Hemorrhagic disease of the newborn (HDN) is a bleeding disorder caused by a deficiency of vitamin K, leading to reduced activity of certain vitamin K-dependent clotting factors (II, VII, IX, and X). In recent years, the incidence of this condition has significantly decreased due to the routine administration of vitamin K1 at birth.
Etiology and Pathogenesis
Vitamin K does not directly participate in the synthesis of clotting factors II, VII, IX, and X. It functions as a coenzyme for vitamin K-dependent carboxylase, which catalyzes the conversion of precursor proteins into active clotting factors. When newborns are deficient in vitamin K, these clotting factors cannot undergo carboxylation and therefore fail to achieve functional clotting activity, resulting in an increased risk of bleeding.
Several factors are associated with the development of this condition:
- Low hepatic stores: Vitamin K has poor placental transfer, with only about 1/10 of the maternal supply reaching the fetus. The use of certain maternal medications during pregnancy, such as anticonvulsants, anticoagulants, or anti-tuberculosis drugs, may interfere with vitamin K storage or function.
- Reduced synthesis: At birth, the neonatal gut microbiota is not yet established, and the administration of broad-spectrum antibiotics may suppress normal gut flora, further limiting vitamin K synthesis.
- Low intake: The vitamin K content in breast milk is significantly lower than that in cow's milk or formula, making this condition more common in exclusively breastfed infants.
- Impaired absorption: Congenital liver and bile duct diseases, diarrhea, or other conditions can affect vitamin K absorption.
Clinical Manifestations
The condition is classified into three types based on the onset of symptoms:
Early-Onset HDN
This occurs within the first 24 hours after birth and is often related to maternal use of medications that interfere with vitamin K metabolism during pregnancy, although the cause remains unknown in some cases.
Clinical severity varies. Mild cases may present with minor skin hemorrhages or umbilical stump oozing, while severe cases may involve multisite and multi-organ bleeding, including the gastrointestinal tract, skin, and intracranial regions. Intracranial bleeding often leads to serious consequences.
Classic HDN
This develops between the second and seventh day of life, although it may occur as late as two weeks in preterm infants.
Common manifestations include skin bruising, umbilical stump oozing, bleeding at puncture or injection sites, and gastrointestinal bleeding. The volume of blood loss is generally small, and the condition is typically self-limiting. However, rare cases with severe bleeding may result in hypovolemic shock.
This form is usually associated with insufficient vitamin K synthesis due to the lack of vitamin K1 injection prophylaxis, exclusive breastfeeding, intestinal dysbiosis, or immature liver function.
Late-Onset HDN
This typically appears between one and three months of age and is more frequently seen in exclusively breastfed infants. Risk factors include chronic diarrhea, liver and biliary diseases, malnutrition, long-term antibiotic use, or prolonged total parenteral nutrition without vitamin K supplementation.
Bleeding may occur in common sites such as the skin and gastrointestinal tract; however, intracranial hemorrhage is also observed and carries a high mortality rate. Surviving infants often develop long-term neurological sequelae.
Auxiliary Examinations
The diagnosis involves evaluating coagulation function, measuring protein induced by vitamin K absence or antagonist-II (PIVKA-II), and assessing vitamin K levels. A PIVKA-II level ≥2 μg/L generally indicates vitamin K deficiency.
Coagulation Testing
Prothrombin time (PT) prolongation is an important diagnostic marker, with a prolongation greater than twice the control being highly significant.
Activated partial thromboplastin time (APTT) may also be prolonged.
Other parameters such as thrombin time (TT), bleeding time, platelet count, and fibrinogen levels are usually normal.
Activity Ratio of Factor II to Total Factor II
A ratio <1 indicates vitamin K deficiency.
PIVKA-II Testing
Enzyme immunoassays or electrophoresis can be used to detect inactive prothrombin. PIVKA-II is a sensitive marker for assessing vitamin K deficiency and evaluating treatment response. It can be detected in the circulating blood before changes in routine coagulation tests occur, indicating subclinical vitamin K deficiency.
Vitamin K Measurement
High-performance liquid chromatography or mass spectrometry can be employed to directly measure vitamin K levels in the blood.
Diagnosis and Differential Diagnosis
The diagnosis can be established based on a history of high-risk factors, the timing of onset, clinical manifestations, laboratory tests, and the efficacy of vitamin K treatment. Differential diagnosis should be considered for the following conditions:
Neonatal Swallowing Syndrome
This condition occurs when the infant swallows maternal blood during delivery, leading to hematemesis and/or melena shortly after birth. The key points for differentiation include the following:
- Absence of bleeding from other sites.
- Normal hemoglobin levels and coagulation function.
- Hematemesis ceases after 1–2 instances of gastric lavage.
The Apt test (alkali denaturation test) helps distinguish maternal blood from infant blood in vomitus. In this test, one part of vomitus is mixed with five parts of water, centrifuged at 2,000 rpm for 10 minutes to collect 4 mL of supernatant, to which 1% sodium hydroxide (1 mL) is added. If the supernatant turns brown within 1–2 minutes, it indicates maternal blood; if it remains pink, it indicates infant blood.
Neonatal Gastrointestinal Bleeding
Conditions such as necrotizing enterocolitis, stress ulcers, or congenital gastric perforation may present with hematemesis or melena. These infants often have a history of asphyxia, infection, or corticosteroid use as underlying conditions. They generally appear more unwell, have notable abdominal signs, and can be differentiated from hemorrhagic disease of the newborn.
Other Hemorrhagic Disorders in Neonates
Thrombocytopenic purpura is characterized by a marked decrease in platelet count.
Disseminated intravascular coagulation (DIC) typically occurs in association with severe underlying conditions and is accompanied by reduced fibrinogen levels and platelet counts.
Hemophilia predominantly affects male infants, often with a family history of the disorder, and is marked by prolonged bleeding following trauma.
Treatment
Intravenous infusion of 1–2 mg of vitamin K1 is effective in stopping bleeding rapidly, with coagulation factor levels rising within hours and full correction achieved within 24 hours. For severe bleeding, fresh frozen plasma at a dose of 10–20 mL/kg or prothrombin complex concentrates may be administered to increase the levels of active clotting factors in the plasma.
Prevention
For mothers taking medications that interfere with vitamin K metabolism during pregnancy, a dose of 10 mg of vitamin K1 should be administered once during the final three months of pregnancy and again prior to delivery. For exclusively breastfed infants, mothers may take oral vitamin K1, 20 mg twice per week. All newborns should receive an intramuscular injection of 0.5–1 mg of vitamin K1 immediately after birth to prevent hemorrhagic disease of the newborn. High-risk infants, including those born prematurely or with liver and biliary diseases, chronic diarrhea, or on long-term total parenteral nutrition, should receive a weekly injection of 0.5–1 mg of vitamin K1.