonize with bacteria, which may have a role in synthesizing vitamin
K
2
(menaquinones). Because Bacteroides species are among the most common bacteria that
inhabit the human intestinal tract, and because strains such as Bacteroides fragilis synthesize
vitamin K, Bacteroidesspecies are more significant in producing human vitamin K in the
intestine thanEscherichia coli.
[15]

Breast milk is a poor source of vitamin K (breast milk levels are 1-4 g/L). The
recommended dietary intake of vitamin K is 1 g/kg/d.
[16]
Exclusively breastfed infants have
intestinal colonization with lactobacilli that do not synthesize vitamin K; thus, reduced
production of menaquinones increases the neonatal risk of developing a hemorrhagic disorder
if not supplemented with vitamin K. Formula-fed infants have higher fecal concentrations of
vitamin K
1
because of dietary intake and significant quantities of fecal menaquinones,
reflecting the guts microflora.
[17]

Preterm infants who are receiving total parenteral nutrition (TPN) are not at risk because they
are receiving vitamin K via the multivitamin additive to the TPN. 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 of TPN, they may develop vitamin K deficiency if they are exclusively fed breast
milk.
EPIDEMIOLOGY
Frequency
United States
In the United States, routine intramuscular administration of vitamin K immediately after
birth has made vitamin K deficiency bleeding an uncommon occurrence. The frequency of
vitamin K deficiency bleeding varies from 0.25-1.7% in the first week of life in infants not
receiving vitamin K prophylaxis. Late vitamin K deficiency bleeding (2-12 wk after birth)
appears to be reduced or prevented with parenteral administration of vitamin K at birth.
International
The frequency of vitamin K deficiency bleeding 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.
[18, 19, 20]

Mortality/Morbidity
Intracranial hemorrhage is uncommon in classic vitamin K deficiency bleeding but 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.
Race
No racial predilection is noted, but breastfeeding practices can result in apparent racial
disparities.
Sex
No predilection to vitamin K deficiency bleeding based on gender is apparent.
Age
Vitamin K deficiency bleeding is mostly 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.
CLINICAL PRESENTATION
History
The maternal history is very important when assessing vitamin K deficiency bleeding
(VKDB), 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
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 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.
Causes
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 in the infant.
In addition to breastfeeding, clinical states that are risk factors for late-onset vitamin K
deficiency bleeding include:
Diarrhea
Hepatitis
Cystic fibrosis
Celiac disease
Alpha1-antitrypin deficiency
Short bowel syndrome
Intestinal bacterial overgrowth
Chronic exposure to broad spectrum antimicrobials

LABORATORY 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.
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 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 test 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. Thrombocytopenia or a
prolonged aPTT should prompt workup for other causes of bleeding during the neonatal
period.
The diagnosis of vitamin K deficiency bleeding is confirmed if administration of vitamin K
halts the bleeding and reduces the PT value.

Imaging Studies
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 and can be fatal.
Investigate any neurologic symptoms with imaging. MRI exposes the neonate to no radiation
and is becoming the preferred way to study the brain because tissue damage can be better
defined.

Other Tests
A full coagulopathy work-up and hematology consultation are required if clinical and
laboratory findings are suggestive of nonvitamin K deficiency bleeding.
A work-up that includes functional tests and imaging are mandatory if liver disease is
suspected.
Hereditary defects in the coagulation system must always be considered among the
differential diagnoses.

Procedures
If the cause of bleeding is not straight forward, the caregiver may need to perform other
procedures like endoscopic retrograde cholangiopancreatography [ERCP] to rule out
hepatobiliary diseases.
Histologic Findings
If liver biopsy is indicated, histopathology with and without special stains or biochemical
analyses may be helpful to rule out hepatitis, biliary atresia,
[21]
tumors, and inherited
metabolic diseases of the liver

TREATMENT
Prevention of vitamin K deficiency bleeding (VKDB) with intramuscular vitamin K is of
primary importance in the medical care of neonates. A single dose of intramuscular vitamin
K after birth effectively prevents classic vitamin K deficiency bleeding. Conversely, oral
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.
[18, 19]

The American Academy of Pediatrics in their policy statements has endorsed the universal
supplementation of vitamin K using the intramuscular injection (IM) because no vitamin K
preparation is licensed for oral use in the United States.
[22, 23, 24]

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.
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
(PCC).
Because the bleeding in classic vitamin K deficiency bleeding usually is not life
threatening, a single dose of parenteral vitamin K is sufficient to stop the bleeding and
return prothrombin time (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 this strategy effectively prevents early and late vitamin K deficiency bleeding.

Medication Summary
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.
Vitamins

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.