Golden Hours: An Approach to Postnatal Stabilization and Improving Outcomes

*Omid Fathi, Roopali Bapat, Edward G. Shepherd and John Wells Logan*

#### **Abstract**

The "Golden Hour" model of care originated in adult trauma medicine. Recently, this concept has been applied to premature neonates and the care they receive immediately after birth. This is not limited to the first hour of life, however, as this approach encompasses the first hours and days after birth. While no universal description defines the Golden Hour model, critical domains include initial delivery room management, thermoregulation, ventilation and oxygenation, glycemic control and prevention of infection. Strong evidence favors standardization of care to improve short- and long-term outcomes. This approach to care for the most at-risk premature infant is typically institution-specific; thus, team-building and quality improvement are critical to the care of these vulnerable patients.

**Keywords:** Golden Hour, prematurity, preterm, neonate, extremely low birth weight infant, resuscitation, quality improvement

#### **1. History and introduction**

The "Golden Hour" concept derives from the adult trauma literature, and generally describes the period after a traumatic injury during which prompt medical attention is needed to prevent death. The term was first introduced by a military surgeon, R. Adams Cowley. Cowley's research was directed primarily at the management of post-traumatic shock. According to Cowley, shock is a "momentary pause" in the pathway leading to death, and the "golden hour" is that period in which life-saving interventions can be initiated to prevent death or extreme morbidity. Cowley's research was instrumental in the study of shock and trauma in the United States, and his contribution has influenced the care of high-risk newborns as well.

For over a decade, neonatologists have been applying this concept to the care of high-risk newborns in the neonatal intensive care unit (NICU) [1]. However, the Golden Hour conveys a slightly different meaning in the NICU. In the NICU, the term generally refers to the first few hours immediately after birth. High-quality, timely, and efficient care, initiated within the Golden Hour window, can mitigate at least some of the risks associated with high-risk newborn care. Golden Hour protocols generally include standards and guidelines based on available evidence that can decrease morbidity and mortality. Here we discuss the Golden Hour concept for care of preterm infants, especially those born less than 28 weeks post-menstrual age (PMA). Extremely preterm newborns are highly vulnerable to complications in the early postnatal period, and adherence to best-evidence standards or guidelines can improve both survival and neurodevelopmental outcomes [2].

The aim of a Golden Hour protocol in the NICU is to apply evidence to clinical practice as safely and efficiently as possible. While the term "Golden Hour" implies the first 60 minutes after birth, the first several hours to days are critical as well [3]. The care of each infant must be individualized, but the Golden Hour concept emphasizes preparedness and adherence to guidelines with the aim of improving the quality of care. One author described the Golden Hour as a "philosophical approach" that reinforces communications, evidence-based protocols and procedures, and standardizes as many elements as possible with the aim of improving care and outcomes [2].

The outcomes improved by Golden Hour care are those most important to parents: survival, chronic lung disease, hearing and vision, and long-term neurodevelopment [3]. Early postnatal metrics are essential in the development of Golden Hour protocols, and there is strong evidence that improving specific components of care improves long-term outcomes as well. Among the most important of these are delivery-room practices such as teamwork, leadership, and communication, the use of oxygen and positive pressure ventilation, hemodynamic management, maintenance of a thermo-neutral environment, glycemic control, and identification and management of infectious risk factors.

While there are no randomized controlled trials evaluating any one comprehensive Golden Hour protocol, there is ample support for the use of evidence-based standards in several clinical domains unique to the early postnatal period. One report of a standardized protocol demonstrated a 67% reduction in mortality over the course of 10 years (1978–1988) [4]. Standardization may be just as important as the specific clinical practice strategy being implemented. This is important because resuscitation teams frequently deviate from resuscitation algorithms [5]. Finer et al. identified several deviations from resuscitation guidelines, including deep oropharyngeal suctioning, excessive stimulation, poor communication of heart rate, and failure to troubleshoot during bag–mask ventilation [6]. Units in the United Kingdom reported marked variations in practice between units with different designations, suggesting that either the level of care or the experience of clinical staff were factors in the quality of care delivered [7]. Similarly, a national survey in the United Kingdom demonstrated marked variations in delivery room practice; and differences persisted 1 year after publication of revised consensus guidelines [8].

#### **2. Burden and global impact**

Adaptation to extra-uterine life occurs during the early postnatal period and is a very high-risk period for premature infants, especially those born extremely preterm. Clinical domains of special interest during the Golden Hours include: delayed clamping of the umbilical cord, appropriate use of supplemental oxygen, non-invasive ventilation, and thermoregulation. Each of these is vitally important components of early postnatal care for the premature infant, and each impacts the others. Multiple studies demonstrate that the complex interplay of interventions in the first few minutes after birth can cause structural changes, trigger inflammatory or pro-oxidant cascades, and predispose premature infants to life-long complications [9]. Therefore, a standardized approach addressing many of these immediate postnatal concerns will likely improve both short and long-term outcomes in extremely premature infants.

An estimated 8 million infants die each year, worldwide. Over half of these deaths occur in the neonatal period, the first 28 days of life. The large majority of infant

**9**

*Golden Hours: An Approach to Postnatal Stabilization and Improving Outcomes*

deaths occur in the first week of life, but the highest risk is on the first day [10]. While developing countries with scarce resources are most affected, the impact of infant and neonatal mortality is significant in industrialized nations as well. In 2010, the United States infant mortality rate was 6.1 infant deaths per 1000 live births, which ranked 26th among similarly industrialized nations. Even after excluding births at less than 24 weeks of gestation, the U.S. infant mortality rate was more than double that of Finland, Sweden and Denmark [11]. Compared to 30 years ago, there has been an overall decrease in infant mortality rates on the first day of life, and this has been attributed largely to advances in delivery room management, non-invasive ventilation, and the use of postnatal surfactant. Nonetheless, infant mortality remains highest on the first day of life, and the first 4 hours is the period of greatest risk [12]. Neonatal mortality continues to be a serious issue, then, even in industrialized nations, and the risk appears to be greatest in the first hours after birth. The risks of adversity are amplified for preterm infants by the unique challenges of transitional physiology, immature adaptive systems, and fragile brain structures. Further, differences in outcomes in similar centers cannot be explained by the characteristics of infants alone, suggesting that differences in care may be responsible for suboptimal outcomes [13]. While this is disturbing, the obvious implication is that interventions aimed at improving early postnatal care can improve outcomes in this high-

Why is the preterm infant at such great risk? Like infants born at term, the preterm

Immature organ function coupled with the stress of physiologic adaptation to early postnatal life increases the likelihood that the preterm infant will be born physiologically unstable. Indeed, extremely premature infants almost universally require cardio-respiratory support in the first hours to days of life. Mechanical ventilation, continuous positive airway pressure (CPAP) and high levels of oxygen are often needed to stabilize oxygenation and ventilation. This, along with persistent fetal circulatory shunts, frequently manifest as hypoxemia and systemic hypotension in the early postnatal period. The preterm infant is also at significant risk of cold stress. Preterm skin is poorly keratinized and vulnerable to radiant heat and water losses. So while the clinical team is focused on ensuring cardio-respiratory stability and appropriate vascular access, the baby must be kept warm, dry and euglycemic.

The preterm brain is especially vulnerable in the early postnatal period [14, 15]. The periventricular germinal matrix is highly vascular, and susceptible to fluctuations in blood pressure and intravascular volume [16]. Postnatal stress and wide swings in blood pressure increase the risk of severe intraventricular hemorrhage

infant must transition from fetal to neonatal life in the first minutes to hours after birth, but the risks that accompany this transition are greater for preterm infants than for infants born at term. Anything that disrupts the normal transition to extrauterine life can have negative effects on physiologic function and outcome. Clearance of lung fluid and lung aeration is perhaps the most important early adaptations to postnatal life. The immature lungs, which are fluid-filled in-utero, must provide gas-exchange immediately after delivery. Similarly, oxygen-delivery to the tissues in-utero is dependent on maternal/placental blood flow, but depends on the infant's immature cardio-vascular system immediately after birth. Once born, the immature myocardium must provide cardiac output in the context of increased systemic vascular resistance and significant circulatory shunts. Various hormonal systems are in transition as well, and organ systems that control thermoregulation, vascular tone, glycemic control and

neuroprotection are functionally immature in the preterm newborn.

*DOI: http://dx.doi.org/10.5772/intechopen.82810*

**3. The newborn transition to postnatal life**

risk population.

#### *Golden Hours: An Approach to Postnatal Stabilization and Improving Outcomes DOI: http://dx.doi.org/10.5772/intechopen.82810*

deaths occur in the first week of life, but the highest risk is on the first day [10]. While developing countries with scarce resources are most affected, the impact of infant and neonatal mortality is significant in industrialized nations as well. In 2010, the United States infant mortality rate was 6.1 infant deaths per 1000 live births, which ranked 26th among similarly industrialized nations. Even after excluding births at less than 24 weeks of gestation, the U.S. infant mortality rate was more than double that of Finland, Sweden and Denmark [11]. Compared to 30 years ago, there has been an overall decrease in infant mortality rates on the first day of life, and this has been attributed largely to advances in delivery room management, non-invasive ventilation, and the use of postnatal surfactant. Nonetheless, infant mortality remains highest on the first day of life, and the first 4 hours is the period of greatest risk [12].

Neonatal mortality continues to be a serious issue, then, even in industrialized nations, and the risk appears to be greatest in the first hours after birth. The risks of adversity are amplified for preterm infants by the unique challenges of transitional physiology, immature adaptive systems, and fragile brain structures. Further, differences in outcomes in similar centers cannot be explained by the characteristics of infants alone, suggesting that differences in care may be responsible for suboptimal outcomes [13]. While this is disturbing, the obvious implication is that interventions aimed at improving early postnatal care can improve outcomes in this highrisk population.

#### **3. The newborn transition to postnatal life**

Why is the preterm infant at such great risk? Like infants born at term, the preterm infant must transition from fetal to neonatal life in the first minutes to hours after birth, but the risks that accompany this transition are greater for preterm infants than for infants born at term. Anything that disrupts the normal transition to extrauterine life can have negative effects on physiologic function and outcome. Clearance of lung fluid and lung aeration is perhaps the most important early adaptations to postnatal life. The immature lungs, which are fluid-filled in-utero, must provide gas-exchange immediately after delivery. Similarly, oxygen-delivery to the tissues in-utero is dependent on maternal/placental blood flow, but depends on the infant's immature cardio-vascular system immediately after birth. Once born, the immature myocardium must provide cardiac output in the context of increased systemic vascular resistance and significant circulatory shunts. Various hormonal systems are in transition as well, and organ systems that control thermoregulation, vascular tone, glycemic control and neuroprotection are functionally immature in the preterm newborn.

Immature organ function coupled with the stress of physiologic adaptation to early postnatal life increases the likelihood that the preterm infant will be born physiologically unstable. Indeed, extremely premature infants almost universally require cardio-respiratory support in the first hours to days of life. Mechanical ventilation, continuous positive airway pressure (CPAP) and high levels of oxygen are often needed to stabilize oxygenation and ventilation. This, along with persistent fetal circulatory shunts, frequently manifest as hypoxemia and systemic hypotension in the early postnatal period. The preterm infant is also at significant risk of cold stress. Preterm skin is poorly keratinized and vulnerable to radiant heat and water losses. So while the clinical team is focused on ensuring cardio-respiratory stability and appropriate vascular access, the baby must be kept warm, dry and euglycemic.

The preterm brain is especially vulnerable in the early postnatal period [14, 15]. The periventricular germinal matrix is highly vascular, and susceptible to fluctuations in blood pressure and intravascular volume [16]. Postnatal stress and wide swings in blood pressure increase the risk of severe intraventricular hemorrhage

*Neonatal Medicine*

(PMA). Extremely preterm newborns are highly vulnerable to complications in the early postnatal period, and adherence to best-evidence standards or guidelines can

The aim of a Golden Hour protocol in the NICU is to apply evidence to clinical practice as safely and efficiently as possible. While the term "Golden Hour" implies the first 60 minutes after birth, the first several hours to days are critical as well [3]. The care of each infant must be individualized, but the Golden Hour concept emphasizes preparedness and adherence to guidelines with the aim of improving the quality of care. One author described the Golden Hour as a "philosophical approach" that reinforces communications, evidence-based protocols and procedures, and standardizes as many elements as possible with the aim of improving care and outcomes [2]. The outcomes improved by Golden Hour care are those most important to parents: survival, chronic lung disease, hearing and vision, and long-term neurodevelopment [3]. Early postnatal metrics are essential in the development of Golden Hour protocols, and there is strong evidence that improving specific components of care improves long-term outcomes as well. Among the most important of these are delivery-room practices such as teamwork, leadership, and communication, the use of oxygen and positive pressure ventilation, hemodynamic management, maintenance of a thermo-neutral environment, glycemic control, and identification and

While there are no randomized controlled trials evaluating any one comprehensive Golden Hour protocol, there is ample support for the use of evidence-based standards in several clinical domains unique to the early postnatal period. One report of a standardized protocol demonstrated a 67% reduction in mortality over the course of 10 years (1978–1988) [4]. Standardization may be just as important as the specific clinical practice strategy being implemented. This is important because resuscitation teams frequently deviate from resuscitation algorithms [5]. Finer et al. identified several deviations from resuscitation guidelines, including deep oropharyngeal suctioning, excessive stimulation, poor communication of heart rate, and failure to troubleshoot during bag–mask ventilation [6]. Units in the United Kingdom reported marked variations in practice between units with different designations, suggesting that either the level of care or the experience of clinical staff were factors in the quality of care delivered [7]. Similarly, a national survey in the United Kingdom demonstrated marked variations in delivery room practice; and differences persisted 1 year after publication of revised consensus guidelines [8].

Adaptation to extra-uterine life occurs during the early postnatal period and is a very high-risk period for premature infants, especially those born extremely preterm. Clinical domains of special interest during the Golden Hours include: delayed clamping of the umbilical cord, appropriate use of supplemental oxygen, non-invasive ventilation, and thermoregulation. Each of these is vitally important components of early postnatal care for the premature infant, and each impacts the others. Multiple studies demonstrate that the complex interplay of interventions in the first few minutes after birth can cause structural changes, trigger inflammatory or pro-oxidant cascades, and predispose premature infants to life-long complications [9]. Therefore, a standardized approach addressing many of these immediate postnatal concerns will likely improve both short and long-term outcomes in

An estimated 8 million infants die each year, worldwide. Over half of these deaths

occur in the neonatal period, the first 28 days of life. The large majority of infant

improve both survival and neurodevelopmental outcomes [2].

management of infectious risk factors.

**2. Burden and global impact**

extremely premature infants.

**8**

(IVH) [17, 18]. Oligodendrocyte precursors, present in the primitive white matter, are susceptible to oxidative injury and can have life-long effects on neuromotor function [19]. Moreover, endogenous neuroprotective systems which might otherwise protect the newborn from injury are immature and unable to provide such protections in the extremely preterm neonate [20, 21]. These, and other clinical factors discussed below, explain why the preterm infants is so vulnerable in the early postnatal period, and why the concept of a "Golden Hour" protocol is so important for this high-risk population.

#### **3.1 Early physiologic instability and the risk of subsequent adversities**

Physiologic depression is common in the newborn period, and heart rate is the most sensitive and reliable indicator of the response to resuscitative efforts [22, 23]. One of the greatest challenges in neonatal resuscitation, however, is the ability to adequately assess the efficacy of resuscitative efforts. Clinicians are unable to accurately assess chest rise from either the head or side of the resuscitation bed [24, 25], and clinical assessment of heart rate by auscultation or palpation is less accurate than assessments with ECG monitoring [26–28]. Further, even normal healthy newborns may not achieve normal oxygen saturation levels until 5–10 minutes of life [29]. These data, and clinical studies in underdeveloped nations, suggest the importance of the early postnatal clinical assessment [30]. In a clinical study in rural Tanzania, which included all live-born, "lifeless", and stillborn infants, early initiation of basic resuscitation interventions significantly reduced birth-asphyxia related mortality. Mortality increased by 16% for every 30 second delay in initiating positive pressure ventilation (PPV) and by 6% for every minute of PPV required [31, 32]. Preterm infants are at great risk, then, of early postnatal physiologically depression, and there is sufficient evidence that efforts to enhance physiologic stability can improve important outcomes.

The Score for Neonatal Acute Physiology-II (SNAP-II), a validated illnessseverity score, derives from clinical data obtained in the first 12 hours after birth [33]. SNAP-II includes six indicators of physiologic instability, among these the lowest recorded blood pressure, the lowest serum pH, the lowest temperature, and the lowest recorded oxygen fraction. In a multi-center epidemiologic study from the Extremely Low Gestational Age Newborn (ELGAN) Study Group, mortality risk was significantly greater among infants with an elevated SNAP-II, and the risk was inversely related to the gestational age at birth [33]. Interestingly, mortality risk persisted even after adjusting for gestational age, suggesting that physiologic instability increases the risk of mortality independent of the risk associated with gestational age. In a separate analysis from the same study cohort, blood gas derangements noted in the first 12 hours after birth were associated with several indicators of inflammation, [34] and these were significantly associated with indicators of brain damage [35]. In a recent publication from the same group, physiologic derangements noted in the first 12 hours were associated with neurocognitive dysfunctions in several testing domains at 10 years of age [36]. Overall, the literature suggests that early postnatal physiologic instability increases the risk of adversity in children born preterm, and efforts to improve physiologic instability could mitigate this risk.

#### **4. Delivery room considerations**

Any discussion of Golden Hour strategies begins with delivery room management. It is here that the initial changes in transitional physiology begin, and here

**11**

building.

**4.1 Delayed cord clamping**

*Golden Hours: An Approach to Postnatal Stabilization and Improving Outcomes*

that several targeted Golden Hour interventions take place. While only 5–10% of neonates require intervention at birth, neonatal resuscitation is the most common form of resuscitation performed in hospitals worldwide [6]. The Neonatal Resuscitation Program (NRP) exists to guide practitioners in the management of neonates that require help with transitioning immediately after birth. Many institutions employ their own supplementary guidelines and protocols for practice in the delivery room. These focus largely on thermoregulation, advanced non-invasive ventilation techniques, and criteria for administering surfactant. Yet despite the availability of supplementary guidelines, studies have shown that even the most experienced teams will deviate from established guidelines [6]. Like any other skill, neonatal resuscitation and Golden Hour care can be improved with focused practice. Studies have demonstrated that standardized scripts can lead to improvements in care and outcomes. In 2009, Reynolds et al. demonstrated that use of resuscitation checklists, videotaped simulations and team debriefing sessions resulted in improvements in rates of chronic lung disease, intraventricular hemorrhage and

It is important to recognize that the quality of a resuscitation is only as good as the quality of the resuscitation team. Skilled resuscitation teams improve not only the quality of resuscitation, but the associated outcomes as well. This has been shown specifically with regard to endotracheal intubation [38]. While endotracheal intubation is not unique to NRP or Golden Hour care, this finding suggests that experienced personnel are more successful in high-risk circumstances than lessexperienced personnel. Golden Hour care of the extremely preterm infant, especially in the delivery room, should be thought of in the same way. It is not sufficient to advocate for Golden Hour care without first having qualified personnel with the appropriate skillset to perform such care. Moreover, current consensus suggests that interdisciplinary training, team development and the practicing of specific Golden Hour care strategies will not only reduce errors, but improves outcomes [39]. This encompasses strategies such as delivery room simulations with both briefing and de-briefing exercises, as well as content knowledge, technical skills and team

Delayed cord clamping (DCC), sometimes referred to as placental transfusion, allows the freshly born neonate to remain attached to the placenta, typically for 30–60 seconds. The goal of DCC is to "recapture" as much circulating blood volume from the placental vasculature as possible. This increases the amount of fetal hemoglobin available to the neonate, thus increasing oxygen content, native cardiac output and oxygen delivery. In the premature population, large meta-analyses have demonstrated that DCC has potential benefits for the neonate. A Cochrane analysis published in 2012 concluded that placental transfusion at birth was associated with fewer blood transfusions, better hemodynamic stability in the first few days of life, fewer intraventricular hemorrhages, and fewer cases of necrotizing enterocolitis [40]. Subsequent publications have mostly re-demonstrated similar findings, albeit with differences in certain morbidities and mortality [41]. The theoretical risks of DCC include volume overload and polycythemia, resulting in hyperbilirubinemia,

While there is currently no consensus regarding the use of DCC, it is generally considered safe in term and preterm infants, as long as treatment for hyperbilirubinemia is available. DCC is routinely performed in term neonates, but many institutions also consider DCC for preterm infants born physiologically stable. The

but these risks have yet to be demonstrated in the literature [42].

*DOI: http://dx.doi.org/10.5772/intechopen.82810*

retinopathy of prematurity [37].

#### *Golden Hours: An Approach to Postnatal Stabilization and Improving Outcomes DOI: http://dx.doi.org/10.5772/intechopen.82810*

that several targeted Golden Hour interventions take place. While only 5–10% of neonates require intervention at birth, neonatal resuscitation is the most common form of resuscitation performed in hospitals worldwide [6]. The Neonatal Resuscitation Program (NRP) exists to guide practitioners in the management of neonates that require help with transitioning immediately after birth. Many institutions employ their own supplementary guidelines and protocols for practice in the delivery room. These focus largely on thermoregulation, advanced non-invasive ventilation techniques, and criteria for administering surfactant. Yet despite the availability of supplementary guidelines, studies have shown that even the most experienced teams will deviate from established guidelines [6]. Like any other skill, neonatal resuscitation and Golden Hour care can be improved with focused practice. Studies have demonstrated that standardized scripts can lead to improvements in care and outcomes. In 2009, Reynolds et al. demonstrated that use of resuscitation checklists, videotaped simulations and team debriefing sessions resulted in improvements in rates of chronic lung disease, intraventricular hemorrhage and retinopathy of prematurity [37].

It is important to recognize that the quality of a resuscitation is only as good as the quality of the resuscitation team. Skilled resuscitation teams improve not only the quality of resuscitation, but the associated outcomes as well. This has been shown specifically with regard to endotracheal intubation [38]. While endotracheal intubation is not unique to NRP or Golden Hour care, this finding suggests that experienced personnel are more successful in high-risk circumstances than lessexperienced personnel. Golden Hour care of the extremely preterm infant, especially in the delivery room, should be thought of in the same way. It is not sufficient to advocate for Golden Hour care without first having qualified personnel with the appropriate skillset to perform such care. Moreover, current consensus suggests that interdisciplinary training, team development and the practicing of specific Golden Hour care strategies will not only reduce errors, but improves outcomes [39]. This encompasses strategies such as delivery room simulations with both briefing and de-briefing exercises, as well as content knowledge, technical skills and team building.

#### **4.1 Delayed cord clamping**

Delayed cord clamping (DCC), sometimes referred to as placental transfusion, allows the freshly born neonate to remain attached to the placenta, typically for 30–60 seconds. The goal of DCC is to "recapture" as much circulating blood volume from the placental vasculature as possible. This increases the amount of fetal hemoglobin available to the neonate, thus increasing oxygen content, native cardiac output and oxygen delivery. In the premature population, large meta-analyses have demonstrated that DCC has potential benefits for the neonate. A Cochrane analysis published in 2012 concluded that placental transfusion at birth was associated with fewer blood transfusions, better hemodynamic stability in the first few days of life, fewer intraventricular hemorrhages, and fewer cases of necrotizing enterocolitis [40]. Subsequent publications have mostly re-demonstrated similar findings, albeit with differences in certain morbidities and mortality [41]. The theoretical risks of DCC include volume overload and polycythemia, resulting in hyperbilirubinemia, but these risks have yet to be demonstrated in the literature [42].

While there is currently no consensus regarding the use of DCC, it is generally considered safe in term and preterm infants, as long as treatment for hyperbilirubinemia is available. DCC is routinely performed in term neonates, but many institutions also consider DCC for preterm infants born physiologically stable. The

*Neonatal Medicine*

for this high-risk population.

important outcomes.

**4. Delivery room considerations**

(IVH) [17, 18]. Oligodendrocyte precursors, present in the primitive white matter, are susceptible to oxidative injury and can have life-long effects on neuromotor function [19]. Moreover, endogenous neuroprotective systems which might otherwise protect the newborn from injury are immature and unable to provide such protections in the extremely preterm neonate [20, 21]. These, and other clinical factors discussed below, explain why the preterm infants is so vulnerable in the early postnatal period, and why the concept of a "Golden Hour" protocol is so important

**3.1 Early physiologic instability and the risk of subsequent adversities**

Physiologic depression is common in the newborn period, and heart rate is the most sensitive and reliable indicator of the response to resuscitative efforts [22, 23]. One of the greatest challenges in neonatal resuscitation, however, is the ability to adequately assess the efficacy of resuscitative efforts. Clinicians are unable to accurately assess chest rise from either the head or side of the resuscitation bed [24, 25], and clinical assessment of heart rate by auscultation or palpation is less accurate than assessments with ECG monitoring [26–28]. Further, even normal healthy newborns may not achieve normal oxygen saturation levels until 5–10 minutes of life [29]. These data, and clinical studies in underdeveloped nations, suggest the importance of the early postnatal clinical assessment [30]. In a clinical study in rural Tanzania, which included all live-born, "lifeless", and stillborn infants, early initiation of basic resuscitation interventions significantly reduced birth-asphyxia related mortality. Mortality increased by 16% for every 30 second delay in initiating positive pressure ventilation (PPV) and by 6% for every minute of PPV required [31, 32]. Preterm infants are at great risk, then, of early postnatal physiologically depression, and there is sufficient evidence that efforts to enhance physiologic stability can improve

The Score for Neonatal Acute Physiology-II (SNAP-II), a validated illnessseverity score, derives from clinical data obtained in the first 12 hours after birth [33]. SNAP-II includes six indicators of physiologic instability, among these the lowest recorded blood pressure, the lowest serum pH, the lowest temperature, and the lowest recorded oxygen fraction. In a multi-center epidemiologic study from the Extremely Low Gestational Age Newborn (ELGAN) Study Group, mortality risk was significantly greater among infants with an elevated SNAP-II, and the risk was inversely related to the gestational age at birth [33]. Interestingly, mortality risk persisted even after adjusting for gestational age, suggesting that physiologic instability increases the risk of mortality independent of the risk associated with gestational age. In a separate analysis from the same study cohort, blood gas derangements noted in the first 12 hours after birth were associated with several indicators of inflammation, [34] and these were significantly associated with indicators of brain damage [35]. In a recent publication from the same group, physiologic derangements noted in the first 12 hours were associated with neurocognitive dysfunctions in several testing domains at 10 years of age [36]. Overall, the literature suggests that early postnatal physiologic instability increases the risk of adversity in children born preterm, and efforts to improve physiologic instability could mitigate this risk.

Any discussion of Golden Hour strategies begins with delivery room management. It is here that the initial changes in transitional physiology begin, and here

**10**

randomized control trial by Tarnow-Mordi et al. in 2017 demonstrated no difference in the combined outcome death or major morbidity at 36 weeks in the delayed cord clamping vs. immediate clamping group [43]. Interestingly, this study found a significant decrease in mortality in the delayed clamping group but no difference in the combined outcome after *post hoc* analyses. In preterm infants, it is important to weigh the benefits of delayed cord clamping *versus* those of delaying resuscitation and other Golden Hour measures.

#### **5. Ventilation and oxygenation**

Support of newborn's respiratory system is fundamental to Golden Hour principles. In utero, gas exchange occurs at the level of the placenta, but an immense shift in cardiopulmonary physiology occurs at birth. Respiratory distress is common, especially in preterm infants, due to this physiologic transition to postnatal life. The most immediate concern in the delivery room is proper support the respiratory system [2]. A recent update to Neonatal Resuscitation Program (NRP) guidelines highlights several important changes related to respiratory care [44]. These include recommendations on the use of oxygen in the delivery room, guidance on the use of pulse oximetry, and oxygen saturation targets based on the postnatal age in minutes. NRP now advises against routine endotracheal intubation to suction meconium in infants born through meconium-stained amniotic fluids. Revised guidelines suggest prompt intubation of neonates not responding to positive pressure ventilation and for infants requiring chest compressions for cardiovascular depression [45]. Adherence to NRP guidelines is important, as standardization improves care, but adherence to NRP guidelines does not preclude the use of institution-specific Golden Hour practices.

Preterm infants face various challenges in the transition to extra-uterine life. Respiratory drive is frequently depressed, muscles of respiration are weak, chest wall elasticity is high, and surfactant deficiency is common in infants born preterm [9]. This manifests clinically as decreased functional residual capacity (FRC), poor lung fluid clearance and aeration, and ventilation/perfusion (V/Q ) mismatch [46]. In addition, the relatively small caliber of the preterm airways leads to greater airway resistance compared to full-term neonates. To overcome this, and to promote lung fluid clearance and expansion, positive end-expiratory pressure (PEEP) are used with great success to support spontaneously breathing preterm infants [47]. The benefits of early CPAP are numerous, including increased FRC, improved ventilation/perfusion matching, and decreased energy expenditure [48]. The need for endotracheal intubation and exogenous surfactant administration reduces, as is the need for mechanical ventilation [2]. While early CPAP has not been shown to reduce bronchopulmonary dysplasia (BPD) rates, it has been shown to reduce other respiratory morbidities at 18–22 months of age [49].

Finally, oxygen should be used judiciously in the delivery room. Avoiding the extremes of both hypoxemia and hyperoxia during the initial phase of resuscitation is crucial. Preterm infants have reduced capacity for mitigating oxidative stress, and are prone to morbidities like BPD, retinopathy of prematurity, intraventricular hemorrhage and necrotizing enterocolitis [2]. For preterm infants, NRP recommends that a pulse oximeter be applied to the right hand or wrist during the start of resuscitation, and that an initial FiO2 of 0.3–0.4 is reasonable. While optimal goal oxygen saturations based on postnatal age in minutes are not known for extremely premature neonates, the current ranges for term newborns are recommended [2].

**13**

[58, 63–70].

*Golden Hours: An Approach to Postnatal Stabilization and Improving Outcomes*

A critical component of Golden Hour care is minimizing the maladaptive patterns that accompany the postnatal transition. The premature neonate is illequipped to deal with many of these challenges due to immature organ structure and function. One area of particular concern is energy metabolism and glucose homeostasis. Preterm infants are at increased risk of hypoglycemia due to the limited availability of hepatic glycogen stores and brown fat and are at increased risk of

hypoglycemia, and its consequences, than are infants born at term gestation. The developing fetus receives its energy from the placenta in the form of glucose, amino acids, free fatty acids and ketones, with the majority of glucose accretion taking place during the third trimester [50]. Glycogen storage typically begins around 27 weeks' gestation and increases until roughly 36 weeks. Following birth and clamping of the umbilical cord, the glucose concentration decreases to a nadir at about 60 to 90 minutes. Neonates born extremely premature are especially vulnerable during this period as they have limited ability to mobilize glucose, and lack the cerebral defense mechanisms present in term neonates to combat hypoglycemia [6, 51]. Further, the incidence of hypoglycemia is inversely proportional to the gestational age [52]. Prevention of hypoglycemia is therefore an essential

Glucose is the primary substrate for cerebral metabolism, and the deleterious short-term effects of neonatal hypoglycemia are well described. Transient hypoglycemia can produce jitteriness, poor feeding, respiratory distress, and in some instances seizures. The risks are greater in premature infants than in term infants. Of greater concern, however, is the potential for long-term neurodevelopmental impairments associated with even transient neonatal hypoglycemia [51, 53, 54]. It is likely that the risks are even greater for sustained or prolonged hypoglycemia. Preterm infants, and infants born small for gestational age, are dependent on exogenous sources of glucose in the early postnatal period. Intravenous access is

Umbilical vein cannulation remains the preferred method of rapid intravenous (IV) access in preterm infants, but a peripheral IV is often adequate. The principle benefits of vascular access are for administering volume resuscitation, maintenance fluids, glucose delivery, and/or medication administration. The presence of a highly skilled, dedicated neonatal resuscitation team is essential for achieving early

Thermoregulation is essential to newborn homeostasis, and this is especially true for the preterm or growth-restricted newborn [56, 57]. NRP guidelines recommend that the temperature of neonates be maintained between 36.5 and 37.5°C after birth through admission and stabilization [58]. Indeed, we have known since 1907 [59] that admission temperature of neonate is a strong predictor of mortality at all gestational ages [60, 61]. Despite these recommendations, it is common for critically ill term and preterm infants to be hypothermic on admission to the NICU; roughly half of preterm infants in the EPICURE Study were admitted to the NICU with a temperature less than 36.5°C [62]. Temperature dysregulation is associated with Apgar scores less than 7, intraventricular hemorrhage, respiratory distress, hypoglycemia, acid–base imbalances, lactic acidosis, and late onset sepsis

**6. Glucose homeostasis and early vascular access**

component of Golden Hour care for preterm neonates.

therefore critical to resuscitative efforts in this population.

vascular access and improved outcomes [55].

**7. Thermoregulation**

*DOI: http://dx.doi.org/10.5772/intechopen.82810*

#### **6. Glucose homeostasis and early vascular access**

*Neonatal Medicine*

and other Golden Hour measures.

