Pharmacological Management of Germinal Matrix-Intraventricular Hemorrhage

Jaewoo Chung; Sang Koo Lee; Chun-Sung Cho; Young Jin Kim; Jung Ho Ko; Jung-Ho Yun; Jin-Shup So; In-Ho Jung

doi:10.3340/jkns.2022.0266

Journal List > J Korean Neurosurg Soc > v.66(3) > 1516082752

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Chung, Lee, Cho, Kim, Ko, Yun, So, and Jung: Pharmacological Management of Germinal Matrix-Intraventricular Hemorrhage

Review Article

PediatricIntraventricular hemorrhage (IVH) and posthemorrhagic hydrocephalus (PHH) in preterm infants

J Korean Neurosurg Soc 2023;66(3):258-262.

Published online: 16 February 2023

DOI: https://doi.org/10.3340/jkns.2022.0266

Pharmacological Management of Germinal Matrix-Intraventricular Hemorrhage

Jaewoo Chung^1,²

, Sang Koo Lee^1,²

, Chun-Sung Cho^1,²

, Young Jin Kim^1,²

, Jung Ho Ko^1,²

, Jung-Ho Yun^1,²

, Jin-Shup So²

, In-Ho Jung²

¹Department of Neurosurgery, Dankook University College of Medicine, Cheonan, Korea

²Department of Neurosurgery, Dankook University Hospital, Cheonan, Korea

Address for reprints : Jaewoo Chung Department of Neurosurgery, Dankook University Hospital, Dankook University College of Medicine, 201 Manghyang-ro, Dongnam-gu, Cheonan 31116, Korea Tel : +82-41-550-6280, E-mail : j.chung@dankook.ac.kr

Received 5 December 2022 Revised 3 February 2023 Accepted 14 February 2023

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Germinal matrix-intraventricular hemorrhage (GM-IVH) is among the devastating neurological complications with mortality and neurodevelopmental disability rates ranging from 14.7% to 44.7% in preterm infants. The medical techniques have improved throughout the years, as the morbidity-free survival rate of very-low-birth-weight infants has increased; however, the neonatal and long-term morbidity rates have not significantly improved. To this date, there is no strong evidence on pharmacological management on GM-IVH, due to the limitation of well-designed randomized controlled studies. However, recombinant human erythropoietin administration in preterm infants seems to be the only effective pharmacological management in limited situations. Hence, further high-quality collaborative research studies are warranted in the future to ensure better outcomes among preterm infants with GM-IVH.

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Keywords: Germinal matrix hemorrhage, Cerebral intraventricular hemorrhage, Preterm infant, Erythropoietin

INTRODUCTION

Germinal matrix-intraventricular hemorrhage (GM-IVH) is among the devastating neurological complications with mortality and neurodevelopmental disability rates ranging from 14.7% to 44.7% in preterm infants [4,12,16,21,23,34]. GM-IVH originates from the hemorrhage of the immature capillary network of the subependymal GM, which disrupts the ependymal lining and burst into the lateral cerebral ventricle [31]. In the United States, the incidence of preterm labor has decreased, but one in 10 babies is still born preterm [22]. The medical techniques have improved throughout the years, as the morbidity-free survival rate of very-low-birth-weight infants has increased; however, the neonatal and long-term morbidity rates have not significantly improved [1,8,15,17]. The knowledge of the nature of preterm infants are limited as the medical conditions vary from each preterm infant in gestational age, weight, and comorbidities, thereby making it hard to conduct a well-designed randomized controlled study. Hence, there are no standardized protocols for the treatment of GM-IVH due to a lack of strong evidence [29]. In this review article, we briefly describe the pharmacological management of GM-IVH based on previous literature.

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PATHOGENESIS OF GM-IVH

The GM is located in the subependymal of the ventricular walls, which later develops to cerebral neuroblasts and glia [2,24,28]. The vasculature in GM is formed at approximately 7–8 weeks of gestation and persists until the beginning of the third trimester [24,28]. The thickness of the GM decreases after 24 weeks, which is late second trimester period of gestation, and the GM almost disappears by 36–37 weeks [2]. The vasculature of the GM lacks muscle or collagen; therefore, it is vulnerable to hemodynamic or mechanical stress. According to the classification of hemorrhages by Papile et al. [20], grade I is defined as the hemorrhage confined to the GM, grade II as the hemorrhage extending into the lateral ventricles, it grade III as the presence of ventricular dilatation; and grade IV as the presence of parenchymal hemorrhage.

Once GM-IVH occurs in preterm infants, they are at a high risk of developing poor neurodevelopmental outcomes, including cerebral palsy, intellectual deficits, deafness, and blindness [6]. Approximately 10% of preterm infants at <32 weeks’ gestational with grade II/III GM-IVH progresses to grade III/IV GM-IVH within 1 week [33]. Moreover, the mortality rate of preterm infants with GM-IVH is >20%; >80% of these infants expire within the first week after birth [11,16,23,25]. Therefore, pharmacological management for GM-IVH in preterm infants is focused on preventing GM-IVH, suppressing the progression of GM-IVH and improving the neurological outcomes after GM-IVH.

