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

Hemorrhagic Disease of Newborn

Dharmendra J Nimavat, MD, FAAP, Assistant Professor of Clinical Pediatrics, Department of Pediatrics, Division of Neonatology, Southern Illinois University School of Medicine
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

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.

Vitamin K cycle.

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

Differential Diagnoses

Consumption Coagulopathy
Von Willebrand Disease

Other Problems to Be Considered

Maternal isoimmune thrombocytopenia
Alloimmune thrombocytopenia
Hepatobiliary disease
Uncommon coagulopathies

Workup

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 non–vitamin 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, tumors, and inherited metabolic diseases of the liver.

Treatment

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.

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.^18,19,20

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.

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.²¹
• A 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,²² 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.²³

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

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

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.

Phytonadione K1

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.

Dosing

Adult

Pediatric

Prophylaxis at birth:
>32 wk gestation: 0.5-1 mg IM
Preterm infants <32 wk gestation:
Birth weight >1000 grams: 0.5 mg IM
Birth weight <1000 grams: 0.3 mg/kg SC/IM
Healthy, term and exclusively breast fed infants: 2 mg PO with the first feeding and then at ages 1, 4, and 8 wk
Daily maternal intake of 5 mg PO significantly increases vitamin K in breast milk and infant plasma
Severe hemorrhagic disease treatment: 1-10 mg slow IV; not to exceed 11 mg/min with constant physician monitoring (see precautions)

Interactions

Incompatible with phenytoin; antagonizes actions of warfarin; does not reverse the action of heparin; solution compatibility includes D5W, D10W, and 0.9% NaCl; terminal injection site compatibility with dextrose, amino acids, amikacin, ampicillin, dobutamine, epinephrine, famotidine, heparin, hydrocortisone succinate, KCl, ranitidine, and sodium bicarbonate

Contraindications

Documented hypersensitivity (anaphylactoid symptoms may occur, even with appropriate doses); PO prophylaxis administration in preterm infants, ill infants, infants taking antibiotics, cholestasis, and diarrhea

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Severe reactions, including death, have been reported with IV administration in adults; IV administration may cause anaphylactoid-like reactions (do not exceed administration rate of 1 mg/min); IM administration can result in hematomas, particularly in infants with evidence of bleeding; hemolytic anemia and hyperbilirubinemia rarely occur with larger doses (10-20 mg); the box warning for AquaMEPHYTON states IM injection should be restricted because of serious risk, but the American Academy of Pediatrics recommends a single IM dose at birth

Follow-up

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.
• Hematocrit levels should be obtained serially and before discharge
• Ensure neurologic complications are stable or resolved before discharge.
• Mild vitamin K deficiency bleeding that has been treated successfully can be monitored on an outpatient basis.

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.

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.

Deterrence/Prevention

• Intramuscular (IM) vitamin K prophylaxis at birth is the standard of care in the United States.
• 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.²⁴

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.

Patient Education

The following are useful links to various governments and educational organizations:

• Australian government publication on vitamin K
• Canadian Pediatric Society statement on vitamin K
• New Zealand consensus on vitamin K administration in the newborn
• Children, Youth, and Women's Health Service from Australia
• Vitamin K information from Stanford University
• Mayo Clinic's statement on vitamin K prophylaxis in the newborn
• American Academy of Pediatrics policy statement on vitamin K

Miscellaneous

Medicolegal Pitfalls

• 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.

Special Concerns

• Many Web sites 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.
• Please see the Web sites provided in Patient Education for more information regarding vitamin K.

Multimedia

Media file 1: Vitamin K cycle.

References

1. Brinnhous KM, Smith HP, Warner ED. Plasma plasma prothrombin level in normal infancy and in hemorrhagic disease of the newborn. Am J Med Sci. April 1937;193:475-81.