**5. Ventilation and oxygenation**

institution-specific Golden Hour practices.

respiratory morbidities at 18–22 months of age [49].

randomized control trial by Tarnow-Mordi et al. in 2017 demonstrated no difference in the combined outcome death or major morbidity at 36 weeks in the delayed cord clamping vs. immediate clamping group [43]. Interestingly, this study found a significant decrease in mortality in the delayed clamping group but no difference in the combined outcome after *post hoc* analyses. In preterm infants, it is important to weigh the benefits of delayed cord clamping *versus* those of delaying resuscitation

Support of newborn's respiratory system is fundamental to Golden Hour principles. In utero, gas exchange occurs at the level of the placenta, but an immense shift in cardiopulmonary physiology occurs at birth. Respiratory distress is common, especially in preterm infants, due to this physiologic transition to postnatal life. The most immediate concern in the delivery room is proper support the respiratory system [2]. A recent update to Neonatal Resuscitation Program (NRP) guidelines highlights several important changes related to respiratory care [44]. These include recommendations on the use of oxygen in the delivery room, guidance on the use of pulse oximetry, and oxygen saturation targets based on the postnatal age in minutes. NRP now advises against routine endotracheal intubation to suction meconium in infants born through meconium-stained amniotic fluids. Revised guidelines suggest prompt intubation of neonates not responding to positive pressure ventilation and for infants requiring chest compressions for cardiovascular depression [45]. Adherence to NRP guidelines is important, as standardization improves care, but adherence to NRP guidelines does not preclude the use of

Preterm infants face various challenges in the transition to extra-uterine life. Respiratory drive is frequently depressed, muscles of respiration are weak, chest wall elasticity is high, and surfactant deficiency is common in infants born preterm [9]. This manifests clinically as decreased functional residual capacity (FRC), poor lung fluid clearance and aeration, and ventilation/perfusion (V/Q ) mismatch [46]. In addition, the relatively small caliber of the preterm airways leads to greater airway resistance compared to full-term neonates. To overcome this, and to promote lung fluid clearance and expansion, positive end-expiratory pressure (PEEP) are used with great success to support spontaneously breathing preterm infants [47]. The benefits of early CPAP are numerous, including increased FRC, improved ventilation/perfusion matching, and decreased energy expenditure [48]. The need for endotracheal intubation and exogenous surfactant administration reduces, as is the need for mechanical ventilation [2]. While early CPAP has not been shown to reduce bronchopulmonary dysplasia (BPD) rates, it has been shown to reduce other

Finally, oxygen should be used judiciously in the delivery room. Avoiding the extremes of both hypoxemia and hyperoxia during the initial phase of resuscitation is crucial. Preterm infants have reduced capacity for mitigating oxidative stress, and are prone to morbidities like BPD, retinopathy of prematurity, intraventricular hemorrhage and necrotizing enterocolitis [2]. For preterm infants, NRP recommends that a pulse oximeter be applied to the right hand or wrist during the start of resuscitation, and that an initial FiO2 of 0.3–0.4 is reasonable. While optimal goal oxygen saturations based on postnatal age in minutes are not known for extremely premature neonates, the current ranges for term newborns are recom-

**12**

mended [2].

A critical component of Golden Hour care is minimizing the maladaptive patterns that accompany the postnatal transition. The premature neonate is illequipped to deal with many of these challenges due to immature organ structure and function. One area of particular concern is energy metabolism and glucose homeostasis. Preterm infants are at increased risk of hypoglycemia due to the limited availability of hepatic glycogen stores and brown fat and are at increased risk of hypoglycemia, and its consequences, than are infants born at term gestation.

The developing fetus receives its energy from the placenta in the form of glucose, amino acids, free fatty acids and ketones, with the majority of glucose accretion taking place during the third trimester [50]. Glycogen storage typically begins around 27 weeks' gestation and increases until roughly 36 weeks. Following birth and clamping of the umbilical cord, the glucose concentration decreases to a nadir at about 60 to 90 minutes. Neonates born extremely premature are especially vulnerable during this period as they have limited ability to mobilize glucose, and lack the cerebral defense mechanisms present in term neonates to combat hypoglycemia [6, 51]. Further, the incidence of hypoglycemia is inversely proportional to the gestational age [52]. Prevention of hypoglycemia is therefore an essential component of Golden Hour care for preterm neonates.

Glucose is the primary substrate for cerebral metabolism, and the deleterious short-term effects of neonatal hypoglycemia are well described. Transient hypoglycemia can produce jitteriness, poor feeding, respiratory distress, and in some instances seizures. The risks are greater in premature infants than in term infants. Of greater concern, however, is the potential for long-term neurodevelopmental impairments associated with even transient neonatal hypoglycemia [51, 53, 54]. It is likely that the risks are even greater for sustained or prolonged hypoglycemia. Preterm infants, and infants born small for gestational age, are dependent on exogenous sources of glucose in the early postnatal period. Intravenous access is therefore critical to resuscitative efforts in this population.

Umbilical vein cannulation remains the preferred method of rapid intravenous (IV) access in preterm infants, but a peripheral IV is often adequate. The principle benefits of vascular access are for administering volume resuscitation, maintenance fluids, glucose delivery, and/or medication administration. The presence of a highly skilled, dedicated neonatal resuscitation team is essential for achieving early vascular access and improved outcomes [55].

#### **7. Thermoregulation**

Thermoregulation is essential to newborn homeostasis, and this is especially true for the preterm or growth-restricted newborn [56, 57]. NRP guidelines recommend that the temperature of neonates be maintained between 36.5 and 37.5°C after birth through admission and stabilization [58]. Indeed, we have known since 1907 [59] that admission temperature of neonate is a strong predictor of mortality at all gestational ages [60, 61]. Despite these recommendations, it is common for critically ill term and preterm infants to be hypothermic on admission to the NICU; roughly half of preterm infants in the EPICURE Study were admitted to the NICU with a temperature less than 36.5°C [62]. Temperature dysregulation is associated with Apgar scores less than 7, intraventricular hemorrhage, respiratory distress, hypoglycemia, acid–base imbalances, lactic acidosis, and late onset sepsis [58, 63–70].

#### **7.1 Strategies to maintain a thermoneutral environment**

Environmental conditions vary significantly from center to center, and even from room to room. One of the most successful interventions is to increase the ambient temperature of the delivery room or operating room to 77–78.8°F (25– 26°C) before the delivery occurs [71, 72]. Some authors have described success by increasing the delivery room temperature to 80°F [37]. Since very preterm and very low birthweight infants are at increased risk of hypothermia, various risk-minimization strategies may be needed, including: covering the infant with heat-resistant plastic wrap, covering the infant's head with a cap, use of exothermic mattresses, stabilization under a radiant warmer, and the use of warmed, humidified resuscitation gases [58, 73]. An updated Cochrane analysis suggests that the best approach to maintaining a thermoneutral environment is not yet clear [74]. Techniques recommended for the term newborn are not universally applicable, but may be appropriate for the mid-to-late preterm newborn, including: pre-warming of linens, drying the infant after delivery, removal of wet linens, swaddling, covering the scalp with a hat/cap, and/or placing the infant skin-to-skin based on the stability of the neonate [58, 75].

Serial monitoring of the infant's temperature is imperative, as there is some risk of hyperthermia using the combination of strategies advocated here [76]. In resource-limited settings, or in the absence of the aforementioned supplies, NRP 2015 recommends the use of clean food-grade plastic bag below the level of the neck, and swaddling the infant after drying [58]. Infants who are hypothermic after resuscitation should be rewarmed slowly [58] to avoid complications such as apnea and arrhythmias. Current evidence is insufficient to recommend a preference for either rapid (0.5°C/h or greater) or slow rewarming (less than 0.5°C/h) of unintentionally hypothermic newborns (temperature less than 36°C) at hospital admission. Additional research is needed.

#### **8. Management of infants at-risk for infection**

Neonates are vulnerable to infection before, during and after delivery. Worldwide, neonatal infection contributes substantially to neonatal mortality [77–79]. Risk factors for early-onset neonatal sepsis (EOS) include prematurity, immunologic immaturity, maternal Group B streptococcal colonization, prolonged rupture of membranes, and maternal intra-amniotic infection [80]. Chorioamnionitis is a major risk factor for spontaneous preterm birth, especially at early gestational ages, and contributes to prematurity-associated morbidity and mortality. Chorioamnionitis is an independent risk factor for neonatal sepsis, and is associated with white matter damage and cerebral palsy in preterm infants [81]. Late-onset neonatal sepsis has been largely attributed to Gram-positive organisms, including coagulase negative Staphylococci and *Staphylococcus aureus*, and is associated with increased morbidity and mortality among premature infants [80]. Therefore, the timely administration of antibiotics is recommended for at-risk infants.

Early initiation of antibiotics in the first hour of life when sepsis is clinically suspected has been shown to prevent some serious sequelae of early onset sepsis [82–84]. Challenges in establishing intravenous access in very premature neonates may delay the initiation of antibiotics. Application of Golden Hour quality improvement initiatives, including dedicated personnel for placement of vascular access and better communication with pharmacy can lead to improvements in antibiotic initiation time [85].

**15**

*Golden Hours: An Approach to Postnatal Stabilization and Improving Outcomes*

Neuronal development begins as early as the 3rd week of gestation and is largely complete by the 20th week of gestation [86]. Neuronal migration begins in early gestation and continues through early childhood. Synaptic pruning, apoptosis, and patterning are important aspects of brain development, and both prenatal and postnatal events play a role in establishing cortical brain development [86]. Biologic and environmental exposures during these critical periods of development can have adverse effects on brain development. Indeed, events or exposures that interfere with these important developmental processes can adversely affect the organization

Exposures common to the NICU have been associated with several indicators of abnormal neurologic function, including poor orientation, low tolerance of handling, poor self-regulation, poor reflexes, and abnormalities of tone [89–91]. Conversely, supportive experiences are associated with stronger brain responses in the developing neonate [87]. A NICU environment that provides developmentallyappropriate cares and supports parental involvement and touch likely improves

Minimizing the frequency of laboratory blood draws, painful procedures, and interruptions to sleep are simple ways of mitigating exposure to stress that can interfere with normal brain growth and development [92]. Noise reduction, human touch, cycling of light, age-appropriate music, and recordings of mother's voice could also be reasonably placed in a Golden Hour protocol to improve the neurodevelopmental outcomes of surviving extremely preterm infants [93]. Neonatal programs caring for high-risk preterm infants should include a developmentallyrich and supportive environment as a core clinical domain for the Golden Hours.

The International Liaison Committee on Resuscitation (ILCOR), the American Academy of Pediatrics (AAP), and the American Heart Association (AHA) have published guidelines or recommendations on specific resuscitation practices supported by evidence [58]. Translating this evidence and implementing it into practice requires the development of institution-specific guidelines or protocols

Low volume centers should develop thresholds or criteria for timely transfer to higher levels of care in addition to developing regionalization of networks of care. Level III/IV centers also should provide leadership and support for regional hospitals and nurseries that make up their referral base, and it is our hope that this publication can be used as a means of enhancing the flow of information to that end [94–96]. Strategies such as the use of checklists, collaboration/teamwork, consistent approach to care, minimizing variation, [37, 97] simulation- based learning with debriefing; [37] development of steps and checklist in Golden Hour protocol, [85] immediate skin to skin in eligible infant [98] have been described in literature to be effective in providing the caregivers ability to remain organized, aware of time

management and provide effective Golden Hour resuscitation measures.

Despite the paucity of evidence supporting specific delivery room protocols, the literature favors standardization of as many elements as possible [71]. The introduction of evidence-based delivery room guidelines has been credited with improvements in the quality of care in a variety of clinical settings [4]. Importantly, utilization of standardized protocols has been associated with improvements in morbidity and mortality [99–101]. Ashmeade et al. focused primarily of 4

**9. Environment and developmental support systems**

*DOI: http://dx.doi.org/10.5772/intechopen.82810*

and function of the developing brain [87, 88].

**10. Quality improvement and sustained outcomes**

that standardize as many elements as possible [71].

long term outcomes.

*Golden Hours: An Approach to Postnatal Stabilization and Improving Outcomes DOI: http://dx.doi.org/10.5772/intechopen.82810*

#### **9. Environment and developmental support systems**

*Neonatal Medicine*

[58, 75].

Additional research is needed.

**8. Management of infants at-risk for infection**

**7.1 Strategies to maintain a thermoneutral environment**

Environmental conditions vary significantly from center to center, and even from room to room. One of the most successful interventions is to increase the ambient temperature of the delivery room or operating room to 77–78.8°F (25– 26°C) before the delivery occurs [71, 72]. Some authors have described success by increasing the delivery room temperature to 80°F [37]. Since very preterm and very low birthweight infants are at increased risk of hypothermia, various risk-minimization strategies may be needed, including: covering the infant with heat-resistant plastic wrap, covering the infant's head with a cap, use of exothermic mattresses, stabilization under a radiant warmer, and the use of warmed, humidified resuscitation gases [58, 73]. An updated Cochrane analysis suggests that the best approach to maintaining a thermoneutral environment is not yet clear [74]. Techniques recommended for the term newborn are not universally applicable, but may be appropriate for the mid-to-late preterm newborn, including: pre-warming of linens, drying the infant after delivery, removal of wet linens, swaddling, covering the scalp with a hat/cap, and/or placing the infant skin-to-skin based on the stability of the neonate

Serial monitoring of the infant's temperature is imperative, as there is some risk of hyperthermia using the combination of strategies advocated here [76]. In resource-limited settings, or in the absence of the aforementioned supplies, NRP 2015 recommends the use of clean food-grade plastic bag below the level of the neck, and swaddling the infant after drying [58]. Infants who are hypothermic after resuscitation should be rewarmed slowly [58] to avoid complications such as apnea and arrhythmias. Current evidence is insufficient to recommend a preference for either rapid (0.5°C/h or greater) or slow rewarming (less than 0.5°C/h) of unintentionally hypothermic newborns (temperature less than 36°C) at hospital admission.

Neonates are vulnerable to infection before, during and after delivery. Worldwide, neonatal infection contributes substantially to neonatal mortality [77–79]. Risk factors for early-onset neonatal sepsis (EOS) include prematurity, immunologic immaturity, maternal Group B streptococcal colonization, prolonged rupture of membranes, and maternal intra-amniotic infection [80]. Chorioamnionitis is a major risk factor for spontaneous preterm birth, especially at early gestational ages, and contributes to prematurity-associated morbidity and mortality. Chorioamnionitis is an independent risk factor for neonatal sepsis, and is associated with white matter damage and cerebral palsy in preterm infants [81]. Late-onset neonatal sepsis has been largely attributed to Gram-positive organisms, including coagulase negative Staphylococci and *Staphylococcus aureus*, and is associated with increased morbidity and mortality among premature infants [80]. Therefore, the timely administration of antibiotics is recommended for at-risk

Early initiation of antibiotics in the first hour of life when sepsis is clinically suspected has been shown to prevent some serious sequelae of early onset sepsis [82–84]. Challenges in establishing intravenous access in very premature neonates may delay the initiation of antibiotics. Application of Golden Hour quality improvement initiatives, including dedicated personnel for placement of vascular access and better communication with pharmacy can lead to improvements in antibiotic

**14**

infants.

initiation time [85].

Neuronal development begins as early as the 3rd week of gestation and is largely complete by the 20th week of gestation [86]. Neuronal migration begins in early gestation and continues through early childhood. Synaptic pruning, apoptosis, and patterning are important aspects of brain development, and both prenatal and postnatal events play a role in establishing cortical brain development [86]. Biologic and environmental exposures during these critical periods of development can have adverse effects on brain development. Indeed, events or exposures that interfere with these important developmental processes can adversely affect the organization and function of the developing brain [87, 88].

Exposures common to the NICU have been associated with several indicators of abnormal neurologic function, including poor orientation, low tolerance of handling, poor self-regulation, poor reflexes, and abnormalities of tone [89–91]. Conversely, supportive experiences are associated with stronger brain responses in the developing neonate [87]. A NICU environment that provides developmentallyappropriate cares and supports parental involvement and touch likely improves long term outcomes.

Minimizing the frequency of laboratory blood draws, painful procedures, and interruptions to sleep are simple ways of mitigating exposure to stress that can interfere with normal brain growth and development [92]. Noise reduction, human touch, cycling of light, age-appropriate music, and recordings of mother's voice could also be reasonably placed in a Golden Hour protocol to improve the neurodevelopmental outcomes of surviving extremely preterm infants [93]. Neonatal programs caring for high-risk preterm infants should include a developmentallyrich and supportive environment as a core clinical domain for the Golden Hours.

#### **10. Quality improvement and sustained outcomes**

The International Liaison Committee on Resuscitation (ILCOR), the American Academy of Pediatrics (AAP), and the American Heart Association (AHA) have published guidelines or recommendations on specific resuscitation practices supported by evidence [58]. Translating this evidence and implementing it into practice requires the development of institution-specific guidelines or protocols that standardize as many elements as possible [71].

Low volume centers should develop thresholds or criteria for timely transfer to higher levels of care in addition to developing regionalization of networks of care. Level III/IV centers also should provide leadership and support for regional hospitals and nurseries that make up their referral base, and it is our hope that this publication can be used as a means of enhancing the flow of information to that end [94–96]. Strategies such as the use of checklists, collaboration/teamwork, consistent approach to care, minimizing variation, [37, 97] simulation- based learning with debriefing; [37] development of steps and checklist in Golden Hour protocol, [85] immediate skin to skin in eligible infant [98] have been described in literature to be effective in providing the caregivers ability to remain organized, aware of time management and provide effective Golden Hour resuscitation measures.

Despite the paucity of evidence supporting specific delivery room protocols, the literature favors standardization of as many elements as possible [71]. The introduction of evidence-based delivery room guidelines has been credited with improvements in the quality of care in a variety of clinical settings [4]. Importantly, utilization of standardized protocols has been associated with improvements in morbidity and mortality [99–101]. Ashmeade et al. focused primarily of 4

processes: interdisciplinary team training to improve communication and care in the delivery room, attention to temperature regulation, respiratory support and timely administration of surfactant, and early initiation of dextrose and amino acid infusion [102].

Developing a protocol for any process or improvement requires careful study, inclusion of key stake-holders, thoughtful protocol development and a comprehensive educational process prior to implementation [103]. Quality improvement, however, requires an ongoing evaluation of systems and processes. This continuous cycle of improvement will lead to improvements in teamwork and collaboration, skills and knowledge, consistency of care, and outcomes [104–106]. Consider using this Golden Hour review as a framework for evaluating systems and processes, for developing clinical guidelines or protocols, and for addressing the challenges unique to your institution [107].

#### **10.1 Teamwork and collaboration**

Standardized protocols, technical skills, and repeated training are the cornerstones of successful resuscitation. Emerging evidence suggests that human factors, including team interaction, communication and leadership, play a pivotal role in compliance with protocols and the success of resuscitations [108, 109]. One unit described their experience with implementation of Golden Hour protocol that included the use of realistic simulation-based learning, followed by team debriefing sessions as critical pieces of the implementation process [37]. Finer et al., improved their resuscitation outcomes by identifying opportunities and improving team and leader performance [6]. They utilized Crew Resource Management (CRM), a methodology developed for air crews from the late 1970s that evolved from a careful evaluation of the role of human error in air crashes. Communication and team leaders are the primary framework of CRM.

#### **11. Conclusion**

Despite advances in medical care, a large number of preterm neonates remain at risk for significant morbidity or mortality. Golden Hour care of the at-risk premature neonate is a philosophical and team-based and highly specialized care that focuses on the first hours and days after birth. It is devised with the understanding that preterm neonates have unique risk factors based on physiology and immature adaptive systems. Key Golden Hour domains include: optimizing delivery room management of ventilation/oxygenation and thermoregulation, early establishment of vascular access, prevention of hypoglycemia, prevention and treatment of infection, and promotion of a developmentally-focused environment that promotes optimal short and long-term outcomes. The available literature supports standardization at the institutional level. In addition, it is critical to have a dedicated team of providers who regularly practice and hone the clinical skills relevant to Golden Hour care. While this discussion can be used as a framework for developing a Golden Hour protocol, each institution, with its own resource limitations and challenges, must devise an approach that captures not only the needs of their patient population, but the knowledge, skills and experience of the team providing care.

#### **Acknowledgments and thanks**

The authors would like to thank their patients and their families, from whom we learn every day. Furthermore, the authors would also like to recognize all of the

**17**

**Author details**

provided the original work is properly cited.

© 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

Omid Fathi\*, Roopali Bapat, Edward G. Shepherd and John Wells Logan Division of Neonatology, Department of Pediatrics, Nationwide Children's Hospital, The Ohio State University College of Medicine, Columbus, OH, USA

\*Address all correspondence to: omid.fathi@nationwidechildrens.org

*Golden Hours: An Approach to Postnatal Stabilization and Improving Outcomes*

provide the best care possible for our most vulnerable patients.

neonatal nurse practitioners, nurses, respiratory therapists, pharmacists, nutritionists, and occupational/physical therapists that work so tirelessly so that we can

The authors declared that they have no conflicts of interest to disclose.

*DOI: http://dx.doi.org/10.5772/intechopen.82810*

**Conflict of interest**

neonatal nurse practitioners, nurses, respiratory therapists, pharmacists, nutritionists, and occupational/physical therapists that work so tirelessly so that we can provide the best care possible for our most vulnerable patients.

### **Conflict of interest**

*Neonatal Medicine*

infusion [102].

to your institution [107].

**10.1 Teamwork and collaboration**

ers are the primary framework of CRM.

**Acknowledgments and thanks**

**11. Conclusion**

processes: interdisciplinary team training to improve communication and care in the delivery room, attention to temperature regulation, respiratory support and timely administration of surfactant, and early initiation of dextrose and amino acid

Developing a protocol for any process or improvement requires careful study, inclusion of key stake-holders, thoughtful protocol development and a comprehensive educational process prior to implementation [103]. Quality improvement, however, requires an ongoing evaluation of systems and processes. This continuous cycle of improvement will lead to improvements in teamwork and collaboration, skills and knowledge, consistency of care, and outcomes [104–106]. Consider using this Golden Hour review as a framework for evaluating systems and processes, for developing clinical guidelines or protocols, and for addressing the challenges unique

Standardized protocols, technical skills, and repeated training are the cornerstones of successful resuscitation. Emerging evidence suggests that human factors, including team interaction, communication and leadership, play a pivotal role in compliance with protocols and the success of resuscitations [108, 109]. One unit described their experience with implementation of Golden Hour protocol that included the use of realistic simulation-based learning, followed by team debriefing sessions as critical pieces of the implementation process [37]. Finer et al., improved their resuscitation outcomes by identifying opportunities and improving team and leader performance [6]. They utilized Crew Resource Management (CRM), a methodology developed for air crews from the late 1970s that evolved from a careful evaluation of the role of human error in air crashes. Communication and team lead-

Despite advances in medical care, a large number of preterm neonates remain at risk for significant morbidity or mortality. Golden Hour care of the at-risk premature neonate is a philosophical and team-based and highly specialized care that focuses on the first hours and days after birth. It is devised with the understanding that preterm neonates have unique risk factors based on physiology and immature adaptive systems. Key Golden Hour domains include: optimizing delivery room management of ventilation/oxygenation and thermoregulation, early establishment of vascular access, prevention of hypoglycemia, prevention and treatment of infection, and promotion of a developmentally-focused environment that promotes optimal short and long-term outcomes. The available literature supports standardization at the institutional level. In addition, it is critical to have a dedicated team of providers who regularly practice and hone the clinical skills relevant to Golden Hour care. While this discussion can be used as a framework for developing a Golden Hour protocol, each institution, with its own resource limitations and challenges, must devise an approach that captures not only the needs of their patient population, but the knowledge, skills and experience of the team providing care.

The authors would like to thank their patients and their families, from whom we learn every day. Furthermore, the authors would also like to recognize all of the

**16**

The authors declared that they have no conflicts of interest to disclose.

### **Author details**

Omid Fathi\*, Roopali Bapat, Edward G. Shepherd and John Wells Logan Division of Neonatology, Department of Pediatrics, Nationwide Children's Hospital, The Ohio State University College of Medicine, Columbus, OH, USA

\*Address all correspondence to: omid.fathi@nationwidechildrens.org

© 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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2014;**80**(3):144-150

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[55] McNamara P, Mak W, Whyte H. Dedicated neonatal retrieval teams improve delivery room resuscitation of outborn premature infants. Journal of

Perinatology. 2005;**25**(5):309

[56] Davis PG, Dawson JA. New concepts in neonatal resuscitation. Current Opinion in Pediatrics.

[57] Narendran V, Hoath SB. Thermal management of the low birth weight infant: A cornerstone of neonatology. The Journal of Pediatrics. 1999;**134**(5):529-531

[58] Wyckoff MH et al. Part 13: Neonatal resuscitation. Circulation. 2015;**132**(18

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2004;**114**(2):361-366

2012;**24**(2):147-153

suppl 2):S543-S560

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severe fetal acidemia. Pediatrics. 2004;**114**(2):361-366

*Neonatal Medicine*

2006;**117**(1):e16-e21

[37] Reynolds RD et al. The Golden Hour: Care of the LBW infant during the first hour of life one unit's experience. Neonatal Network. 2009;**28**(4):211-219, quiz 255-8

for cardiopulmonary resuscitation and emergency cardiovascular care. Circulation. 2015;**132**(18 Suppl 2):

[46] Hillman NH, Kallapur SG, Jobe AH. Physiology of transition from intrauterine to extrauterine life. Clinics in Perinatology. 2012;**39**(4):769-783

[47] Schmolzer GM et al. Reducing lung injury during neonatal resuscitation of preterm infants. The Journal of Pediatrics. 2008;**153**(6):741-745

[48] Tingay DG et al. Effect of sustained inflation vs. stepwise PEEP strategy at birth on gas exchange and lung mechanics in preterm lambs. Pediatric

Research. 2014;**75**(2):288-294

2014;**165**(2):240-249, e4

[49] Stevens TP et al. Respiratory outcomes of the surfactant positive pressure and oximetry randomized trial (SUPPORT). The Journal of Pediatrics.

[50] Castrodale V, Rinehart S. The Golden Hour: Improving the stabilization of the very low birthweight infant. Advances in Neonatal Care. 2014;**14**(1):9-14, quiz 15-6

[51] Kaiser JR et al. Association between transient newborn hypoglycemia and fourth-grade achievement test proficiency: A population-based study. JAMA Pediatrics. 2015;**169**(10):913-921

hypoglycaemia. British Medical Journal.

[52] Lucas A, Morley R, Cole TJ. Adverse neurodevelopmental outcome of moderate neonatal

1988;**297**(6659):1304-1308

2008;**122**(2):440-441

[54] Salhab WA et al. Initial hypoglycemia and neonatal brain injury in term infants with

[53] Inder T. How low can I go? The impact of hypoglycemia on the immature brain. Pediatrics.

S543-S560

[38] O'Donnell CP et al. Endotracheal intubation attempts during neonatal resuscitation: Success rates, duration, and adverse effects. Pediatrics.

[39] Perlman JM et al. Neonatal resuscitation: 2010 international consensus on cardiopulmonary resuscitation and emergency cardiovascular care science with

2010;**126**(5):e1319-e1344

treatment recommendations. Pediatrics.

[40] Rabe H et al. Effect of timing of umbilical cord clamping and other strategies to influence placental transfusion at preterm birth on maternal and infant outcomes. Cochrane Database of Systematic Reviews;**2012**(8):Cd003248

[41] Fogarty M et al. Delayed vs early umbilical cord clamping for preterm infants: A systematic review and metaanalysis. American Journal of Obstetrics and Gynecology. 2018;**218**(1):1-18

[42] Katheria AC et al. Placental transfusion: A review. Journal of Perinatology. 2017;**37**(2):105-111

[43] Tarnow-Mordi W et al. Delayed versus immediate cord clamping in preterm infants. The New England Journal of Medicine.

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[44] Weiner GM, Zaichkin J, editors. Textbook of Neonatal Resuscitation. 7th ed. Elk Grove Village, IL: American Academy of Pediatrics and American

**20**

[55] McNamara P, Mak W, Whyte H. Dedicated neonatal retrieval teams improve delivery room resuscitation of outborn premature infants. Journal of Perinatology. 2005;**25**(5):309

[56] Davis PG, Dawson JA. New concepts in neonatal resuscitation. Current Opinion in Pediatrics. 2012;**24**(2):147-153

[57] Narendran V, Hoath SB. Thermal management of the low birth weight infant: A cornerstone of neonatology. The Journal of Pediatrics. 1999;**134**(5):529-531

[58] Wyckoff MH et al. Part 13: Neonatal resuscitation. Circulation. 2015;**132**(18 suppl 2):S543-S560

[59] Budin P. The Nursling: The Feeding and Hygiene of Premature and Full-Term Infants. London, The Caxton Publishing Company; New York, Imperial Publishing Company. 1907

[60] Laptook AR, Salhab W, Bhaskar B. Admission temperature of low birth weight infants: Predictors and associated morbidities. Pediatrics. 2007;**119**(3):e643-e649

[61] Sharma D. Golden Hour of neonatal life: Need of the hour. Maternal Health, Neonatology and Perinatology. 2017;**3**(1):16

[62] Costeloe K et al. The EPICure study: Outcomes to discharge from hospital for infants born at the threshold of viability. Pediatrics. 2000;**106**(4):659-671

[63] Chang H-Y et al. Short-and longterm outcomes in very low birth weight infants with admission hypothermia. PLoS One. 2015;**10**(7):e0131976

[64] Gandy GM et al. Thermal environment and acid-base homeostasis in human infants during the first few

hours of life. The Journal of Clinical Investigation. 1964;**43**(4):751-758

[65] García-Muñoz FR, Rivero SR, Siles CQ. Hypothermia risk factors in the very low weight newborn and associated morbidity and mortality in a neonatal care unit. In Anales de Pediatria (Barcelona, Spain: 2003). 2014 2014;**80**(3):144-150

[66] Carroll PD et al. Use of polyethylene bags in extremely low birth weight infant resuscitation for the prevention of hypothermia. The Journal of Reproductive Medicine. 2010;**55**(1-2):9-13

[67] Bartels D et al. Population based study on the outcome of small for gestational age newborns. Archives of Disease in Childhood-Fetal and Neonatal Edition. 2005;**90**(1):F53-F59

[68] Lenclen R et al. Use of a polyethylene bag: A way to improve the thermal environment of the premature newborn at the delivery room. Archives de Pediatrie: Organe Officiel de la Societe Francaise de Pediatrie. 2002;**9**(3):238-244

[69] Mullany LC. Neonatal hypothermia in low-resource settings. In: Semin Perinatol. Elsevier; 2010;**34**(6):426-433

[70] Deshpande S, Platt MW. Association between blood lactate and acid-base status and mortality in ventilated babies. Archives of Disease in Childhood-Fetal and Neonatal Edition. 1997;**76**(1):F15-F20

[71] Wyckoff MH. Initial resuscitation and stabilization of the periviable neonate: the Golden-Hour approach. In: Semin Perinatol. 2014;**38**(1):12-16

[72] Jia Y et al. Effect of delivery room temperature on the admission temperature of premature infants: A randomized controlled trial. Journal of Perinatology. 2013;**33**(4):264

[73] Kattwinkel J et al. Part 15: Neonatal resuscitation. Circulation. 2010;**122** (18 suppl 3):S909-S919

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[75] Crenshaw JT. Healthy birth practice #6: Keep mother and baby together—It's best for mother, baby, and breastfeeding. The Journal of Perinatal Education. 2014;**23**(4):211

[76] Singh A et al. Improving neonatal unit admission temperatures in preterm babies: Exothermic mattresses, polythene bags or a traditional approach? Journal of Perinatology. 2010;**30**(1):45

[77] Lawn JE et al. 4 million neonatal deaths: When? Where? Why? The Lancet. 2005;**365**(9462):891-900

[78] Lawn JE et al. Every newborn: Progress, priorities, and potential beyond survival. The Lancet. 2014;**384**(9938):189-205

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(18 suppl 3):S909-S919

2014;**164**(2):271-275 e1

[75] Crenshaw JT. Healthy birth practice #6: Keep mother and baby together—It's best for mother, baby, and breastfeeding. The Journal of Perinatal

[76] Singh A et al. Improving neonatal unit admission temperatures in

preterm babies: Exothermic mattresses,

[77] Lawn JE et al. 4 million neonatal deaths: When? Where? Why? The Lancet. 2005;**365**(9462):891-900

[78] Lawn JE et al. Every newborn: Progress, priorities, and potential beyond survival. The Lancet. 2014;**384**(9938):189-205

[79] Lozano R et al. Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: A systematic analysis for the global burden of disease study 2010. The Lancet.

[80] Shane AL, Stoll BJ. Neonatal sepsis: Progress towards improved outcomes. Journal of Infection. 2014;**68**:S24-S32

CP. Chorioamnionitis: Important risk factor or innocent bystander for neonatal outcome? Neonatology.

[82] Kissoon N, Orr RA, Carcillo JA. Updated American College of Critical Care Medicine—Pediatric advanced life support guidelines for management of pediatric and neonatal septic shock:

2012;**380**(9859):2095-2128

[81] Thomas W, Speer

2011;**99**(3):177-187

polythene bags or a traditional approach? Journal of Perinatology.

2010;**30**(1):45

Education. 2014;**23**(4):211

[73] Kattwinkel J et al. Part 15: Neonatal resuscitation. Circulation. 2010;**122**

Relevance to the emergency care clinician. Pediatric Emergency Care.

[83] Dellinger RP et al. Surviving Sepsis campaign: International guidelines for management of severe sepsis and septic shock, 2012. Intensive Care Medicine.

[84] El-Wiher N et al. Management and treatment guidelines for sepsis in pediatric patients. The Open Inflammation journal. 2011;**4**(Suppl

[85] Lambeth TM et al. First Golden Hour of life: A quality improvement initiative. Advances in Neonatal Care.

