Thrombosis Research 127 Suppl. 3 (2011) S120–S122

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Thrombosis Research 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 r o m r e s

Neonatal IVH – mechanisms and management Gili Kenetb,f, *, Amir A. Kupermana,e , Tzipora Straussb,d,f , Benjamin Brennerc,e a Pediatric

Hematology clinic, Thrombosis and Hemostasis service, Institute of Hematology Western Galilee hospital, Naharriya, Israel unit, National Hemophilia Center, Sheba Medical center, Tel Hashomer, Israel 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 b Thrombosis c

article info

abstract

Keywords: Neonatal intra-ventricular hemorrhage (IVH) Low birth weight premature infants Pro-coagulant therapy Long-term neurological sequels

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

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 (ShebaMedical Center) from 2005 show that the incidence of severe GMIVH (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 occurrencesince 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

* 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: [email protected] (G. Kenet). 0049-3848 /$ – see front matter © 2011 Elsevier Ltd. All rights reserved.

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

G. Kenet et al. / Thrombosis Research 127 (2011) S120–S122

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Grade 3-4 IVH in Israel 2000-2004 ; N=7655 WEIGHT (grams)

all

1400–1500

5.8

3.9

2.1

0.9

1.4

0.9

1.3

0.0

2.6

1300–1399

12.9 7.9

5.5

1.3

0.0

0.0

0.0

3.5

1200–1299

6.2

6.0

2.6

3.6

0.9

0.0

0.0

4.2

1100–1199

20.5 7.9

4.1

1.0

2.1

1.5

2.7

1000–1099

28.0 20.9 8.8

4.7

2.5

1.7

0.0

900–999

28.6 19.9 6.3

9.2

0.0

0.0

800–899

31.7 18.9 17.3 6.1 16.7

6.6 10.0 13.8 18.0

700–799

26.4 37.0 22.6 15.8 10.8

23.4

600–699

40.4 31.2 29.4

31.6

500–599

50.9

36.4

<500 all Gestational age (weeks) <23

20.9 50.5 39.0 33.3 24.0 18.5 8.4 23

24

25

26

27

28

6.8

3.5

2.1

29

30

31

0.8

0.8

0.4

1.5

1.6

3.0

32

33

34

35

36

>36

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 administration 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. References [1] Levene MI, Wigglesworth JS, Dubowitz V. Cerebral structure and intraventricular haemorrhage in the neonate: a real-time ultrasound study. Arch Dis Child 1981;56(6):416–24. [2] Volpe JJ. Neurology of the Newborn. 4th ed. Philadelphia: W.B. Saunders Company; 2001. [3] Improved outcome into the 1990s for infants weighing 500–999 g at birth. The Victorian Infant Collaborative Study Group. Arch Dis Child Fetal Neonatal Ed 1997;77(2):F91–4. [4] Ahmann PA, Lazzara A, Dykes FD, Brann AW, Jr., Schwartz JF. Intraventricular hemorrhage in the high-risk preterm infant: incidence and outcome. Ann Neurol 1980;7(2):118–24. [5] Sheth RD. Trends in incidence and severity of intraventricular hemorrhage. J Child Neurol 1998;13(6):261–4. [6] Hintz SR, Kendrick DE, Vohr BR, Poole WK, Higgins RD. Changes in neurodevelopmental outcomes at 18 to 22 months’ corrected age among infants of less than 25 weeks’ gestational age born in 1993–1999. Pediatrics 2005;115(6):1645–51. [7] Horbar JD, Badger GJ, Carpenter JH, Fanaroff AA, Kilpatrick S, LaCorte M, et al. Trends in mortality and morbidity for very low birth weight infants, 1991– 1999. Pediatrics 2002;110(1 Pt 1):143–51.

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