2. Gelston CF. On the etiology of hemorrhagic disease of the newborn. Arch Pediatr Adol Med. Oct 1921;22:351-7.

3. Bandyopadhyay PK. Eight. In: Vitamins and Hormones. Vol 78. Elsevier Inc; 2008:157-84. [Full Text].

4. Hougie C, Barrow EM, Graham JB. Stuart clotting defect. I. Segregation of an hereditary hemorrhagic state from the heterogeneous group heretofore called stable factor (SPCA, proconvertin, factor VII) deficiency. J Clin Invest. Mar 1957;36(3):485-96. [Medline].

5. Clarke P, Shearer MJ. Vitamin K deficiency bleeding: the readiness is all. Arch Dis Child. Sep 2007;92(9):741-3. [Medline].

6. Victora C. Vitamin K deficiency and haemorrhagic disease of the newborn: a public health problem in less developed countries?. New York: UNICEF; Feb 1997. UNICEF Staff Working Papers; Evaluation, Policy, and Planning Series. [Full Text].

7. Sutor AH, von Kries R, Cornelissen EA, McNinch AW, Andrew M. Vitamin K deficiency bleeding (VKDB) in infancy. ISTH Pediatric/Perinatal Subcommittee. International Society on Thrombosis and Haemostasis. Thromb Haemost. Mar 1999;81(3):456-61. [Medline].

8. Pichler E, Pichler L. The neonatal coagulation system and the vitamin K deficiency bleeding - a mini review. Wien Med Wochenschr. 2008;158(13-14):385-95. [Medline].

9. Oldenburg J, Marinova M, Müller-Reible C, Watzka M. The vitamin K cycle. Vitam Horm. 2008;78:35-62. [Medline].

10. Widdershoven J, van Munster P, De Abreu R, et al. Four methods compared for measuring des-carboxy-prothrombin (PIVKA-II). Clin Chem. Nov 1987;33(11):2074-8. [Medline].

11. Benno Y, Sawada K, Mitsuoka T. The intestinal microflora of infants: fecal flora of infants with vitamin K deficiency. Microbiol Immunol. 1985;29(3):243-50. [Medline].

12. Paiva SA, Sepe TE, Booth SL, et al. Interaction between vitamin K nutriture and bacterial overgrowth in hypochlorhydria induced by omeprazole. Am J Clin Nutr. Sep 1998;68(3):699-704. [Medline].

13. Greer FR. Vitamin K status of lactating mothers and their infants. Acta Paediatr Suppl. Aug 1999;88(430):95-103. [Medline].

14. von Kries R, Shearer MJ, Widdershoven J, Motohara K, Umbach G, Gobel U. Des-gamma-carboxyprothrombin (PIVKA II) and plasma vitamin K1 in newborns and their mothers. Thromb Haemost. Oct 5 1992;68(4):383-7. [Medline].

15. Gibbons RJ, Engle LP. Vitamin K compounds in bacteria that are obligate anaerobes. Science. Dec 4 1964;146:1307-9. [Medline].

16. Booth SL, Suttie JW. Dietary intake and adequacy of vitamin K. J Nutr. May 1998;128(5):785-8. [Medline].

17. Greer FR, Mummah-Schendel LL, Marshall S, Suttie JW. Vitamin K1 (phylloquinone) and vitamin K2 (menaquinone) status in newborns during the first week of life. Pediatrics. Jan 1988;81(1):137-40. [Medline].

18. [Guideline] American Academy of Pediatrics Committee on Nutrition. Vitamin K compounds and their water soluble analogues. Pediatrics. Sept 1961;28:501-7.

19. [Guideline] American Academy of Pediatrics Committee on Fetus and Newborn. Controversies concerning vitamin K and the newborn. Pediatrics. Jul 2003;112(1 Pt 1):191-2. [Medline].

20. American Academy of Pediatrics, Committee on Nutrition. Nutrional Needs of Preterm Infants. In: Ronald E. Kleinman, MD. Nutritional needs of preterm infants. In: Pediatrics Nutrition Handbook. 5th. Elk Grove Village, IL: American Academy of Pediatrics; 1998:23-46.

21. Greer FR, Marshall SP, Foley AL, Suttie JW. Improving the vitamin K status of breastfeeding infants with maternal vitamin K supplements. Pediatrics. Jan 1997;99(1):88-92. [Medline].

