Intracerebral hemorrhage due to hemorrhagic disease of the newborn and failure to administer vitamin K at birth.

Abstract: In infants, intracerebral hemorrhage (ICH) is most likely the result of trauma or disturbances of coagulation function. Routine and standard care of the newborn includes the administration of vitamin K to prevent hemorrhagic disease of the newborn. We present two infants, the products of home deliveries, who did not receive vitamin K at birth. Both infants developed ICH at 5 weeks of age and presented with signs and symptoms of increased IC pressure. In both cases, recombinant factor VIIa was administered to correct coagulation function and allow immediate surgical intervention which included craniotomy and hematoma evacuation in one patient and placement of a ventriculostomy in the other to treat increased IC pressure. Despite this therapy, both infants were left with severe neurologic sequelae. These two cases illustrate that hemorrhagic disease of the newborn can occur when prophylactic vitamin K is not administered and that it can have devastating consequences. Given these issues, the routine administration of vitamin K to all infants is mandatory and should not be considered optional.

Key Words: intracerebral hemorrhage, hemorrhagic disease of the newborn, vitamin K, recombinant factor VIIa

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When compared with the adult population, intracerebral hemorrhage (ICH) is rare in infants and children. ICH in adults is primarily related to prolonged hypertension, amyloid angiopathy, or arteriovenous malformations, whereas ICH in infants is more likely to be the result of trauma or disturbances in coagulation function. (1) In adults, intracerebral hemorrhage has the highest mortality of any type of stroke with only 38% of patients surviving beyond 1 year. (1) A significant factor in the eventual morbidity and mortality of ICH is the volume of the hematoma. (2) Although initial theories regarding ICH assumed that the entire bleed occurred as a single event with limited increase in size over time, the more recent prospective trials have demonstrated that hematoma growth occurs in 38% of patients. (3) Given these data, it is possible that interventions which prevent hematoma growth may have a favorable effect on outcome. In addition, in patients with increased ICP, surgical intervention may be required for decompressive craniectomy, placement of CSF drainage catheters or removal of intracerebral hematoma. In such cases, rapid control of coagulation function may allow for earlier surgical intervention.

We present two infants who did not receive routine vitamin K prophylaxis after birth and who subsequently presented with ICH related to hemorrhagic disease of the newborn due to vitamin K deficiency. These cases emphasize the importance of the continued routine administration of vitamin K following birth and the potential devastating sequelae when this practice is ignored. Recombinant factor VIIa (rFVIIa) was administered to correct coagulation function and allow for early surgical interventions. The potential therapeutic role of rFVIIa in preventing hematoma growth and allowing early surgical intervention in such cases is discussed.

