Surgical evacuation of neonatal intracranial hemorrhage due to vitamin k deficiency bleeding

Four types are generally described: SAH, intracerebral hemor-rhage, IVH, and SDH.3,34,35 In 1894, Charles Townsend first described the syndrome of hemorrhagic disease of the newborn that

IntracranIal hemorrhage in the neonatal period is a

well-recognized and frequent occurrence Four types

are generally described: SAH, intracerebral

hemor-rhage, IVH, and SDH.3,34,35 In 1894, Charles Townsend

first described the syndrome of hemorrhagic disease of

the newborn that usually occurs 1–5 days after birth in

infants with nonclassic hemophilia.4,6,14

Vitamin K is an essential fat-soluble vitamin that was discovered in 1929 by Danish biochemist Henrick Dam—

K stands for koagulation.4 There are 2 types of vitamin K: vitamin K1 (phylloquinone), from plants and vegetable oils, whose absorption from the small intestine needs the presence of bile salts;10 and vitamin K2 (menaquinone), which is synthesized by the intestinal flora.5 Vitamin K

is required for the posttransitional gamma carboxylation

of the coagulation factors II, VII, IX, and X (prothrom-bin complex).21,30 Vitamin K1 does not cross the placenta easily,15 and its concentration in blood is less than 10% of the mean maternal serum level.29 Thus, newborn babies

Surgical evacuation of neonatal intracranial hemorrhage due

to vitamin K deficiency bleeding

Clinical article

A shrAf s hAker Z idAn , M.d., 1 And h eshAM A bdel -h Ady , M.d 2

Departments of 1 Neurosurgery and 2 Pediatrics, Faculty of Medicine, Mansoura University, Mansoura, Egypt

Object Although the incidence of vitamin K deficiency bleeding (VKDB) in neonates has dramatically

de-creased in the developed world since the adoption of routine vitamin K prophylaxis, in developing countries the incidence is still high Intracranial hemorrhage (ICH) is the most dangerous complication Early recognition and management are important to decrease the mortality rate and neurological sequelae The authors conducted a prospec-tive study between January 2008 and June 2010 They included all full-term neonates referred to the Department of Neurosurgery at Mansoura University Children’s Hospital with ICH complicating VKDB and necessitating surgical evacuation The objective was to evaluate the clinical presentation, diagnosis, hospital course, and outcome of ICH

in full-term neonates with VKDB after surgical evacuation

Methods Thirty-two neonates with ICH due to VKDB were included Diagnosis and classification of ICH were

based on detailed history, physical examination, and the interpretation of CT or MR imaging studies The diagnosis

of VKDB was based on pretreatment coagulation studies (prothrombin time [PT] and partial thromboplastin time [PTT]), which are grossly abnormal, together with a normal platelet count and correction of coagulation results to normal after vitamin K administration.

Results The mean age (± SD) at onset of symptoms was 20.4 ± 4.9 days Two neonates (6.25%) had early

VKDB, 7 (21.9%) had classic VKDB, and 23 (71.9%) had late VKDB The most common neurological manifesta-tions included focal seizures, disturbed consciousness level, and tense anterior fontanel The most common general manifestations included pallor, respiratory distress, and bleeding from other sites Radiological findings varied from acute subdural hemorrhage (SDH) in 18 cases (56.3%), intracerebral hemorrhage in 10 (31.3%), and acute SDH with underlying intracerebral hemorrhage, intraventricular hemorrhage, and/or subarachnoid hemorrhage in 4 (12.5%) Before administration of vitamin K, the PT was 72.1 ± 45.0 seconds and the PTT was 112.4 ± 57.6 seconds Six to

12 hours after administration of vitamin K, the PT was 14.6 ± 1.6 seconds and the PTT was 34.4 ± 1.0 seconds All patients underwent surgery for evacuation of the ICH after correction of PT, prothrombin activity, and international normalized ratio Evacuation of the ICH was done by either free or osteoblastic bone flap Six patients (18.8%) died, and the other 26 patients had variable degrees of morbidity during the follow-up period (3–24 months).

