Neonatal IVH mechanisms and management

IVH prevalence in premature Israeli infants according to weight and gestational age hemorrhage; grade 2: blood within the lateral ventricular system without ventricular dilation; grade 3

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j o u r n a l h o m e p a g e : w w w e l s ev i e r c o m / l o c a t e / t h ro m re s

Neonatal IVH – mechanisms and management

a Pediatric Hematology clinic, Thrombosis and Hemostasis service, Institute of Hematology Western Galilee hospital, Naharriya, Israel

b Thrombosis unit, National Hemophilia Center, Sheba Medical center, Tel Hashomer, Israel

c Thrombosis and Hemostasis Unit, Institute of Hematology, Rambam Medical Center; Israel

d Neonatology department, The Safra Children’s hospital, Tel Hashomer, Israel

e The Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel

f Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel

a r t i c l e i n f o

Keywords:

Neonatal intra-ventricular hemorrhage

(IVH)

Low birth weight premature infants

Pro-coagulant therapy

Long-term neurological sequels

a b s t r a c t

Intra-ventricular hemorrhage (IVH) occurs predominantly in very low birth weight premature infants Survivors of severe IVH frequently experience long-term consequences including major neurological deficits Advances in neonatal and obstetric care in the last decades, have led to a steady decline in mortality and in the incidence of IVH However, significant improvements in the survival rates small premature infants have led to an increase in the population of newborns prone

to IVH The pathogenesis of IVH is multifactorial Prematurity of the germinal matrix, fluctuations in cerebral blood flow, hypoxic ischemic cerebral injury and developmental hemostatic abnormalities

of newborns are important risk factors The following manuscript will address the epidemiology and pathogenesis of IVH and review studies regarding potential pro-coagulant therapy.

© 2011 Elsevier Ltd All rights reserved.

Background

Intra-ventricular hemorrhage (IVH) is the most common type

of intracranial hemorrhage (ICH) and occurs predominantly in

very low birth weight (VLBW-defined as below 1500 g), and

extremely low birth weight (ELBW, defined as <1000 g) premature

infants [1] Survivors of severe IVH frequently experience long-term

consequences including post hemorrhagic hydrocephalus, seizures,

paralysis, cerebral palsy, and other neurological deficits [2]

Advances in neonatal and obstetric care in the last decades, have

led to a steady decline in mortality and in the incidence of IVH in

premature infants [3–6] Nevertheless, significant improvements in

the survival rates of VLBW and ELBW infants in the last decades [7,

8], together with increased preterm delivery rate, have led to an

increase in the population of newborns prone to IVH Consequently,

the number of newborns surviving with severe IVH and therefore at

risk of long-term neurological sequels remains relatively high [9]

Epidemiology and pathogenesis of IVH

Prematurity and low birth weight, prevail among risk factors for IVH

occurrence [10] Data from the National Institute of Child Health and

Human Development (NICHD) Neonatal Research Network show

that 30% of VLBW infants with birth weight 401–1500 grams who

had cranial sonograms developed IVH compared to 3% of infants

* Corresponding author Dr Gili Kenet M.D Thrombosis unit, National

Hemophilia Center, Sheba Medical center, Tel Hashomer, Israel.

Tel.: +972 3 5302950; fax: +972 3 5351806.

E-mail address: Gili.kenet@sheba.health.gov.il (G Kenet).

with birth weight between 1251–1500 grams [11] The rate of severe IVH is significantly higher in infants with birth weight equal to or less than 1000 grams compared to infants with birth weight 1001

to 1500 grams [12] Data from Gertner institute in Israel (Sheba-Medical Center) from 2005 show that the incidence of severe GM-IVH (grade 3–4) in infants with birth weigh of 1250–1500 grams

is 2.8% compared to 30.6% of infants with birth weight between 500–749 grams (Fig 1) The particular vulnerability of premature infants is thought to stem from a sub-ependymal germinal matrix that is rich in immature vessels poorly supported by connective tissue [13,14] This immaturity of the germinal matrix as well as fluctuations in cerebral blood flow [15] – with pressure changes easily transmitted to fragile venous system and choroid plexus, and hypoxic ischemic cerebral injury [16], promote IVH occurrence-since there is evidence of a viscous cycle; ischemia followed

by reperfusion plays a role in the pathogenesis of IVH, while cerebral ischemia may result from IVH Among the multifactorial pathogenetic risks for IVH, abnormalities of the hemostatic and coagulation systems certainly play a role [17–19] While IVH is rarely present at birth, 80–90% of cases occur between birth and the 3rd day of life and 40 to 50% occur on the 1st day [13,20] Thus early diagnosis and treatment should be aimed for, in order to evade future complications