Case Reports

Patient No. 1

The care provided to this patient before the day of admission was given by physicians outside of our healthcare system. A previously healthy 5-week-old, 4.0-kg infant developed severe irritability and was inconsolable the morning of admission. The patient's past medical history was significant for a home delivery. Subsequent review (after his arrival in the Pediatric ICU) revealed that vitamin K was not administered following his birth. The parents were told that the circumcision, performed at 10 days of age, took longer than usual because of bleeding. Nine days before admission, the mother accidentally cut his finger while trimming his nails. His finger continued to bleed for 2 days. One week before admission, the parents noticed a bruise with a nodule on the patient's left chest wall. A chest x-ray revealed no abnormality; however, an ultrasound of the chest wall mass revealed a resolving hematoma. The mother also noted that the baby was fussier than her other infants had been, but was otherwise doing well until the morning of admission when he was crying inconsolably and not nursing as well. He was afebrile with normal urine and stool output. The patient had been seen earlier that day at an urgent care clinic because he was screaming, fussy, and acting differently than normal. At that time, he was noted to have palatal petechiae and a rapid strep was performed which was negative. He was discharged home with the diagnosis of a possible viral infection versus onset of colic. The patient remained fussy throughout the day and then refused to nurse despite an interval of 5 hours between feeds. The mother noticed that his left eyelid was drooping and that he had rapid deep breathing and an irregular pulse. The patient was not responding appropriately and patient's right upper extremity started to shake while the lower extremities were stiff and extended. The patient was brought to the emergency room. After endotracheal intubation and placement of a peripheral IV cannula, he was admitted to the Pediatric Intensive Care Unit (PICU). At arrival to the PICU, the patient was unresponsive with a bulging anterior fontanelle. The left pupil was fixed and dilated at 5 mm, the right pupil measured 3 mm and was minimally responsive. A 4 mm hematoma was present along the left chest wall in the midaxillary line. Mannitol (1 g/kg) was administered. Computed tomography of the head revealed a large left IC hemorrhage, subfalcine herniation, a 1 cm midline shift, and cerebral edema (Fig. 1). The initial laboratory evaluation revealed a prothrombin time (PT) greater than 90 seconds, partial thromboplastin time (PTT) greater than 150 seconds, an international normalized ratio (INR) of 30.5 and normal fibrinogen. After neurosurgical consultation, a decision was made to proceed to the operating room. After obtaining informed consent from the parents, rFVIIa (100 [micro]g/kg) was administered and the patient was transported to the operating room. Fresh frozen plasma (FFP) and packed red blood cells (PRBCs) were ordered from the blood bank to be sent to the operating room. Approximately 20 minutes after the administration of rFVIIa and before the administration of FFP, the surgical incision was made. A left parietal craniotomy was performed. There was minimal blood loss (20 mL) with the scalp incision and no problems noted clinically with coagulation function. Approximately 60 minutes after the request was sent to the blood bank, the FFP arrived in the operating room. During the 2.5-hour surgical procedure, the estimated blood loss was 50 mL. Two hours after the initial dose, a second dose of rFVIIa (100 [micro]g/kg) was administered in the operating room. After the evacuation of the hematoma, a bone flap was left out to allow for decompression in the event that there was increasing cerebral edema. The skin was closed and the infant returned to the PICU. Six hours after the initial set of coagulation parameters, the PT was 8 seconds, the PTT was 36.3 seconds, and INR was 0.4. Postoperatively, the infant's cardiorespiratory function was stable. Mannitol was administered to control IC pressure (ICP) and phenobarbital administered to control seizure activity. Studies on the initial serum sample revealed vitamin K dependent factors II, VII, IX, and X to be <7%, 13%, 2%, and <7% of normal, respectively. Factor V, a non-vitamin K dependent factor, produced by the liver, was normal. The patient's trachea was extubated on hospital Day 8. A barium swallow study revealed no evidence of aspiration and the infant was transitioned from nasojejunal feeds to breast feeding. The infant was discharged home on hospital Day 15 with neurology, neurosurgery, and developmental clinic follow up. Ongoing follow up has revealed severe developmental delay and failure to attain normal development milestones.

Patient No. 2

A 5-week old infant who was the product of a home birth developed irritability. The parents initially took the infant to a chiropractor who performed cranial manipulation. The infant remained irritable over the ensuing 48 hours and the day before admission to our institution, the report from the family's pediatrician was that the only abnormal physical finding was scleral icterus. No blood work was performed at that time. On the day of admission, the infant ceased nursing and became less responsive. The parents took the infant to a nearby emergency room where laboratory evaluation revealed a hemoglobin of 6.4 g/dL, a hematocrit of 18.4% and a platelet count of 782,000/mm. (3) CT scan at the outside emergency room revealed the presence of subarachnoid blood, a right intracerebral hemorrhage and acute hydrocephalus (Fig. 2). The infant's trachea was intubated, and he was transferred to our institution. At arrival, the infant's fontanel was bulging. He displayed no eye opening or motor response to pain. The right pupil was 3 mm and fixed, the left pupil was 1 mm. Corneal and gag reflexes were intact. Initial laboratory evaluation revealed a PT greater than 90 seconds, INR of 30.5, and a PTT greater than 150 seconds. After informed parental consent was obtained, rFVIIa (90 [micro]g/kg) was administered intravenously to allow for emergency placement of a ventriculostomy catheter. Repeat coagulation parameters after the administration of rFVIIa revealed a PT of 14.6 seconds, INR 1.2, and PTT of 53.5 seconds. Placement of the ventricular catheter proceeded without consequence and revealed an opening pressure of 30 cm [H.sub.2]O (normal less than 20 cm [H.sub.2]O). Following the ventriculostomy placement, the infant's pupils were equal and reactive, and he responded to painful stimuli. Subsequent history was obtained which revealed that the infant had been a home delivery and had not received vitamin K. FFP was subsequently administered to correct the coagulation disturbance. More than 40 mL/kg of FFP was needed to normalize coagulation function. The patient had a protracted 2-week hospital course and was subsequently discharged from the hospital. However, he suffered significant developmental delay with failure to thrive due to poor swallow function. His parents declined further invasive therapy, and he died at home before 1 year of life.