[86] Stiles J, Jernigan TL. The basics of brain development. Neuropsychology

Review. 2010;**20**(4):327-348

2017;**27**(7):1048-1054

1997;**100**(4):724-727

[87] Maitre NL et al. The dual nature of early-life experience on somatosensory processing in the human infant brain. Current Biology.

[88] Noise: A hazard for the fetus and newborn. American Academy of Pediatrics Committee on Environmental Health. Pediatrics.

[89] Pineda RG et al. Patterns of altered neurobehavior in preterm infants within the neonatal intensive care unit. Journal

[90] Smith GC et al. Neonatal intensive care unit stress is associated with brain development in preterm infants. Annals of Neurology. 2011;**70**(4):541-549

of Pediatrics. 2013;**162**(3):470

[91] Symington A, Pinelli J.

in preterm infants. Cochrane Database of Systematic Reviews.

2006;**2**:CD001814

Developmental care for promoting development and preventing morbidity

2010;**26**(11):867-869

2013;**39**(2):165-228

2016;**16**(4):264-272

1-M11):101

[74] de Almeida MFB et al. Hypothermia and early neonatal mortality in preterm infants. The Journal of Pediatrics.

**22**

[93] Perlman JM. The genesis of cognitive and behavioral deficits in premature graduates of intensive care. Minerva Pediatrica. 2003;**55**(2):89-101

[94] Lorch SA et al. The differential impact of delivery hospital on the outcomes of premature infants. Pediatrics. 2012;**130**(2):270-278

[95] Phibbs CS et al. Level and volume of neonatal intensive care and mortality in very-low-birth-weight infants. New England Journal of Medicine. 2007;**356**(21):2165-2175

[96] Cifuentes J et al. Mortality in low birth weight infants according to level of neonatal care at hospital of birth. Pediatrics. 2002;**109**(5):745-751

[97] Logan J et al. Congenital diaphragmatic hernia: A systematic review and summary of best-evidence practice strategies. Journal of Perinatology. 2007;**27**(9):535

[98] Neczypor JL, Holley SL. Providing evidence-based care during the Golden Hour. Nursing for Women's Health. 2017;**21**(6):462-472

[99] Coccia C et al. Management of extremely low-birth-weight infants. Acta Paediatrica. 1992;**81**(s382):10-12

[100] Mehler K et al. Outcome of extremely low gestational age newborns after introduction of a revised protocol to assist preterm infants in their transition to extrauterine life. Acta Paediatrica. 2012;**101**(12):1232-1239

[101] Varga P et al. Changes in the outcome for infants, with birth weight under 500 grams, at our department (First Department of Obstetrics and Gynecology, Semmelweis University, Budapest). Orvosi Hetilap. 2015;**156**(10):404-408

[102] Ashmeade TL et al. Outcomes of a neonatal Golden Hour implementation project. American Journal of Medical Quality. 2016;**31**(1):73-80

[103] Sant'Anna G, Keszler M. Developing a neonatal unit ventilation protocol for the preterm baby. Early Human Development. 2012;**88**(12):925-929

[104] Mercer JS et al. Evidence-based practices for the fetal to newborn transition. Journal of Midwifery & Women's Health. 2007;**52**(3):262-272

[105] Morey JC et al. Error reduction and performance improvement in the emergency department through formal teamwork training: Evaluation results of the MedTeams project. Health Services Research. 2002;**37**(6):1553-1581

[106] Helmreich, RL and Schaefer HG, Team Performance in the Operating Room. 1994

[107] Batalden PB, Davidoff F. What Is "Quality Improvement" and how Can it Transform Healthcare? BMJ Quality & Safety. 2007;**16**:2-3

[108] Thomas E et al. Teamwork and quality during neonatal care in the delivery room. Journal of Perinatology. 2006;**26**(3):163

[109] Hunziker S et al. Human factors in resuscitation: Lessons learned from simulator studies. Journal of Emergencies, Trauma, and Shock. 2010;**3**(4):389-394

**25**

**Chapter 3**

**Abstract**

*Mehmet Şah İpek*

meningitis in newborn infants.

of the global under-5 deaths [3].

births and 40–58%, respectively [7].

**1. Introduction**

**Keywords:** neonate, meningitis, diagnosis, treatment, outcome

Neonatal Bacterial Meningitis

Despite improvements in neonatal intensive care, neonatal bacterial meningitis continues to be a serious disease with mortality rates varying between 10 and 15%. Additionally, long-term complications are observed among 20–50% of survivors, depending on time of diagnosis and therapy and virulence of the infecting pathogen. It is more common during the neonatal period than at any other age with the estimated incidence of 0.25 per 1000 live births. The absence of specific clinical presentation makes diagnosis of meningitis more difficult in neonates than in older children. Culture of cerebrospinal fluid is the traditional gold standard for diagnosis of bacterial meningitis, so all newborn infants with proven or suspected sepsis should undergo lumbar puncture. However, deciding when to perform lumbar puncture and interpretation of the results are challenging. Although the pathophysiology of neonatal meningitis is complex and not fully understood, researches on diagnostic and prognostic tools are ongoing. Prevention of neonatal sepsis, early recognition of infants at risk, development of novel, rapid diagnostics and adjunctive therapies, and appropriate and aggressive antimicrobial treatment to sterilize cerebrospinal fluid as soon as possible may prevent the lifelong squeal of bacterial

Along with the Millennium Development Goals, under-5 mortality rate reduced

Neonatal meningitis is a devastating disease associated with significant mortality and morbidity in both developed and developing countries. The improvements in healthcare delivery systems over the last several decades, especially in developed countries, resulted in a decline in mortality, but the rate of neurological morbidities in infants who survive remains substantial and ranged from 20 to 50% [4–8]. However, the incidence and mortality of neonatal meningitis in developing countries remain unacceptably high, variably reported as 0.8–6.1 per 1000 live

Bacterial meningitis is more common in the neonatal period than at any other time, with higher incidence in preterm and chronically hospitalized infants [9–11]. Additionally, the epidemiology of bacterial meningitis, the corresponding pathogens, the immature immune system and its response to infection and outcomes are

by an impressive 53% globally, from 1990 until 2015 [1]. Forty-five percent of under-5 mortality now occurs in the first month of life. Besides intrapartum causes and preterm birth complications, infections are one of the leading causes of neonatal deaths [2]. Neonatal sepsis and meningitis are collectively responsible for 6.8%

#### **Chapter 3**

## Neonatal Bacterial Meningitis

*Mehmet Şah İpek*

#### **Abstract**

Despite improvements in neonatal intensive care, neonatal bacterial meningitis continues to be a serious disease with mortality rates varying between 10 and 15%. Additionally, long-term complications are observed among 20–50% of survivors, depending on time of diagnosis and therapy and virulence of the infecting pathogen. It is more common during the neonatal period than at any other age with the estimated incidence of 0.25 per 1000 live births. The absence of specific clinical presentation makes diagnosis of meningitis more difficult in neonates than in older children. Culture of cerebrospinal fluid is the traditional gold standard for diagnosis of bacterial meningitis, so all newborn infants with proven or suspected sepsis should undergo lumbar puncture. However, deciding when to perform lumbar puncture and interpretation of the results are challenging. Although the pathophysiology of neonatal meningitis is complex and not fully understood, researches on diagnostic and prognostic tools are ongoing. Prevention of neonatal sepsis, early recognition of infants at risk, development of novel, rapid diagnostics and adjunctive therapies, and appropriate and aggressive antimicrobial treatment to sterilize cerebrospinal fluid as soon as possible may prevent the lifelong squeal of bacterial meningitis in newborn infants.

**Keywords:** neonate, meningitis, diagnosis, treatment, outcome

#### **1. Introduction**

Along with the Millennium Development Goals, under-5 mortality rate reduced by an impressive 53% globally, from 1990 until 2015 [1]. Forty-five percent of under-5 mortality now occurs in the first month of life. Besides intrapartum causes and preterm birth complications, infections are one of the leading causes of neonatal deaths [2]. Neonatal sepsis and meningitis are collectively responsible for 6.8% of the global under-5 deaths [3].

Neonatal meningitis is a devastating disease associated with significant mortality and morbidity in both developed and developing countries. The improvements in healthcare delivery systems over the last several decades, especially in developed countries, resulted in a decline in mortality, but the rate of neurological morbidities in infants who survive remains substantial and ranged from 20 to 50% [4–8]. However, the incidence and mortality of neonatal meningitis in developing countries remain unacceptably high, variably reported as 0.8–6.1 per 1000 live births and 40–58%, respectively [7].

Bacterial meningitis is more common in the neonatal period than at any other time, with higher incidence in preterm and chronically hospitalized infants [9–11]. Additionally, the epidemiology of bacterial meningitis, the corresponding pathogens, the immature immune system and its response to infection and outcomes are

#### *Neonatal Medicine*

distinctive to the neonatal period [12, 13]. A cerebral insult related to meningitis has a greater impact on the vulnerable, developing brain, so a younger age during disease is usually associated with a poorer outcome [14]. Therefore, overall improved recognition, evaluation, and aggressive antimicrobial treatment of bacterial meningitis in newborn infants are essential to lead to a reduction in the mortality and the lifelong squeals.

This chapter will focus on the epidemiology, etiology, pathogenesis, diagnosis, treatment, and outcome of neonatal bacterial meningitis.

#### **2. Definition**

Meningitis is defined as infection and inflammation of the meninges, subarachnoid space and brain vasculature [15]. Since epidemiology of neonatal meningitis is similar to that of neonatal sepsis, neonatal meningitis is also divided into earlyonset and late-onset meningitis, based on timing of infection and presumed mode of transmission [16, 17]. The cutoff for these definitions is variable throughout the literature. Early-onset meningitis is typically defined as meningitis occurring within the first 3 or 7 days after birth, and especially those in the first 2 days after birth reflect vertical transmission of invasive organism from maternal genital tract flora. Late-onset meningitis is usually defined as infection occurring as early as 4 or 8 days after birth and as late as 28 days after birth, and it is attributed to organisms acquired from interaction with the hospital environment or the community [16–18]. In very low-birth weight preterm and high-risk term infants, many of whom have prolonged hospital stays, the description of late-onset meningitis may be applicable until hospital discharge regardless of the age at the time of the infection [16]. The distinction between two patterns is useful to guide therapy. However, this distinction does not necessarily be valid in the developing world, where unsanitary birth practices and newborn care at home or in hospitals confront newborns with the risk of acquiring environmental pathogens at or soon after birth [19, 20].

#### **3. Epidemiology**

Worldwide, the incidence of neonatal bacterial meningitis is between 0.22 and 2.66 per 1000 live births. However, the incidence varies by countries of different income levels [11, 20–22].

The incidence of culture-proven neonatal meningitis is estimated between 0.21 and 0.3 per 1000 live births in developed countries [4, 11, 23]. This number is probably underestimated since a lumbar puncture is not performed in up to 50% of infants who were evaluated for sepsis in the intensive care nursery [4], and when it is performed, it may be done after the initiation of antibiotics, likely biasing culture results [4, 24]. The incidence in very-low-birth weight (VLBW) infants may be as high as 1.4%, and about 5% of those with at least one lumbar puncture performed during the hospital stay suffer from late-onset meningitis [25]. Bacterial meningitis occurs in 25% of neonates with bacteremia [17], whereas in LVBW infants with meningitis, the rate of blood culture positivity is as much as 55% [25].

In developed countries, mortality from neonatal meningitis was nearly 50% in the 1970s, and then it has dropped to figures ranging from 10 to 15% [5, 7, 26–29]. However, long-term sequelae rates did not change, with up to 50% of survivors having long-term neurodevelopmental complications [4–8, 27]. In a prospective study including 444 cases of confirmed meningitis during 2001–2007, it was reported

**27**

*Neonatal Bacterial Meningitis*

preterm babies (25%) [29].

regions [20].

**4. Etiology**

and nosocomial infection.

**Causative pathogen** Group B *Streptococcus*

*Escherichia coli*

*onset meningitis.*

**Table 1.**

*Listeria monocytogenes For more, see Ref. [18].*

*DOI: http://dx.doi.org/10.5772/intechopen.87118*

infection in the preterm and VLBW infants [30].

*Staphylococcus epidermidis*†*,* and *Staphylococcus aureus*)

*Bacteria causing neonatal meningitis in developed countries.*

*Proteus* species, *Citrobacter* species, and *Serratia marcescens*)

that the case fatality for neonatal bacterial meningitis was 13%, but much higher in

The most common organisms associated with neonatal meningitis are Group B Streptococcus (GBS), *Escherichia coli*, and *Listeria monocytogenes*, and GBS and *E coli* account for approximately two-thirds of all cases of neonatal meningitis [8, 30]. Thanks to the program consists of identifying pregnant women who are GBS carriers by screening and/or identifying the presence of risk factors that predispose the infants to infection, the incidence of early onset neonatal GBS sepsis in the United States has declined from 1.5 per 1000 live birth to 0.3 per 1000 live births. However, the incidence in late onset neonatal GBS infection appears to remain unchanged or even increasing [30–35]. Additionally, there is an increased incidence of Gram-negative bacteria, specifically antibiotic-resistant *E coli*, in early-onset

The types and distribution of organisms that commonly cause neonatal meningitis depend on age at presentation, location, and gestational age. The distribution of organisms observed in neonatal meningitis is similar to that of neonatal sepsis (**Table 1**) [4, 18, 23]. So, meningitis may be a component of early-onset, late-onset,

The group B streptococcus (especially capsular serotype III) is the major causative pathogen, implicated in up to 50% of cases. Late-onset GBS sepsis is more likely to be complicated by meningitis when compared to early-onset GBS

Other streptococci and staphylococci (including especially group D streptococci, *Streptococcus pneumoniae*,

Other Gram-negative enteric bacteria (including *Pseudomonas aeruginosa*, *Klebsiella* and *Enterobacter* species,

Others (including *Haemophilus influenzae*, *Salmonella* species, and *Flavobacterium meningosepticum*)

*†Coagulase-negative staphylococci are particularly common etiologies in very-low-birth-weight infants with late-*

It may be difficult to estimate the incidence in developing countries due to under-developed surveillance systems. A few community-based studies published from developing countries tend to reveal higher incidence of neonatal meningitis [20]. In these studies, the incidence of neonatal meningitis in the first week of life ranged from 0.8 to 6.1 per 1000 live births [4, 5, 20]. In developing countries, mortality from neonatal meningitis ranges from 40 to 58% [7]. It is very likely that most of the studies from developing countries have biases in selection of study population, which may have underestimated true incidence rates. Additionally, the lack of laboratory-based confirmation as well as varied clinical criteria and access to health care facilities and limited resources may lead to underreporting in these

#### *Neonatal Bacterial Meningitis DOI: http://dx.doi.org/10.5772/intechopen.87118*

*Neonatal Medicine*

and the lifelong squeals.

**2. Definition**

**3. Epidemiology**

income levels [11, 20–22].

distinctive to the neonatal period [12, 13]. A cerebral insult related to meningitis has a greater impact on the vulnerable, developing brain, so a younger age during disease is usually associated with a poorer outcome [14]. Therefore, overall improved recognition, evaluation, and aggressive antimicrobial treatment of bacterial meningitis in newborn infants are essential to lead to a reduction in the mortality

This chapter will focus on the epidemiology, etiology, pathogenesis, diagnosis,

Meningitis is defined as infection and inflammation of the meninges, subarachnoid space and brain vasculature [15]. Since epidemiology of neonatal meningitis is similar to that of neonatal sepsis, neonatal meningitis is also divided into earlyonset and late-onset meningitis, based on timing of infection and presumed mode of transmission [16, 17]. The cutoff for these definitions is variable throughout the literature. Early-onset meningitis is typically defined as meningitis occurring within the first 3 or 7 days after birth, and especially those in the first 2 days after birth reflect vertical transmission of invasive organism from maternal genital tract flora. Late-onset meningitis is usually defined as infection occurring as early as 4 or 8 days after birth and as late as 28 days after birth, and it is attributed to organisms acquired from interaction with the hospital environment or the community [16–18]. In very low-birth weight preterm and high-risk term infants, many of whom have prolonged hospital stays, the description of late-onset meningitis may be applicable until hospital discharge regardless of the age at the time of the infection [16]. The distinction between two patterns is useful to guide therapy. However, this distinction does not necessarily be valid in the developing world, where unsanitary birth practices and newborn care at home or in hospitals confront newborns with the risk

treatment, and outcome of neonatal bacterial meningitis.

of acquiring environmental pathogens at or soon after birth [19, 20].

meningitis, the rate of blood culture positivity is as much as 55% [25].

Worldwide, the incidence of neonatal bacterial meningitis is between 0.22 and 2.66 per 1000 live births. However, the incidence varies by countries of different

In developed countries, mortality from neonatal meningitis was nearly 50% in the 1970s, and then it has dropped to figures ranging from 10 to 15% [5, 7, 26–29]. However, long-term sequelae rates did not change, with up to 50% of survivors having long-term neurodevelopmental complications [4–8, 27]. In a prospective study including 444 cases of confirmed meningitis during 2001–2007, it was reported

The incidence of culture-proven neonatal meningitis is estimated between 0.21 and 0.3 per 1000 live births in developed countries [4, 11, 23]. This number is probably underestimated since a lumbar puncture is not performed in up to 50% of infants who were evaluated for sepsis in the intensive care nursery [4], and when it is performed, it may be done after the initiation of antibiotics, likely biasing culture results [4, 24]. The incidence in very-low-birth weight (VLBW) infants may be as high as 1.4%, and about 5% of those with at least one lumbar puncture performed during the hospital stay suffer from late-onset meningitis [25]. Bacterial meningitis occurs in 25% of neonates with bacteremia [17], whereas in LVBW infants with

**26**

that the case fatality for neonatal bacterial meningitis was 13%, but much higher in preterm babies (25%) [29].

It may be difficult to estimate the incidence in developing countries due to under-developed surveillance systems. A few community-based studies published from developing countries tend to reveal higher incidence of neonatal meningitis [20]. In these studies, the incidence of neonatal meningitis in the first week of life ranged from 0.8 to 6.1 per 1000 live births [4, 5, 20]. In developing countries, mortality from neonatal meningitis ranges from 40 to 58% [7]. It is very likely that most of the studies from developing countries have biases in selection of study population, which may have underestimated true incidence rates. Additionally, the lack of laboratory-based confirmation as well as varied clinical criteria and access to health care facilities and limited resources may lead to underreporting in these regions [20].

The most common organisms associated with neonatal meningitis are Group B Streptococcus (GBS), *Escherichia coli*, and *Listeria monocytogenes*, and GBS and *E coli* account for approximately two-thirds of all cases of neonatal meningitis [8, 30]. Thanks to the program consists of identifying pregnant women who are GBS carriers by screening and/or identifying the presence of risk factors that predispose the infants to infection, the incidence of early onset neonatal GBS sepsis in the United States has declined from 1.5 per 1000 live birth to 0.3 per 1000 live births. However, the incidence in late onset neonatal GBS infection appears to remain unchanged or even increasing [30–35]. Additionally, there is an increased incidence of Gram-negative bacteria, specifically antibiotic-resistant *E coli*, in early-onset infection in the preterm and VLBW infants [30].

#### **4. Etiology**

The types and distribution of organisms that commonly cause neonatal meningitis depend on age at presentation, location, and gestational age. The distribution of organisms observed in neonatal meningitis is similar to that of neonatal sepsis (**Table 1**) [4, 18, 23]. So, meningitis may be a component of early-onset, late-onset, and nosocomial infection.

The group B streptococcus (especially capsular serotype III) is the major causative pathogen, implicated in up to 50% of cases. Late-onset GBS sepsis is more likely to be complicated by meningitis when compared to early-onset GBS


#### **Table 1.**

*Bacteria causing neonatal meningitis in developed countries.*

sepsis [36]. Colonization of the neonate with GBS may be acquired from maternal genital tract during delivery or from nosocomial sources [17]. The attack rate of the colonized newborn is approximately 1%. The risk factors that influence the attack rate include prematurity, dose and virulence of the organism, prolonged duration of ruptured membrane prior to the delivery, and maternal fever during labor [31]. Despite intrapartum antibiotic prophylaxis (IAP) to reduce vertical transmission of GBS infection, not all cases of early-onset GBS are prevented, and GBS continues to be the most common cause of early-onset disease in term neonates [4, 21, 37]. However, it is uncommon in developing countries, even if the prevalence of colonization in women has been reported as high as 22% and implementation of IAP is not possible [16, 38].

*Escherichia coli* is the second most common pathogen and represents 50% of gram-negative bacteria which account for 30–40% of cases of neonatal meningitis [4, 11, 30]. Most of *E coli* (80%) strains causing meningitis possessed the K1 polysaccharide capsular antigen which inhibits phagocytosis and resists antibodyindependent serum bactericidal activity [39, 40]. With the implementation of IAP against GBS, *E Coli* has emerged as the most common cause of early-onset sepsis and meningitis among VLBW infants [41, 42], and it has become the leading cause of sepsis-related mortality in this weight group [43]. Additionally, there is a growing concern on emerging antimicrobial resistance in *E coli* infections [41]. *Klebsiella* spp. are the second most important Gram-negative bacteria causing neonatal meningitis, especially in developing countries [4, 7]. The other Gram-negative organisms less commonly isolated include *Enterobacter* spp.*, Pseudomonas aeruginosa, Citrobacter* spp., and *Serratia* spp. [17]. *Citrobacter* spp. are usually associated with brain abscesses, emphasizing the importance of brain imaging as part of the evaluation whenever *Citrobacter* is isolated from the CSF [23].

It has been estimated that *Listeria monocytogenes* accounts for approximately 5–7% of cases of neonatal meningitis [5, 28], since the incidence of neonatal *Listeria* infections has decreased substantially in recent years [44]. It continues to be important in contribution to significant morbidity and mortality because of its association with thrombo-encephalitis. Similar to GBS neonatal infections, early-onset Listeria disease is often sepsis whereas late-onset Listeria disease is often meningitis [45]. *Listeria* serotype IVb is responsible for almost all cases of meningitis caused by this organism [46]. *Listeria* may be acquired following placental invasion during pregnancy, passively during the birth process or following horizontal transmission from environmental sources [17, 45].

Coagulase-negative staphylococcus (CNS) and *Staphylococcus aureus* are commonly seen in very premature and high-risk neonates who require prolonged hospitalization, central venous catheters, external devices and ventilator support [5]. Other less common but important pathogens associated with neonatal meningitis include enterococcus, *Streptococcus pneumoniae*, *Neisseria meningitidis*, and *Haemophilus influenzae* [8, 18, 21]. Moreover, there is a wider range of more unusual and potentially antibiotic-resistant organisms causing late-onset meningitis in hospitalized patients [11, 18, 47–49].

#### **5. Pathogenesis**

Meningitis most commonly results as a consequence of hematogenous dissemination of bacteria via choroid plexus and cerebral microvasculature into the central nervous system during the course of sepsis [4, 15]. Rarely, meningitis may develop following the spread of an infection in the scalp or skull, and a contamination of open neural tube defect, congenital sinus tract, or ventricular device [4, 18, 50].

**29**

*Neonatal Bacterial Meningitis*

*DOI: http://dx.doi.org/10.5772/intechopen.87118*

common cause and pathogenesis.

The early- and late-onset patterns of the disease have been associated with sepsis during the first month of life, as invasion of the meninges occurs in as many as 25% of infants with bacteremia [23, 50]. So, meningitis and sepsis typically share a

Neonates are the most vulnerable of all age groups to infectious pathogens, because of immaturity of the immune system, as well as decreased placental passage of maternal antibodies, especially in preterm infants [16, 37]. All limitations of both initiate and adaptive immunity, decreased inflammatory and immune effector responses, and the deficient expression of complement and of antimicrobial proteins make fetus and neonate, particularly the premature neonate, susceptible to a wide variety of microorganisms [18, 51]. In addition to host susceptibility, obstetric and nursery practices, socioeconomic status, and the health and nutrition of mothers are important in determining neonates at risk for infection, and similarly,

Initial colonization of the neonate usually occurs in utero from ascending bacteria entering the uterus from vaginal environment after rupture of amniotic membranes [18, 37]. If delivery is delayed, microbial invasion of amniotic fluid may cause an acute inflammation of the fetal membranes, which is defined as chorioamnionitis [18, 37]. Infected amniotic fluid may lead to fetal systemic inflammatory response syndrome, stillbirth, preterm delivery, or neonatal sepsis following invasion of bacteria into the fetus through respiratory tract (fetal breathing), gastrointestinal tract (swallowing), skin, and ear [52]. Additionally, the neonate may be colonized with potentially pathogenic bacteria through the birth canal during delivery. Microorganism acquired by the neonate just before or during birth colonizes the skin and mucosa of multiple sites including the nasopharynx, conjunctivae, oropharynx, umbilical cord, and in the female infant, the external genitalia. Microorganisms can invade through any site where skin or mucosal barrier is disrupted [15, 17]. Bacteria may proliferate at the initial site of attachment without causing serious illness, or then, pass into the subepithelial blood vessel from where they can be transported to other parts of the body including the CNS [15, 18]. Transplacental hematogenous infection is also possible. *Listeria monocytogenes* is usually acquired transplacentally [4, 45]. In rare cases, hematogenous transmission of GBS, *S pneumoniae*, and *N meningitidi*s from maternal bacteremia

has been reported as causes of early-onset neonatal meningitis [18, 37, 53].

As infants grow up, they are exposed to environmental microorganisms that might be pathogenic to them. Poor hand hygiene among caregivers and hospital personnel, nutritional sources, and contaminated equipment all can transfer microorganism from infected infants to uninfected infants [13, 37, 53]. Most VLBW and high-risk infants have one or more procedures that expose them to risk of infection during their hospital stay. Invasive devices such as venous or arterial catheters, endotracheal tubes, ventricular shunts, urinary catheters, and feeding tubes can insert pathogen into the body of the infant. Parenteral nutrition, exposure to prolonged courses of empiric antibiotics, H2-receptor blocker or proton pump inhibitor use can also result in increased risk for late-onset infections [13, 18, 37, 54, 55]. Once the bacterium has entered into the systemic circulation, the polysaccharide capsule of the pathogen plays a key role in the survival of the pathogen in the hostile environment of the blood [15, 17, 56]. The polysaccharide capsule mediates resistance to complement-mediated lysis and phagocytosis by polymorphonuclear leukocytes and macrophages [15, 57]. The potential sites for bacteria entering the CNS are the cerebral microvascular endothelium of the arachnoid membrane and the choroid plexus epithelium where capillary endothelial cells are fused along the terminal edge by tight junctions [17]. The attachment of bacteria to microvascular endothelial cells and passage through the blood brain barrier (BBB) are promoted

in the pathogenesis of neonatal sepsis and meningitis [18, 37].

#### *Neonatal Bacterial Meningitis DOI: http://dx.doi.org/10.5772/intechopen.87118*

*Neonatal Medicine*

possible [16, 38].

sepsis [36]. Colonization of the neonate with GBS may be acquired from maternal genital tract during delivery or from nosocomial sources [17]. The attack rate of the colonized newborn is approximately 1%. The risk factors that influence the attack rate include prematurity, dose and virulence of the organism, prolonged duration of ruptured membrane prior to the delivery, and maternal fever during labor [31]. Despite intrapartum antibiotic prophylaxis (IAP) to reduce vertical transmission of GBS infection, not all cases of early-onset GBS are prevented, and GBS continues to be the most common cause of early-onset disease in term neonates [4, 21, 37]. However, it is uncommon in developing countries, even if the prevalence of colonization in women has been reported as high as 22% and implementation of IAP is not

*Escherichia coli* is the second most common pathogen and represents 50% of gram-negative bacteria which account for 30–40% of cases of neonatal meningitis [4, 11, 30]. Most of *E coli* (80%) strains causing meningitis possessed the K1 polysaccharide capsular antigen which inhibits phagocytosis and resists antibodyindependent serum bactericidal activity [39, 40]. With the implementation of IAP against GBS, *E Coli* has emerged as the most common cause of early-onset sepsis and meningitis among VLBW infants [41, 42], and it has become the leading cause of sepsis-related mortality in this weight group [43]. Additionally, there is a growing concern on emerging antimicrobial resistance in *E coli* infections [41]. *Klebsiella* spp. are the second most important Gram-negative bacteria causing neonatal meningitis, especially in developing countries [4, 7]. The other Gram-negative organisms less commonly isolated include *Enterobacter* spp.*, Pseudomonas aeruginosa, Citrobacter* spp., and *Serratia* spp. [17]. *Citrobacter* spp. are usually associated with brain abscesses, emphasizing the importance of brain imaging as part of the

It has been estimated that *Listeria monocytogenes* accounts for approximately 5–7% of cases of neonatal meningitis [5, 28], since the incidence of neonatal *Listeria* infections has decreased substantially in recent years [44]. It continues to be important in contribution to significant morbidity and mortality because of its association with thrombo-encephalitis. Similar to GBS neonatal infections, early-onset Listeria disease is often sepsis whereas late-onset Listeria disease is often meningitis [45]. *Listeria* serotype IVb is responsible for almost all cases of meningitis caused by this organism [46]. *Listeria* may be acquired following placental invasion during pregnancy, passively during the birth process or following horizontal transmission

Coagulase-negative staphylococcus (CNS) and *Staphylococcus aureus* are commonly seen in very premature and high-risk neonates who require prolonged hospitalization, central venous catheters, external devices and ventilator support [5]. Other less common but important pathogens associated with neonatal meningitis include enterococcus, *Streptococcus pneumoniae*, *Neisseria meningitidis*, and *Haemophilus influenzae* [8, 18, 21]. Moreover, there is a wider range of more unusual and potentially antibiotic-resistant organisms causing late-onset meningitis in

Meningitis most commonly results as a consequence of hematogenous dissemination of bacteria via choroid plexus and cerebral microvasculature into the central nervous system during the course of sepsis [4, 15]. Rarely, meningitis may develop following the spread of an infection in the scalp or skull, and a contamination of open neural tube defect, congenital sinus tract, or ventricular device [4, 18, 50].

evaluation whenever *Citrobacter* is isolated from the CSF [23].

from environmental sources [17, 45].

hospitalized patients [11, 18, 47–49].

**5. Pathogenesis**

**28**

The early- and late-onset patterns of the disease have been associated with sepsis during the first month of life, as invasion of the meninges occurs in as many as 25% of infants with bacteremia [23, 50]. So, meningitis and sepsis typically share a common cause and pathogenesis.

Neonates are the most vulnerable of all age groups to infectious pathogens, because of immaturity of the immune system, as well as decreased placental passage of maternal antibodies, especially in preterm infants [16, 37]. All limitations of both initiate and adaptive immunity, decreased inflammatory and immune effector responses, and the deficient expression of complement and of antimicrobial proteins make fetus and neonate, particularly the premature neonate, susceptible to a wide variety of microorganisms [18, 51]. In addition to host susceptibility, obstetric and nursery practices, socioeconomic status, and the health and nutrition of mothers are important in determining neonates at risk for infection, and similarly, in the pathogenesis of neonatal sepsis and meningitis [18, 37].

Initial colonization of the neonate usually occurs in utero from ascending bacteria entering the uterus from vaginal environment after rupture of amniotic membranes [18, 37]. If delivery is delayed, microbial invasion of amniotic fluid may cause an acute inflammation of the fetal membranes, which is defined as chorioamnionitis [18, 37]. Infected amniotic fluid may lead to fetal systemic inflammatory response syndrome, stillbirth, preterm delivery, or neonatal sepsis following invasion of bacteria into the fetus through respiratory tract (fetal breathing), gastrointestinal tract (swallowing), skin, and ear [52]. Additionally, the neonate may be colonized with potentially pathogenic bacteria through the birth canal during delivery. Microorganism acquired by the neonate just before or during birth colonizes the skin and mucosa of multiple sites including the nasopharynx, conjunctivae, oropharynx, umbilical cord, and in the female infant, the external genitalia. Microorganisms can invade through any site where skin or mucosal barrier is disrupted [15, 17]. Bacteria may proliferate at the initial site of attachment without causing serious illness, or then, pass into the subepithelial blood vessel from where they can be transported to other parts of the body including the CNS [15, 18]. Transplacental hematogenous infection is also possible. *Listeria monocytogenes* is usually acquired transplacentally [4, 45]. In rare cases, hematogenous transmission of GBS, *S pneumoniae*, and *N meningitidi*s from maternal bacteremia has been reported as causes of early-onset neonatal meningitis [18, 37, 53].

As infants grow up, they are exposed to environmental microorganisms that might be pathogenic to them. Poor hand hygiene among caregivers and hospital personnel, nutritional sources, and contaminated equipment all can transfer microorganism from infected infants to uninfected infants [13, 37, 53]. Most VLBW and high-risk infants have one or more procedures that expose them to risk of infection during their hospital stay. Invasive devices such as venous or arterial catheters, endotracheal tubes, ventricular shunts, urinary catheters, and feeding tubes can insert pathogen into the body of the infant. Parenteral nutrition, exposure to prolonged courses of empiric antibiotics, H2-receptor blocker or proton pump inhibitor use can also result in increased risk for late-onset infections [13, 18, 37, 54, 55].

