eMedicine Specialties > Pediatrics: Cardiac Disease and Critical Care Medicine > Neonatology

Hemorrhagic Disease of Newborn

Author: Dharmendra J Nimavat, MD, FAAP, Assistant Professor of Clinical Pediatrics, Department of Pediatrics, Division of Neonatology, Southern Illinois University School of Medicine
Coauthor(s): Michael P Sherman, MD, Professor, Department of Child Health, University of Missouri-Columbia School of Medicine; Director, Fellowship Training Program in Neonatal-Perinatal Medicine, NICU, Columbia Regional Hospital; Professor Emeritus, Department of Pediatrics, University of California, Davis, School of Medicine
Contributor Information and Disclosures

Updated: Sep 14, 2009

Introduction

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 K–dependent 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
  • 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

Currently, the following 3 forms of vitamin K are known:

• K₁: 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 K₁.
• K₂: Menaquinone 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

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 infant’s 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 μ g/L). The recommended dietary intake of vitamin K is 1 μ 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 gut’s 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.

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.

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

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

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