Conclusions Vitamin K deficiency bleeding, especially the late-onset form, is an important cause of neonatal

ICH In the present study, the most frequent form of ICH in neonates was SDH Focal seizures, disturbed conscious-ness level, tense anterior fontanel, unexplained anemia, and respiratory distress were the major presenting signs Despite early surgical evacuation, these cases are associated with high mortality rate and neurological disabilities

Vitamin K prophylaxis at birth may reduce these severe complications (DOI: 10.3171/2010.12.PEDS10473)

k ey W ords       •      vitamin K deficiency bleeding      •      intracranial hemorrhage      •      newborn      •      surgical evacuation

Abbreviations used in this paper: ICH = intracranial hemorrhage;

IVH = intraventricular hemorrhage; PT = prothrombin time; PTT =

partial thromboplastin time; SAH = subarachnoid hemorrhage; SDH

= subdural hemorrhage; VKDB = vitamin K deficiency bleeding.

receive vitamin K in small amounts from the mother at

birth Prothrombin complex levels will decrease at 1–2

weeks of age and become normal at 6 weeks–6 months

of age.20

Vitamin K deficiency bleeding in infants was

for-merly known as hemorrhagic disease of the newborn.32

It is defined as hemorrhage in infants due to vitamin K

deficiency shown by low activity of vitamin K–dependent

factors (II, VII, IX, and X), normal activity of vitamin K–

independent coagulation factors (I, V, VIII, XI, XII, and

XIII), and the presence of protein induced by vitamin K

absence (PIVKA II); also, administration of vitamin K is

followed by shortening of the PT and correction of

coag-ulation abnormalities after 30–60 minutes.31 There are 3

types of VKDB in infants defined according to the

etiolo-gy and the age at hemorrhage onset: early VKDB (occurs

within 24 hours of birth), classic VKDB (occurs between

2 and 7 days after birth), and late VKDB (occurs more

than 1 week after birth) Although VKDB is rare in most

developed countries, the prognosis of the few in whom it

develops is potentially catastrophic, with more than 50%

of infants with late-onet VKDB presenting with ICH.22

Methods

In this prospective study, all full-term neonates

(ges-tational age ≥ 37 weeks at birth and < 1 month old)

diag-nosed with ICH due to VKDB and referred to the

Neu-rosurgery Department in Mansoura University Children’s

Hospital between January 2008 and June 2010 were

in-cluded Mansoura University Children’s Hospital is one of

the largest pediatric medical centers in Egypt; it is a

refer-ral center for patients from 5 governorates from the Delta

region of Egypt serving a population of approximately 7

million children with 101,000 outpatient visits, 110,000

emergency department visits, and 35,000 patient

admis-sions annually During the study period, 48 neonates with

ICH due to VKDB were evaluated, and only 32 required

surgical evacuation for clinical signs of increased

intra-cranial pressure or radiological evidence of mass effect

(midline shift) Of the 32 patients, 22 were boys and 10

were girls; their ages ranged from 1 day to 4 weeks (mean

20.4 ± 4.9 days); their delivery histories were uneventful;

none were delivered via forceps or vacuum extraction;

