Description of the condition

Prematurity remains the major risk factor for developing germinal matrix‐intraventricular hemorrhage (GMH‐IVH), which occurs in 25% of very low birth weight (VLBW) infants (Vermont Oxford Network 2013). Complications of germinal matrix‐intraventricular hemorrhage, including periventricular hemorrhagic infarction (PVHI), posthemorrhagic ventricular dilatation (PHVD), cerebellar hemorrhagic injury (CHI) and periventricular leukomalacia (PVL) are critical determinants of neonatal morbidity, mortality, and long‐term neurodevelopmental sequelae (Sherlock 2005). Although modern perinatal medicine has led to a significant decrease in the overall incidence of GMH‐IVH in preterm infants (from 50% in the late 1970s to the current 15% to 25% (Hamrick 2004; Horbar 2002; Philip 1989)), GMH‐IVH continues to be a significant problem in the modern neonatal intensive care unit. Advances in neonatal‐perinatal medicine have led to a higher incidence of preterm births and a major increase in the survival of preterm infants, reaching as high as 85% to 90% (EXPRESS 2009; Ishii 2013). In addition, the incidence of birth and survival of the smallest preterm infants who are at the highest risk for developing GMH‐IVH and its complications has increased during the last decade. Specifically, the incidence of GMH‐IVH reaches 45% in infants with birth weights less than 750 grams, and 35% of these lesions are severe (Wilson‐Costello 2005). It has been suggested that the encouraging decrease in the overall incidence of GMH‐IVH may have reached a plateau during the last decade (Horbar 2002; Horbar 2012).

These trends may lead to the survival of more critically ill infants and as a consequence increase the rate of neurodevelopmental problems caused both by extreme prematurity and GMH‐IVH. Approximately 50% to 75% of preterm survivors with IVH (any grade) develop cerebral palsy, mental retardation, PHVD, or a combination of these conditions, with serious sequelae on neurodevelopmental outcome (Luu 2009). Moreover, around a quarter of non‐disabled survivors develop psychiatric disorders and problems with executive function (Indredavik 2010; Nosarti 2007; Whitaker 2011). Hence, GMH‐IVH and its resultant neurologic and psychiatric sequelae continues to be an important public health concern worldwide. GMH‐IVH in preterm infants is typically diagnosed during the first days of life, 50% on the first day and 90% within the first four days. Between 20% and 40% of these infants undergo progression of hemorrhage during these first days of life (Volpe 2008). The incidence of antenatal IVH is unclear, although an estimate for intracranial bleeding of 1 in 10,000 pregnancies has been suggested (Vergani 1996). Antenatal fetal intracranial hemorrhages may occur spontaneously or in association with various maternal or fetal conditions. Predisposing maternal conditions include platelet and coagulation disorders, medications (warfarin), illicit drugs (cocaine), seizure, smoking, trauma, amniocentesis, and febrile disease; fetal conditions include twin–twin transfusion, demise of a co‐twin, hydrops fetalis, congenital tumors, and feto‐maternal hemorrhage (Kutuk 2014). IVH may undergo spontaneous resolution or, especially for grade 3 and 4, may cause the development of PHVD.

Furthermore, both low‐ and high‐grade GMH‐IVH may affect cerebellar growth, resulting in reduced cerebellum volumes and impaired white matter and motor tract microstructure (Morita 2015; Sancak 2016;Sancak 2017;Srinivasan 2006;Tam 2009;Tam 2011). The cerebellum is the fastest growing portion of the brain, its volume increasing fivefold from 24 to 40 weeks of postmenstrual age (Volpe 2009). During this period, extravasation of hemoglobin due to GMH‐IVH into cerebrospinal fluid (CSF) and further hemolysis of free hemoglobin may result in deposition of hemosiderin on the cerebellar surface, disturbing the normal development of the cerebellar cortex (Fukumizu 1995; Koeppen 2008;Messerschmidt 2005). It is well recognized that the cerebellum plays a crucial role not only in motor function but also in many higher‐order cognitive and affective functions, such as executive functions, working memory and emotional processing (van Overwalle 2014; Volpe 2009). Thus, preventing GMH‐IVH would also help to preserve cerebellum integrity.