Discussion

We present two infants with severe ICH related to hemorrhagic disease of the newborn (HDN), both of whom suffered devastating neurologic sequelae related to the hemorrhage. Both had been the products of home delivery and did not receive vitamin K therapy. These cases demonstrate that there can be significant consequences of hemorrhagic disease of the newborn and further emphasize the importance of the routine administration of vitamin K to all newborns, regardless of the time or place of delivery.

Coagulation factors II, VII, IX, and X are dependent on vitamin K for their synthesis in the liver. Low levels of vitamin K have been noted in cord blood and in livers of aborted fetuses. Only 10% of maternally administered vitamin K is delivered to the fetus. Bleeding from vitamin K deficiency (VKDB) during the newborn period can be divided into early, classic, and late variants. (4) The early form occurs within the first 24 hours after birth and cannot be prevented by postnatal vitamin K prophylaxis. (4) It occurs in infants of mothers taking medications that interfere with vitamin K stores or function (warfarin, anticonvulsants, rifampin, or isoniazid). Pregnant women taking these medications should receive 5 mg of vitamin K daily during the third trimester to prevent bleeding complications in the newborn. The classic form of HDN usually presents on day of life 2 to 5 with gastrointestinal, nasal, skin, or circumcision site bleeding. Potential contributing factors include the low placental transfer of vitamin K, low concentrations of vitamin K in breast milk (especially when compared with cow's milk), decreased oral intake during the first few days of life, and lack of endogenous flora in the GI tract. (5,6) The frequency of classic HDN has been reported to be as high as 1 in 200 to 400 infants who do not receive prophylactic vitamin K. (5,6) The late form of VKDB occurs 2 to 12 weeks after birth and at least half may present as IC hemorrhage. The late form may be associated with failure to administer prophylactic vitamin K, but there may also be complicating factors which interfere with vitamin absorption from the GI tract, including malabsorption, infectious diarrhea, cystic fibrosis, [[alpha].sub.1]-antitrypsin deficiency, hepatic dysfunction, or celiac disease.

[FIGURE 1 OMITTED]

Hemorrhagic disease of the newborn (HDN) was first described by Townsend (7) as hemorrhages from multiple sites in otherwise healthy infants. In 1929, Dam (8) first made the connection between vitamin K deficiency and spontaneous hemorrhaging in chicks. Prothrombin concentrations were noted to be decreased and prothrombin times increased on day of life 2 to 4 in newborns who had not received vitamin K. (5,9) Subsequently, vitamin K was used to treat infants with HDN, and many began to recommend prophylactic vitamin K. (10) This was later questioned when it was noted that levels of other coagulation proteins were also low in newborns, and it was postulated that bleeding in neonates was due to causes other than vitamin K deficiency. (7,11,12) In addition, part of the reluctance to recommend widespread use of vitamin K prophylaxis at the time resulted from adverse effects related to now outdated forms of vitamin K, such as a water-soluble form (V[K.sub.3] or menadione) which resulted in hemolytic anemia and kernicterus in some infants. (13) Therefore, vitamin K prophylaxis was suspended in some healthy term infants resulting in a recurrence of HDN.

[FIGURE 2 OMITTED]

Additional controversy regarding vitamin K prophylaxis was provided in 1990 by Golding et al, (14,15) who reported an increased risk of developing childhood oncologic diseases associated with parenteral vitamin K prophylaxis during the newborn period. After reviewing the evidence, Ross and Davies (16) found no evidence to link parenteral vitamin K prophylaxis and cancer in childhood. Further support of the lack of an association between vitamin K and childhood cancer was provided by Draper and Stiller, (17) who used data from the National Registry of Childhood Tumors to estimate the cumulative incidence of childhood leukemia. They compared this to data of IM vitamin K use over the same time period, including estimates from Golding. Their analyses revealed that there was no correlation between the use of parenteral vitamin K and the incidence of childhood leukemia. The Vitamin K Ad Hoc Task Force of the American Academy of Pediatrics (AAP) (18) concluded that there was no association with childhood leukemia or other cancers, that the risk was minimal, and the benefits of prophylaxis with vitamin K were substantial. The current standard of care set by the American Academy of Pediatrics (AAP) since 1961 has been to recommend vitamin K to all newborns as a single IM dose of 0.5 to 1 mg to prevent hemorrhagic disease of the newborn. (12,18)

Also included in the AAP recommendations is that healthcare professionals should promote awareness of the risk of late VKDB associated with inadequate vitamin K prophylaxis from current oral dosage regimens, especially for exclusively breastfed neonates. Although the efficacy of vitamin K prophylaxis in either oral or parenteral forms has been shown to be effective in preventing the early form of VKDB, more research needs to be conducted on the prevention of late VKDB with oral vitamin K. (19-21) If the oral route is used to administer vitamin K, then multiple doses may be needed to prevent the late form of disease. The American Academy of Pediatrics continues to recommend parenteral vitamin K to prevent late VKDB.