Once the bacterium has entered into the systemic circulation, the polysaccharide capsule of the pathogen plays a key role in the survival of the pathogen in the hostile environment of the blood [15, 17, 56]. The polysaccharide capsule mediates resistance to complement-mediated lysis and phagocytosis by polymorphonuclear leukocytes and macrophages [15, 57]. The potential sites for bacteria entering the CNS are the cerebral microvascular endothelium of the arachnoid membrane and the choroid plexus epithelium where capillary endothelial cells are fused along the terminal edge by tight junctions [17]. The attachment of bacteria to microvascular endothelial cells and passage through the blood brain barrier (BBB) are promoted

by the interaction of specific bacterial factors with host receptors [57]. To facilitate crossing the BBB, *Streptococcus pneumoniae* interacts with cell wall phosphorylcholine and platelet activating factor receptor [8]. *Streptococcus agalactiae* uses the lipoprotein laminin-binding protein and K1 *E Coli* express type 1 fimbriae and the OmpA protein to contribute to the bacterium binding to cerebral endothelial cells [57–59]. The bacteria can cross the BBB transcellularly, paracellularly, and in infected phagocytes. Transcellular traversal occurs when the microorganism penetrates the cells without any evidence in the cells or intracellular tight-junction disruption [58]. *Streptococcus pneumoniae*, *Streptococcus agalactiae*, and *E. coli* can all cross the BBB via this mechanism [58]. Paracellular traversal occurs when microorganism penetrates between barrier cells [17]. *L monocytogenes* crosses the BBB by microbial penetration using transmigration within *L monocytogenes*-infected monocytes or myeloid cells across the BBB by a so-called Trojan horse mechanism [15, 58].

Once bacteria enter the cerebrospinal fluid, they are free to replicate and spread unchecked at least initially, as phagocytes, immunoglobulins, and complement components are excluded by the BBB. This bacterial multiplication goes on until bacteria die following the stationary growth phase or the exposure to the treatment with β-lactams that causes antibiotic-induced bacteriolysis. The subsequent release of subcapsular bacterial products such as peptidoglycan, lipoteichoic acids, lipoproteins, lipopolysaccharides, and bacterial DNA leads to an increased inflammatory response in the host [15, 59]. Many brain cells including astrocytes, glial cells, endothelial cells, ependymal cells, and resident macrophages can produce proinflammatory and anti-inflammatory cytokines in response to bacterial replication and its components [60, 61]. Although this inflammation is needed to eliminate the bacteria and allow the host to recover, it is also a major cause of brain injury in meningitis [11, 61].

Neuronal injury in bacterial meningitis is caused by several mechanisms, which have been identified by experimental studies during the last years [15, 60–62]. Neuronal injury likely results from a combination of the following events: dysfunctioning cerebral blood flow (increased BBB permeability, cerebral edema, vasospasm, vasculitis, cerebral venous thrombosis, and systemic hypotension), detrimental effects of inflammatory mediators (e.g., tumor necrosis factor-alpha, interleukin-1, and nitric oxide) and infiltrating cells (leukocytes, macrophages, and microglia), neurotoxicity (free radicals, proteases, and some microbial compounds), increased CSF outflow resistance, and excitatory amino acids, which finally lead to energy failure and cell death executed by caspases [15, 17, 60–63]. The mode of neuronal cell death in different regions of the brain depends on the strength and type of the noxious stimulus and may be a form of apoptotic, necrotic, or hybrid [62, 63]. For example, neuronal cell death occurs mostly as apoptosis in the dentate gyrus of the hippocampal formation, whereas it occurs mostly as necrosis due to focal ischemia in the cortex [15, 62, 63].

#### **6. Risk factors**

Since meningitis is most commonly a complication of bacteremia, the risk factors are similar to those that contribute to neonatal sepsis [4–6]. Risk factors for neonatal sepsis include maternal factors, neonatal host factors, and virulence of infecting organism. The most important neonatal factor is prematurity or low birth weight. Small preterm infants have a 3–10 times higher incidence of infection than full-term normal birth weight infants [4–6]. Immaturity of the immune system and diminishing transplacentally acquired maternal immunoglobulins in premature infants contribute

**31**

well they appear [66].

*Neonatal Bacterial Meningitis*

**7. Clinical presentation**

*DOI: http://dx.doi.org/10.5772/intechopen.87118*

establish an early diagnosis of meningitis [18].

cases and nuchal rigidity in only 15% [28].

more likely to have specific signs of meningitis [28].

to increased risk of infections. Additionally, preterm infants often require prolonged hospital stay and so have one or more procedures such as parenteral nutrition, intubation, and central catheters that place them at risk for infection [18, 37]. Other host factors include hypoxia, acidosis, hyperbilirubinemia, hypothermia, galactosemia, indomethacin, lipid administration, and parenteral iron supplementation [37]. Maternal risk factors include GBS colonization or GBS bacteriuria, prolonged rupture of membranes of 18–24 hours or greater, chorioamnionitis, urinary tract infections,

The earliest signs and symptoms of neonates with meningitis may be subtle and nonspecific, especially more problematic in premature infants [5]. The clinical presentation of neonatal meningitis is similar to those of neonatal sepsis without meningitis. Most commonly reported clinical features include temperature instability (62%), irritability or lethargy (52%), and poor feeding or vomiting (48%) [18]. However, in preterm infants, respiratory decompensation consisting of an increased number of apnea and bradycardia episodes and increased oxygen requirement are prominent clinical signs [50]. Term infants are more likely to have fever (>37.2°C), whereas preterm infants more frequently have hypothermia (<36°C) [64]. Other findings associated with neonatal meningitis include respiratory distress, jaundice, diarrhea and hepatosplenomegaly. However, all these features could not help to

Neurologic signs of neonatal meningitis include irritability, alteration in consciousness, poor tone, tremors, seizures, high-pitched cry, twitching of facial or an extremity, focal signs including hemiparesis, gaze deviation, and cranial nerve deficits [4, 18]. Seizures are generally focal and seen in 40% of cases, and considering subtle ones is also possible [5, 18]. Since cranial sutures in the neonate are open and allow for expansion of the intracranial contents and for increasing head size, meningeal signs are not commonly seen. Bulging fontanelle occurs in about 25% of

Early-onset neonatal infections are generally presented as sepsis or pneumonia, so meningitis is relatively less common. The signs of early-onset infection get to appear within the first 24–48 hours of life in 90% of affected cases [65]. However, late-onset sepsis, in addition to bacteremia, is frequently manifested as focal infections such as meningitis and osteomyelitis resulting from hematogenous seeding [11, 18]. Neonatal meningitis can complicate 14% of episodes of early-onset GBS sepsis and 54% of episodes of late-onset GBS sepsis [36], so the later condition is

Lack of data on the timing of onset of features listed above makes it difficult for the early recognition of a baby with meningitis. Additionally, these features are likely to be affected by other factors such as gestational age, partial antibiotic treatment, and postnatal age [6]. Classical meningitic signs such as convulsions, bulging fontanel, altered mental status, and nuchal rigidity are often late findings that are associated with a worse outcome [5, 6]. So, the timing of the onset of clinical features may be crucial for early recognition, prompt management and potentially, better outcome [6]. Although several useful clinical features were defined to predict meningitis in children, the most accurate combination of clinical features to raise or lower suspicion of meningitis is still unclear. Furthermore, small infants presenting nonspecific but concerning features such as fever, lethargy, poor feeding, or irritability, should be approached with a high index of suspicion regardless of how

multiple pregnancies, and septic or traumatic delivery [13, 18, 37].

#### *Neonatal Bacterial Meningitis DOI: http://dx.doi.org/10.5772/intechopen.87118*

to increased risk of infections. Additionally, preterm infants often require prolonged hospital stay and so have one or more procedures such as parenteral nutrition, intubation, and central catheters that place them at risk for infection [18, 37]. Other host factors include hypoxia, acidosis, hyperbilirubinemia, hypothermia, galactosemia, indomethacin, lipid administration, and parenteral iron supplementation [37]. Maternal risk factors include GBS colonization or GBS bacteriuria, prolonged rupture of membranes of 18–24 hours or greater, chorioamnionitis, urinary tract infections, multiple pregnancies, and septic or traumatic delivery [13, 18, 37].

#### **7. Clinical presentation**

*Neonatal Medicine*

[15, 58].

meningitis [11, 61].

the cortex [15, 62, 63].

**6. Risk factors**

by the interaction of specific bacterial factors with host receptors [57]. To facilitate crossing the BBB, *Streptococcus pneumoniae* interacts with cell wall phosphorylcholine and platelet activating factor receptor [8]. *Streptococcus agalactiae* uses the lipoprotein laminin-binding protein and K1 *E Coli* express type 1 fimbriae and the OmpA protein to contribute to the bacterium binding to cerebral endothelial cells [57–59]. The bacteria can cross the BBB transcellularly, paracellularly, and in infected phagocytes. Transcellular traversal occurs when the microorganism penetrates the cells without any evidence in the cells or intracellular tight-junction disruption [58]. *Streptococcus pneumoniae*, *Streptococcus agalactiae*, and *E. coli* can all cross the BBB via this mechanism [58]. Paracellular traversal occurs when microorganism penetrates between barrier cells [17]. *L monocytogenes* crosses the BBB by microbial penetration using transmigration within *L monocytogenes*-infected monocytes or myeloid cells across the BBB by a so-called Trojan horse mechanism

Once bacteria enter the cerebrospinal fluid, they are free to replicate and spread

Neuronal injury in bacterial meningitis is caused by several mechanisms, which

Since meningitis is most commonly a complication of bacteremia, the risk factors are similar to those that contribute to neonatal sepsis [4–6]. Risk factors for neonatal sepsis include maternal factors, neonatal host factors, and virulence of infecting organism. The most important neonatal factor is prematurity or low birth weight. Small preterm infants have a 3–10 times higher incidence of infection than full-term normal birth weight infants [4–6]. Immaturity of the immune system and diminishing transplacentally acquired maternal immunoglobulins in premature infants contribute

have been identified by experimental studies during the last years [15, 60–62]. Neuronal injury likely results from a combination of the following events: dysfunctioning cerebral blood flow (increased BBB permeability, cerebral edema, vasospasm, vasculitis, cerebral venous thrombosis, and systemic hypotension), detrimental effects of inflammatory mediators (e.g., tumor necrosis factor-alpha, interleukin-1, and nitric oxide) and infiltrating cells (leukocytes, macrophages, and microglia), neurotoxicity (free radicals, proteases, and some microbial compounds), increased CSF outflow resistance, and excitatory amino acids, which finally lead to energy failure and cell death executed by caspases [15, 17, 60–63]. The mode of neuronal cell death in different regions of the brain depends on the strength and type of the noxious stimulus and may be a form of apoptotic, necrotic, or hybrid [62, 63]. For example, neuronal cell death occurs mostly as apoptosis in the dentate gyrus of the hippocampal formation, whereas it occurs mostly as necrosis due to focal ischemia in

unchecked at least initially, as phagocytes, immunoglobulins, and complement components are excluded by the BBB. This bacterial multiplication goes on until bacteria die following the stationary growth phase or the exposure to the treatment with β-lactams that causes antibiotic-induced bacteriolysis. The subsequent release of subcapsular bacterial products such as peptidoglycan, lipoteichoic acids, lipoproteins, lipopolysaccharides, and bacterial DNA leads to an increased inflammatory response in the host [15, 59]. Many brain cells including astrocytes, glial cells, endothelial cells, ependymal cells, and resident macrophages can produce proinflammatory and anti-inflammatory cytokines in response to bacterial replication and its components [60, 61]. Although this inflammation is needed to eliminate the bacteria and allow the host to recover, it is also a major cause of brain injury in

**30**

The earliest signs and symptoms of neonates with meningitis may be subtle and nonspecific, especially more problematic in premature infants [5]. The clinical presentation of neonatal meningitis is similar to those of neonatal sepsis without meningitis. Most commonly reported clinical features include temperature instability (62%), irritability or lethargy (52%), and poor feeding or vomiting (48%) [18]. However, in preterm infants, respiratory decompensation consisting of an increased number of apnea and bradycardia episodes and increased oxygen requirement are prominent clinical signs [50]. Term infants are more likely to have fever (>37.2°C), whereas preterm infants more frequently have hypothermia (<36°C) [64]. Other findings associated with neonatal meningitis include respiratory distress, jaundice, diarrhea and hepatosplenomegaly. However, all these features could not help to establish an early diagnosis of meningitis [18].

Neurologic signs of neonatal meningitis include irritability, alteration in consciousness, poor tone, tremors, seizures, high-pitched cry, twitching of facial or an extremity, focal signs including hemiparesis, gaze deviation, and cranial nerve deficits [4, 18]. Seizures are generally focal and seen in 40% of cases, and considering subtle ones is also possible [5, 18]. Since cranial sutures in the neonate are open and allow for expansion of the intracranial contents and for increasing head size, meningeal signs are not commonly seen. Bulging fontanelle occurs in about 25% of cases and nuchal rigidity in only 15% [28].

Early-onset neonatal infections are generally presented as sepsis or pneumonia, so meningitis is relatively less common. The signs of early-onset infection get to appear within the first 24–48 hours of life in 90% of affected cases [65]. However, late-onset sepsis, in addition to bacteremia, is frequently manifested as focal infections such as meningitis and osteomyelitis resulting from hematogenous seeding [11, 18]. Neonatal meningitis can complicate 14% of episodes of early-onset GBS sepsis and 54% of episodes of late-onset GBS sepsis [36], so the later condition is more likely to have specific signs of meningitis [28].

Lack of data on the timing of onset of features listed above makes it difficult for the early recognition of a baby with meningitis. Additionally, these features are likely to be affected by other factors such as gestational age, partial antibiotic treatment, and postnatal age [6]. Classical meningitic signs such as convulsions, bulging fontanel, altered mental status, and nuchal rigidity are often late findings that are associated with a worse outcome [5, 6]. So, the timing of the onset of clinical features may be crucial for early recognition, prompt management and potentially, better outcome [6]. Although several useful clinical features were defined to predict meningitis in children, the most accurate combination of clinical features to raise or lower suspicion of meningitis is still unclear. Furthermore, small infants presenting nonspecific but concerning features such as fever, lethargy, poor feeding, or irritability, should be approached with a high index of suspicion regardless of how well they appear [66].

#### *Neonatal Medicine*

Brain abscess, which can be presented by the findings of increased intracranial pressure, focal neurologic deficit, poor clinical response to antibiotic therapy, and new-onset focal seizures, occurs in about 13% of neonates with neonatal meningitis. However, the risk of brain abscess is increased in cases of meningitis caused by *Citrobacter koseri* (up to 75%), *Serratia marcescens*, *Proteus mirabilis*, and *Enterobacter sakazakii*. Therefore, when these pathogens are detected as the cause of the disease, neuroimaging should be performed even with no clinical indication [18, 28].

#### **8. Diagnosis**

Since the clinical signs and symptoms are nonspecific and similar to those seen in sepsis, CSF examination via lumbar puncture (LP) is essential to establish the diagnosis of bacterial meningitis and to identify the causative organism with antibiotic susceptibility testing [4]. LP should be performed in all neonates whose blood culture is positive and be considered in all neonates when sepsis is possible. As many as 40% of infants with meningitis who have a gestational age of ≥34 weeks do not have a positive blood culture at the time of their diagnosis [67]. Similarly, among VLBW infants who survived >3 days, one third of cases of meningitis have negative blood cultures [25]. Therefore, if LP is performed based on the presence of blood culture positivity, a significant number of cases of meningitis will be overlooked [11]. This means that if sepsis or meningitis is suspected, performing LP is mandatory.

Debate continues as to whether an LP should be performed on all babies suspected of sepsis or only on symptomatic babies. In the past, the LP had been a routine part of the evaluation of infants suspected of having sepsis, in conjunction with a complete blood cell count and blood cultures [17]. Meningitis in preterm infants with respiratory distress syndrome is unlikely, so an LP is not mandatory unless sepsis is suspected [68, 69]. Similarly, the yield of an LP from babies who are asymptomatic with or without maternal risk factors is likely to be very low [70]. However, during the first week of life, if the blood cultures yield a pathogenic organism or clinical features of sepsis exist, evaluation of CSF should be done [18]. It should be kept in mind that the use of intrapartum antibiotics makes blood culture results unreliable. In every infant older than 1 week, an LP is indicated as a routine part of the work-up for sepsis [17]. Performance of the LP is sometimes delayed due to cardiorespiratory instability, extreme prematurity with the risk of intraventricular hemorrhage, or thrombocytopenia, resulting in delay in diagnosis and prolonged and possibly inappropriate antibiotic use [25]. If it is not possible to perform an LP in the infant with presumed sepsis and meningitis, antimicrobials in doses sufficient for the treatment of meningitis should be initiated immediately following obtaining blood for culture. When the infant is stabilized, even if antibiotic therapy is being taken for several days, LP should be performed. A delayed LP is still likely to show the presence of CSF pleocytosis and abnormal CSF chemistry and thus confirms the diagnosis of meningitis, although CSF culture may be negative [4, 11, 23]. In such cases, real-time polymerase chain reaction (PCR) may have an important role as a better diagnostic tool, although its routine use in the context of neonatal infection is currently limited [11, 71].

Infants with suspected bacterial meningitis or late-onset sepsis should undergo a full laboratory evaluation consisting of a complete blood count with differential, blood culture, a urine analysis and culture (useful only after the third day of life), and lumbar puncture to examine the CSF [50]. Ancillary tests such as complete blood cell count, C-reactive protein, interleukin-6, and procalcitonin

**33**

*†*

*excluded.*

**Table 2.**

*Neonatal Bacterial Meningitis*

*DOI: http://dx.doi.org/10.5772/intechopen.87118*

nied by clinical features of infection [23, 37, 50].

**9. Examination of cerebrospinal fluid**

Term neonates evaluated in the nursery setting†

8 days to 6 months (n: 140)\*

≤7 days (n: 130) Median (IQR):

≤28 days (n: 3467) [74] Mean: 5.5; 95th

<28 days (n: 278) [75] Mean (range): 6.1

28–56 days (n: 318) [75] Mean (range): 3.1

Preterm very low birth weight (<1500 g) neonates ≤7 days (n: 88) [76] Mean (range): 7.1

≤28 days (n: 45) [77] Mean (range): 5

*CSF was obtained from infants evaluated for sepsis in the NICU setting. \*In this study, only a small proportion of infants were aged >28 days.*

*intensive care unit; and n: number of cases.*

Term neonates evaluated in the emergency department setting‡

of false CSF culture negativity in those with meningitis [4].

have suboptimal sensitivity and specificity for the diagnosis of neonatal sepsis, but these diagnostic tests may be useful in supporting the diagnosis of infection as well as determining the length of therapy when they are serial abnormal and accompa-

CSF culture is the gold standard method for diagnosing bacterial meningitis. So, it is important to perform an LP early in the course of illness, ideally before the administration of antibiotic therapy [72]. However, infants may be exposed to intrapartum or empiric antibiotics before performing an LP, making CSF parameters helpful in determining the likelihood of meningitis, because of the possibility

Although examination of the CSF is highly important in supporting the diagnosis of meningitis, interpretation of CSF findings can be challenging in newborn infants [72]. Values for both the cellular and chemical parameters of CSF are different for neonates than for older infants and children, and also vary according to gestational age, birth weight, and chronologic age (**Table 2**) [73–77]. The cell content and protein concentration in the CSF of a healthy neonate are higher than those of older infants, whereas CSF glucose levels may be as low as 30 mg/dl in

**Age [Ref.] WBC/mm3 Protein (mg/dL) Glucose (mg/dL)**

Median (IQR): 78 (60–100); 95th percentile: 137

Median (IQR): 57 (42–77); 95th percentile: 158

Mean (±SD): 69.9 (±25.7); upper bound: 127

Mean (range): 75.4 (15.8–131.0)

Mean (range): 58.9 (5.5–105.5)

Mean (range): 144 (51–270)

Mean (range): 148 (54–370)

Median (IQR): 50 (44–56); 5th percentile: 35

Median (IQR): 52 (45–64); 5th percentile: 38

Mean (±SD): 45.7 (±8.0); lower bound: 25

Mean (range): 45.3 (30.0–61.0)

Mean (range): 48.0 (30.5–65.5)

Mean (range): 50.4 (11–138)

Mean(range): 67 (33–217)

[73]

3 (1–6); 95th percentile: 23

Median (IQR): 2 (1–4); 95th percentile: 32

percentile: 16

(0–18.0)

(0–8.5)

(0–30)

(0–44)

*Characteristics of cerebrospinal fluid in term and preterm neonates without bacterial meningitis.*

*WBC: white blood cell count; SD: standard deviation; IQR: interquartile range; CSF: cerebrospinal fluid; neonatal* 

*‡CSF was obtained in the emergency department during evaluation for possible infection; infection was excluded by sterile cultures (CSF, blood, and urine). Infants with positive polymerase chain reaction for enterovirus were also*  *Neonatal Bacterial Meningitis DOI: http://dx.doi.org/10.5772/intechopen.87118*

*Neonatal Medicine*

indication [18, 28].

**8. Diagnosis**

mandatory.

Brain abscess, which can be presented by the findings of increased intracranial

pressure, focal neurologic deficit, poor clinical response to antibiotic therapy, and new-onset focal seizures, occurs in about 13% of neonates with neonatal meningitis. However, the risk of brain abscess is increased in cases of meningitis caused by *Citrobacter koseri* (up to 75%), *Serratia marcescens*, *Proteus mirabilis*, and *Enterobacter sakazakii*. Therefore, when these pathogens are detected as the cause of the disease, neuroimaging should be performed even with no clinical

Since the clinical signs and symptoms are nonspecific and similar to those seen in sepsis, CSF examination via lumbar puncture (LP) is essential to establish the diagnosis of bacterial meningitis and to identify the causative organism with antibiotic susceptibility testing [4]. LP should be performed in all neonates whose blood culture is positive and be considered in all neonates when sepsis is possible. As many as 40% of infants with meningitis who have a gestational age of ≥34 weeks do not have a positive blood culture at the time of their diagnosis [67]. Similarly, among VLBW infants who survived >3 days, one third of cases of meningitis have negative blood cultures [25]. Therefore, if LP is performed based on the presence of blood culture positivity, a significant number of cases of meningitis will be overlooked [11]. This means that if sepsis or meningitis is suspected, performing LP is

Debate continues as to whether an LP should be performed on all babies suspected of sepsis or only on symptomatic babies. In the past, the LP had been a routine part of the evaluation of infants suspected of having sepsis, in conjunction with a complete blood cell count and blood cultures [17]. Meningitis in preterm infants with respiratory distress syndrome is unlikely, so an LP is not mandatory unless sepsis is suspected [68, 69]. Similarly, the yield of an LP from babies who are asymptomatic with or without maternal risk factors is likely to be very low [70]. However, during the first week of life, if the blood cultures yield a pathogenic organism or clinical features of sepsis exist, evaluation of CSF should be done [18]. It should be kept in mind that the use of intrapartum antibiotics makes blood culture results unreliable. In every infant older than 1 week, an LP is indicated as a routine part of the work-up for sepsis [17]. Performance of the LP is sometimes delayed due to cardiorespiratory instability, extreme prematurity with the risk of intraventricular hemorrhage, or thrombocytopenia, resulting in delay in diagnosis and prolonged and possibly inappropriate antibiotic use [25]. If it is not possible to perform an LP in the infant with presumed sepsis and meningitis, antimicrobials in doses sufficient for the treatment of meningitis should be initiated immediately following obtaining blood for culture. When the infant is stabilized, even if antibiotic therapy is being taken for several days, LP should be performed. A delayed LP is still likely to show the presence of CSF pleocytosis and abnormal CSF chemistry and thus confirms the diagnosis of meningitis, although CSF culture may be negative [4, 11, 23]. In such cases, real-time polymerase chain reaction (PCR) may have an important role as a better diagnostic tool, although its routine use in the context of

Infants with suspected bacterial meningitis or late-onset sepsis should undergo a full laboratory evaluation consisting of a complete blood count with differential, blood culture, a urine analysis and culture (useful only after the third day of life), and lumbar puncture to examine the CSF [50]. Ancillary tests such as complete blood cell count, C-reactive protein, interleukin-6, and procalcitonin

**32**

neonatal infection is currently limited [11, 71].

have suboptimal sensitivity and specificity for the diagnosis of neonatal sepsis, but these diagnostic tests may be useful in supporting the diagnosis of infection as well as determining the length of therapy when they are serial abnormal and accompanied by clinical features of infection [23, 37, 50].

CSF culture is the gold standard method for diagnosing bacterial meningitis. So, it is important to perform an LP early in the course of illness, ideally before the administration of antibiotic therapy [72]. However, infants may be exposed to intrapartum or empiric antibiotics before performing an LP, making CSF parameters helpful in determining the likelihood of meningitis, because of the possibility of false CSF culture negativity in those with meningitis [4].

#### **9. Examination of cerebrospinal fluid**

Although examination of the CSF is highly important in supporting the diagnosis of meningitis, interpretation of CSF findings can be challenging in newborn infants [72]. Values for both the cellular and chemical parameters of CSF are different for neonates than for older infants and children, and also vary according to gestational age, birth weight, and chronologic age (**Table 2**) [73–77]. The cell content and protein concentration in the CSF of a healthy neonate are higher than those of older infants, whereas CSF glucose levels may be as low as 30 mg/dl in


*WBC: white blood cell count; SD: standard deviation; IQR: interquartile range; CSF: cerebrospinal fluid; neonatal intensive care unit; and n: number of cases.*

*† CSF was obtained from infants evaluated for sepsis in the NICU setting.*

*\*In this study, only a small proportion of infants were aged >28 days.*

*‡CSF was obtained in the emergency department during evaluation for possible infection; infection was excluded by sterile cultures (CSF, blood, and urine). Infants with positive polymerase chain reaction for enterovirus were also excluded.*

#### **Table 2.**

*Characteristics of cerebrospinal fluid in term and preterm neonates without bacterial meningitis.*

term infants and as low as 20 mg/dl in preterm infants [77]. CSF protein is higher in preterm versus term infants. Moreover, the values of CSF parameters in neonates with and without confirmed meningitis may overlap [72].

Characteristic CSF findings of neonatal bacterial meningitis include polymorphonuclear pleocytosis, hypoglycorrhachia, and increased protein concentrations [8]. Cerebrospinal fluid white blood cell (WBC) counts of >21 cells/ mm3 in infants with gestational age ≥ 34 weeks have a sensitivity and specificity of approximately 80% to suggest confirmed meningitis. However, this cut off may be resulted in a missed diagnosis in 13% of infants with confirmed meningitis, since neonatal meningitis can also occur with normal CSF parameters without bacteremia [4, 67]. If CSF is examined so early, before meninges are not inflamed enough, CSF findings may not be definitive for bacterial meningitis, requiring the repeat LP 24–48 hours later. In a neonate, a CSF WBC count of >20 cells/mm3 is consistent with meningeal inflammation, and suggests bacterial meningitis [4]. The number of WBCs in the CSF is higher in neonates with meningitis caused by Gram-negative bacteria than those caused by Grampositive bacteria [78], and can be up to thousands, with predominantly polymorphonuclear leukocytes in the early course of the disease [18, 28]. The level of CSF protein is considered a poor predictor of neonatal meningitis because of considerable overlap of values between infants with and without confirmed meningitis [4, 67]. In general practice, a CSF protein of 170 mg/dl in preterm and > 100 mg/dl in term infants is interpreted in favor of neonatal bacterial meningitis. However, caution should be employed when interpreting CSF parameters in preterm infants [79, 80].

Antibiotic treatment before the LP is a common practice because LPs are not being performed in all cases [5]. When patients with true meningitis are exposed to antibiotics for up to 24–36 hours, CSF WBC values remain elevated without significance. However, CSF protein values decrease but still remain higher than normative values, whereas CSF glucose values show rapid normalization [72, 81]. So, because of limited impact of pretreatment antibiotics on CSF WBC, it does not prevent the diagnosis of meningitis up to 24 hours. Additionally, once CSF is obtained, the sample should be analyzed as soon as possible, otherwise a delay in laboratory analysis may result in the decline in measured WBC [82].

Gram stain of CSF is useful in providing an early presumptive etiologic diagnosis, especially Gram-negative bacteria, since the culture of CSF can take up to 48 hours [6]. Its positivity rates depend on the CSF concentration of bacteria, so the absence of the organism on Gram stain does not exclude meningitis [8]. In cases of meningitis caused by *L. monocytogenes*, Gram stain is frequently negative due to the low number of bacteria in the CSF [17].

Traumatic LP is defined as the presence of blood in the CSF obtained, and occurs very frequently in neonates, with reported incidences ranging from 35 to 46% [72]. This condition makes the interpretation of CSF results more complicated. Adjustment of CSF WBC in traumatic LPs does not improve the diagnosis of neonatal bacterial meningitis, and adjustment can result in loss of sensitivity with marginal gain in specificity [72]. CSF protein may be elevated in the presence of blood contamination from a traumatic LP [83]. It may be useful to repeat the LP 24–48 hours later, so that normal WBC can exclude bacterial meningitis, but frequently it is inconclusive. Neonates in whom the LP is traumatic should be treated with antibiotic presumed meningitis, until results of CSF culture are available.

Among nonculture tests of CSF, the PCR has been useful in the identification of infecting bacteria including *Streptococcus pneumoniae*, *E coli*, GBS, *S aureus*, and *L monocytogenes*, with higher detection rate of any CSF pathogen compared with traditional cultures (72% vs. 48%) in patients with antibiotic administration

**35**

*Neonatal Bacterial Meningitis*

**10. Differential diagnosis**

and leukocyte counts. [18, 50].

**11. Antimicrobial treatment**

susceptibility tests, as indicated.

*DOI: http://dx.doi.org/10.5772/intechopen.87118*

[71]. However, the use of PCR is limited to selected cases for now, and before used routinely, requires further researches and institutional facilities [84, 85]. Since PCR neither detects all causes of CNS infection nor provides any information on antimicrobial susceptibility, it should be used in conjunction with standard microbiologic tests. A number of CSF biomarkers such as tumor necrosis factor a, interleukin (IL) 1b, IL-6, IL-8, IL-10, IL-12, IL-17, C-reactive protein, procalcitonin, and lipocalin 2 have been examined for differentiating bacterial meningitis from viral meningitis and noninfectious origins, and the results have been encouraging [8, 86]. However, the validity and use of these biomarkers in clinical practice have been limited, and the interpretation of the results of these assays should be done with caution.

Besides sepsis and other specific infections, symptoms and signs may be due to noninfectious conditions such as cardiac, pulmonary, gastrointestinal, and metabolic disorders [11, 18]. Disorders mimicking the neurological features of meningitis include intracranial hemorrhage, ischemic stroke, hypoxic–ischemic encephalopathy, injuries, and inborn errors of metabolism [11, 18]. Conditions where CSF culture is negative despite CSF changes include infectious and noninfectious causes of aseptic meningitis, partially treated bacterial meningitis, parameningeal infected focus such as abscess, and intraventricular hemorrhage. Since some of the pathogens that cause aseptic meningitis have specific therapy, a comprehensive evaluation including viral, anaerobic, mycoplasma, and fungal cultures, antigen detection, PCR, and serology should be performed [18]. Elevated CSF protein values and leukocyte counts and hypoglycorrhachia may develop in preterm infants after intraventricular hemorrhage. Many nonpyogenic congenital infections (toxoplasmosis, cytomegalovirus, herpes simplex virus, and syphilis producing aseptic meningitis) can also produce alterations in CSF protein values

Eradication of the infecting pathogen from the CSF is entirely dependent on antimicrobial therapy which should be initiated as soon as possible after the evaluation which is suggestive of bacterial meningitis [8]. Since clinical presentation may be subtle and nonspecific and the outcome may be devastating, a low threshold for initiating antimicrobial therapy is necessary without knowledge of the specific pathogen [6]. Decisions on which antibiotics to use empirically are designed to cover the likely pathogens based on the age of the patient (e.g., early-onset

meningitis), specific risk factors, data regarding pathogens and their susceptibility within nursery, and the ability to penetrate the CSF [8, 87, 88]. The initial choice of intravenous antibiotics for neonates suspected of having meningitis must cover both Gram-positive and Gram-negative organisms [89]. Efficient elimination of bacteria depends also on the relationship between the concentration of antibiotic in the CSF and the minimal bactericidal concentration (MBC) for the infecting pathogen [17]. Then, antibiotics are modified according to culture and antibiotic

Initial empirical therapy for early-onset bacterial meningitis must include a combination regimen containing ampicillin and an aminoglycoside (e.g., gentamicin) to cover GBS, *E coli*, and *L monocytogenes*, whereas a regimen including a thirdgeneration cephalosporin (e.g., cefotaxime) is preferred when meningitis resulting

*Neonatal Medicine*

of >20 cells/mm3

in preterm infants [79, 80].

mm3

term infants and as low as 20 mg/dl in preterm infants [77]. CSF protein is higher in preterm versus term infants. Moreover, the values of CSF parameters in neonates

Characteristic CSF findings of neonatal bacterial meningitis include polymorphonuclear pleocytosis, hypoglycorrhachia, and increased protein concentrations [8]. Cerebrospinal fluid white blood cell (WBC) counts of >21 cells/

bacterial meningitis [4]. The number of WBCs in the CSF is higher in neonates with meningitis caused by Gram-negative bacteria than those caused by Grampositive bacteria [78], and can be up to thousands, with predominantly polymorphonuclear leukocytes in the early course of the disease [18, 28]. The level of CSF protein is considered a poor predictor of neonatal meningitis because of considerable overlap of values between infants with and without confirmed meningitis [4, 67]. In general practice, a CSF protein of 170 mg/dl in preterm and > 100 mg/dl in term infants is interpreted in favor of neonatal bacterial meningitis. However, caution should be employed when interpreting CSF parameters

Antibiotic treatment before the LP is a common practice because LPs are not being performed in all cases [5]. When patients with true meningitis are exposed to antibiotics for up to 24–36 hours, CSF WBC values remain elevated without significance. However, CSF protein values decrease but still remain higher than normative values, whereas CSF glucose values show rapid normalization [72, 81]. So, because of limited impact of pretreatment antibiotics on CSF WBC, it does not prevent the diagnosis of meningitis up to 24 hours. Additionally, once CSF is obtained, the sample should be analyzed as soon as possible, otherwise a delay in laboratory

Gram stain of CSF is useful in providing an early presumptive etiologic diagnosis, especially Gram-negative bacteria, since the culture of CSF can take up to 48 hours [6]. Its positivity rates depend on the CSF concentration of bacteria, so the absence of the organism on Gram stain does not exclude meningitis [8]. In cases of meningitis caused by *L. monocytogenes*, Gram stain is frequently negative due to the

Traumatic LP is defined as the presence of blood in the CSF obtained, and occurs very frequently in neonates, with reported incidences ranging from 35 to 46% [72]. This condition makes the interpretation of CSF results more complicated. Adjustment of CSF WBC in traumatic LPs does not improve the diagnosis of neonatal bacterial meningitis, and adjustment can result in loss of sensitivity with marginal gain in specificity [72]. CSF protein may be elevated in the presence of blood contamination from a traumatic LP [83]. It may be useful to repeat the LP 24–48 hours later, so that normal WBC can exclude bacterial meningitis, but frequently it is inconclusive. Neonates in whom the LP is traumatic should be treated with antibiotic presumed meningitis, until results of CSF culture are available. Among nonculture tests of CSF, the PCR has been useful in the identification of infecting bacteria including *Streptococcus pneumoniae*, *E coli*, GBS, *S aureus*, and *L monocytogenes*, with higher detection rate of any CSF pathogen compared with traditional cultures (72% vs. 48%) in patients with antibiotic administration

 in infants with gestational age ≥ 34 weeks have a sensitivity and specificity of approximately 80% to suggest confirmed meningitis. However, this cut off may be resulted in a missed diagnosis in 13% of infants with confirmed meningitis, since neonatal meningitis can also occur with normal CSF parameters without bacteremia [4, 67]. If CSF is examined so early, before meninges are not inflamed enough, CSF findings may not be definitive for bacterial meningitis, requiring the repeat LP 24–48 hours later. In a neonate, a CSF WBC count

is consistent with meningeal inflammation, and suggests

with and without confirmed meningitis may overlap [72].

analysis may result in the decline in measured WBC [82].

low number of bacteria in the CSF [17].