Grading of IVH

The sonographic grading system for IVH [21,22] differentiates hemorrhage grade according to severity Grade 1: blood in the peri-ventricular germinal matrix regions or germinal matrix

Gestational

Grade 3-4 IVH in Israel 2000-2004 ; N=7655

US SCAN PERFORMED TILL DAY 28*

Fig 1 IVH prevalence in premature Israeli infants according to weight and gestational age

hemorrhage; grade 2: blood within the lateral ventricular system

without ventricular dilation; grade 3: blood acutely distending the

lateral ventricles; grade 4: blood within the ventricular system and

parenchyma

Role of coagulation factors in the pathogenesis and attempted

therapy of IVH

The coagulation proteins, independently synthesized by the

fetus, begin to appear by 10 weeks gestational age, and their

concentration gradually increases with gestational age The vitamin

K dependent proteins approach adult levels only by 6 months of

life [17,23,24] Thrombin generation has been shown to be lower in

neonates compared to older children or adults and clot formation

tends to improve with age [25] Consequently, the hemostatic

system in the term infant has little reserve capacity and preterm

infants are even more predisposed to hemorrhagic complications

including IVH

The current standard therapy for newborns includes

administra-tion of vitamin K at the first day of life, in order to reduce the risk

of hemorrhagic disease of the newborn (HDN) However, IVH of

preterm is still a major therapeutic challenge An interesting piece

of work that supports our thesis shows that after administration of

1 mg vitamin K to healthy preterm and small-for-date neonates, no

accelerated increase is seen in coagulation factor activities [26]

Streif et al studied thrombin generation in preterm, term and

adult plasma and evaluated the effect of rFVIIa administration in

these populations [27] Interestingly, there was a very short lag

time to thrombin generation in preterm plasma as compared to

adult samples that may stem from physiologically lower activity

of coagulation inhibitors in neonatal plasma [17], theoretically

increasing the risk for perinatal thrombosis Thirty years ago few

studies were published addressing factor concentrate (including

prothrombin complex concentrates – PCC) administration to sick

preterm infants Gupta et al performed coagulation studies on

128 preterm babies with RDS Of these 44/128 had abnormal

coagulation parameters and prothrombin complex concentrate was

given to 21/44 Rates of death from IVH were high (10/44),

potentially due to late administration of therapy [28] Another

clinical trial of correction of hemostatic defects in high risk neonates

by administration of blood products such as platelet concentrates,

cryoprecipitate or PCC [29] did not show reduced mortality n the treatment group, yet lower IVH rate was noted at autopsy

A small pilot study of 10 preterm infants, aged 23 to 28 weeks of gestation, that were treated with 100mg/kg rFVIIa bolus dose within the first 2 hours, followed by 100mg/kg rFVIIa every 4 hours, for the first 72 hours – resulted in 20% of IVH grade III or IV, which is similar to the rate in studies in which rFVIIa was not given [30] However, good tolerability and safety were shown, and it should be remembered that none of the small pilot studies mentioned could provide the sample size to assess any effect of hemostatic therapy

on the incidence of IVH

In summary, the role of coagulation abnormalities in the pathogenesis of IVH is not clear The studies published in the last decades were inconclusive with regard to yield of prophylaxis with various hemostatic agents due to heterogeneity of agents, doses and timing of the intervention and small sample sizes The relationship between premature coagulation and IVH deserves further attention and potential role of currently available hemostatic agents in IVH therapy should be further studied, with high caution

Conflict of Interest Statement

None of the authors has any conflict of interest to declare

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