As manifested by our patients, failure to administer routine vitamin K prophylaxis at birth can have devastating consequences. After the diagnosis was achieved, the second issue raised by our patients was the need to rapidly treat their coagulation disturbance as they both required emergent surgical intervention for surgical decompression of the hematoma and removal of a bone flap for the treatment of increased ICP in our first patient and for ventriculostomy placement to treat obstructive hydrocephalus in the second case. However, normalization of coagulation function was required before surgical intervention. In most clinical scenarios, the correction of coagulation function is guided by laboratory parameters with the administration of platelets, FFP or cryoprecipitate. There may be several problems with the administration of FFP when there is an urgent need to correct coagulopathies in pediatric patients. The initial dose of FFP (10-20 mL/kg) may not adequately correct coagulation function, time is required to obtain and perform a blood type and crossmatch, FFP must be thawed, and time is required to administer the blood products. During this time, the underlying process may be progressing and worsening the coagulopathy. In our first patient, approximately 60 minutes were required from the time the type and cross was sent until the FFP arrived in the operating room. Volume overload is also a consideration for pediatric patients, especially in patients with brain injury who may develop cerebral edema. Other potential problems include transmission of infectious disease, anaphylactoid reactions, and alterations in serum ionized calcium with hypotension. (22)

Recombinant factor VIIa (rFVIIa, NovoSeven, Novo Nordisk, Princeton, NJ) is a novel hemostatic agent, manufactured using recombinant DNA technology. Its initial application and currently its only FDA-approved application is in the treatment of bleeding episodes or as prophylaxis before surgical procedures in patients with hemophilia and autoantibodies against factor VIII (inhibitors). Following its efficacy in the hemophilia population, there has been an increasing body of clinical experience with rFVIIa in the nonhemophiliac population with coagulation disturbances and bleeding of various etiologies. Although the experience is primarily anecdotal, in many of these cases, rFVIIa has been used to control life-threatening hemorrhage even when conventional therapy has failed. (23,24)

More recently, Mayer et al (25) randomly assigned 399 adult patients with ICH to received either placebo or 1 of 3 doses of rFVIIa (40, 80, 120 [micro]g/kg) within 1 hour of the diagnosis. They noted that hematoma volume increased more in the placebo group when compared with patients receiving rFVIIa (29% versus 16%, 14%, and 11% in the 3 rFVIIa groups respectively, P = 0.01 for rFVIIa versus placebo). Death or severe disability occurred in 69% of placebo patients versus 55%, 49%, and 54% of the patients in the 3 rFVIIa groups (P = 0.004). The authors concluded that treatment within 4 hours of the onset of ICH resulted in limitation of hematoma growth, decreased mortality and improved functional outcome.

In both of our patients, rFVIIa effectively reversed coagulation dysfunction allowing for early surgical interventions in an attempt to treat the consequences of the ICH. As there are no randomized trials in the pediatric population in this or any other clinical scenario to evaluate therapy with rFVIIa, no specific recommendations for its use can be made. However, clinical experience with its use in this and other scenarios has suggested its efficacy. (23,24) Recombinant factor VIIa requires tissue factor for activation. Because tissue factor is released only with vascular damage, the risk for excessive thrombogenesis is theoretically small; however, thrombotic sequelae have been reported. As the use of rFVIIa is off label, we would recommend obtaining informed consent when feasible. In addition, cost is an issue, as the current acquisition price for rFVIIa is approximately $1/[micro]g, or $1,200 for a 1.2 mg vial.

Despite aggressive therapy including the use of rFVIIa and early surgical intervention, both of our patients were left with severe neurologic sequelae. These two cases emphasize the importance of IM vitamin K prophylaxis regardless of the time or place of birth. With current preparations, there are no serious risks with the use of IM vitamin K. There are no data to link vitamin K with childhood malignancies. The AAP continues to recommend vitamin K prophylaxis for all newborns.

References

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2. Mayer SA. Ultra-early hemostatic therapy for intracerebral hemorrhage. Stroke 2003;34:224-229.

3. Chen ST, Chen SD, Hsu CY, et al. Progression of hypertensive intracerebral hemorrhage. Neurology 1989;39:1509-1514.

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6. Haroon Y, Shearer MJ, Rahim S, et al. The content of phylloquinone (vitamin K1) in human milk, cow's milk and infant formula foods determined by high-performance liquid chromatography. J Nutr 1982;112:1105-1117.