**34**

[71]. However, the use of PCR is limited to selected cases for now, and before used routinely, requires further researches and institutional facilities [84, 85]. Since PCR neither detects all causes of CNS infection nor provides any information on antimicrobial susceptibility, it should be used in conjunction with standard microbiologic tests. A number of CSF biomarkers such as tumor necrosis factor a, interleukin (IL) 1b, IL-6, IL-8, IL-10, IL-12, IL-17, C-reactive protein, procalcitonin, and lipocalin 2 have been examined for differentiating bacterial meningitis from viral meningitis and noninfectious origins, and the results have been encouraging [8, 86]. However, the validity and use of these biomarkers in clinical practice have been limited, and the interpretation of the results of these assays should be done with caution.

#### **10. Differential diagnosis**

Besides sepsis and other specific infections, symptoms and signs may be due to noninfectious conditions such as cardiac, pulmonary, gastrointestinal, and metabolic disorders [11, 18]. Disorders mimicking the neurological features of meningitis include intracranial hemorrhage, ischemic stroke, hypoxic–ischemic encephalopathy, injuries, and inborn errors of metabolism [11, 18]. Conditions where CSF culture is negative despite CSF changes include infectious and noninfectious causes of aseptic meningitis, partially treated bacterial meningitis, parameningeal infected focus such as abscess, and intraventricular hemorrhage. Since some of the pathogens that cause aseptic meningitis have specific therapy, a comprehensive evaluation including viral, anaerobic, mycoplasma, and fungal cultures, antigen detection, PCR, and serology should be performed [18]. Elevated CSF protein values and leukocyte counts and hypoglycorrhachia may develop in preterm infants after intraventricular hemorrhage. Many nonpyogenic congenital infections (toxoplasmosis, cytomegalovirus, herpes simplex virus, and syphilis producing aseptic meningitis) can also produce alterations in CSF protein values and leukocyte counts. [18, 50].

#### **11. Antimicrobial treatment**

Eradication of the infecting pathogen from the CSF is entirely dependent on antimicrobial therapy which should be initiated as soon as possible after the evaluation which is suggestive of bacterial meningitis [8]. Since clinical presentation may be subtle and nonspecific and the outcome may be devastating, a low threshold for initiating antimicrobial therapy is necessary without knowledge of the specific pathogen [6]. Decisions on which antibiotics to use empirically are designed to cover the likely pathogens based on the age of the patient (e.g., early-onset meningitis), specific risk factors, data regarding pathogens and their susceptibility within nursery, and the ability to penetrate the CSF [8, 87, 88]. The initial choice of intravenous antibiotics for neonates suspected of having meningitis must cover both Gram-positive and Gram-negative organisms [89]. Efficient elimination of bacteria depends also on the relationship between the concentration of antibiotic in the CSF and the minimal bactericidal concentration (MBC) for the infecting pathogen [17]. Then, antibiotics are modified according to culture and antibiotic susceptibility tests, as indicated.

Initial empirical therapy for early-onset bacterial meningitis must include a combination regimen containing ampicillin and an aminoglycoside (e.g., gentamicin) to cover GBS, *E coli*, and *L monocytogenes*, whereas a regimen including a thirdgeneration cephalosporin (e.g., cefotaxime) is preferred when meningitis resulting

from a Gram-negative organism is strongly suspected [8, 18]. This empirical antimicrobial therapy should be continued until the pathogen and its antibiotic susceptibility are identified. Since eradication of Gram-negative bacteria from CSF is often delayed and high rates of ampicillin resistance among E. coli isolates have been reported, cefotaxime is the agent of choice, thanks to its higher CSF bactericidal activity [89, 90]. However, when the use of cefotaxime is routine, rapid emergence of cephalosporin-resistant strains, especially *Enterobacter cloaca*, *Klebsiella pneumoniae*, *Pseudomonas aeruginosa*, *E coli*, and *Serratia* species, can occur (via inducible beta-lactamases), even during therapy [91–94]. It is recommended that such infections should be treated with a carbapenem (usually meropenem), in combination with an aminoglycoside, since carbapenem resistance has recently emerged among Gram-negative bacilli [50, 95, 96]. Therefore, meningitis caused by Gram-negative bacteria need to be closely monitored, which includes repeating LP for documentation of CSF sterility and brain imaging studies with clinical indications [8, 97].

There is a synergy for ampicillin and gentamycin in the treatment of meningitis caused by GBS, and this combination should be continued until sterility of the CSF has been documented [17]. Afterwards, single therapy with penicillin or ampicillin should be used for 14 days [97]. Although GBS is also susceptible to cephalosporins, the use of the narrower agent, like penicillin, will minimize any potential impact on antibiotic resistance among other pathogens [87]. Infection caused by *L monocytogenes* and *Enterococcus* should be treated with ampicillin and gentamycin, since both are resistant to cephalosporins [17, 87]. When the CSF has been sterilized and the patient has improved clinically, ampicillin alone can be used to complete therapy. Because of high rate of ampicillin resistance among *E. coli* and other Gram-negative organisms, a combination of cefotaxime (or ceftazidime in the case of *P. aeruginosa*) and an aminoglycoside, usually gentamicin, is preferable. Once sterility of the CSF is documented, the aminoglycoside can be discontinued and the appropriate betalactam should be continued for a minimum of 21 or 14 days after the CSF is sterile, whichever is the longest [17–19, 87, 97].

Initial empirical therapy for late-onset bacterial meningitis usually depends on whether the infection is community or hospital acquired. For babies admitted from home, an empiric antibiotic combination of amoxicillin or ampicillin and cefotaxime is likely to provide excellent cover for possible pathogens, with good CSF penetration [5, 11, 88]. In areas where there are high rates of cephalosporins resistance among *Streptococcus pneumonia,* initial treatment of meningitis may include high doses of third-generation cephalosporins in association with vancomycin before the results of antibiotic susceptibility [98]. Although the implementation of pneumococcal vaccination led to a near disappearance of vaccine serotypes resistant to β-lactams, it also contributed to the emergence of the 19A serotype, which was particularly resistant to antibiotics [98]. Some community-based studies from developing countries have reported increasing resistance, particularly of Gramnegative organism to first-line and even second-line antibiotics [88]. Therefore, in the choice of empirical antibiotics, the resistance pattern of possible pathogens in the community should also be considered.

For babies already in hospital or discharged recently from hospital, initial antimicrobial therapy should be chosen according to the pathogen commonly seen in that particular nursery and their susceptibility pattern [11]. There are various factors that may influence the likely spectrum of causative pathogens, especially their risk of unusual or multidrug resistant bacteria [5, 18]. These include prior exposure to broad-spectrum antibiotics, the presence of central venous lines, ventriculoperitoneal shunt, or ventricular reservoir, parenteral nutrition, and their risk of acquiring infections through nosocomial transmission [5, 55, 99, 100]. Therefore,

**37**

*Neonatal Bacterial Meningitis*

[4, 50, 87, 97, 103, 104].

*DOI: http://dx.doi.org/10.5772/intechopen.87118*

*Bacteroides fragilis* and other anaerobic organisms [18, 50].

place and persistently positive CSF cultures [101].

positive CSF cultures, and abnormal neuroimaging [50].

proven bacterial meningitis [97, 106].

empirical therapy may include ampicillin (if GBS, *L monocytogenes* or enterococci are suspected), nafcillin, or vancomycin and an aminoglycoside, and cefotaxime, or meropenem, depending on the predominant pathogen seen in the neonatal unit [50, 97]. Meningitis with organisms such as CNS, which is more common in neonates requiring prolonged hospitalization, need for central venous catheters, and surgical manipulations or placement of a ventriculoperitoneal shunt due to intraventricular hemorrhage and hydrocephalus [55, 100], can be treated with nafcillin or vancomycin, assuming that the isolate is susceptible [18, 50, 101]. The duration of therapy is generally 14–21 days after CSF sterilization, with removal of any foreign body if possible [18, 50, 101]. Meropenem is recommended for treatment of neonatal meningitis that is caused by MDR Gram-negative organisms, although it is approved for use only in infants aged older than 3 months for bacterial meningitis or complicated intra-abdominal infections due to limited data on meropenem use in neonates [97, 102]. Metronidazole is the treatment of choice for infection caused by

The recommended antimicrobial treatment based on causative organism and dosage of common antibiotics used for neonatal meningitis are provided in **Tables 3** and **4**

Although the intraventricular or intrathecal route of administration of antibiotics is able to achieve higher antibiotic concentrations in the CSF and eliminate the bacteria more quickly, intraventricular antibiotics in combination with intravenous antibiotics resulted in a three-fold increased relative risk for mortality compared to standard treatment with intravenous antibiotics alone and should be avoided [105]. However, it remains an option in patients who already have a ventricular drain in

In the cases of neonates with bacteremia and CSF findings indicative of meningitis with negative CSF culture (obtained before or after antibiotic therapy), the antimicrobial therapy should be continued with meningeal doses as if they have

The role of routinely repeating CSF evaluation during treatment in a neonate with confirmed meningitis is controversial. Some experts recommended that an LP should be repeated routinely at 48–72 hours after initiation of appropriate antimicrobial therapy to document CSF sterilization, as persistence of positive cultures despite treatment may result in a greater risk of complications and poor outcomes [87, 107]. Gram-positive bacteria usually clear rapidly (within 24–48 hours) from the CSF, whereas Gram-negative bacteria may persist for several days in severe cases [18, 97]. A delayed clearance of a Gram-negative organism may be an indication for antimicrobial resistance and prompts a change in therapy or diagnostic neuroimaging showing a purulent focus of the disease such as an emphysema, obstructive ventriculitis, or brain abscess requiring additional intervention or increased duration of antimicrobial therapy [18, 97, 108]. Additionally, performing repeating LP is also reasonable for discontinuing combination therapy. Delayed sterilization of the CSF is associated with an increased risk of poor outcome [17, 87, 109]. So, a repeat LP may have therapeutic and prognostic significance. Conversely, some experts recommend a repeat LP only if the patient does not exhibit a satisfactory clinical response by 24–72 hours after initiation of antimicrobial therapy or show a complicated clinical course, including seizures, abnormal neuroimaging, or prolonged positive CSF cultures [4, 110]. The decision of whether to perform an LP before completion of therapy in the neonates with meningitis caused by GBS, *L. monocytogenes*, and Gram-negative bacteria can be based on clinical course including seizures, significant hypotension, prolonged

#### *Neonatal Bacterial Meningitis DOI: http://dx.doi.org/10.5772/intechopen.87118*

*Neonatal Medicine*

whichever is the longest [17–19, 87, 97].

the community should also be considered.

from a Gram-negative organism is strongly suspected [8, 18]. This empirical antimicrobial therapy should be continued until the pathogen and its antibiotic susceptibility are identified. Since eradication of Gram-negative bacteria from CSF is often delayed and high rates of ampicillin resistance among E. coli isolates have been reported, cefotaxime is the agent of choice, thanks to its higher CSF bactericidal activity [89, 90]. However, when the use of cefotaxime is routine, rapid emergence of cephalosporin-resistant strains, especially *Enterobacter cloaca*, *Klebsiella pneumoniae*, *Pseudomonas aeruginosa*, *E coli*, and *Serratia* species, can occur (via inducible beta-lactamases), even during therapy [91–94]. It is recommended that such infections should be treated with a carbapenem (usually meropenem), in combination with an aminoglycoside, since carbapenem resistance has recently emerged among Gram-negative bacilli [50, 95, 96]. Therefore, meningitis caused by Gram-negative bacteria need to be closely monitored, which includes repeating LP for documentation of CSF sterility and brain imaging studies with clinical indications [8, 97].

There is a synergy for ampicillin and gentamycin in the treatment of meningitis caused by GBS, and this combination should be continued until sterility of the CSF has been documented [17]. Afterwards, single therapy with penicillin or ampicillin should be used for 14 days [97]. Although GBS is also susceptible to cephalosporins, the use of the narrower agent, like penicillin, will minimize any potential impact on antibiotic resistance among other pathogens [87]. Infection caused by *L monocytogenes* and *Enterococcus* should be treated with ampicillin and gentamycin, since both are resistant to cephalosporins [17, 87]. When the CSF has been sterilized and the patient has improved clinically, ampicillin alone can be used to complete therapy. Because of high rate of ampicillin resistance among *E. coli* and other Gram-negative organisms, a combination of cefotaxime (or ceftazidime in the case of *P. aeruginosa*) and an aminoglycoside, usually gentamicin, is preferable. Once sterility of the CSF is documented, the aminoglycoside can be discontinued and the appropriate betalactam should be continued for a minimum of 21 or 14 days after the CSF is sterile,

Initial empirical therapy for late-onset bacterial meningitis usually depends on whether the infection is community or hospital acquired. For babies admitted from home, an empiric antibiotic combination of amoxicillin or ampicillin and cefotaxime is likely to provide excellent cover for possible pathogens, with good CSF penetration [5, 11, 88]. In areas where there are high rates of cephalosporins resistance among *Streptococcus pneumonia,* initial treatment of meningitis may include high doses of third-generation cephalosporins in association with vancomycin before the results of antibiotic susceptibility [98]. Although the implementation of pneumococcal vaccination led to a near disappearance of vaccine serotypes resistant to β-lactams, it also contributed to the emergence of the 19A serotype, which was particularly resistant to antibiotics [98]. Some community-based studies from developing countries have reported increasing resistance, particularly of Gramnegative organism to first-line and even second-line antibiotics [88]. Therefore, in the choice of empirical antibiotics, the resistance pattern of possible pathogens in

For babies already in hospital or discharged recently from hospital, initial antimicrobial therapy should be chosen according to the pathogen commonly seen in that particular nursery and their susceptibility pattern [11]. There are various factors that may influence the likely spectrum of causative pathogens, especially their risk of unusual or multidrug resistant bacteria [5, 18]. These include prior exposure to broad-spectrum antibiotics, the presence of central venous lines, ventriculoperitoneal shunt, or ventricular reservoir, parenteral nutrition, and their risk of acquiring infections through nosocomial transmission [5, 55, 99, 100]. Therefore,

**36**

empirical therapy may include ampicillin (if GBS, *L monocytogenes* or enterococci are suspected), nafcillin, or vancomycin and an aminoglycoside, and cefotaxime, or meropenem, depending on the predominant pathogen seen in the neonatal unit [50, 97]. Meningitis with organisms such as CNS, which is more common in neonates requiring prolonged hospitalization, need for central venous catheters, and surgical manipulations or placement of a ventriculoperitoneal shunt due to intraventricular hemorrhage and hydrocephalus [55, 100], can be treated with nafcillin or vancomycin, assuming that the isolate is susceptible [18, 50, 101]. The duration of therapy is generally 14–21 days after CSF sterilization, with removal of any foreign body if possible [18, 50, 101]. Meropenem is recommended for treatment of neonatal meningitis that is caused by MDR Gram-negative organisms, although it is approved for use only in infants aged older than 3 months for bacterial meningitis or complicated intra-abdominal infections due to limited data on meropenem use in neonates [97, 102]. Metronidazole is the treatment of choice for infection caused by *Bacteroides fragilis* and other anaerobic organisms [18, 50].

The recommended antimicrobial treatment based on causative organism and dosage of common antibiotics used for neonatal meningitis are provided in **Tables 3** and **4** [4, 50, 87, 97, 103, 104].

Although the intraventricular or intrathecal route of administration of antibiotics is able to achieve higher antibiotic concentrations in the CSF and eliminate the bacteria more quickly, intraventricular antibiotics in combination with intravenous antibiotics resulted in a three-fold increased relative risk for mortality compared to standard treatment with intravenous antibiotics alone and should be avoided [105]. However, it remains an option in patients who already have a ventricular drain in place and persistently positive CSF cultures [101].

In the cases of neonates with bacteremia and CSF findings indicative of meningitis with negative CSF culture (obtained before or after antibiotic therapy), the antimicrobial therapy should be continued with meningeal doses as if they have proven bacterial meningitis [97, 106].

The role of routinely repeating CSF evaluation during treatment in a neonate with confirmed meningitis is controversial. Some experts recommended that an LP should be repeated routinely at 48–72 hours after initiation of appropriate antimicrobial therapy to document CSF sterilization, as persistence of positive cultures despite treatment may result in a greater risk of complications and poor outcomes [87, 107]. Gram-positive bacteria usually clear rapidly (within 24–48 hours) from the CSF, whereas Gram-negative bacteria may persist for several days in severe cases [18, 97]. A delayed clearance of a Gram-negative organism may be an indication for antimicrobial resistance and prompts a change in therapy or diagnostic neuroimaging showing a purulent focus of the disease such as an emphysema, obstructive ventriculitis, or brain abscess requiring additional intervention or increased duration of antimicrobial therapy [18, 97, 108]. Additionally, performing repeating LP is also reasonable for discontinuing combination therapy. Delayed sterilization of the CSF is associated with an increased risk of poor outcome [17, 87, 109]. So, a repeat LP may have therapeutic and prognostic significance. Conversely, some experts recommend a repeat LP only if the patient does not exhibit a satisfactory clinical response by 24–72 hours after initiation of antimicrobial therapy or show a complicated clinical course, including seizures, abnormal neuroimaging, or prolonged positive CSF cultures [4, 110]. The decision of whether to perform an LP before completion of therapy in the neonates with meningitis caused by GBS, *L. monocytogenes*, and Gram-negative bacteria can be based on clinical course including seizures, significant hypotension, prolonged positive CSF cultures, and abnormal neuroimaging [50].


*S. aureus; PO, periorally. †Adapted from Ref. [50].*

#### **Table 3.**

*Recommended antimicrobial treatment for neonatal bacterial meningitis.†*

**39**

**Table 4.**

*Neonatal Bacterial Meningitis*

**Antibiotic Susceptible** 

Ampicillin GBS

Cefotaxime *E. coli*

Meropenem *E. coli* 

Vancomycin Coagulase-

Nafcillin Methicillin-

*†Adapted from Refs. [4, 87, 97, 102, 103].*

Gentamicin/ Amikacin

*DOI: http://dx.doi.org/10.5772/intechopen.87118*

**bacteria**

Penicillin G GBS 100,000 U

*L. monocytogenes Enterococcus* sp.

*E. coli Klebsiella* sp. *Enterobacter* sp. *Pseudomonas* sp. *Citrobacter* sp. *Serratia* sp.

*Klebsiella* sp. *Enterobacter* sp. *Citrobacter* sp. *Serratia* sp.

*Klebsiella* sp. *Enterobacter* sp. *Citrobacter* sp. *Serratia* sp. *Pseudomonas* sp.

negative staphylococci *S. aureus Enterococcus* sp.

sensitive *S. aureus*

*GBS, group B streptococcus; CNS, central nervous system; g, gram; d, day.*

*Dosage of antibacterial drugs commonly used to treat neonatal meningitis.†*

**Body weight ≤ 2000 g**

≤7d old, every 12 h 8–28 d old, every 8 h

50 mg ≤7d old, every 12 h 8–28 d old, every 8 h

5 mg/15 mg ≤7d old, every 48 h 8–28 d old, every 36 h

50 mg ≤7d old, every 12 h 8–28 d old, every 8–12 h

40 mg ≤14 d old, every 12 h 14–28 d old, every 8 h

15 mg ≤7d old, every 24 h 8–28 d old, every 12 h

50 mg ≤7d old, every 12 h 8–28 d old, every 8 h

**Dose per kilogram Comments**

Monotherapy acceptable if GBS is confirmed by culture and clinical improvement is observed

17–78% of *E. coli* isolates are resistant Poor CNS penetration

Poor CNS penetration Synergistic effect with ampicillin in treatment of *L. monocytogenes Pseudomonas* sp. may require combination therapy with a second agent Require therapeutic drug monitoring

Good CNS penetration Used instead of gentamicin in cases of suspected or confirmed meningitis Not active against *L. monocytogenes* or *Enterococcus* sp.

Good CNS penetration Limit use to multidrug resistant organisms (e.g., extendedspectrum betalactamase-producing organisms)

Variable CNS penetration Effective against methicillin-resistant *S. aureus* Requires therapeutic drug monitoring

Good CNS penetration Superior to vancomycin for treatment of methicillin-sensitive *S. aureus*

**Body weight > 2000 g**

100,000 U ≤7 d old, every 8 h 8–28 d old, every 6 h

50 mg ≤7d old, every 12 h 8–28 d old, every 8 h

4 mg/15 mg ≤7d old, every 24 h 8–28 d old, every 24 h

50 mg ≤7d old, every 12 h 8–28 d old, every 8 h

40 mg ≤14 d old, every 8 h 14–28 d old, every 8 h

15 mg ≤7d old, every 12 h 8–28 d old, every 8 h

50 mg ≤7d old, every 8 h 8–28 d old, every 6 h

*Neonatal Medicine*

unknown

Initial therapy, CSF abnormal but organism

Coliform bacteria (*E coli*, *Klebsiella* sp., *Enterobacter* sp., *Citrobacter* sp., and

*Serratia* sp.)

*Chryseobacterium meningosepticum*

Other streptococcal

*Staphylococcus epidermidis* (or any coagulasenegative staphylococci)

*S. aureus; PO, periorally. †Adapted from Ref. [50].*

species

**Causative organism Recommended therapy Comment**

Ampicillin IV *and* gentamicin IV, IM *and* cefotaxime IV

*Bacteroides fragilis* spp. Metronidazole IV Alternative: meropenem.

Vancomycin IV *and* rifampin

*and* gentamicin IV, IM

gentamicin IV, IM; for ampicillin-resistant organisms: vancomycin *and* gentamicin

cefotaxime IV, IM

gentamicin IV, IM

vancomycin IV

aminoglycoside IV, IM

*Mycoplasma hominis* Clindamycin *or* doxycycline IV Alternatives: ciprofloxacin *IM, intramuscularly; IV, intravenously; MSSA: methicillin-susceptible S. aureus; MRSA: methicillin-resistant* 

azithromycin IV

*Recommended antimicrobial treatment for neonatal bacterial meningitis.†*

Penicillin *or* ampicillin IV, IM

*Haemophilus influenzae* Cefotaxime IV, IM Ampicillin if β-lactamase negative

Cefotaxime IV, IM, *and*

gentamicin

IV, PO

Group A *streptococcus* Penicillin G *or* ampicillin IV Group B *streptococcus* Ampicillin *or* penicillin G IV

*Enterococcus* spp. Ampicillin IV, IM, *and*

Gonococcal Ceftriaxone IV, IM *o*r

*Listeria monocytogenes* Ampicillin IV, IM, *and*

*Staphylococcus aureus* MSSA: nafcillin IV; MRSA:

*Pseudomonas aeruginosa* Ceftazidime IV, IM *and*

*Ureaplasma* spp. Doxycycline IV *or*

Cefotaxime is added if meningitis is suspected or cannot be excluded. Alternatives to ampicillin in nurseryacquired infections: vancomycin or

Alternatives to cefotaxime: ceftazidime, cefepime, or meropenem (limit use to multidrug-resistant organisms in nursery (e.g., extended-spectrum b-lactamase-

Discontinue gentamicin when clinical and microbiologic response is documented. Alternative: ampicillin if organism is susceptible; meropenem or cefepime for

Lumbar intrathecal or intraventricular gentamicin usually not beneficial.

Discontinue gentamicin when clinical and microbiologic response is documented

Gentamicin only if synergy documented

nafcillin.

producing organisms).

multiresistant organisms.

ciprofloxacin

(5–10 days?)

Vancomycin IV Add rifampin if cultures are persistently positive

Alternatives: clindamycin and

Duration of therapy uncertain

sterilization is achieved

Alternative: linezolid

sensitive S aureus

alternatives

Gentamicin is synergistic in vitro with ampicillin but can be discontinued when

Gentamicin may provide synergy; rifampin if cultures are persistently positive. Nafcillin is superior to vancomycin for treatment of methicillin-

Meropenem *or* cefepime are suitable

Alternatives: ciprofloxacin

**38**

**Table 3.**


*GBS, group B streptococcus; CNS, central nervous system; g, gram; d, day. †Adapted from Refs. [4, 87, 97, 102, 103].*

#### **Table 4.**

*Dosage of antibacterial drugs commonly used to treat neonatal meningitis.†*

#### **12. Neuroimaging**

Neuroimaging is recommended to assist in defining the potential complications of neonatal meningitis [50, 87]. Ultrasonography, which is a safe, convenient, and noninvasive method, can be done at bedside early in the course of the disease. It provides rapid and reliable information regarding ventricular size, the presence of hemorrhage, and development of hydrocephalus [111, 112]. It is also useful to detect periventricular white matter injury which may initially be manifested by increased periventricular echogenicity and later by cystic periventricular leukomalacia, ventriculitis, echogenic sulci, and extracerebral fluid collections [113, 114]. Computed tomography is rapid and easy imaging modality, but carries the risk of neonatal brain to radiation. It is useful to provide information on whether the course of meningitis has been complicated by hydrocephalus, brain abscess, or subdural collection. These findings may have a role in decision-making for potential neurosurgical interventions or duration of antimicrobial therapy [28, 87]. Magnetic resonance imaging (MRI) is the best currently available modality for evaluation of the neonatal brain [115]. It provides information on the status of white matter, cortex, subdural and epidural spaces, and even the posterior fossa, when performed either early or late in the course of the disease. It is useful to document the distribution pattern, severity, and complications of the disease [115, 116]. It has also been used in providing the best prognostic information [28]. For these reasons, it is recommended that at least one brain MRI should be performed on every case of neonatal meningitis, especially those caused by organisms that have a propensity for formation of intracranial abscesses [17, 28, 87]. Ideally in all cases, MRI scans must include pre-contrast and post-contrast-enhanced T1-weighted and T2-weighted images in at least two perpendicular planes. Fluid attenuated inversion recovery (FLAIR) sequence and diffusion weighted imaging (DWI) are preferred whenever purulent collections are suspected because of their high sensitivity in showing pus accumulation [115].

#### **13. Adjunctive therapy**

Bacterial meningitis in the newborn infant is characterized by high risk of mortality and serious neurological sequelae among most survivors. It is believed that most sequelae occur as a result of neural injury during the acute inflammatory process that characterizes bacterial meningitis. Given that corticosteroids may help attenuate the acute inflammatory process, adjuvant corticosteroid treatment in children with bacterial meningitis may reduce mortality in *S pneumoniae* meningitis but not in *H. influenzae* nor *N. meningitidis* meningitis, and severe hearing loss among children with *H. influenza* meningitis but not among those with meningitis due to non-Haemophilus species [117]. Additionally, these beneficial effects of corticosteroids have been reported in the reports from highincome countries, but not in those from low-income countries, probably due to the types of pathogens prevalent in the developing world, delay in the initiation of appropriate antibiotic treatment, partial treatment involving indiscriminate antibiotic use outside of hospitals, or lack of facilities [7]. A few studies suggest that some reduction in death and hearing loss is evident when adjunctive steroids are used in the treatment of neonatal meningitis, but experimental animal studies reported that adjunctive treatment with corticosteroid is associated with an increase in hippocampal neuronal apoptosis [118]. In conclusion, it should not be used routinely in the treatment of neonatal meningitis due to limited data [119].

**41**

*Neonatal Bacterial Meningitis*

bacterial meningitis [4].

**14. Complications**

empyema. [28, 121].

**15. Outcome**

tion of antimicrobial treatment may be required.

*DOI: http://dx.doi.org/10.5772/intechopen.87118*

Similarly, the limited studies showed that glycerol, when used as osmotic therapy, may reduce neurological deficiency and deafness in adults and children with acute bacterial meningitis [120], but it is not currently recommended in neonates with

Short-term neurological complication of neonatal bacterial meningitis includes cerebral edema, increased intracranial pressure, ventriculitis, cerebritis, hydrocephalus, brain abscess, cerebrovascular disease including ischemic arterial stroke and cerebral venous thrombosis, and subdural effusion or empyema [18, 121]. Cerebral edema results from vasogenic changes, cytotoxic cell injury, and occasionally inappropriate antidiuretic hormone secretion [28]. Ventriculitis, which occurs in about 20% of neonates with meningitis caused by Gram-negative organisms, is a result of bacterial entry into the CNS through the choroid plexus [28, 121, 122]. Inflammatory exudate covers the epidermal lining and the choroid plexus, disrupts ependymal lining, and causes subependymal venous thrombosis and eventually necrosis [28]. It is usually associated with obstruction of CSF outflow [121]. Cerebritis results from extension of exudate along perivascular space [18, 28]. Hydrocephalus, which occurs in approximately one-quarter of neonates with meningitis, develops as a result of fibrous inflammatory exudate obstructing CSF flow through the ventricular system or dysfunction of arachnoid villi [18, 28, 122, 123]. Cerebral infarction occurs in approximately 30% of neonates with meningitis and is frequently hemorrhagic [28, 124]. The mechanisms leading to cerebrovascular complications in bacterial meningitis are not completely understood and likely are multifactorial [15, 62]. Brain abscesses, which occur in approximately 10 percent of patients with neonatal meningitis, may result from a hematogenous spread of microorganism into infarcted brain, or by local spread [28, 121]. Subdural effusions occur in approximately 11% of neonates with meningitis and rarely cause clinically significant finding and lead to

Neonates with bacterial meningitis should be monitored for signs of these complications throughout their treatment. It must be suspected when there is a failure to respond clinically and microbiologically to appropriate antimicrobial therapy, or a focal neurologic deficit, or new-onset seizures, especially focal seizures, or when there are signs of increased intracranial pressure such as bulging fontanelle, accelerated head growth, bradycardia, hypertension, and separation of the cranial sutures [18, 121]. Acute deterioration in an otherwise stable neonate with meningitis can occur if the abscess ruptures into ventricular system or subarachnoid space [28, 121]. In case of suspicion regarding these complications, additional evaluation including neuroimaging studies, neurosurgical consultation, and prolonged dura-

In developed countries, the rate of mortality from bacterial meningitis among neonates has declined substantially from nearly 50% in the 1970s to figures currently ranging from 10 to 15% [4, 5, 26–29]. In developing countries, the mortality rate is much higher at 40–58% [7]. Mortality is higher among preterm infants, in cases with meningitis caused by microorganism that causes vasculitis and brain abscess and in late-onset cases [26–29]. Risk factors involved in higher mortality rate and severe disability are low birth weight or prematurity, history of symptoms Similarly, the limited studies showed that glycerol, when used as osmotic therapy, may reduce neurological deficiency and deafness in adults and children with acute bacterial meningitis [120], but it is not currently recommended in neonates with bacterial meningitis [4].

#### **14. Complications**

*Neonatal Medicine*

**12. Neuroimaging**

sensitivity in showing pus accumulation [115].

