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Hemorrhagic Disease of Newborn

Background
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. [1]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. [2]

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. [3, 4, 5] The term vitamin K
originated from koagulations-vitamin in German. [5] 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. [6]

Clarke and Shearer wrote a brief but excellent history of vitamin K deficiency
bleeding (VKDB) in neonates. [7] 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

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 discussed below. [8]
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 or antituberculosis
medication. 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 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.

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


Classic vitamin K deficiency bleeding usually occurs after 24 hours and as late as
the first week of life. Classic vitamin K deficiency bleeding is observed in infants who
have not received prophylactic vitamin K at birth.
The incidence of classic vitamin K deficiency bleeding ranges from 0.25-1.7 cases
per 100 births.
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.
Infants who have classic vitamin K deficiency bleeding are often ill, have delayed
feeding, or both. 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


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.
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 and ranges from
1-4 mcg/L.
Industrial contaminants in breast milk have been implicated in promoting vitamin K
deficiency bleeding.
More than half of these infants present with acute intracranial hemorrhages. [8]
Forms of vitamin K
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. [5] These vitamin Kdependent proteins are known as Gla-proteins. The
image below outlines the 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


K1) 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 K2 (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, Bacteroides species are more significant in
producing human vitamin K in the intestine than Escherichia 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 K1 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.

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 the following:
Diarrhea
Hepatitis
Cystic fibrosis
Celiac disease
Alpha1-antitrypin deficiency
Short bowel syndrome
Intestinal bacterial overgrowth
Chronic exposure to broad spectrum antimicrobials

Diagnostic ConsiderationsImportant
considerationsSpecial considerations
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 medical record of the infant. [21]
Many Websites have information that oppose vitamin K prophylaxis for newborn
infants. Misinformation is related to an increased risk of cancer, toxicity from
additives, and even an increased risk of autism. Many parents do not have balanced
information regarding the benefits of vitamin K versus the limited risk of side effects.
Prenatal and intrapartum education should cover the subject. The education should
address the negative claims about vitamin K on the Internet and discuss scientific
studies that show the claims cannot be substantiated. The benefits of vitamin K
should be emphasized.
See the resource links provided in Patient Education for more information regarding
vitamin K.
Differential Diagnoses
Alloimmune Thrombocytopenia
Consumption Coagulopathy
Hepatobiliary Disease
Maternal Isoimmune Thrombocytopenia
Pediatric Von Willebrand Disease
Uncommon Ccoagulopathies

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 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. For example, maternal transfer of
antiplatelet antibodies in mothers with immune thrombocytopenia via
breastfeeding may be associated with persistent neonatal thrombocytopenia. [22]
The diagnosis of vitamin K deficiency bleeding is confirmed if administration of
vitamin K halts the bleeding and reduces the PT value.
Median platelet count and platelet mass have been reported to be significantly
associated with intracranial hemorrhage in neonates at days 1, 2, and 3 after
diagnosis of gram-negative sepsis. [23]
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,21tumors, and inherited metabolic diseases of the liver.

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.
Neonatal sepsis due to gram-negative bacteria
(eg, Enterobacter species) is also a cause of intracranial bleeding. [23]
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.

Medical Care
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. [24,25, 26]
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 (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.
Studies from different countries have reported evidence of a rise in vitamin
K prophylaxis being refused or neglected. A Canadian study, for example,
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. 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. [27, 28, 29]
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.

Surgical Care
Normally, vitamin K deficiency bleeding infants 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.

Diet
The best sources are green leafy vegetables, legumes, soybean and olive
oils.
Breastfed infants should receive vitamin K supplementation; if mothers
refuse prophylaxis, they should be counseled. Because breast milk is not a
good source of vitamin K, infants of mothers who refuse prophylaxis and
who exclusively breastfeed should have receive oral supplementation of
vitamin K. [30]
A relatively recent recommendation for oral vitamin K supplementation in
term infants suggests weekly administration of 1 mg until age 12 weeks or
2 mg at birth repeated at age 1 week and age 4 weeks, [31] but this
recommendation emphasizes a lack of information related to dosing of oral
vitamin K in preterm infants. An additional oral dose of 2 mg at age 8 weeks
has also been suggested.

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.

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.

Further Outpatient Care


Follow-up interval after discharge depends on the nature and severity of
bleeding, the hematocrit at discharge, and any neurologic abnormalities
that could recur.

Further Inpatient Care


In patients with vitamin K deficiency bleeding (VKDB), follow-up for
continued bleeding after vitamin K administration is indicated because
other causes may be present

Deterrence/Prevention
Intramuscular (IM) vitamin K prophylaxis at birth is the standard of care in
the United States. [21]
Commercial infant formulas in the United States contain supplemental
vitamin K.
These measures have served to make vitamin K deficiency bleeding 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.

Complications
Intracranial hemorrhage is the primary serious complication of vitamin K
deficiency bleeding.
Complications of treatment include anaphylactoidlike reactions during
intravenous (IV) vitamin K administration, hyperbilirubinemia or hemolytic
anemia after high doses of vitamin K, and hematomas at the site of
injection, if administered IM.

Prognosis
In the absence of intracranial hemorrhage, the prognosis for vitamin K
deficiency bleeding 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