7. Townsend CW. The haemorrhagic disease of the newborn. Arch Paediatr 1894;11:559-562.

8. Dam CPH. Cholesterinstoffwechsel in Huhnereierin und Huhnchen. Biochem Zeitschr 1929;215:475-478.

9. Waddell WW, Guerry D. The role of vitamin K in the etiology, prevention, and treatment of hemorrhage in the newborn infant: part II J Pediatr 1939;15:802-811.

10. American Academy of Pediatrics, Committee on Nutrition. Vitamin K compounds and the water-soluble analogues: use in therapy and prophylaxis in pediatrics. Pediatrics 1961;28:501-507.

11. Kugelmass IN. The management of hemorrhagic problems in infant and childhood. JAMA 1932;99:895-897.

12. Clifford SH. Hemorrhagic disease of the newborn: a critical consideration. J Pediatr 1941;18:333-335.

13. Lucey JF, Dolan RG. Hyperbilirubinemia of newborn infants associated with the parenteral administration of a vitamin K analogue to the mothers. Pediatrics 1959;23:553-560.

14. Golding J, Paterson M, Kinlen LJ. Factors associated with childhood cancer in a national cohort study. Br J Cancer 1990:62:304-308.

15. Golding J, Greenwood R, Birmingham K, et al. Childhood cancer, intramuscular vitamin K, and pethidine given during labour. BMJ 1992;305:341-346.

16. Ross JA, Davies SM. Vitamin K prophylaxis and childhood cancer. Med Pediatr Oncol 2000;34:434-437.

17. Draper GJ, Stiller CA. Intramuscular vitamin K and childhood cancer. BMJ 1992;305:709-711.

18. American Academy of Pediatrics, Vitamin K Ad Hoc Task Force. Controversies concerning vitamin K and the newborn (revised). Pediatrics 2003;112:191-192.

19. Cornelissen EA, Kollee LA, De Abreau RA, et al. Effects of oral and intramuscular vitamin K prophylaxis on vitamin KI, PIVKA-II, and clotting factors in breast fed infants. Arch Dis Child 1992;67:1250-1254.

20. Cornelissen M, Von Kries R, Loughnan P, et al. Prevention of vitamin K deficiency bleeding: efficacy of different multiple oral dose schedules of vitamin K. Eur J Pediatr 1997;156:126-130.

21. Greer FR, Marshall SP, Severson RR, et al. A new mixed micellar preparation for oral vitamin K prophylaxis: randomized controlled comparison with an intramuscular formulation in breastfed infants. Arch Dis Child 1998;79:300-305.

22. Cote CJ, Drop LJ, Hoaglin DC, et al. Ionized hypocalcemia after fresh frozen plasma administration to thermally injured children: effects of infusion rate, duration, and treatment with calcium chloride. Anesth Analg 1988;67:152-160.

23. Tobias JD, Groeper K, Berkenbosch JW. Preliminary experience with the use of recombinant factor VIIa to treat coagulation disturbances in pediatric patients. South Med J 2003;96:12-16.

24. Tobias JD. Recombinant factor VIIa in pediatric patients. TATM 2003;5:40-44.

25. Mayer SA, Brun NC, Begtrup K, et al. Recombinant activated factor VII for acute intracerebral hemorrhage. N Engl J Med 2005;352:777-785.

Dena Hubbard, MD, and Joseph D. Tobias, MD

From the Departments of Pediatrics and Anesthesiology, University of Missouri, Columbia, MO.

Reprint requests to Joseph D. Tobias, MD, Vice-Chairman, Department of Anesthesiology, Chief, Division of Pediatric Anesthesiology, Russell and Mary Shelden Chair in Pediatric Intensive Care Medicine, Professor of Anesthesiology and Child Health, University of Missouri, Department of Anesthesiology, 3W-27G HSC, One Hospital Drive, Columbia, MO 65212. Email: [e-mail]

Accepted April 19, 2006.

RELATED ARTICLE: Key Points

* Hemorrhagic disease of the newborn can occur when prophylactic vitamin K is not administered.

* The consequences of hemorrhagic disease in the newborn can lead to devastating consequences.

* The routine administration of vitamin K to all infants should be mandatory and is currently recommended by the American Academy of Pediatrics.

* Intracerebral hemorrhage (ICH) in adults is primarily related to prolonged hypertension, amyloid angiopathy, or arteriovenous malformations, whereas ICH in infants is more likely to be the result of trauma or disturbances in coagulation function.