**13. Adjunctive therapy**

Neuroimaging is recommended to assist in defining the potential complications of neonatal meningitis [50, 87]. Ultrasonography, which is a safe, convenient, and noninvasive method, can be done at bedside early in the course of the disease. It provides rapid and reliable information regarding ventricular size, the presence of hemorrhage, and development of hydrocephalus [111, 112]. It is also useful to detect periventricular white matter injury which may initially be manifested by increased periventricular echogenicity and later by cystic periventricular leukomalacia, ventriculitis, echogenic sulci, and extracerebral fluid collections [113, 114]. Computed tomography is rapid and easy imaging modality, but carries the risk of neonatal brain to radiation. It is useful to provide information on whether the course of meningitis has been complicated by hydrocephalus, brain abscess, or subdural collection. These findings may have a role in decision-making for potential neurosurgical interventions or duration of antimicrobial therapy [28, 87]. Magnetic resonance imaging (MRI) is the best currently available modality for evaluation of the neonatal brain [115]. It provides information on the status of white matter, cortex, subdural and epidural spaces, and even the posterior fossa, when performed either early or late in the course of the disease. It is useful to document the distribution pattern, severity, and complications of the disease [115, 116]. It has also been used in providing the best prognostic information [28]. For these reasons, it is recommended that at least one brain MRI should be performed on every case of neonatal meningitis, especially those caused by organisms that have a propensity for formation of intracranial abscesses [17, 28, 87]. Ideally in all cases, MRI scans must include pre-contrast and post-contrast-enhanced T1-weighted and T2-weighted images in at least two perpendicular planes. Fluid attenuated inversion recovery (FLAIR) sequence and diffusion weighted imaging (DWI) are preferred whenever purulent collections are suspected because of their high

Bacterial meningitis in the newborn infant is characterized by high risk of mortality and serious neurological sequelae among most survivors. It is believed that most sequelae occur as a result of neural injury during the acute inflammatory process that characterizes bacterial meningitis. Given that corticosteroids may help attenuate the acute inflammatory process, adjuvant corticosteroid treatment in children with bacterial meningitis may reduce mortality in *S pneumoniae* meningitis but not in *H. influenzae* nor *N. meningitidis* meningitis, and severe hearing loss among children with *H. influenza* meningitis but not among those with meningitis due to non-Haemophilus species [117]. Additionally, these beneficial effects of corticosteroids have been reported in the reports from highincome countries, but not in those from low-income countries, probably due to the types of pathogens prevalent in the developing world, delay in the initiation of appropriate antibiotic treatment, partial treatment involving indiscriminate antibiotic use outside of hospitals, or lack of facilities [7]. A few studies suggest that some reduction in death and hearing loss is evident when adjunctive steroids are used in the treatment of neonatal meningitis, but experimental animal studies reported that adjunctive treatment with corticosteroid is associated with an increase in hippocampal neuronal apoptosis [118]. In conclusion, it should not be used routinely in the treatment of neonatal meningitis due to limited data [119].

**40**

Short-term neurological complication of neonatal bacterial meningitis includes cerebral edema, increased intracranial pressure, ventriculitis, cerebritis, hydrocephalus, brain abscess, cerebrovascular disease including ischemic arterial stroke and cerebral venous thrombosis, and subdural effusion or empyema [18, 121]. Cerebral edema results from vasogenic changes, cytotoxic cell injury, and occasionally inappropriate antidiuretic hormone secretion [28]. Ventriculitis, which occurs in about 20% of neonates with meningitis caused by Gram-negative organisms, is a result of bacterial entry into the CNS through the choroid plexus [28, 121, 122]. Inflammatory exudate covers the epidermal lining and the choroid plexus, disrupts ependymal lining, and causes subependymal venous thrombosis and eventually necrosis [28]. It is usually associated with obstruction of CSF outflow [121]. Cerebritis results from extension of exudate along perivascular space [18, 28]. Hydrocephalus, which occurs in approximately one-quarter of neonates with meningitis, develops as a result of fibrous inflammatory exudate obstructing CSF flow through the ventricular system or dysfunction of arachnoid villi [18, 28, 122, 123]. Cerebral infarction occurs in approximately 30% of neonates with meningitis and is frequently hemorrhagic [28, 124]. The mechanisms leading to cerebrovascular complications in bacterial meningitis are not completely understood and likely are multifactorial [15, 62]. Brain abscesses, which occur in approximately 10 percent of patients with neonatal meningitis, may result from a hematogenous spread of microorganism into infarcted brain, or by local spread [28, 121]. Subdural effusions occur in approximately 11% of neonates with meningitis and rarely cause clinically significant finding and lead to empyema. [28, 121].

Neonates with bacterial meningitis should be monitored for signs of these complications throughout their treatment. It must be suspected when there is a failure to respond clinically and microbiologically to appropriate antimicrobial therapy, or a focal neurologic deficit, or new-onset seizures, especially focal seizures, or when there are signs of increased intracranial pressure such as bulging fontanelle, accelerated head growth, bradycardia, hypertension, and separation of the cranial sutures [18, 121]. Acute deterioration in an otherwise stable neonate with meningitis can occur if the abscess ruptures into ventricular system or subarachnoid space [28, 121]. In case of suspicion regarding these complications, additional evaluation including neuroimaging studies, neurosurgical consultation, and prolonged duration of antimicrobial treatment may be required.

#### **15. Outcome**

In developed countries, the rate of mortality from bacterial meningitis among neonates has declined substantially from nearly 50% in the 1970s to figures currently ranging from 10 to 15% [4, 5, 26–29]. In developing countries, the mortality rate is much higher at 40–58% [7]. Mortality is higher among preterm infants, in cases with meningitis caused by microorganism that causes vasculitis and brain abscess and in late-onset cases [26–29]. Risk factors involved in higher mortality rate and severe disability are low birth weight or prematurity, history of symptoms for >24 hours before admission, leukopenia (<5000/mm3 ) and neutropenia (<1000/mm3 ), seizures lasting longer than 72 hours, coma, focal neurologic deficits, ventilator support, the need for inotropes, higher CSF protein level, and delayed sterilization of the CSF [4, 5, 24, 26–29, 109, 121–125].

Long-term complications in survivors are mental and motor disabilities including mental retardation, learning disabilities, cerebral palsy, and behavioral problems, seizures, hydrocephalus, language disorders, hearing loss, and impaired visual acuity [4, 5, 14, 27]. Approximately 20% of survivors have severe disability and another 35% have mild to moderate disability [4, 5, 122]. Neonatal meningitis caused by *S. pneumoniae* and Gram-negative bacteria carries a worse prognosis [24, 50, 122, 126]. All infants experienced with bacterial meningitis should be followed long-term for development of neurological sequelae.

#### **16. Prevention**

Intrapartum antibiotic prophylaxis for GBS colonized women or based on the presence of clinical risk factors is efficacious against early onset GBS disease but has no impact on late-onset disease, when most GBS meningitis occurs [5, 127]. The incidence of late-onset GBS disease remains unaffected by IAP use [33, 35]. Vaccines against GBS can reduce the number of missed opportunities due to various reasons. So, maternal immunity to the most common serotypes of GBS (serotypes Ia, Ib, and III) can be transferred passively to the fetus and protect against invasive infection in infancy due to covered serotypes [128]. Clinical trials of a trivalent GBS vaccine are encouraging in this regard. In the case of pneumococcal meningitis, the 10- and 13-valent conjugate vaccines may be protective for infants aged <3 months [5].

The prevention of the spread of the pathogens responsible for neonatal sepsis and meningitis also has an impact on disease burden [6]. Several interventions, which can be introduced at the community level, with prevention strategies applied during the antenatal, intrapartum, and early neonatal period, will reduce the number of early-onset diseases [16, 129]. Prevention of nosocomial infections is based on strategies that aim to limit susceptibility to infections by enhancing host defenses, interrupting transmission of organisms by healthcare workers, and by promoting the judicious use of antimicrobials [130].

#### **17. Summary**

Bacterial meningitis is associated with significant morbidity and mortality in the neonatal population. Although overall incidence and mortality have declined over the last several decades, morbidity associated with neonatal meningitis remains unchanged. Prompt diagnosis and treatment are mandatory to improve both shortand long-term outcomes. CSF culture obtained via LP is the gold-standard method for the diagnosis of meningitis, which is the key to rapid institution of effective antimicrobial therapy. Prevention strategies, adjunctive therapies, improved diagnostic strategies, and development of vaccines may further reduce the burden of this devastating disease.

**43**

**Author details**

Mehmet Şah İpek

Diyarbakir, Turkey

Division of Neonatology, Department of Pediatrics, Memorial Dicle Hospital,

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

\*Address all correspondence to: md.msipek@yahoo.com

provided the original work is properly cited.

*Neonatal Bacterial Meningitis*

*DOI: http://dx.doi.org/10.5772/intechopen.87118*

#### **Conflict of interest**

The author declares no conflicts of interest.

*Neonatal Bacterial Meningitis DOI: http://dx.doi.org/10.5772/intechopen.87118*

*Neonatal Medicine*

(<1000/mm3

**16. Prevention**

infants aged <3 months [5].

**17. Summary**

of this devastating disease.

**Conflict of interest**

for >24 hours before admission, leukopenia (<5000/mm3

lowed long-term for development of neurological sequelae.

promoting the judicious use of antimicrobials [130].

The author declares no conflicts of interest.

cits, ventilator support, the need for inotropes, higher CSF protein level, and delayed sterilization of the CSF [4, 5, 24, 26–29, 109, 121–125].

Long-term complications in survivors are mental and motor disabilities including mental retardation, learning disabilities, cerebral palsy, and behavioral problems, seizures, hydrocephalus, language disorders, hearing loss, and impaired visual acuity [4, 5, 14, 27]. Approximately 20% of survivors have severe disability and another 35% have mild to moderate disability [4, 5, 122]. Neonatal meningitis caused by *S. pneumoniae* and Gram-negative bacteria carries a worse prognosis [24, 50, 122, 126]. All infants experienced with bacterial meningitis should be fol-

Intrapartum antibiotic prophylaxis for GBS colonized women or based on the presence of clinical risk factors is efficacious against early onset GBS disease but has no impact on late-onset disease, when most GBS meningitis occurs [5, 127]. The incidence of late-onset GBS disease remains unaffected by IAP use [33, 35]. Vaccines against GBS can reduce the number of missed opportunities due to various reasons. So, maternal immunity to the most common serotypes of GBS (serotypes Ia, Ib, and III) can be transferred passively to the fetus and protect against invasive infection in infancy due to covered serotypes [128]. Clinical trials of a trivalent GBS vaccine are encouraging in this regard. In the case of pneumococcal meningitis, the 10- and 13-valent conjugate vaccines may be protective for

The prevention of the spread of the pathogens responsible for neonatal sepsis and meningitis also has an impact on disease burden [6]. Several interventions, which can be introduced at the community level, with prevention strategies applied during the antenatal, intrapartum, and early neonatal period, will reduce the number of early-onset diseases [16, 129]. Prevention of nosocomial infections is based on strategies that aim to limit susceptibility to infections by enhancing host defenses, interrupting transmission of organisms by healthcare workers, and by

Bacterial meningitis is associated with significant morbidity and mortality in the neonatal population. Although overall incidence and mortality have declined over the last several decades, morbidity associated with neonatal meningitis remains unchanged. Prompt diagnosis and treatment are mandatory to improve both shortand long-term outcomes. CSF culture obtained via LP is the gold-standard method for the diagnosis of meningitis, which is the key to rapid institution of effective antimicrobial therapy. Prevention strategies, adjunctive therapies, improved diagnostic strategies, and development of vaccines may further reduce the burden

), seizures lasting longer than 72 hours, coma, focal neurologic defi-

) and neutropenia

**42**

### **Author details**

Mehmet Şah İpek Division of Neonatology, Department of Pediatrics, Memorial Dicle Hospital, Diyarbakir, Turkey

\*Address all correspondence to: md.msipek@yahoo.com

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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streptococcal prophylaxis? The Journal

infections in neonates. NeoReviews.

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[48] İpek MS, Ozbek E, Guldemir D, et al. Neonatal meningitis caused by Actinomyces: A case report of the most probably new strain. Journal of Pediatric Infectious Diseases. 2017;**12**:138-141

[49] Uchida Y, Morita H, Adachi S, et al. Bacterial meningitis and

Feb;**53**:119-120

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[57] Kim KS, Itabashi H, Gemski P, et al. The K1 capsule is the critical determinant in the development of *Escherichia coli* meningitis in the rat. The Journal of Clinical Investigation. 1992;**90**:897-905

[58] Kim KS. Mechanisms of microbial traversal of the blood-brain barrier. Nature Reviews. Microbiology. 2008;**6**(8):625-634

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[66] Curtis S, Stobart K, Vandermeer B, et al. Clinical features suggestive of meningitis in children: A systematic review of prospective data. Pediatrics. 2010;**126**:952-960

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[129] Lassi ZS, Bhutta ZA. Communitybased intervention packages for reducing maternal and neonatal

morbidity and mortality and improving

[130] Borghesi A, Stronati M. Strategies for the prevention of hospital-acquired infections in the neonatal intensive care unit. The Journal of Hospital Infection.

neonatal outcomes. Cochrane Database of Systematic Reviews.

in northern India. Indian Journal of

[124] Tibussek D, Sinclair A, Yau I, et al. Late-onset group B streptococcal meningitis has cerebrovascular

*Neonatal Bacterial Meningitis DOI: http://dx.doi.org/10.5772/intechopen.87118*

in northern India. Indian Journal of Pediatrics. 2015;**82**:315-320

*Neonatal Medicine*

neonatal infection. Pediatrics and Neonatology. 2016;**57**:167-173

[115] Schneider JF, Hanquinet S, Severino M, et al. MR imaging of neonatal brain infections. Magnetic Resonance Imaging Clinics of North

[116] Jaremko JL, Moon AS, Kumbla S. Patterns of complications of neonatal and infant meningitis on MRI by organism: A 10 year review. European Journal of Radiology. 2011;**80**:821-827

[117] Brouwer MC, McIntyre P, Prasad K, et al. Corticosteroids for acute bacterial meningitis. Cochrane Database of Systematic Reviews. 2013;**6**:CD004405

[119] Ogunlesi TA, Odigwe CC, Oladapo OT. Adjuvant corticosteroids for reducing death in neonatal bacterial meningitis. Cochrane Database of Systematic Reviews. 2015;**11**:CD010435

[120] Wall EC, Ajdukiewicz KM, Bergman H, et al. Osmotic therapies added to antibiotics for acute bacterial meningitis. Cochrane Database of Systematic Reviews. 2018;**2**:CD008806

[121] Edwards MS, Baker CJ. Bacterial meningitis in the neonate: Neurologic complications. In: Kaplan SL, Weisman LE, Nordli DR, editors. UpToDate. Waltam, MA: UpToDate Inc. Available from: https://www.uptodate.com [Accessed: September 16, 2018]

[122] Unhanand M, Mustafa MM, McCracken GH Jr, et al. Gram-negative enteric bacillary meningitis: A twentyone-year experience. The Journal of

[123] Kumar R, Singhi P, Dekate P, et al. Meningitis related ventriculitis— Experience from a tertiary care centre

Pediatrics. 1993;**122**:15-21

[118] Spreer A, Gerber J, Hanssen M, et al. Dexamethasone increases hippocampal neuronal apoptosis in a rabbit model of *Escherichia coli* meningitis. Pediatric Research.

2006;**60**:210-215

America. 2011;**19**:761-775

[107] Lebel MH, McCracken GH Jr. Delayed cerebrospinal fluid sterilization and adverse outcome of bacterial meningitis in infants and children.

[108] Tunkel AR, Scheld WM. Issues in the management of bacterial

[109] Greenberg RG, Benjamin DK Jr, Cohen-Wolkowiez M, et al. Repeat lumbar punctures in infants with meningitis in the neonatal intensive care unit. Journal of Perinatology.

[110] Agarwal R, Emmerson AJ. Should repeat lumbar punctures be routinely done in neonates with bacterial meningitis? Results of a survey into clinical practice. Archives of Disease in

[111] Perlman JM, Rollins N, Sanchez PJ. Late-onset meningitis in sick, verylow-birth-weight infants. Clinical and sonographic observations. American Journal of Diseases of Children.

[112] Gupta N, Grover H, Bansal I, et al. Neonatal cranial sonography: Ultrasound findings in neonatal meningitis-a pictorial review.

Quantitative Imaging in Medicine and

[113] Raju VS, Rao MN, Rao VS. Cranial sonography in pyogenic meningitis in neonates and infants. Journal of Tropical Pediatrics. 1995;**41**:68-73

Childhood. 2001;**84**:451-452

1992;**146**:1297-1301

Surgery. 2017;**7**:123-131

[114] Yikilmaz A, Taylor GA. Sonographic findings in bacterial meningitis in neonates and young infants. Pediatric Radiology.

2008;**38**:129-137

meningitis. American Family Physician.

Pediatrics. 1989;**83**:161-167

1997;**56**:1355-1362

2011;**31**:425-429

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[124] Tibussek D, Sinclair A, Yau I, et al. Late-onset group B streptococcal meningitis has cerebrovascular complications. The Journal of Pediatrics. 2015;**166**:1187-1192

[125] Klinger G, Chin CN, Beyene J, et al. Predicting the outcome of neonatal bacterial meningitis. Pediatrics. 2000;**106**:477-482

[126] Baş AY, Demirel N, Aydin M, et al. Pneumococcal meningitis in the newborn period in a prevaccination era: A 10-year experience at a tertiary intensive care unit. The Turkish Journal of Pediatrics. 2011;**53**:142-148

[127] Heath PT, Schuchat A. Perinatal group B streptococcal disease. Best Practice & Research. Clinical Obstetrics & Gynaecology. 2007;**21**:411-424

[128] Oster G, Edelsberg J, Hennegan K, et al. Prevention of group B streptococcal disease in the first 3 months of life: Would routine maternal immunization during pregnancy be cost-effective? Vaccine. 2014;**32**:4778-4785

[129] Lassi ZS, Bhutta ZA. Communitybased intervention packages for reducing maternal and neonatal morbidity and mortality and improving neonatal outcomes. Cochrane Database of Systematic Reviews. 2015;**3**:CD007754

[130] Borghesi A, Stronati M. Strategies for the prevention of hospital-acquired infections in the neonatal intensive care unit. The Journal of Hospital Infection. 2008;**68**:293-300

**53**

**Chapter 4**

**Abstract**

newborn, sepsis, ECMO

**1. Introduction**

Platelets in the Newborn

*Danilyn M. Angeles and Danilo S. Boskovic*

*Ijeoma Esiaba, Iman Mousselli, Giulia M. Faison,* 

Platelets were first described in the mid-nineteenth century. Since then, their roles were identified in hemostasis and thrombosis, inflammation, leukocyte interactions, angiogenesis, and cancer growth. But there is little information about such platelet functions in the newborn. Several studies highlighted some platelet differences between newborns and adults. Yet, in spite of these differences, healthy newborns appear to be adequately protected. A number of factors, however, were reported to negatively affect neonatal platelets. These include maternal hypertensive disorders or infections, neonatal asphyxia or respiratory distress, therapies such as ampicillin or indomethacin, and treatment modalities such as ventilators, nitric oxide, or extracorporeal membrane oxygenation (ECMO). Their effects on newborn platelets are usually transitory, lasting from several hours to a few days or weeks. If these effects are well characterized, they could serve as reporters for diagnosis and monitoring during therapy. Careful studies of neonatal platelets are needed to improve the understanding of basic physiology and pathophysiology in

this cohort and to identify possible targets for intervention and therapy.

discovered and the mechanisms for some of them are now clearer.

**Keywords:** platelet function, hemostasis, prematurity, platelet transfusion,

Platelets are small discoid cellular particles, produced by megakaryocytes, and best known for their role in thrombus or platelet plug formation. Since their initial description in the mid-nineteenth century, further details have emerged about their structure and function. More recently, their roles in processes as wide ranging as tissue repair and wound healing, angiogenesis, tumor killing, tumor growth and metastasis, inflammation, and host defense have come to light [1, 2]. Platelets perform these varied functions and diverse interactions because of several receptors and ligands on their surface, and a store of over 300 proteins within their cytoplasm and granules. With newer technological advances, more platelet functions were

Platelets mediate primary hemostasis, a dynamic process involving several reactions resulting in thrombus formation. Initially, platelets aggregate to form a platelet plug at the site of injury [3, 4]. In secondary hemostasis, thrombin is generated after a cascade of enzymatic reactions. The generated thrombin subsequently cleaves fibrinogen to fibrin [5]. Fibrin spontaneously polymerizes forming a fibrous network which stabilizes the platelet plug [6]. The process of tertiary hemostasis, or fibrinolysis, restricts clot formation to the site of injury, dissolves clots after the

## **Chapter 4** Platelets in the Newborn

*Ijeoma Esiaba, Iman Mousselli, Giulia M. Faison, Danilyn M. Angeles and Danilo S. Boskovic*

#### **Abstract**

Platelets were first described in the mid-nineteenth century. Since then, their roles were identified in hemostasis and thrombosis, inflammation, leukocyte interactions, angiogenesis, and cancer growth. But there is little information about such platelet functions in the newborn. Several studies highlighted some platelet differences between newborns and adults. Yet, in spite of these differences, healthy newborns appear to be adequately protected. A number of factors, however, were reported to negatively affect neonatal platelets. These include maternal hypertensive disorders or infections, neonatal asphyxia or respiratory distress, therapies such as ampicillin or indomethacin, and treatment modalities such as ventilators, nitric oxide, or extracorporeal membrane oxygenation (ECMO). Their effects on newborn platelets are usually transitory, lasting from several hours to a few days or weeks. If these effects are well characterized, they could serve as reporters for diagnosis and monitoring during therapy. Careful studies of neonatal platelets are needed to improve the understanding of basic physiology and pathophysiology in this cohort and to identify possible targets for intervention and therapy.

**Keywords:** platelet function, hemostasis, prematurity, platelet transfusion, newborn, sepsis, ECMO

#### **1. Introduction**

Platelets are small discoid cellular particles, produced by megakaryocytes, and best known for their role in thrombus or platelet plug formation. Since their initial description in the mid-nineteenth century, further details have emerged about their structure and function. More recently, their roles in processes as wide ranging as tissue repair and wound healing, angiogenesis, tumor killing, tumor growth and metastasis, inflammation, and host defense have come to light [1, 2]. Platelets perform these varied functions and diverse interactions because of several receptors and ligands on their surface, and a store of over 300 proteins within their cytoplasm and granules. With newer technological advances, more platelet functions were discovered and the mechanisms for some of them are now clearer.

Platelets mediate primary hemostasis, a dynamic process involving several reactions resulting in thrombus formation. Initially, platelets aggregate to form a platelet plug at the site of injury [3, 4]. In secondary hemostasis, thrombin is generated after a cascade of enzymatic reactions. The generated thrombin subsequently cleaves fibrinogen to fibrin [5]. Fibrin spontaneously polymerizes forming a fibrous network which stabilizes the platelet plug [6]. The process of tertiary hemostasis, or fibrinolysis, restricts clot formation to the site of injury, dissolves clots after the

damaged endothelium has been repaired, and prevents the formation of pathologic thrombi [7, 8]. These reactions are tightly regulated to minimize the risk of either bleeding or thrombosis. Components of the hemostatic system are usually preformed and circulate in their respective inactive forms. Apart from their role in hemostasis, some of these factors also play a role in other physiological processes such as embryonic development, angiogenesis, or immunity [9].

Most of the information about platelets is based on studies conducted in adults or in animal models. Despite recognized roles of platelets in processes as wide ranging as inflammation and angiogenesis, information about these roles of neonatal platelets is limited. However, clinical observations suggest that there likely are some functional differences between neonatal and adult platelets. Newborns are at greater risk of contracting infections and may not cope adequately with inflammatory stresses [10]. New blood vessels are formed to meet the demands of rapidly growing tissues. The roles of platelets in these processes and reactions in the newborn are not yet well described. Additionally, certain prematurity-related morbidities such as intraventricular hemorrhage, retinopathy of prematurity, and necrotizing enterocolitis are associated with bleeding and inflammation [11, 12]. Platelets or their functional deficits are believed to be involved in these disorders. Studying platelet function in the newborn is difficult, but emerging methodological approaches requiring small volumes of newborn's blood are making such studies feasible. Following a general description of platelet structure and functions, this review will highlight documented differences in the newborn.

#### **2. Platelet structure and functions**

Platelets mediate primary hemostasis and play roles in procoagulant and fibrinolytic processes [13]. They are nonnucleated fragments derived from bone marrow megakaryocytes. The adult human produces about 1011 platelets daily, rising by more than 20-fold during increased need [14]. In the fetus and neonate, platelets are produced largely in the liver and spleen [15, 16]. Thrombopoietin maintains platelet homeostasis by regulating thrombopoiesis [17, 18]. The resting platelet is disk shaped with a diameter of about 1.5 μm and a lifespan of 7–10 days [19]. Its surface does not promote coagulation or aggregation. In circulation, the platelets' resting state is further supported by the release of prostacyclin and nitric oxide from endothelial cells, by the expression of CD39 (an ADPase) on the endothelial surface, and by the inability of normal plasma vWF to bind spontaneously to the platelet surface [20].

Platelets have a complex internal structure with a series of organelles. Lacking a nucleus, they nevertheless contain some nucleic acid in the form of ribonucleic acid (RNA), which is used for synthesis of new proteins, especially during or after platelet activation [21]. The secretory granules comprise the α-granules and dense or δ-granules. The α-granules contain adhesion molecules important for platelet interactions with other platelets and blood cells, angiogenic and mitogenic factors, plasma proteins, and several factors relevant for coagulation and fibrinolysis [22]. The dense- or δ-granules contain non-protein molecules such as adenosine diphosphate (ADP), adenosine triphosphate (ATP), calcium and serotonin [22]. These play central roles in amplification of platelet activation and aggregation and in modulation of vascular endothelium and leukocyte functions. Within lysosomes are membrane proteins and acid hydrolases that digest the material in platelet aggregates through hydrolytic degradation [23]. Over 300 proteins are secreted from these granules during activation [24]. In the unstimulated platelets, the granule contents remain internalized. When stimulated, however, platelets release such contents through an open canalicular system [25].

**55**

*Platelets in the Newborn*

the hemostatic plug [32].

*DOI: http://dx.doi.org/10.5772/intechopen.86715*

A number of factors and agonists can stimulate platelets. These include shear stress during blood flow, agonists such as thrombin, collagen, or ADP, and recognition of and interaction with viruses, bacteria, or damaged vascular endothelium [26, 27]. Typically, platelet activation is triggered when there is a break in the vascular endothelium. The activated platelets first adhere to the damaged endothelium by binding to von Willebrand factor (vWF) through its surface membrane glycoprotein Ib (GPIb). Further interactions of platelet glycoprotein VI (GPVI) with fibrillary collagen and platelet β1 integrin with laminin, collagen, and fibro-

Following activation, platelet membrane phospholipid distribution changes to include exposure of phosphatidylserine on the outer surface, thus promoting the condensation of vitamin K-dependent coagulation factors on this surface, and inducing the activation of the procoagulant cascade [28]. Additionally, a rearrangement of the cytoskeleton leads to a change in platelet structure [29] from the resting discoid form, via an intermediate spherical shape, to a fully activated amoeboid form with numerous extending pseudopodia able to interact with some nearby surfaces [29]. Meanwhile, the contents of α- and δ-granules are released into the immediate environment, further amplifying the original activation signal [23]. As a result, in response to a number of biological mediators, the activated platelets adhere to each other, to leukocytes and

During extension of platelet plug formation, activated platelets accumulate on top of the initial monolayer of platelets bound to collagen of the sub-endothelium [3]. Expressed receptors on each platelet allow binding of agonists such as ADP, thrombin, and thromboxane A2, which are released from activated platelets [31]. Consequently, more platelets are recruited to the site of injury, thereby consolidating the initial hemostatic plug. Binding of fibrin to aggregated platelets through activated receptor glycoprotein GPIIb/IIIa (integrin αIIbβ3) helps to further stabilize

Several proteins are released during platelet aggregation at a damaged blood vessel surface [22]. Some are believed to be responsible for repair of damaged blood vessels and development of new ones. Although precise mechanisms are not well understood, it was suggested that platelets are necessary for formation of new blood vessels [33]. Supporting this are observations of reduced retinal neovascularization in a mouse hypoxia-induced retinal angiogenesis model due to thrombocytopenia or in response to treatment with inhibitors of platelet aggregation [33]. In this context, platelet granules are believed to contain pro- and anti-angiogenic compounds [34, 35]. Similarly, platelet interactions with cancer cells appear to play a role in the development of metastases and tumor angiogenesis [36]. While cerebrovascular remodeling is known to occur in the newborn in the first few postnatal weeks [37], the roles of platelets in this developmental process are not yet well described. Platelets may also play a role in newborn's inflammatory processes and host defense. Neonates are generally believed to be at least partially immunologically incompetent and susceptible to a variety of infections. In this context, it is of interest that platelets have toll-like receptors (TLRs) that directly recognize and interact with a number of microorganisms or their products. Platelets may be responsible for killing microbes directly by phagocytosis, by release of microbicidal agents, or as sentinels communicating information about microbial encounters to cells of the innate immune system [15]. Bacterial infections, found in preterm newborns admitted to the neonatal intensive care unit (NICU), appear similar to infections found in adults with severe neutropenia [38]. This suggests reduced neutrophil functions in these babies. Neonates rely heavily on innate immunity for protection because their adaptive immunity is not yet fully developed [39]. Neutrophils are usually the first cells to be recruited to infection sites. They kill pathogens by various mechanisms

nectin maintain platelet adhesion to exposed extracellular matrix [8].

endothelial cells, and to components of the sub-endothelial matrix [30].

#### *Platelets in the Newborn DOI: http://dx.doi.org/10.5772/intechopen.86715*

*Neonatal Medicine*

damaged endothelium has been repaired, and prevents the formation of pathologic thrombi [7, 8]. These reactions are tightly regulated to minimize the risk of either bleeding or thrombosis. Components of the hemostatic system are usually preformed and circulate in their respective inactive forms. Apart from their role in hemostasis, some of these factors also play a role in other physiological processes

Most of the information about platelets is based on studies conducted in adults

Platelets mediate primary hemostasis and play roles in procoagulant and fibrinolytic processes [13]. They are nonnucleated fragments derived from bone marrow megakaryocytes. The adult human produces about 1011 platelets daily, rising by more than 20-fold during increased need [14]. In the fetus and neonate, platelets are produced largely in the liver and spleen [15, 16]. Thrombopoietin maintains platelet homeostasis by regulating thrombopoiesis [17, 18]. The resting platelet is disk shaped with a diameter of about 1.5 μm and a lifespan of 7–10 days [19]. Its surface does not promote coagulation or aggregation. In circulation, the platelets' resting state is further supported by the release of prostacyclin and nitric oxide from endothelial cells, by the expression of CD39 (an ADPase) on the endothelial surface, and by the inability of

Platelets have a complex internal structure with a series of organelles. Lacking a nucleus, they nevertheless contain some nucleic acid in the form of ribonucleic acid (RNA), which is used for synthesis of new proteins, especially during or after platelet activation [21]. The secretory granules comprise the α-granules and dense or δ-granules. The α-granules contain adhesion molecules important for platelet interactions with other platelets and blood cells, angiogenic and mitogenic factors, plasma proteins, and several factors relevant for coagulation and fibrinolysis [22]. The dense- or δ-granules contain non-protein molecules such as adenosine diphosphate (ADP), adenosine triphosphate (ATP), calcium and serotonin [22]. These play central roles in amplification of platelet activation and aggregation and in modulation of vascular endothelium and leukocyte functions. Within lysosomes are membrane proteins and acid hydrolases that digest the material in platelet aggregates through hydrolytic degradation [23]. Over 300 proteins are secreted from these granules during activation [24]. In the unstimulated platelets, the granule contents remain internalized. When stimulated, however, platelets release such

or in animal models. Despite recognized roles of platelets in processes as wide ranging as inflammation and angiogenesis, information about these roles of neonatal platelets is limited. However, clinical observations suggest that there likely are some functional differences between neonatal and adult platelets. Newborns are at greater risk of contracting infections and may not cope adequately with inflammatory stresses [10]. New blood vessels are formed to meet the demands of rapidly growing tissues. The roles of platelets in these processes and reactions in the newborn are not yet well described. Additionally, certain prematurity-related morbidities such as intraventricular hemorrhage, retinopathy of prematurity, and necrotizing enterocolitis are associated with bleeding and inflammation [11, 12]. Platelets or their functional deficits are believed to be involved in these disorders. Studying platelet function in the newborn is difficult, but emerging methodological approaches requiring small volumes of newborn's blood are making such studies feasible. Following a general description of platelet structure and functions, this

such as embryonic development, angiogenesis, or immunity [9].

review will highlight documented differences in the newborn.

normal plasma vWF to bind spontaneously to the platelet surface [20].

contents through an open canalicular system [25].

**2. Platelet structure and functions**

**54**

A number of factors and agonists can stimulate platelets. These include shear stress during blood flow, agonists such as thrombin, collagen, or ADP, and recognition of and interaction with viruses, bacteria, or damaged vascular endothelium [26, 27]. Typically, platelet activation is triggered when there is a break in the vascular endothelium. The activated platelets first adhere to the damaged endothelium by binding to von Willebrand factor (vWF) through its surface membrane glycoprotein Ib (GPIb). Further interactions of platelet glycoprotein VI (GPVI) with fibrillary collagen and platelet β1 integrin with laminin, collagen, and fibronectin maintain platelet adhesion to exposed extracellular matrix [8].

Following activation, platelet membrane phospholipid distribution changes to include exposure of phosphatidylserine on the outer surface, thus promoting the condensation of vitamin K-dependent coagulation factors on this surface, and inducing the activation of the procoagulant cascade [28]. Additionally, a rearrangement of the cytoskeleton leads to a change in platelet structure [29] from the resting discoid form, via an intermediate spherical shape, to a fully activated amoeboid form with numerous extending pseudopodia able to interact with some nearby surfaces [29]. Meanwhile, the contents of α- and δ-granules are released into the immediate environment, further amplifying the original activation signal [23]. As a result, in response to a number of biological mediators, the activated platelets adhere to each other, to leukocytes and endothelial cells, and to components of the sub-endothelial matrix [30].