and none had a history of trauma, drug intake, or

famil-ial bleeding tendency The neonates presented with acute

neurological manifestations, especially seizures and/or

general manifestations, particularly lethargy Urgent CT

scans of the brain were obtained in patients except one

in whom MR imaging was performed Laboratory

inves-tigations were performed in all cases including complete

blood workup (to exclude anemia and thrombocytopenia),

PT, prothrombin activity, INR (international normalized

ratio), and PTT at the time of presentation and 6–12 hours

after receiving vitamin K

The diagnosis of VKDB was based on the presence

of grossly abnormal PT, PTT, and correction of

coagula-tion results after vitamin K administracoagula-tion with normal

platelet, fibrinogen, and liver function tests.33 Patients

with the other bleeding disorders and secondary,

late-onset hemorrhagic disease of the newborn were not

in-cluded in the study Diagnosis and classification of ICH were based on the interpretation of cranial CT or MR imaging studies Surgical intervention was based on the evaluation of clinical and radiographic findings Anticon-vulsant therapy (phenobarbital, diphenylhydantoin) was instituted in all patients Dexamethasone and mannitol were administered in 21 patients, and acetazolamide was used in 7 patients during the acute phase Twenty-three patients required mechanical ventilation, and 19 patients received dopamine to correct hypotension

Mean results are presented ± SD or as number (%)

Results

The age at onset of symptoms was 20.4 ± 4.9 days The male/female sex ratio was 2.2:1.0 (22:10) Neuro-logical manifestations included focal seizures, disturbed consciousness level, tense anterior fontanel, progressive head enlargement, sunset appearance of both eyes, hyper-tonia, diminished or absent neonatal reflexes, generalized seizures, and hypotonia General manifestations

includ-ed pallor, respiratory distress, lethargy or irritability, or bleeding from other sites (Table 1) Before administration

of vitamin K, the PT was 72.1 ± 45.0 seconds and PTT was 112.4 ± 57.6 seconds The PT and PTT were

correct-ed within 6 to 12 hours after administration of vitamin K—PT was 14.6 ± 1.6 seconds and PTT was 34.4 ± 1.0 seconds Neurological condition deteriorated during that period and necessitated neurosurgical intervention At the time of admission, alanine aminotransferase, aspartate aminotransferase, and bilirubin levels were normal, and the hemoglobin level was 7.8 ± 2.5 g/dl (range 3.5–12.3 g/ dl) Two patients had early VKDB, 7 had classic VKDB, and 23 had late VKDB (Table 2) Brain CT scanning was conducted in all cases, and MR imaging was performed

in 1 neonate Radiological findings included acute SDH

in 18 patients, intracerebral hemorrhage in 10, and acute SDH with underlying intracerebral hemorrhage, IVH, and/or SAH in 4 (Table 3; Figs 1–3)

All infants received vitamin K (1 mg/kg

intramus-TABLE 1: Summary of clinical manifestations in 32 patients

Clinical Findings Patients (%)No of

disturbed consciousness level 26 (81.3)

progressive head enlargement 25 (78.1) sunset appearance of both eyes 25 (78.1) diminished/absent neonatal reflexes 8 (25)

bleeding in another site (gastrointestinal tract, skin) 6 (18.8)

cularly), 9 (28.1%) received fresh-frozen plasma, and 18

(56.3%) received fresh blood for correction of anemia All

neonates underwent surgery for evacuation of the ICH

af-ter correction of PT and PTT Evacuation of the ICH was

done by either free or osteoblastic bone flap In 5 patients

with acute SDH, surgery was performed using free bone

flap, but the bone flap was not replaced in the same

sur-gery because the brain was tense The flap was preserved

in the anterior abdominal wall of these patients; it was

re-positioned again after 2 weeks in 2 patients only; the

oth-er 3 patients died Six patients died, and the othoth-er 26 cases

experienced marked improvement with varying degrees

of morbidity during the follow-up period (3–24 months);

hydrocephalus developed in 3 patients, persistent seizure

disorder in 8 patients, major motor disturbance in 4, and

vegetative state in 2 (Table 4)

Discussion

Intracranial hemorrhage in the neonatal period is a

well-recognized and frequent occurrence Spontaneous

neonatal ICH may be due to VKDB,22 germinal matrix

hemorrhage extending to brain parenchyma,17,36 or

rup-ture of vascular malformations

Three patterns of VKDB are recognized in infancy:

1) early, 2) classic, and 3) late Early VKDB occurs

with-in the first 24 hours of birth, usually with-in a baby born to

mother who has been taking certain drugs

(anticonvul-sants [barbiturates, phenytoin],11 antituberculous drugs

[rifampin], and vitamin K antagonist).26 The mortality

rate is high in this type of VKDB In our study, 2 infants

(6.25%) had early VKDB, 1 whose mother took

antitu-berculous drugs early in her pregnancy These 2 patients

underwent surgery for evacuation of the ICH, and 1 died

due to the severity of bleeding (this patient also had a low

preoperative Glasgow Coma Scale score) Classic VKDB

occurs at 2–7 days of age and is usually due to vitamin

K deficiency from low vitamin intake and low storage at

birth Classic VKDB was found in infants who did not

receive vitamin K after birth It is associated with a low

mortality rate18 and bleeding usually occurs in the

gas-trointestinal tract, skin, or intracranially In our series, 7

patients (21.9%) had ICH due to classic VKDB, with none

having received vitamin K at birth, and 1 (14.3%) of the 7 patients died due to associated extensive gastrointestinal bleeding Late VKDB occurs more than 1 week after birth and is usually associated with a high rate of ICH as a pre-senting feature.8 Another common feature is widespread deep ecchymosis or nodular purpura.24 Known risk fac-tors include breast feeding alone and failure to give vita-min K prophylaxis at birth An association between late VKDB and undiagnosed abnormalities of liver function has been reported in surveillance programs from several countries,23 especially cholestatic liver diseases.12,22 In our study, 23 patients (71.9%) had late VKDB; only 1 neonate had biliary atresia and died of rapid deterioration of liver function postoperatively

Clinical presentations of ICH in neonates are non-specific Any presentation of the core neurological symp-toms (for example, seizure, fever, reduced consciousness,

TABLE 2: Classification according to age at onset of bleeding

after birth

No of Patients (%) Age at Onset of Hemorrhage

2 (6.25) early (w/in 24 hrs of birth)

7 (21.9) classic (w/in 2–7 days of birth)

23 (781.9) late (1 wk after birth)

TABLE 3: Classification according to the radiological findings

No of Patients (%) Type of Hemorrhage

18 (56.3) acute SDH

10 (31.3) intracerebral hemorrhage

4 (12.5) acute SDH w/ underlying intracerebral hemor-

rhage, IVH, &/or SAH

F ig 1 Case 1 Acute SDH Preoperative T1-weighted MR image (A), preoperative T2-weighted MR image (B), postoperative T1-weighted

MR image (C), and postoperative T2-weighted MR image (D).

F ig 2 Case 2 Intracerebral hematoma Preoperative (left) and postoperative (right) CT scans.

generalized hypotonia, and increased intracranial

pres-sure) may be indicative of ICH Hanigan et al.16 reported

that the most common presenting symptoms in infants

with ICH were seizures, respiratory distress, and apnea

within 2 days of birth (in 24 [72%] of 33 infants) In

an-other study, it was found that the most frequent

present-ing symptoms were pallor (77.4%), seizures (58%), altered

consciousness (58%), vomiting (44%), and poor feeding

(35%) Pulsatile fontanel was found in 61% and bulging

in 26% Seven patients (22.5%) had a history of antibiotic

use.27 In a more recent study,25 the initial presentation of

ICH included seizures in 11 neonates (46%), cyanosis in

7 (29%), tachypnea in 5 (21%), and fever, hypothermia,

and poor feeding (1 child in each category [4%]) These

findings were consistent with those of the current study

More than half of the full-term infants with ICH in

this study also exhibited anemia Anemia or abnormal

hematological findings may suggest the presence of

in-ternal hemorrhage, including ICHs (that is, large SDHs)