22. Van Winckel M, De Bruyne R, Van De Velde S, Van Biervliet S. Vitamin K, an update for the paediatrician. Eur J Pediatr. Feb 2009;168(2):127-34. [Medline].

23. Young TE, Mangum B. Vitamins and Minerals. In: NEOFAX 2008. edition. Montavale, NJ: Thomson Reuters; 2008:288-9.

24. McNinch A, Busfield A, Tripp J. Vitamin K deficiency bleeding in Great Britain and Ireland: British Paediatric Surveillance Unit Surveys, 1993 94 and 2001-02. Arch Dis Child. Sep 2007;92(9):759-66. [Medline].

Keywords

hemorrhagic disease of newborn, HDN, vitamin K deficiency bleeding, VKDB, early-onset VKDB, classic VKDB coagulopathy, late-onset VKDB, GI neonatal bleeding, intracranial hemorrhage, ICH, umbilical cord bleeding, leukemia, cholestasis, intracranial hemorrhage, apnea, seizures, diarrhea, hepatitis, cystic fibrosis, celiac disease, short bowel syndrome, intestinal bacterial overgrowth, treatment, diagnosis

Contributor Information and Disclosures

Author

Dharmendra J Nimavat, MD, FAAP, Assistant Professor of Clinical Pediatrics, Department of Pediatrics, Division of Neonatology, Southern Illinois University School of Medicine
Dharmendra J Nimavat, MD, FAAP is a member of the following medical societies: American Academy of Pediatrics and American Association of Physicians of Indian Origin
Disclosure: Nothing to disclose.

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
Michael P Sherman, MD is a member of the following medical societies: American Academy of Pediatrics, American Association of Immunologists, American Pediatric Society, American Society for Microbiology, European Society for Paediatric Research, Perinatal Research Society, and Society for Pediatric Research
Disclosure: Nothing to disclose.

Medical Editor

Oussama Itani, MD, FAAP, FACN, Clinical Associate Professor of Pediatrics and Human Development, Michigan State University; Medical Director, Department of Neonatology, Borgess Medical Center
Oussama Itani, MD, FAAP, FACN is a member of the following medical societies: American Academy of Pediatrics, American College of Nutrition, American College of Physician Executives, and American Heart Association
Disclosure: Nothing to disclose.

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine
Disclosure: Pfizer Inc Stock Investment from financial planner; Avanir Pharma Stock Investment from financial planner ; WebMD Salary and stock Employment and investment from financial planner

Managing Editor

David A Clark, MD, Chairman, Professor, Department of Pediatrics, Albany Medical College
David A Clark, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Pediatrics, American Pediatric Society, Christian Medical & Dental Society, Medical Society of the State of New York, New York Academy of Sciences, and Society for Pediatric Research
Disclosure: Nothing to disclose.

CME Editor

Carol L Wagner, MD, Professor of Pediatrics, Medical University of South Carolina
Carol L Wagner, MD is a member of the following medical societies: American Academy of Pediatrics, American Chemical Society, American Medical Women's Association, American Public Health Association, American Society for Bone and Mineral Research, American Society for Clinical Nutrition, Massachusetts Medical Society, National Perinatal Association, and Society for Pediatric Research
Disclosure: Nothing to disclose.

Chief Editor

Ted Rosenkrantz, MD, Professor, Departments of Pediatrics and Obstetrics/Gynecology, Division of Neonatal-Perinatal Medicine, University of Connecticut School of Medicine
Ted Rosenkrantz, MD is a member of the following medical societies: American Academy of Pediatrics, American Medical Association, American Pediatric Society, Connecticut State Medical Society, Eastern Society for Pediatric Research, and Society for Pediatric Research
Disclosure: Nothing to disclose.

The authors appreciate the review of this article and helpful suggestions for improvement from Professor Daniel Batton, the Director of the Neonatology Division at Southern Illinois University School of Medicine.

© 1994- by Medscape.
All Rights Reserved
(http://www.medscape.com/public/copyright)