During extension of platelet plug formation, activated platelets accumulate on top of the initial monolayer of platelets bound to collagen of the sub-endothelium [3]. Expressed receptors on each platelet allow binding of agonists such as ADP, thrombin, and thromboxane A2, which are released from activated platelets [31]. Consequently, more platelets are recruited to the site of injury, thereby consolidating the initial hemostatic plug. Binding of fibrin to aggregated platelets through activated receptor glycoprotein GPIIb/IIIa (integrin αIIbβ3) helps to further stabilize the hemostatic plug [32].

Several proteins are released during platelet aggregation at a damaged blood vessel surface [22]. Some are believed to be responsible for repair of damaged blood vessels and development of new ones. Although precise mechanisms are not well understood, it was suggested that platelets are necessary for formation of new blood vessels [33]. Supporting this are observations of reduced retinal neovascularization in a mouse hypoxia-induced retinal angiogenesis model due to thrombocytopenia or in response to treatment with inhibitors of platelet aggregation [33]. In this context, platelet granules are believed to contain pro- and anti-angiogenic compounds [34, 35]. Similarly, platelet interactions with cancer cells appear to play a role in the development of metastases and tumor angiogenesis [36]. While cerebrovascular remodeling is known to occur in the newborn in the first few postnatal weeks [37], the roles of platelets in this developmental process are not yet well described.

Platelets may also play a role in newborn's inflammatory processes and host defense. Neonates are generally believed to be at least partially immunologically incompetent and susceptible to a variety of infections. In this context, it is of interest that platelets have toll-like receptors (TLRs) that directly recognize and interact with a number of microorganisms or their products. Platelets may be responsible for killing microbes directly by phagocytosis, by release of microbicidal agents, or as sentinels communicating information about microbial encounters to cells of the innate immune system [15]. Bacterial infections, found in preterm newborns admitted to the neonatal intensive care unit (NICU), appear similar to infections found in adults with severe neutropenia [38]. This suggests reduced neutrophil functions in these babies. Neonates rely heavily on innate immunity for protection because their adaptive immunity is not yet fully developed [39]. Neutrophils are usually the first cells to be recruited to infection sites. They kill pathogens by various mechanisms

including (a) direct phagocytosis and chemical killing by degranulation and (b) by formation of neutrophil extracellular traps (NETs) [40]. Recent studies showed that platelet interactions with neutrophils are important for optimal neutrophil functions [41–44]. One such aspect of neutrophil function involves their chemotaxis and extravasation to sites of infection. Platelets were observed to act as "pathfinders" guiding neutrophils to infection sites, and platelet inhibition resulted in poor neutrophil chemotaxis [45, 46]. Interaction of platelets with leukocytes may induce inflammation. Understanding the role and mechanisms involved in platelet-leukocyte interactions in the newborn, particularly those born prematurely, could lead to development of more rational approaches to morbidities common to this group.

#### **3. Newborn platelets**

Thrombopoietin, a protein regulator of platelet synthesis and homeostasis [18], was detected in the fetal liver as early as the sixth week of gestation [18]. In turn, megakaryocytes, the precursor cells that form and release platelets into circulation, were detected in the liver and circulation at the eighth week [19]. The megakaryocyte numbers were observed to be, at least in part, inversely correlated to gestational age, so that healthy preterm newborns characteristically have higher levels, while levels in healthy full term newborns and adults are similar [47, 48]. Neonatal megakaryocyte progenitor cells are more sensitive and have higher proliferative potential in response to thrombopoietin compared to adult cells, and this sensitivity is even greater in preterm newborns [49]. However, neonatal megakaryocytes, tending to be smaller and with a lower ploidy than adult cells, produce fewer platelets per megakaryocyte [48, 50, 51]. Newborn and adult platelets are ultra-structurally similar [52, 53] and contain comparable membrane receptor glycoproteins (GPs) [54] and thromboxane receptors [55]. However, newborn platelets tend to include more immature forms, with the ability to form fewer pseudopods, fewer developed microtubular structures, and fewer α-granules [53]. Additionally, neonatal platelets have fewer adrenergic receptors [56]. Although they store comparably adult levels of ADP, ATP and serotonin in their dense granules, the overall dense granule release during platelet activation is lower in the newborn [57].

Platelet count is dependent on gestational age, increasing during fetal life, but usually reaches the expected adult range of 150,000 to 450,000/µL [58] from about 22 weeks of gestation [59]. The percentage of reticulated platelets, an indication of newly produced platelets, is higher in the newborn circulation [60], while the mean platelet volume (MPV), a measure of platelet size, tends to be comparable to adults.

Platelet adhesion to, and coverage of, sub-endothelial extracellular matrix is higher in the newborns than in adults [61, 62]. This is in spite of comparable collagen binding or platelet aggregation [61]. The enhanced neonatal platelet adhesion is believed to be mediated by the neonatal plasma von Willebrand factor (vWF) [61], which was reported to include unusually large multimers [63, 64]. Nevertheless, compared to full-term newborns, platelet adhesion tended to be lower in earlier gestational age neonates [62]. In part, these observations could help to explain how hemostatic function is usually maintained in full-term newborns, despite decreased intrinsic platelet activation, and why the preterm neonates are progressively decompensated the earlier their gestational age.

The phospholipid content and baseline exposure of platelet surface phosphatidylserine is comparable in adults and newborns [65, 66]. However, more platelet microparticles are generated and more phosphatidylserine molecules are exposed in the term and preterm platelets when thrombin or calcium ionophores were used as activators [67]. Microparticles or exposed phosphatidylserine is expected to induce a procoagulant state. Yet, the procoagulant activity, especially in the preterm newborn,

**57**

*Platelets in the Newborn*

*DOI: http://dx.doi.org/10.5772/intechopen.86715*

cord and peripheral blood is lower compared to adults [69].

is generally lower despite the higher levels of generated microparticles and exposed phosphatidylserine [67]. Supplementing neonatal plasma with coagulation factors improves its procoagulant activity so that it becomes comparable to adults. This implies that newborn platelets can often present adequate procoagulant surface, but the apparent poor activity may in part be due to a deficiency of humoral factors [68]. P-selectin expression, as an index of α-granule secretion, was reported lower in newborn platelets compared to adults, especially in the <30 week gestation group [69, 70]. Neonatal dense granule secretion, measured by secreted serotonin, was similar to that in adults when inositol triphosphate, 1-oleoyl-2-acetyl-glycerol, or thrombin was used as an agonist. Collagen-mediated stimulation, however, resulted in lower serotonin secretion in cord blood, although the number of dense granules in adults and neonates was found to be similar [57, 68]. GPIIb/IIIa receptors are expressed early during gestation. Yet, the fraction of active GPIIb/IIIa in neonatal

During the first few days of life, platelet activation appears to be less effective, as indicated by flow cytometric studies [69]. However, these activation profiles approach the adult patterns between the tenth and the fourteenth day of life [71]. Proposed explanations for this observed hypo-responsiveness include: relative deficiencies of phospholipid metabolism including thromboxane production, differential regulation of GPIIb/IIIa activation, impaired mobilization of calcium and intracellular signaling, impaired granule secretion, and lower aggregation [72]. These could result from lower intrinsic signal transduction in neonatal platelets [72]. Such effects are further enhanced by lower expression of protease-activated receptor-1 (PAR-1)

and PAR-4 [73, 74], which mediate thrombin-dependent platelet activation.

**4. Perinatal factors affecting platelet function in the newborn**

hours or days after the triggering condition is removed.

Various components of the hemostatic system in the fetus and neonate are qualitatively and quantitatively different from those in adults [8]. Such differences could be explained either by lower synthesis, higher clearance, or higher consumption [75, 76]. Although the hemostatic system is sometimes thought to be incomplete at birth [72], it nevertheless appears to be adequate for the majority of healthy full-term newborns.

Acquired platelet dysfunctions are common during the neonatal period especially in preterm newborns. These disorders are usually secondary to perinatal or neonatal conditions such as maternal and neonatal state of health, presence of infections, medications given to mother or to newborn, or interventions for the newborn (**Tables 1** and **2**). Platelet count and function are usually restored several

**4.1 Prenatal and maternal factors associated with neonatal platelet dysfunction**

There are several maternal factors that can impact neonatal platelet function especially during the days preceding delivery. These include maternal hypertensive

Hypertensive disorders of pregnancy are associated with platelet dysfunctions in the newborn. Pregnancy-induced hypertension (PIH) is a risk factor for early onset thrombocytopenia in the newborn [77]. This is especially true for babies born prior to 36 weeks of gestation [78, 79]. Neonatal platelet counts tend to be inversely correlated to maternal blood pressure [79]. These platelets also exhibited lower adhesion properties [80]. Babies with low birth weight, meconium aspiration, or infections are also at greater risk for thrombocytopenia [81, 82]. Flow cytometric analyses of platelets from premature newborns from preeclamptic mothers demonstrated lower expression of

disorders and prenatal use of aspirin, magnesium sulfate, or antibiotics.

#### *Platelets in the Newborn DOI: http://dx.doi.org/10.5772/intechopen.86715*

*Neonatal Medicine*

**3. Newborn platelets**

including (a) direct phagocytosis and chemical killing by degranulation and (b) by formation of neutrophil extracellular traps (NETs) [40]. Recent studies showed that platelet interactions with neutrophils are important for optimal neutrophil functions [41–44]. One such aspect of neutrophil function involves their chemotaxis and extravasation to sites of infection. Platelets were observed to act as "pathfinders" guiding neutrophils to infection sites, and platelet inhibition resulted in poor neutrophil chemotaxis [45, 46]. Interaction of platelets with leukocytes may induce inflammation. Understanding the role and mechanisms involved in platelet-leukocyte interactions in the newborn, particularly those born prematurely, could lead to development of more rational approaches to morbidities common to this group.

Thrombopoietin, a protein regulator of platelet synthesis and homeostasis [18], was detected in the fetal liver as early as the sixth week of gestation [18]. In turn, megakaryocytes, the precursor cells that form and release platelets into circulation, were detected in the liver and circulation at the eighth week [19]. The megakaryocyte numbers were observed to be, at least in part, inversely correlated to gestational age, so that healthy preterm newborns characteristically have higher levels, while levels in healthy full term newborns and adults are similar [47, 48]. Neonatal megakaryocyte progenitor cells are more sensitive and have higher proliferative potential in response to thrombopoietin compared to adult cells, and this sensitivity is even greater in preterm newborns [49]. However, neonatal megakaryocytes, tending to be smaller and with a lower ploidy than adult cells, produce fewer platelets per megakaryocyte [48, 50, 51]. Newborn and adult platelets are ultra-structurally similar [52, 53] and contain comparable membrane receptor glycoproteins (GPs) [54] and thromboxane receptors [55]. However, newborn platelets tend to include more immature forms, with the ability to form fewer pseudopods, fewer developed microtubular structures, and fewer α-granules [53]. Additionally, neonatal platelets have fewer adrenergic receptors [56]. Although they store comparably adult levels of ADP, ATP and serotonin in their dense granules, the overall dense granule release during platelet activation is lower in the newborn [57]. Platelet count is dependent on gestational age, increasing during fetal life, but usually reaches the expected adult range of 150,000 to 450,000/µL [58] from about 22 weeks of gestation [59]. The percentage of reticulated platelets, an indication of newly produced platelets, is higher in the newborn circulation [60], while the mean platelet

volume (MPV), a measure of platelet size, tends to be comparable to adults.

pensated the earlier their gestational age.

Platelet adhesion to, and coverage of, sub-endothelial extracellular matrix is higher in the newborns than in adults [61, 62]. This is in spite of comparable collagen binding or platelet aggregation [61]. The enhanced neonatal platelet adhesion is believed to be mediated by the neonatal plasma von Willebrand factor (vWF) [61], which was reported to include unusually large multimers [63, 64]. Nevertheless, compared to full-term newborns, platelet adhesion tended to be lower in earlier gestational age neonates [62]. In part, these observations could help to explain how hemostatic function is usually maintained in full-term newborns, despite decreased intrinsic platelet activation, and why the preterm neonates are progressively decom-

The phospholipid content and baseline exposure of platelet surface phosphatidylserine is comparable in adults and newborns [65, 66]. However, more platelet microparticles are generated and more phosphatidylserine molecules are exposed in the term and preterm platelets when thrombin or calcium ionophores were used as activators [67]. Microparticles or exposed phosphatidylserine is expected to induce a procoagulant state. Yet, the procoagulant activity, especially in the preterm newborn,

**56**

is generally lower despite the higher levels of generated microparticles and exposed phosphatidylserine [67]. Supplementing neonatal plasma with coagulation factors improves its procoagulant activity so that it becomes comparable to adults. This implies that newborn platelets can often present adequate procoagulant surface, but the apparent poor activity may in part be due to a deficiency of humoral factors [68].

P-selectin expression, as an index of α-granule secretion, was reported lower in newborn platelets compared to adults, especially in the <30 week gestation group [69, 70]. Neonatal dense granule secretion, measured by secreted serotonin, was similar to that in adults when inositol triphosphate, 1-oleoyl-2-acetyl-glycerol, or thrombin was used as an agonist. Collagen-mediated stimulation, however, resulted in lower serotonin secretion in cord blood, although the number of dense granules in adults and neonates was found to be similar [57, 68]. GPIIb/IIIa receptors are expressed early during gestation. Yet, the fraction of active GPIIb/IIIa in neonatal cord and peripheral blood is lower compared to adults [69].

During the first few days of life, platelet activation appears to be less effective, as indicated by flow cytometric studies [69]. However, these activation profiles approach the adult patterns between the tenth and the fourteenth day of life [71]. Proposed explanations for this observed hypo-responsiveness include: relative deficiencies of phospholipid metabolism including thromboxane production, differential regulation of GPIIb/IIIa activation, impaired mobilization of calcium and intracellular signaling, impaired granule secretion, and lower aggregation [72]. These could result from lower intrinsic signal transduction in neonatal platelets [72]. Such effects are further enhanced by lower expression of protease-activated receptor-1 (PAR-1) and PAR-4 [73, 74], which mediate thrombin-dependent platelet activation.

Various components of the hemostatic system in the fetus and neonate are qualitatively and quantitatively different from those in adults [8]. Such differences could be explained either by lower synthesis, higher clearance, or higher consumption [75, 76]. Although the hemostatic system is sometimes thought to be incomplete at birth [72], it nevertheless appears to be adequate for the majority of healthy full-term newborns.

#### **4. Perinatal factors affecting platelet function in the newborn**

Acquired platelet dysfunctions are common during the neonatal period especially in preterm newborns. These disorders are usually secondary to perinatal or neonatal conditions such as maternal and neonatal state of health, presence of infections, medications given to mother or to newborn, or interventions for the newborn (**Tables 1** and **2**). Platelet count and function are usually restored several hours or days after the triggering condition is removed.

#### **4.1 Prenatal and maternal factors associated with neonatal platelet dysfunction**

There are several maternal factors that can impact neonatal platelet function especially during the days preceding delivery. These include maternal hypertensive disorders and prenatal use of aspirin, magnesium sulfate, or antibiotics.

Hypertensive disorders of pregnancy are associated with platelet dysfunctions in the newborn. Pregnancy-induced hypertension (PIH) is a risk factor for early onset thrombocytopenia in the newborn [77]. This is especially true for babies born prior to 36 weeks of gestation [78, 79]. Neonatal platelet counts tend to be inversely correlated to maternal blood pressure [79]. These platelets also exhibited lower adhesion properties [80]. Babies with low birth weight, meconium aspiration, or infections are also at greater risk for thrombocytopenia [81, 82]. Flow cytometric analyses of platelets from premature newborns from preeclamptic mothers demonstrated lower expression of


#### **Table 1.**

*Maternal factors affecting platelets in the newborn.*


#### **Table 2.**

*Neonatal factors affecting platelets in the newborn.*

CD62P (P-selectin), CD63 (platelet activation marker), or CD36 (platelet glycoprotein IV (GPIV)) after thrombin stimulation, compared to full-term neonates [83]. However, when compared to other similar preterms, the expression of platelet CD62P and CD63 was relatively higher in newborns from preeclamptic mothers [84]. Additionally, this cohort was also characterized by lower platelet and megakaryocyte counts [84], implying possible disturbances in platelet production [85]. Infants born to hypertensive mothers tend to be hypoxic [86]. Animal model studies suggest that hypoxia tends to favor erythropoiesis over megakaryopoiesis, leading to lower platelet counts [87].

Low dose aspirin (LDA), about 60–100 mg, is sometimes given to pregnant women, who are at risk of developing a hypertensive disorder, or whose fetus has

**59**

*Platelets in the Newborn*

collagen stimulation [97].

antigen presenting cells) on their platelets [101].

closure time, but not with altered bleeding time [108].

**the newborn**

*DOI: http://dx.doi.org/10.5772/intechopen.86715*

intrauterine growth restriction [88, 89]. Aspirin inhibits cyclooxygenase, which catalyzes the initial steps in conversion of arachidonic acid to prostaglandins and thromboxanes [90]. Thromboxane A2 (TxA2) serves to amplify the signal during platelet activation [91]. Nevertheless, while some reports suggest that prenatal aspirin does not alter cord blood platelet count and aggregation [92] or thromboxane B2 (TxB2) inhibition [93], others challenge this with clear TxB2 differences in newborns of mothers exposed to LDA even several days after the medication was stopped [94]. This apparent contradiction may be resolved by taking into account the actual timing of LDA treatment prior to delivery. It was noted that newborn platelet dysfunction, including reduced collagen-stimulated platelet aggregation, is generally observable if the mother had aspirin within a week of delivery [95]. In this context, aspirin also increases the risk for mucocutaneous bleeding in the newborn,

especially if the mother took it within five days of delivery [72, 95].

While aspirin is perhaps the best described with respect to its potential to alter

platelet functions, it is not the only drug to do so. Indomethacin, given to the mother as a tocolytic, increased the risk of subsequent neonatal intraventricular hemorrhage (IVH) [96], presumably by affecting cerebral blood flow and by altering platelet and neutrophil functions. Similarly, platelets in newborns, from mothers receiving tocolytic magnesium sulfate, tended to be less effective in forming aggregates in response to ADP-mediated activation, but not so in response to

**4.2 Postnatal and neonatal factors associated with platelet dysfunction in** 

Neonatal infections tend to lead to platelet consumption. This is implied by the observed upregulation of thrombopoietin and elevated megakaryocyte progenitor cells in septic newborns [98]. Reduced platelet adhesion was also reported in such neonates [99]. However, enhanced granule secretion and aggregate formation in response to agonists during experimental conditions [100] suggest that these circulating platelets may already be to some extent primed and not in their resting state. Furthermore, neonates born following chorioamnionitis had significantly higher levels of soluble P-selectin and higher CD40L (CD40 ligand, able to bind CD40 protein on

Antibiotics are often used to treat infections and sepsis, and some of them could alter hemostatic responses. Prolonged template bleeding and PFA-100 closure times were correlated with duration and dosage of neonatal ampicillin treatment [102, 103]. Nonsteroidal anti-inflammatory drugs (NSAIDs) are known to affect platelet function in adults. Yet, they are sometimes given to newborns as a treatment for patent ductus arteriosus (PDA). Indomethacin is associated with prolonged bleeding time and gastrointestinal bleeding in preterm newborns [104]. These effects tend to last up to 48 h [105], but normal platelet values are restored about the tenth day [106]. Nevertheless, in preterm newborns with intracranial hemorrhage, indomethacin administration for treatment of PDA did not extend the hemorrhage [107]. In contrast, ibuprofen treatment is associated with prolonged PFA-100

Inhaled nitric oxide (NO) is used as a selective pulmonary vasodilator to treat hypoxemic respiratory failure or pulmonary hypertension in newborns (≥34 week gestation) [109]. Inhaled NO prolongs bleeding time in adults [110]. Persistent pulmonary hypertension and treatment with inhaled NO were reported to alter neonatal platelet thromboelastogram (TEG) values [109]. Bleeding time was also prolonged in such babies [111]. These clinical tests, however, returned to normal after about 24 h of stopping therapy. It is of interest that newborns receiving NO therapy did not

*Neonatal Medicine*

**58**

CD62P (P-selectin), CD63 (platelet activation marker), or CD36 (platelet glycoprotein IV (GPIV)) after thrombin stimulation, compared to full-term neonates [83]. However, when compared to other similar preterms, the expression of platelet CD62P and CD63 was relatively higher in newborns from preeclamptic mothers [84]. Additionally, this cohort was also characterized by lower platelet and megakaryocyte counts [84], implying possible disturbances in platelet production [85]. Infants born to hypertensive mothers tend to be hypoxic [86]. Animal model studies suggest that hypoxia tends to favor erythropoiesis over megakaryopoiesis, leading to lower platelet counts [87]. Low dose aspirin (LDA), about 60–100 mg, is sometimes given to pregnant women, who are at risk of developing a hypertensive disorder, or whose fetus has

**Neonatal factor Effect on newborn platelet**

Ibuprofen • Prolonged PFA-100 closure time [108]

**Factor Effect on newborn platelet**

Hypertension in mother • Reduced platelet adhesion and surface coverage [80] • Low platelet count [78, 79]

Magnesium sulfate (prenatal) • Reduced ADP-mediated platelet aggregation [97]

Low dose aspirin (prenatal) • Reduced platelet aggregation [95]

Nitric oxide • Abnormal thromboelastogram values [109]

Asphyxia and RDS • Reduced platelet count [113, 118, 120]

*RDS, respiratory distress syndrome; MPV, mean platelet volume; PDW, platelet distribution width.*

Mechanical ventilation • Reduced platelet count [121]

Extracorporeal membrane oxygenation

*Maternal factors affecting platelets in the newborn.*

*Neonatal factors affecting platelets in the newborn.*

(ECMO)

**Table 2.**

**Table 1.**

Therapeutic hypothermia • Abnormal thromboelastogram values, associated with bleeding [199]

• Prolonged prothrombin time [109] • Prolonged bleeding time [111]

• Decreased secretion and expression of CD62P, CD63, and CD36 [83]

• Increased expression of CD62P and CD63 [84] • Low platelet and megakaryocyte counts [84]

• No change in platelet count and aggregation [92, 93]

• Reduced prostacyclin and prostaglandin levels [104]

• Abnormal platelet aggregation up to 4 days after medication [106]

• Reduced thromboxane B2 production [94] Indomethacin • Prolonged bleeding time and gastrointestinal hemorrhage [104, 105]

• Reduced platelet count [123, 200]

• High MPV and PDW [113, 117] • Increased thrombopoietin level [118] • Increased thromboxane level [120]

• Reduced platelet count [125, 126] • Reduced platelet activation [126]

• Prolonged bleeding time and PFA 100 closure time [201]

intrauterine growth restriction [88, 89]. Aspirin inhibits cyclooxygenase, which catalyzes the initial steps in conversion of arachidonic acid to prostaglandins and thromboxanes [90]. Thromboxane A2 (TxA2) serves to amplify the signal during platelet activation [91]. Nevertheless, while some reports suggest that prenatal aspirin does not alter cord blood platelet count and aggregation [92] or thromboxane B2 (TxB2) inhibition [93], others challenge this with clear TxB2 differences in newborns of mothers exposed to LDA even several days after the medication was stopped [94]. This apparent contradiction may be resolved by taking into account the actual timing of LDA treatment prior to delivery. It was noted that newborn platelet dysfunction, including reduced collagen-stimulated platelet aggregation, is generally observable if the mother had aspirin within a week of delivery [95]. In this context, aspirin also increases the risk for mucocutaneous bleeding in the newborn, especially if the mother took it within five days of delivery [72, 95].

While aspirin is perhaps the best described with respect to its potential to alter platelet functions, it is not the only drug to do so. Indomethacin, given to the mother as a tocolytic, increased the risk of subsequent neonatal intraventricular hemorrhage (IVH) [96], presumably by affecting cerebral blood flow and by altering platelet and neutrophil functions. Similarly, platelets in newborns, from mothers receiving tocolytic magnesium sulfate, tended to be less effective in forming aggregates in response to ADP-mediated activation, but not so in response to collagen stimulation [97].

#### **4.2 Postnatal and neonatal factors associated with platelet dysfunction in the newborn**

Neonatal infections tend to lead to platelet consumption. This is implied by the observed upregulation of thrombopoietin and elevated megakaryocyte progenitor cells in septic newborns [98]. Reduced platelet adhesion was also reported in such neonates [99]. However, enhanced granule secretion and aggregate formation in response to agonists during experimental conditions [100] suggest that these circulating platelets may already be to some extent primed and not in their resting state. Furthermore, neonates born following chorioamnionitis had significantly higher levels of soluble P-selectin and higher CD40L (CD40 ligand, able to bind CD40 protein on antigen presenting cells) on their platelets [101].

Antibiotics are often used to treat infections and sepsis, and some of them could alter hemostatic responses. Prolonged template bleeding and PFA-100 closure times were correlated with duration and dosage of neonatal ampicillin treatment [102, 103].

Nonsteroidal anti-inflammatory drugs (NSAIDs) are known to affect platelet function in adults. Yet, they are sometimes given to newborns as a treatment for patent ductus arteriosus (PDA). Indomethacin is associated with prolonged bleeding time and gastrointestinal bleeding in preterm newborns [104]. These effects tend to last up to 48 h [105], but normal platelet values are restored about the tenth day [106]. Nevertheless, in preterm newborns with intracranial hemorrhage, indomethacin administration for treatment of PDA did not extend the hemorrhage [107]. In contrast, ibuprofen treatment is associated with prolonged PFA-100 closure time, but not with altered bleeding time [108].

Inhaled nitric oxide (NO) is used as a selective pulmonary vasodilator to treat hypoxemic respiratory failure or pulmonary hypertension in newborns (≥34 week gestation) [109]. Inhaled NO prolongs bleeding time in adults [110]. Persistent pulmonary hypertension and treatment with inhaled NO were reported to alter neonatal platelet thromboelastogram (TEG) values [109]. Bleeding time was also prolonged in such babies [111]. These clinical tests, however, returned to normal after about 24 h of stopping therapy. It is of interest that newborns receiving NO therapy did not

experience increased risk of intracranial hemorrhage [72]. Nitric oxide is known to inhibit platelet adhesion and aggregation by inhibiting GPIIb/IIIa activation [110]. A reduction in expressed P-selectin and activated GPIIb/IIIa on collagen-stimulated platelets was reported after NO treatment in adults and newborns [112].

Term newborns who were small for gestational age tended to have lower platelet counts but higher mean platelet volumes (MPVs) [113, 114]. A similar pattern was also observed in asphyxiated term newborns [113]. MPV is a measure of average platelet size [115] and may serve as a marker of platelet production, consumption, or severity of some disorder of bone marrow, thrombosis, or infection [116, 117]. For example, MPV was elevated in preterm newborns with respiratory distress [117], suggesting potential issues in platelet production, consumption, or both. Asphyxia is associated with upregulation of thrombopoietin concentration, which in turn is negatively correlated to platelet count up to the 7th day of life [118]. Thrombocytopenia, however, when associated with perinatal asphyxia, does not tend to resolve until about the 19th to 21st day of life [119]. Increased thromboxane levels in asphyxiated newborns [120] suggest platelet activation, and possibly consumption, as an explanation for the observed thrombocytopenia. Hypoxia leads to preferential upregulation of erythropoiesis over megakaryopoiesis [87, 114], consistent with elevated thrombopoietin observed [118].

Mechanical ventilation is generally used to resuscitate hypoxic or asphyxiated newborns. It was reported that mechanical ventilation led to reduced platelet counts in newborns with respiratory distress, or in rabbit models, regardless of the oxygen concentration used [121]. However, using newborn piglet models of hypoxia, it was found that various platelet indices were affected particularly by high oxygen level used [122]. Resuscitation with 100% oxygen led to enhanced collagen-stimulated platelet aggregation, while using 18–21% oxygen did not do so [122].

To prevent permanent brain damage following perinatal asphyxia, the newborns are sometimes treated with therapeutic hypothermia. The hypothermia treatment, in turn, led to decreased platelet counts, but had an overall protective effect by reducing risk of cerebral hemorrhage [123] and restoring other hemostatic parameters [124]. Similarly, extracorporeal membrane oxygenation (ECMO) is used to rescue term newborns with persistent pulmonary hypertension, asphyxia, or congenital diaphragmatic hernia [125]. Platelet counts and rates of activation were reduced during ECMO therapy, and were not fully restored with transfusion, until several hours post-ECMO [125, 126].

#### **5. Platelets and sepsis**

Sepsis is a complex syndrome characterized by disordered immune, endocrine, and metabolic responses to infection [127]. The exaggerated responses can lead to multi-organ failure (MOF), shock, and death [127]. Sepsis is generally considered if a documented or suspected infection is present with at least one additional finding (e.g., fever/hypothermia, elevated heart rate, and leukocytosis/leukopenia). In contrast to infection, however, sepsis is defined by additional evidence of organ dysfunction and a dysregulated host immune response [127], its key features. Notably, interactions between the innate immune system and the hemostatic system, including platelets and coagulation factors, were identified as principal steps in the pathogenesis of sepsis. Progressive thrombocytopenia and coagulopathy are strong negative prognostic findings in severe sepsis and have recently been included in the updated definition of the disease [127]. Platelets are able to release cytokines, recruit leukocytes, interact with bacteria and the endothelium, and contribute to formation of microthrombi [128]. These processes are adaptive and protective in the context of

**61**

*Platelets in the Newborn*

**Table 3.**

*DOI: http://dx.doi.org/10.5772/intechopen.86715*

platelets in the pathogenesis of multi-organ failure.

*MOF, multi-organ failure; ALI, acute lung injury; TPO, thrombopoietin.*

*Platelet-related biomarkers of sepsis severity in human studies.*

with its severity [133] (**Table 3**).

bacteria, like *S. aureus* [134].

particularly in the newborn.

**5.1 Conclusions**

a localized infection, but may become dysregulated and "maladaptive" during sepsis, contributing to organ damage [129]. A low platelet count is a well-known biomarker for disease severity. More recently, attention has been focused on the active role of

**Biomarker Association References** Thrombocytopenia Mortality [133] Impaired platelet function MOF, mortality [132, 133] Impaired platelet aggregation ALI [133] P-selectin MOF [133] Platelet-neutrophil aggregates Sepsis progression [132, 133] Immature platelet fraction MOF [133]

The correlation between thrombocytopenia and sepsis is well documented [130]. Platelet count below <50,000/μL is a strong negative prognostic marker in patients with sepsis and is thought to result from platelet activation and consumption [131, 132]. A number of platelet function markers were proposed as biomarkers for sepsis correlating

Moreover, platelets interact with neutrophils in the formation of NETs (neutrophil extracellular traps) resulting in the trapping and killing of pathogens [133]. They also play a central role in driving and modulating host inflammatory and immune responses, influencing directly the function of endothelial cells, neutrophils, and lymphocytes [134]. Platelets are the most numerous blood cells with immune function, able to interact with bacteria in several ways: (1) direct interaction between platelet glycoproteins and bacterial surface proteins, as occurs between GPIb and *S. sanguis* SrpA [134]; (2) indirect interactions, such as the interaction of platelet αIIbβ3 with fibrinogen to which the clumping factors of *S. aureus* bind [134]; and (3) upon activation, platelets release a series of factors which can modulate the immune response or have direct microbicidal effects. For example, released thrombin-induced platelet microbicidal protein (tPMP-1) can directly lyse

In addition to hemostasis, platelets actively participate in the innate immune defense system. Participating in the recognition of pathogens, signal transduction, or the release of cytokines/chemokines, they reveal a functional similarity with leucocytes in sepsis and septic shock. There is abundant evidence that platelets can influence key host responses to sepsis. Further studies are needed to address the effects of platelet transfusion or inhibition toward sepsis prevention and treatment

**6. Platelets in neonates with extracorporeal membrane oxygenation**

Extracorporeal membrane oxygenators are used to provide gas exchange in severe respiratory failure employing venovenous (VV) circuits or, increasingly, if associated with concurrent cardiac failure, veno-arterial (VA) circuits, while


#### **Table 3.**

*Neonatal Medicine*

experience increased risk of intracranial hemorrhage [72]. Nitric oxide is known to inhibit platelet adhesion and aggregation by inhibiting GPIIb/IIIa activation [110]. A reduction in expressed P-selectin and activated GPIIb/IIIa on collagen-stimulated

Term newborns who were small for gestational age tended to have lower platelet counts but higher mean platelet volumes (MPVs) [113, 114]. A similar pattern was also observed in asphyxiated term newborns [113]. MPV is a measure of average platelet size [115] and may serve as a marker of platelet production, consumption, or severity of some disorder of bone marrow, thrombosis, or infection [116, 117]. For example, MPV was elevated in preterm newborns with respiratory distress [117], suggesting potential issues in platelet production, consumption, or both. Asphyxia is associated with upregulation of thrombopoietin concentration, which in turn is negatively correlated to platelet count up to the 7th day of life [118]. Thrombocytopenia, however, when associated with perinatal asphyxia, does not tend to resolve until about the 19th to 21st day of life [119]. Increased thromboxane levels in asphyxiated newborns [120] suggest platelet activation, and possibly consumption, as an explanation for the observed thrombocytopenia. Hypoxia leads to preferential upregulation of erythropoiesis over megakaryopoiesis [87, 114],

Mechanical ventilation is generally used to resuscitate hypoxic or asphyxiated newborns. It was reported that mechanical ventilation led to reduced platelet counts in newborns with respiratory distress, or in rabbit models, regardless of the oxygen concentration used [121]. However, using newborn piglet models of hypoxia, it was found that various platelet indices were affected particularly by high oxygen level used [122]. Resuscitation with 100% oxygen led to enhanced collagen-stimulated

To prevent permanent brain damage following perinatal asphyxia, the newborns are sometimes treated with therapeutic hypothermia. The hypothermia treatment, in turn, led to decreased platelet counts, but had an overall protective effect by reducing risk of cerebral hemorrhage [123] and restoring other hemostatic parameters [124]. Similarly, extracorporeal membrane oxygenation (ECMO) is used to rescue term newborns with persistent pulmonary hypertension, asphyxia, or congenital diaphragmatic hernia [125]. Platelet counts and rates of activation were reduced during ECMO therapy, and were not fully restored with transfusion, until

Sepsis is a complex syndrome characterized by disordered immune, endocrine, and metabolic responses to infection [127]. The exaggerated responses can lead to multi-organ failure (MOF), shock, and death [127]. Sepsis is generally considered if a documented or suspected infection is present with at least one additional finding (e.g., fever/hypothermia, elevated heart rate, and leukocytosis/leukopenia). In contrast to infection, however, sepsis is defined by additional evidence of organ dysfunction and a dysregulated host immune response [127], its key features. Notably, interactions between the innate immune system and the hemostatic system, including platelets and coagulation factors, were identified as principal steps in the pathogenesis of sepsis. Progressive thrombocytopenia and coagulopathy are strong negative prognostic findings in severe sepsis and have recently been included in the updated definition of the disease [127]. Platelets are able to release cytokines, recruit leukocytes, interact with bacteria and the endothelium, and contribute to formation of microthrombi [128]. These processes are adaptive and protective in the context of

platelets was reported after NO treatment in adults and newborns [112].

consistent with elevated thrombopoietin observed [118].

several hours post-ECMO [125, 126].