A diagnosis of intracranial SDH should be considered in

such cases, especially when anemia is left unexplained

The presence of one or more of the common presenting

signs in full-term neonates should alert physicians to the

possibility of ICH

In the present study, the most frequent form of ICH in

neonates was acute SDH (56.3%); this was followed by

in-tracerebral hemorrhage (31.3%) and multiple-compartment

hemorrhage (12.5%) In our study, all patients received

pre-operative vitamin K to correct the coagulation defect, as

well as blood to correct anemia (if present) Fresh-frozen

plasma was given to patients with severe ICH in whom

blood transfusion was not required to achieve rapid

hemo-stasis Fresh-frozen plasma contains all blood-clotting

fac-tors and is recommended for neonates with severe VKDB

A common dosing regimen is 10–20 ml/kg every 12–24

hours depending on the clinical situation,3,13 together with

dehydrating measures to reduce the elevated intracranial

pressure Open surgery is then performed using either

os-teoblastic or free bone flaps for evacuation of acute SDH

and/or intracerebral hematoma as early as possible

The prognosis in infants with neonatal ICH due to

VKDB depends on early diagnosis, rapid and adequate

correction of the coagulation defect, and the general

con-dition of the patient, including factors such as the presence

of anemia and rapid surgical intervention Symptomatic

ICH in neonates is associated with a relatively low mor-tality rate (11% at 3-year follow-up), but it remains a cause

of neurological morbidity in survivors.19 Our findings revealed a high rate of disability among survivors This may vary with the type of ICH Jhawar et al.19 performed

a follow-up study of term infants with ICH and found that the most favorable outcomes were seen in those with acute SDH (80% had no reported problems in cognitive

or motor development), whereas the worst outcomes were seen in infants with SAH and those with multiple-com-partment involvement We also found that ICH involving multiple compartments (with SAH, SDH, or IVH) tended

to be associated with poorer developmental outcomes: the

4 infants with multiple-compartment involvement exhib-ited abnormal outcomes

Vitamin K deficiency bleeding is a significant neona-tal threat that is entirely preventable in newborns by uni-versal prophylaxis with a safe and inexpensive interven-tion that is akin to immunizainterven-tion Public health policy in developing countries should underscore intramuscular in-jection of vitamin K for all newborns A recent Cochrane Review supports use of vitamin K for all newborns at birth.28 The weight of evidence indicates that injection of vitamin K has the advantage over oral administration be-cause 1 dose suffices for injection, whereas when admin-istered orally, more than 3 doses are required.9 In their policy statements, the American Academy of Pediatrics has endorsed the universal supplementation of vitamin K delivered via intramuscular injection.1,2 Although intra-muscular administration of vitamin K has been

report-ed to be associatreport-ed with an increasreport-ed risk of childhood cancer, subsequent extensive studies have yielded no evi-dence of any such relationship.7

Conclusions

Vitamin K deficiency bleeding, especially the late-onset form, is an important cause of neonatal ICH The most frequent form of ICH in term neonates in the present study was SDH Focal seizures, disturbed consciousness level, tense anterior fontanel, unexplained anemia, and respiratory distress were the major presenting signs De-spite early surgical evacuation, these cases are associated with a high mortality rate and neurological disabilities Vitamin K prophylaxis at birth may reduce these severe complications

Disclosure

The authors report no conflict of interest concerning the

mate-TABLE 4: Mortality and morbidity following surgical evacuation

of neonatal ICH

Patient Outcome No of Patients (%)

persistent seizure disorder 8 (25) major motor disturbance 4 (12.5)

F ig 3 Case 3 Acute SDH Preoperative (left) and postoperative

(right) CT scans.

rials or methods used in this study or the findings specified in this

paper.

Author contributions to the study and manuscript preparation

include the following Conception and design: Zidan Acquisition of

data: both authors Analysis and interpretation of data: both authors

Drafting the article: Zidan Reviewed final version of the manuscript

and approved it for submission: both authors

Administrative/techni-cal/material support: Abdel-Hady Study supervision: both authors.

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Manuscript submitted October 22, 2010.

Accepted December 23, 2010.

Address correspondence to: Ashraf Shaker Zidan, M.D., Faculty

of Medicine, Mansoura University, Mansoura 35516, Egypt email: ournour2004@yahoo.com.