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PHARMACOLOGICAL MANAGEMENT OF GM-IVH

Pharmacological management for preventing GM-IVH

Phenobarbitone

In theory, reducing hemodynamic stress on the immature vessel network in GM might prevent GM-IVH or at least reduce the possibility of suppressing the increment of the amount of IVH. An early observational study showed that phenobarbitone has possibility of regulation of systemic blood pressure and have protective effect after brain ischemic injury [32]. A 2013 Cochrane review of 12 controlled trials involving 982 preterm infants revealed controversial results on the effect of phenobarbitone on the incidence of GM-IVH [26]. This meta-analysis study showed that the use of phenobarbitone did not have a significant reduction in the risk of IVH, posthemorrhagic ventricular dilatation, neurodevelopmental impairment, or in-hospital death. However, it had increased the risk of the need for mechanical ventilation. In conclusion, based on this strong evidence, postnatal phenobarbital cannot be recommended as a prophylaxis for GM-IVH in preterm infants [26].

Pharmacological management for suppressing the progression of GM-IVH

Ethamsylate (diethylammonium 1,4-dihydroxy-3-benzene sulfonate)

The vessel network of GM in preterm infants lack basement membrane deposition, tight junctions, and glial endfoot investiture, which makes it vulnerable to cerebral blood flow. Therefore, reinforcing basement stability and accelerating hemostasis are expected to suppress the progression of GM-IVH theoretically. Although the exact mechanism is unclear, ethamsylate reduces bleeding time and blood loss from wounds [30]. Therefore, using ethamsylate was suggested in preterm infants with GM-IVH [18]. A Cochrane database systematic review of 1410 preterm infants from seven trials revealed that ethamsylate significantly reduces the risk of grade III and IV GM-IVH among infants at <35 weeks’ gestation [14]. However, in a single group of GM-IVH infants at <32 weeks’ gestation with, ethamsylate did not show a significant reduction in the progression of GM-IVH [14]. However, from this review, use of ethamsylate in preterm infants did not show a significant difference in neonatal mortality rate or neurodevelopmental outcome at 2 years. The adverse side-effect of ethamsylate is hypotension; however, the systematic review showed that there was no significant difference in the hypotension rate between infants treated with ethamsylate and those receiving a placebo drug. In conclusion, the use of ethamsylate in preterm infants is safe and has protective effects against the progression of GM-IVH in limited situations; however, there is a lack of evidence showing that it improves the mortality rate or neurodevelopmental outcome.

Pharmacological management for improving the neurological outcomes after GM-IVH

Recombinant human erythropoietin (EPO)

Once the occurrence of mortality due to GM-IVH has been controlled in preterm infants, improving or at least preventing the progression of neurodevelopmental impairments is the next step. EPO accelerates red blood cell production owing to its hematopoietic properties; therefore, recombinant human EPO (rhEPO) is used in various types of anemia and in cases requiring reduction in the number of blood transfusions. rhEPO is also known to have a neuroprotective effect. Hence, it is expected to have a major role in GM-IVH. High-dose rhEPO administration in very-preterm infants (<32 weeks) resulted in significantly higher hematocrit level, reticulocyte count, and white blood cell count and lower platelet count without increasing the rates of mortality or short-term major adverse events, including retinopathy, IVH, sepsis, necrotizing enterocolitis and bronchopulmonary dysplasia [9,10]. A Cochrane database systematic review of 34 studies involving 3643 preterm infants revealed that early rhEPO treatment is safe and significantly decreased the rates of IVH, periventricular leukomalacia, and necrotizing enterocolitis [19]. As the long-term neurodevelopmental outcomes of early rhEPO treatment still remain unclear, the authors do not recommend its routine use due to its limited benefits in preterm infants. However, a recent research study showed rhEPO has benefits in improving the mortality rate and neurodevelopmental outcomes, including atrophy and cognition [13,27]. The beneficial neuroprotective effect of the early administration of rhEPO in preterm infants needs more firm evidence, as it is proven to be safe and it seems to be the only promising treatment for improving long-term neurodevelopmental outcomes.

Vitamin E (tocopherol)

Vitamin E is known for its potent antioxidant properties and it is presumed to scavenge free radicals and protect the capillary endothelial cells of the matrix from injury [3]. Brion et al. [5] conducted a pooled analysis of 26 randomized clinical trials, which showed that vitamin E did not significantly reduce the morbidity or mortality rate. Although vitamin E supplement significantly reduced the risk of GM-IVH, it increases the rate of sepsis among preterm infants. The results of the subgroup analyses showed that high-dose intravenous vitamin E supplementation increased the risk of sepsis and while decrease parenchymal cerebral hemorrhage. Moreover, besides the intravenous route of vitamin E supplementation, other modes of supplementation reduced risk of GM-IVH and its progression. Finally, if the serum tocopherol level is >3.5 mg/dL, the risk of sepsis increases while the risk of severe retinopathy decreases. As most included studies were conducted in the 1970s and 1980s, when the mortality rate of preterm infants was high, the result of this analysis should be carefully interpreted [7]. A recent study showed that vitamin E supplementation did not significantly decrease the risk of GM-IVH in preterm infants, which contradicts the results of the previous pooled analysis [3]. In conclusion, no strong evidence supports the routine use of vitamin E in preterm infants to prevent GM-IVH or suppress its progression.

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CONCLUSION

To this date, there is no strong evidence on pharmachological management on GM-IVH, due to the limitation of well-designed randomized controlled studies. However, rhEPO admisistration in preterm infants seems to be the only effective pharmacological management in limited situations. Hence, further high-quality collaborative research studies are warranted in the future to ensure better outcomes among preterm infants with GM-IVH.

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Notes

Conflicts of interest

No potential conflict of interest relevant to this article was reported.

Informed consent

This type of study does not require informed consent.

Author contributions

Conceptualization : JC; Data curation : JC; Formal analysis : JC; Methodology : JC; Project administration : JC; Writing - original draft : JC; Writing - review & editing : SKL, CSC, YJK, JHK, JHY, JSS, IHJ

Data sharing

None

Preprint

None

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