The etiology of GMH‐IVH is multifactorial, complex, and heterogeneous. An inherent fragility of the germinal matrix vasculature predisposes for hemorrhage, and fluctuation in the cerebral blood flow induces the rupture of vasculature. The association between cerebral blood flow (CBF) fluctuations and IVH appearance in ventilated neonates with RDS in the first day of life was suggested by Perlman and colleagues (Perlman 1983). In a subsequent study of the same group it has been shown that the elimination of CBF fluctuation by neuromuscular paralysis (pancuronium) resulted in reduction of IVH (Perlman 1985). The question remained as to whether the fluctuations in CBF were due to breathing against the respirator, which could be explained by increased pleural pressure fluctuations. Two studies confirmed that CBF fluctuations were related to RDS extent and pleural pressure fluctuations and that those could be damped by mechanical ventilation (Mullaart 1994; Perlman 1988). To date, it has been suggested that loss of cerebral autoregulation, which is important to maintain constant CBF, may predispose preterm infants to hemorrhagic and ischemic cerebral injury (Boylan 2000; Tsuji 1998). However, the subsequent studies on impaired autoregulation were not predictive of the subsequent development of IVH; nevertheless it was correlated to higher mortality (Soul 2007; Wong 2008). Vaginal delivery, low Apgar score, severe respiratory distress syndrome, pneumothorax, hypoxia, hypercapnia, seizures, patent ductus arteriosus, infection, and other conditions seem to increase primarily the fluctuations in the cerebral blood flow and thus represent important risk factors to the development of IVH (Ballabh 2014). If there are associated platelet or coagulation disorders, the homeostasis mechanisms are impaired, which might accentuate the hemorrhage. Furthermore, the germinal matrix lies within an arterial end zone, and it is directly connected to the deep galenic venous system (Nakamura 1990; Pape 1979), thereby exposing it to insults of arterial ischemia‐reperfusion and to venous congestion (Pape 1979; Takashima 1978). The immature deep galenic system is prone to venous congestion and stasis, making it of potentially major importance for the development of GMH‐IVH and its complications (Pape 1979; Volpe 2008).

Besides the interventions aimed at possibly halting GMH‐IVH progression and reducing its complications, several preventive approaches to GMH‐IVH were proposed which include antenatal and postnatal measures. Several antenatal pharmacologic interventions have been proposed. Antenatal corticosteroids are currently the only modality repeatedly shown in several studies to be associated with a reduction in the incidence of GMH‐IVH and overall reduction in mortality rates (Roberts 2006). Another appealing antenatal treatment is magnesium sulfate, commonly used for tocolysis but also with vascular stabilizing, anti‐inflammatory, and neuroprotective properties. Some authors have suggested a reduction in the incidence of GMH‐IVH following maternal administration of magnesium sulfate (Di Renzo 2005); however, most data do not show any benefit on the incidence of GMH‐IVH per se. Other antenatal therapeutics, such as phenobarbital and vitamin K, seemed not to be beneficial for the prevention of GMH‐IVH (Whitelaw 2001).

Because GMH‐IVH is strongly associated with both intrinsic and extrinsic hemodynamic effectors, optimal ventilation and strict hemodynamic control of the preterm infant are among the cornerstones of preventing GMH‐IVH and its progression. The postnatal GMH‐IVH preventive measures will be analyzed in this overview.

Description of the interventions

Neonatal pain has been poorly understood and often unrecognized until the 1980s, when research describing the developmental physiology of nociception and adverse responses of neonates to noxious stimuli emerged (Anand 1987a; Anand 1987b). Despite early maturation of the ascending neural pathways responsible for nociception, the descending inhibitory pathways, which localize and mitigate pain, do not form until later in maturation (Fitzgerald 1986). Moreover, normal brain development is abruptly interrupted by preterm birth, which results in a unique susceptibility to neurologic remodeling after repetitive noxious stimuli (Taddio 2009). Despite the growing knowledge about long‐term consequences of neonatal pain and discomfort, the consensus regarding a safe and effective strategy for controlling these complications in many routine clinical situations is still missing. Non‐pharmacological therapies, including non‐nutritive sucking and swaddling, form the foundation of neonatal pain and agitation relief, but they are unlikely to be adequate alone to provide comfort for moderate to intense pain (Brummelte 2012; Golianu 2007).

The most common indication for sedation is distress during mechanical ventilation. In this setting sedation may be needed to alleviate stress and facilitate mechanical ventilation (Quinn 1993), thus preventing some of its complications, such as pneumothorax and IVH (Greenough 1983; Perlman 1985).

How the intervention might work

Multiple pharmacological interventions might help to prevent the occurrence of IVH, the onset of which is typically in the first days of life. A reduction in IVH could be achieved through both direct and indirect mechanisms, such as by avoiding the pain, stress and discomfort caused by multiple manual procedures and mechanical ventilation.

Why it is important to do this overview

There are now numerous intervention reviews available for the prevention of GMH‐IVH in preterm infants. The totality of evidence from RCTs of postnatal pharmacological interventions for pain and sedation management has never been assembled before in a systematic and comprehensive way. An 'overview of reviews' will provide a clinically meaningful summary of one of the most important topics in neonatology. The overview provides a coherent and up‐to‐date summary of the totality of evidence, without the need to access many individual systematic reviews. This may help clinicians, policy makers, childbirth educators and consumers.