**5. Platelets and sepsis**

platelet aggregation, while using 18–21% oxygen did not do so [122].

**60**

*Platelet-related biomarkers of sepsis severity in human studies.*

a localized infection, but may become dysregulated and "maladaptive" during sepsis, contributing to organ damage [129]. A low platelet count is a well-known biomarker for disease severity. More recently, attention has been focused on the active role of platelets in the pathogenesis of multi-organ failure.

The correlation between thrombocytopenia and sepsis is well documented [130]. Platelet count below <50,000/μL is a strong negative prognostic marker in patients with sepsis and is thought to result from platelet activation and consumption [131, 132]. A number of platelet function markers were proposed as biomarkers for sepsis correlating with its severity [133] (**Table 3**).

Moreover, platelets interact with neutrophils in the formation of NETs (neutrophil extracellular traps) resulting in the trapping and killing of pathogens [133]. They also play a central role in driving and modulating host inflammatory and immune responses, influencing directly the function of endothelial cells, neutrophils, and lymphocytes [134]. Platelets are the most numerous blood cells with immune function, able to interact with bacteria in several ways: (1) direct interaction between platelet glycoproteins and bacterial surface proteins, as occurs between GPIb and *S. sanguis* SrpA [134]; (2) indirect interactions, such as the interaction of platelet αIIbβ3 with fibrinogen to which the clumping factors of *S. aureus* bind [134]; and (3) upon activation, platelets release a series of factors which can modulate the immune response or have direct microbicidal effects. For example, released thrombin-induced platelet microbicidal protein (tPMP-1) can directly lyse bacteria, like *S. aureus* [134].

#### **5.1 Conclusions**

In addition to hemostasis, platelets actively participate in the innate immune defense system. Participating in the recognition of pathogens, signal transduction, or the release of cytokines/chemokines, they reveal a functional similarity with leucocytes in sepsis and septic shock. There is abundant evidence that platelets can influence key host responses to sepsis. Further studies are needed to address the effects of platelet transfusion or inhibition toward sepsis prevention and treatment particularly in the newborn.

#### **6. Platelets in neonates with extracorporeal membrane oxygenation**

Extracorporeal membrane oxygenators are used to provide gas exchange in severe respiratory failure employing venovenous (VV) circuits or, increasingly, if associated with concurrent cardiac failure, veno-arterial (VA) circuits, while

waiting for organ recovery to occur. Support by cardiopulmonary bypass (CPB) systems decreased the morbidity and mortality of children, especially those who require surgery for life-threatening anatomical heart defects [135, 136]. ECMO contributed to decreased mortality for children with severe cardiac or respiratory failure [137, 138]. While annually thousands of neonates are helped by ECMO support, thromboembolic complications also frequently occur [139]. Nevertheless, for many neonatal patients, survival is made possible only because of ECMO support [136]. ECMO is used to treat a variety of conditions in neonatal patients, including respiratory and cardiac failure as a result of persistent pulmonary hypertension (PPHN), congenital diaphragmatic hernia (CDH), meconium aspiration syndrome (MAS), respiratory distress syndrome (RDS), pneumonia, severe air-leak syndromes, or sepsis [140].

Both bleeding and clotting complications can occur during ECMO support, often coexist in the same patient, and are associated with significant morbidity and mortality [141]. Moreover, patients requiring ECMO are critically ill, thus making it difficult to distinguish the relative contributions of the underlying pathology from that of the ECMO circuit as such. Rates of reported ECMOassociated venous thromboembolism (VTE) in general population, ranging from 18 to 85% in various centers, may be at least partly dependent on anticoagulation regimens [141]. Severe hemorrhage is reported in nearly 40% and intracranial hemorrhage in 16–21% of patients [142, 143]. At the same time, there is broad variation in practice, without clear consensus, on the administration and monitoring of anticoagulation during ECMO, or the management of ECMO-related hemorrhage and VTE [144].

Activation of the coagulation system is initiated by the exposure of blood to foreign synthetic surfaces and by shear stresses of the circuit, especially from device pumps. The shift to a pro-coagulant state appears to be mediated primarily by thrombin, while an excessive fibrinolytic tendency is mediated by plasmin, resulting in a consumption of clotting factors, impaired platelet function, thrombocytopenia, and fibrinolysis [145]. Initial fibrinogen deposition and subsequent activation of coagulation and complement factors allow platelets and leukocytes to adhere to oxygenator surfaces further enhancing thrombin generation. Such changes contribute to higher rates of thrombosis in these patients [145]. Meanwhile, several of a series of processes contribute to higher bleeding rates. (a) Primary hemostasis is impaired because of platelet dysfunction and loss of key adhesive molecules. (b) Shear stress causes the development of an acquired von Willebrand defect. (c) Widespread fibrin deposits on surfaces trigger an enhanced fibrinolytic response. (d) Administration of systemic anticoagulation, required to maintain circuit patency, raises bleeding risks [146].

Balancing the relative risks of bleeding and thrombosis can be difficult. Factors related to patient's illness, the extracorporeal support, and the interplay between pro-inflammatory and anti-inflammatory processes vary among patients.

#### **6.1 Platelet dysfunction during ECMO**

If the ECMO circuit is primed only with crystalloid or RBCs and plasma, then dilutional coagulopathy and dilutional thrombocytopenia develop as the ECMO is initiated. Dilutional coagulopathy is generally not severe, but will complement the systemic anticoagulation. Dilutional thrombocytopenia, however, may further aggravate any preexisting thrombocytopenia or platelet dysfunction, frequently present in premature neonates. Accurate assessment of platelet function under these circumstances can be difficult, further complicating evaluation of patient's

**63**

coagulopathy [153].

**6.2 Platelet counts during ECMO**

*Platelets in the Newborn*

*DOI: http://dx.doi.org/10.5772/intechopen.86715*

bleeding or thrombotic potential. Impairment of platelets can occur as early as

and interact with activated components of the coagulation and complement systems [147]. Elevated shear flow from the ECMO circuit causes some platelet receptor shedding. Of particular interest are the losses of key platelet adhesion glycoproteins GPI and GPVI, and the associated reduction of high molecular weight vWF multimers. GPI serves as a receptor for vWF and GPVI as a receptor for collagen [126]. Adhesive proteins, vWF, and fibrinogen assist platelets to bind to damaged vessel wall surface and to other platelets [148]. As platelet thrombus is being formed, the prothrombinase enzyme complex assembles on the activated platelet surfaces to produce thrombin. In turn, thrombin cleaves fibrinogen to form fibrin, which spontaneously polymerizes to form the fibrin meshwork, which further strengthens the thrombus [149]. Consequently, shedding of GPI and loss of high molecular weight vWF lead to dysfunctional platelet responses to vascular injury. This persists despite platelet transfusion and throughout the period of ECMO use [126]. Subsequently, lower levels of platelet aggregation are observed by light aggregometry using various agonists including ADP, ristocetin, collagen, or epinephrine [150]. Such decreased potential for platelet aggregation may lead to increased bleeding risk particularly when combined with the effects of anticoagulants or antiplatelet agents. Flow cytometry of blood, from those receiving ECMO support, showed severely reduced membrane-bound P-selectin (CD62P) and

Platelets adhere to the protein-coated monolayer of the ECMO circuit surfaces

15 min after starting ECMO and last until it is discontinued [125].

CD63, both of which modulate platelet spreading [151].

Despite reduced aggregation and lower expression of key platelet adhesion and structural molecules, there is a time-dependent platelet activation marked by increased levels of circulating matrix metalloproteinase-2 (MMP-2) and soluble P-selectin [126]. This is not associated with significant activation of the endothelium [126], but may be due to the release of platelet granules [152]. Furthermore, this time-dependent platelet activation is also accompanied by platelet receptor shedding and the release of platelet microparticles (PMPs) [153]. These are small cell-derived particles, typically 0.1–1 μm in size, that are produced from activated platelets in situations of shear stress [154]. While these PMPs can present a prothrombotic surface, it is not clear whether they are a major contributor to the prothrombotic phenotype or to the pathogenesis of ECMO-associated

Thrombocytopenia is common in critically ill patients. A constant shear force,

caused by the ECMO pump, is implicated in acquired platelet dysfunctions. Appropriate anticoagulation is difficult to achieve during ECMO since severe thrombocytopenia of <50,000/μL may be present even prior to ECMO. This situation increases the practice of platelet transfusions [155]. Minimal target platelet counts vary from 25,000 to 100,000/μL between hospitals. However, if bleeding occurs or is expected, then target platelet counts are increased to 150,000/μL or higher, particularly if platelet dysfunction is suspected. As in any setting of thrombocytopenia, it is important to try and identify the cause and treat appropriately [156, 157]. Bleeding in critically ill patients with a platelet count of 30,000/μL is believed to be associated with additional disturbances of hemostasis [158]. Platelet transfusion is recommended in bleeding patients with either primary or secondary platelet abnormalities regardless of platelet counts [158]. Required thresholds for prophylactic platelet transfusions, however, are

#### *Platelets in the Newborn DOI: http://dx.doi.org/10.5772/intechopen.86715*

*Neonatal Medicine*

hemorrhage and VTE [144].

circuit patency, raises bleeding risks [146].

**6.1 Platelet dysfunction during ECMO**

waiting for organ recovery to occur. Support by cardiopulmonary bypass (CPB) systems decreased the morbidity and mortality of children, especially those who require surgery for life-threatening anatomical heart defects [135, 136]. ECMO contributed to decreased mortality for children with severe cardiac or respiratory failure [137, 138]. While annually thousands of neonates are helped by ECMO support, thromboembolic complications also frequently occur [139]. Nevertheless, for many neonatal patients, survival is made possible only because of ECMO support [136]. ECMO is used to treat a variety of conditions in neonatal patients, including respiratory and cardiac failure as a result of persistent pulmonary hypertension (PPHN), congenital diaphragmatic hernia (CDH), meconium aspiration syndrome (MAS), respiratory distress syndrome (RDS),

Both bleeding and clotting complications can occur during ECMO support, often coexist in the same patient, and are associated with significant morbidity and mortality [141]. Moreover, patients requiring ECMO are critically ill, thus making it difficult to distinguish the relative contributions of the underlying pathology from that of the ECMO circuit as such. Rates of reported ECMOassociated venous thromboembolism (VTE) in general population, ranging from 18 to 85% in various centers, may be at least partly dependent on anticoagulation regimens [141]. Severe hemorrhage is reported in nearly 40% and intracranial hemorrhage in 16–21% of patients [142, 143]. At the same time, there is broad variation in practice, without clear consensus, on the administration and monitoring of anticoagulation during ECMO, or the management of ECMO-related

Activation of the coagulation system is initiated by the exposure of blood to foreign synthetic surfaces and by shear stresses of the circuit, especially from device pumps. The shift to a pro-coagulant state appears to be mediated primarily by thrombin, while an excessive fibrinolytic tendency is mediated by plasmin, resulting in a consumption of clotting factors, impaired platelet function, thrombocytopenia, and fibrinolysis [145]. Initial fibrinogen deposition and subsequent activation of coagulation and complement factors allow platelets and leukocytes to adhere to oxygenator surfaces further enhancing thrombin generation. Such changes contribute to higher rates of thrombosis in these patients [145]. Meanwhile, several of a series of processes contribute to higher bleeding rates. (a) Primary hemostasis is impaired because of platelet dysfunction and loss of key adhesive molecules. (b) Shear stress causes the development of an acquired von Willebrand defect. (c) Widespread fibrin deposits on surfaces trigger an enhanced fibrinolytic response. (d) Administration of systemic anticoagulation, required to maintain

Balancing the relative risks of bleeding and thrombosis can be difficult. Factors related to patient's illness, the extracorporeal support, and the interplay between

If the ECMO circuit is primed only with crystalloid or RBCs and plasma, then dilutional coagulopathy and dilutional thrombocytopenia develop as the ECMO is initiated. Dilutional coagulopathy is generally not severe, but will complement the systemic anticoagulation. Dilutional thrombocytopenia, however, may further aggravate any preexisting thrombocytopenia or platelet dysfunction, frequently present in premature neonates. Accurate assessment of platelet function under these circumstances can be difficult, further complicating evaluation of patient's

pro-inflammatory and anti-inflammatory processes vary among patients.

pneumonia, severe air-leak syndromes, or sepsis [140].

**62**

bleeding or thrombotic potential. Impairment of platelets can occur as early as 15 min after starting ECMO and last until it is discontinued [125].

Platelets adhere to the protein-coated monolayer of the ECMO circuit surfaces and interact with activated components of the coagulation and complement systems [147]. Elevated shear flow from the ECMO circuit causes some platelet receptor shedding. Of particular interest are the losses of key platelet adhesion glycoproteins GPI and GPVI, and the associated reduction of high molecular weight vWF multimers. GPI serves as a receptor for vWF and GPVI as a receptor for collagen [126]. Adhesive proteins, vWF, and fibrinogen assist platelets to bind to damaged vessel wall surface and to other platelets [148]. As platelet thrombus is being formed, the prothrombinase enzyme complex assembles on the activated platelet surfaces to produce thrombin. In turn, thrombin cleaves fibrinogen to form fibrin, which spontaneously polymerizes to form the fibrin meshwork, which further strengthens the thrombus [149]. Consequently, shedding of GPI and loss of high molecular weight vWF lead to dysfunctional platelet responses to vascular injury. This persists despite platelet transfusion and throughout the period of ECMO use [126]. Subsequently, lower levels of platelet aggregation are observed by light aggregometry using various agonists including ADP, ristocetin, collagen, or epinephrine [150]. Such decreased potential for platelet aggregation may lead to increased bleeding risk particularly when combined with the effects of anticoagulants or antiplatelet agents. Flow cytometry of blood, from those receiving ECMO support, showed severely reduced membrane-bound P-selectin (CD62P) and CD63, both of which modulate platelet spreading [151].

Despite reduced aggregation and lower expression of key platelet adhesion and structural molecules, there is a time-dependent platelet activation marked by increased levels of circulating matrix metalloproteinase-2 (MMP-2) and soluble P-selectin [126]. This is not associated with significant activation of the endothelium [126], but may be due to the release of platelet granules [152]. Furthermore, this time-dependent platelet activation is also accompanied by platelet receptor shedding and the release of platelet microparticles (PMPs) [153]. These are small cell-derived particles, typically 0.1–1 μm in size, that are produced from activated platelets in situations of shear stress [154]. While these PMPs can present a prothrombotic surface, it is not clear whether they are a major contributor to the prothrombotic phenotype or to the pathogenesis of ECMO-associated coagulopathy [153].

#### **6.2 Platelet counts during ECMO**

Thrombocytopenia is common in critically ill patients. A constant shear force, caused by the ECMO pump, is implicated in acquired platelet dysfunctions. Appropriate anticoagulation is difficult to achieve during ECMO since severe thrombocytopenia of <50,000/μL may be present even prior to ECMO. This situation increases the practice of platelet transfusions [155]. Minimal target platelet counts vary from 25,000 to 100,000/μL between hospitals. However, if bleeding occurs or is expected, then target platelet counts are increased to 150,000/μL or higher, particularly if platelet dysfunction is suspected. As in any setting of thrombocytopenia, it is important to try and identify the cause and treat appropriately [156, 157]. Bleeding in critically ill patients with a platelet count of 30,000/μL is believed to be associated with additional disturbances of hemostasis [158]. Platelet transfusion is recommended in bleeding patients with either primary or secondary platelet abnormalities regardless of platelet counts [158]. Required thresholds for prophylactic platelet transfusions, however, are

generally at platelet levels above 20,000/μL, given the requirements of invasive procedures and potential bleeding risk [158]. Many centers describe targeting a platelet count of >100,000/µL during an ECMO [159]. Research to support this practice, however, is lacking and urgently needed.

#### **6.3 Anticoagulation during ECMO**

Unfractionated heparin is the most widely used anticoagulant during ECMO [160]. Heparin levels tend to be monitored primarily indirectly by activated clotting time (ACT) [159]. While there are a number of devices that promise to describe certain characteristics of platelet function, it is not yet clear to what extent the data produced by them actually reflect the physiological platelet interactions and roles. Viscoelastic tests using rotational thromboelastometry (ROTEM) assess whole blood coagulation, and thus provide information on the dynamics of clot development, stabilization, and dissolution. Several reports suggest that ROTEMguided coagulation management could reduce bleeding episodes in ECMO patients [160, 161]. Similarly, whole blood platelet aggregometry using the Multiplate (Roche Diagnostics, Munich, Germany) demonstrated decreased platelet aggregation in ECMO patients [161].

Other intravenous anticoagulants, such as bivalirudin and argatroban, are used increasingly, particularly if heparin-induced thrombocytopenia (HIT), heparin resistance, or allergy is suspected [162, 163]. At present, there is no clear consensus on administration and monitoring of anticoagulation during ECMO or on management of ECMO-related hemorrhage and VTE [164]. The current aim of anticoagulation is to reduce thrombin generation. This, however, increases the risk of hemorrhage. The ideal therapeutic agent, which would reduce thrombotic risk without increasing the risk of bleeding, remains elusive.

#### **6.4 Heparin-induced thrombocytopenia**

Heparin-induced thrombocytopenia (HIT) is an immune-mediated coagulation side effect of heparin therapy characterized by a prothrombotic state mediated by platelets, leukocytes, and antibodies against complexes of platelet factor 4 (PF4) with long chain heparins [165]. Rapid platelet consumption leads to thrombocytopenia. HIT was considered to be very rare in the pediatric population. However, more recent reports indicate that it occurs in children receiving unfractionated heparin therapy with an incidence similar to that seen in adults [166]. The highest incidence of pediatric HIT was found in pediatric intensive care units supporting patients following cardiac surgery [167].

At least 70 cases of reported HIT were documented in pediatric patients [168], with the majority occurring during care following cardiac surgery. HIT in children was reported to occur in all age groups, but with a bimodal distribution. The higher incidences occur a) early in life, between 0–2, and b) during puberty, between 11–17 years of age [168, 169]. The balance between the risk of procoagulant and thromboembolic events on one hand and the risk of severe, sometimes fatal, bleeding on the other hand can be very challenging in ECMO patients with HIT. Pollak et al. reported a case of HIT with evidence of small vessel arterial thrombosis in a 5-dayold newborn receiving ECMO for congenital diaphragmatic hernia. It was assumed that the leading cause of death in this patient was massive disseminated intravascular coagulation. In this case, however, it is more likely that repeated platelet transfusions proved fatal and, retrospectively speaking, should have been avoided [170]. Although HIT is a recognizable and treatable complication, its relative infrequency increases the risk for delayed diagnosis leading to significant morbidity.

**65**

hemorrhagic events [184].

*Platelets in the Newborn*

danaparoid) [162, 174].

management in this cohort.

**7. Platelet transfusions in neonates**

**6.5 Conclusions**

*DOI: http://dx.doi.org/10.5772/intechopen.86715*

Diagnostic studies for HIT tend to be unreliable. Therefore, early intervention using alternative anticoagulants is a crucial step when HIT is suspected. This can hopefully lead to improved outcomes in these patients. Treatment of confirmed or suspected HIT in patients on ECMO includes removing unfractionated heparin, and possibly the entire ECMO circuit. Certain modern ECMO circuit components are heparin bonded in an effort to reduce immune reactivity to foreign surfaces [171–173]. If platelet recovery does not occur after withdrawal of heparin, it is possible that ongoing exposure to heparin bonding may be a factor [173]. Options for alternative anticoagulation if HIT is suspected include direct thrombin inhibitors (argatroban and bivalirudin) as well as short heparinoids (fondaparinux and

The predominant challenge for the clinician caring for a patient on ECMO is making an informed assessment of bleeding and clotting risks. The goal is to minimize bleeding and transfusion requirements while avoiding formation of micro or macro thrombi either in the circuit or within the patient's cardiovascular system [175]. Assessment of the patient's hemostasis includes consideration of the pathophysiology, type and severity of organ failure, and extent of tissue trauma during cannulation. A holistic approach to hemostatic management is needed to balance all these factors. ROTEM and whole blood platelet aggregometry provide rapid information on whole blood coagulation, and may be helpful in providing blood product support, factor replacement, anti-coagulation therapy and anti-fibrinolytics. Further research using ROTEM and whole blood platelet aggregometry in ECMO patients is needed to demonstrate efficacy in support of real-time hemostatic

Transfusion of blood products in neonates is not an uncommon practice in neonatal intensive care units. Extremely premature neonates (<28 week gestation) or extremely low birth weight (ELBW) infants (<1000 g) receive at least one packed red blood cell (pRBC) transfusion per hospital admission [176]. Platelet transfusions are also quite prevalent in ELBW infants, occurring in up to 90% of those weighing less than 750 g [177]. Unfortunately, while platelet transfusions for thrombocytopenia may be helpful, they are not without risk. Further, because the guidelines for transfusion thresholds in neonates are not based on a well-developed body of evidence, there is considerable variability in circumstances for such trans-

Thrombocytopenia is defined by a platelet count of less than 150,000/μL,

and is further sub-classified as mild (100,000–149,000/µL), moderate (50,000–99,000/µL), or severe (<50,000/μL) [178]. The reference values for very low birth weight (VLBW) babies (<1500 g), however, remain controversial [179]. Thrombocytopenia affects 18–35% of all neonates in the neonatal intensive care unit [180, 181] and up to 73% of ELBW infants [182]. While clinical significance of platelet counts between 100,000 and 150,000/µL is debatable, it is well known that platelet counts below 20,000/µL are associated with increased risk of hemorrhage, at least in the adult population [183]. The relationship between thrombocytopenia and hemorrhage, however, remains one of the associations. It is not clear that neonatal thrombocytopenia directly causes

fusions, and in particular clinical scenarios triggering them.

#### *Platelets in the Newborn DOI: http://dx.doi.org/10.5772/intechopen.86715*

Diagnostic studies for HIT tend to be unreliable. Therefore, early intervention using alternative anticoagulants is a crucial step when HIT is suspected. This can hopefully lead to improved outcomes in these patients. Treatment of confirmed or suspected HIT in patients on ECMO includes removing unfractionated heparin, and possibly the entire ECMO circuit. Certain modern ECMO circuit components are heparin bonded in an effort to reduce immune reactivity to foreign surfaces [171–173]. If platelet recovery does not occur after withdrawal of heparin, it is possible that ongoing exposure to heparin bonding may be a factor [173]. Options for alternative anticoagulation if HIT is suspected include direct thrombin inhibitors (argatroban and bivalirudin) as well as short heparinoids (fondaparinux and danaparoid) [162, 174].

#### **6.5 Conclusions**

*Neonatal Medicine*

generally at platelet levels above 20,000/μL, given the requirements of invasive procedures and potential bleeding risk [158]. Many centers describe targeting a platelet count of >100,000/µL during an ECMO [159]. Research to support this

Unfractionated heparin is the most widely used anticoagulant during ECMO

Other intravenous anticoagulants, such as bivalirudin and argatroban, are used increasingly, particularly if heparin-induced thrombocytopenia (HIT), heparin resistance, or allergy is suspected [162, 163]. At present, there is no clear consensus on administration and monitoring of anticoagulation during ECMO or on management of ECMO-related hemorrhage and VTE [164]. The current aim of anticoagulation is to reduce thrombin generation. This, however, increases the risk of hemorrhage. The ideal therapeutic agent, which would reduce thrombotic risk

Heparin-induced thrombocytopenia (HIT) is an immune-mediated coagulation side effect of heparin therapy characterized by a prothrombotic state mediated by platelets, leukocytes, and antibodies against complexes of platelet factor 4 (PF4) with long chain heparins [165]. Rapid platelet consumption leads to thrombocytopenia. HIT was considered to be very rare in the pediatric population. However, more recent reports indicate that it occurs in children receiving unfractionated heparin therapy with an incidence similar to that seen in adults [166]. The highest incidence of pediatric HIT was found in pediatric intensive care units supporting patients following

At least 70 cases of reported HIT were documented in pediatric patients [168], with the majority occurring during care following cardiac surgery. HIT in children was reported to occur in all age groups, but with a bimodal distribution. The higher incidences occur a) early in life, between 0–2, and b) during puberty, between 11–17 years of age [168, 169]. The balance between the risk of procoagulant and thromboembolic events on one hand and the risk of severe, sometimes fatal, bleeding on the other hand can be very challenging in ECMO patients with HIT. Pollak et al. reported a case of HIT with evidence of small vessel arterial thrombosis in a 5-dayold newborn receiving ECMO for congenital diaphragmatic hernia. It was assumed that the leading cause of death in this patient was massive disseminated intravascular coagulation. In this case, however, it is more likely that repeated platelet transfusions proved fatal and, retrospectively speaking, should have been avoided [170]. Although HIT is a recognizable and treatable complication, its relative infrequency

increases the risk for delayed diagnosis leading to significant morbidity.

[160]. Heparin levels tend to be monitored primarily indirectly by activated clotting time (ACT) [159]. While there are a number of devices that promise to describe certain characteristics of platelet function, it is not yet clear to what extent the data produced by them actually reflect the physiological platelet interactions and roles. Viscoelastic tests using rotational thromboelastometry (ROTEM) assess whole blood coagulation, and thus provide information on the dynamics of clot development, stabilization, and dissolution. Several reports suggest that ROTEMguided coagulation management could reduce bleeding episodes in ECMO patients [160, 161]. Similarly, whole blood platelet aggregometry using the Multiplate (Roche Diagnostics, Munich, Germany) demonstrated decreased platelet aggrega-

practice, however, is lacking and urgently needed.

without increasing the risk of bleeding, remains elusive.

**6.4 Heparin-induced thrombocytopenia**

**6.3 Anticoagulation during ECMO**

tion in ECMO patients [161].

cardiac surgery [167].

**64**

The predominant challenge for the clinician caring for a patient on ECMO is making an informed assessment of bleeding and clotting risks. The goal is to minimize bleeding and transfusion requirements while avoiding formation of micro or macro thrombi either in the circuit or within the patient's cardiovascular system [175]. Assessment of the patient's hemostasis includes consideration of the pathophysiology, type and severity of organ failure, and extent of tissue trauma during cannulation. A holistic approach to hemostatic management is needed to balance all these factors. ROTEM and whole blood platelet aggregometry provide rapid information on whole blood coagulation, and may be helpful in providing blood product support, factor replacement, anti-coagulation therapy and anti-fibrinolytics. Further research using ROTEM and whole blood platelet aggregometry in ECMO patients is needed to demonstrate efficacy in support of real-time hemostatic management in this cohort.

#### **7. Platelet transfusions in neonates**

Transfusion of blood products in neonates is not an uncommon practice in neonatal intensive care units. Extremely premature neonates (<28 week gestation) or extremely low birth weight (ELBW) infants (<1000 g) receive at least one packed red blood cell (pRBC) transfusion per hospital admission [176]. Platelet transfusions are also quite prevalent in ELBW infants, occurring in up to 90% of those weighing less than 750 g [177]. Unfortunately, while platelet transfusions for thrombocytopenia may be helpful, they are not without risk. Further, because the guidelines for transfusion thresholds in neonates are not based on a well-developed body of evidence, there is considerable variability in circumstances for such transfusions, and in particular clinical scenarios triggering them.

Thrombocytopenia is defined by a platelet count of less than 150,000/μL, and is further sub-classified as mild (100,000–149,000/µL), moderate (50,000–99,000/µL), or severe (<50,000/μL) [178]. The reference values for very low birth weight (VLBW) babies (<1500 g), however, remain controversial [179]. Thrombocytopenia affects 18–35% of all neonates in the neonatal intensive care unit [180, 181] and up to 73% of ELBW infants [182]. While clinical significance of platelet counts between 100,000 and 150,000/µL is debatable, it is well known that platelet counts below 20,000/µL are associated with increased risk of hemorrhage, at least in the adult population [183]. The relationship between thrombocytopenia and hemorrhage, however, remains one of the associations. It is not clear that neonatal thrombocytopenia directly causes hemorrhagic events [184].

Thrombocytopenia may be described by time of onset, where early onset (occurring in the first 72 h of life) is distinguished from late onset (occurring after the first 72 h of life) [179, 184]. In the premature population, the early onset thrombocytopenia is most often mild to moderate, develops gradually, and tends to be related to causes of chronic fetal hypoxia, as seen with intra-uterine growth restriction (IUGR), pregnancy-induced hypertension (PIH), hemolysis, elevated liver enzymes and low platelet count (HELLP) syndrome, or preeclampsia [185]. In term neonates, however, platelet destruction tends to be antibody-mediated [184]. In contrast to early onset, late onset thrombocytopenia tends to be more severe, more acute, and most frequently associated with infections (NEC, sepsis, and viral infections) [184].

#### **7.1 Indications for platelet transfusion**

Due to limited understanding of neonatal platelet functions, transfusion practice in the newborn is generally extrapolated from what is recognized as beneficial within the pediatric and adult populations. However, neonates are vulnerable to particular illnesses with varying underlying disease processes. Moreover, they tend to have developmental differences in regulation of primary hemostasis [178]. Nevertheless, platelet transfusions are typically given in two distinct clinical scenarios: (a) acutely, as a life-saving procedure and (b) prophylactically, under the presumption that they diminish the risk for hemorrhage. Surprisingly, an overwhelming majority of neonatal transfusions are done prophylactically, accounting for 98% of platelet transfusions [59]. Yet, it is not clear that this practice is beneficial. Prophylactic platelet transfusion in clinically stable neonates with no active bleeding remains controversial at best [186], consistent with the wide range of national and international clinical practices by neonatologists [177]. In this context, the severity of thrombocytopenia does not correlate with increased risk of intraventricular hemorrhage (IVH), and platelet transfusion for mild to moderate thrombocytopenia does not appear to prevent or reduce the incidence of intracranial hemorrhage [183, 187].

Although adequate quantities of platelets are necessary for hemostasis, increased risk of hemorrhage appears to be dependent on factors other than thrombocytopenia alone. Additional relevant platelet parameters include functional competency, immature platelet fraction, and developmental differences in neonatal thrombopoiesis [49, 188, 189]. Underlying clinical conditions associated with increased risk of hemorrhage include: preterm premature rupture of membranes, low birth weight, sepsis, shock, pulmonary hypertension, respiratory distress, NEC, and premature gestational age [182, 190–192]. Thus, recommendations to transfuse platelets should not be solely based on thrombocytopenia, but also on the presence of such other contributory factors [178, 190]. In spite of such considerations, it appears that management of thrombocytopenia in the newborn still lacks adequately rigorous scientific basis [179].

#### **7.2 Clinical guidelines for platelet transfusion in neonates**

In the United States, there are currently no national guidelines for neonatal platelet transfusion and only two published randomized controlled trials assessing prophylactic transfusions [183, 193]. Most countries recommend therapeutic transfusion in actively bleeding neonates when platelets fall below 50,000/μL. However, there is no agreement regarding prophylactic transfusions when platelets are anywhere between 20,000 and 90,000/μL [184, 194, 195]. A wide range of thrombocytopenia thresholds are employed, tending to be markedly higher in the United States, between 50,000 and 149,000/µL [187, 196, 197]. Nonetheless, such trends are based on clinical experience and judgment, rather than on reliable and consistent data.

**67**

*Platelets in the Newborn*

**8. Conclusions**

**Acknowledgements**

**Conflict of interest**

*DOI: http://dx.doi.org/10.5772/intechopen.86715*

**7.3 Adverse outcomes of platelet transfusions**

topenia transfusion thresholds from 50,000 to 25,000/μL [193].

improving the standard of care, intervention, and therapy.

This work was supported in part by NIH grant R01 NR011209-08.

The authors declare that they have no conflict of interest.

A growing number of adverse effects of platelet transfusions are being documented, including but not limited to increased risk of infection, transfusion-related injuries in various organs, alloimmunization, hemolytic reactions, febrile reactions, allergic reactions, anaphylaxis, and NEC [177, 185]. Randomized controlled trials comparing thresholds for platelet transfusion in thrombocytopenic neonates concluded that the frequency of IVH is not reduced by more aggressive thresholds [183]. Additionally, platelet transfusions, themselves, are implicated in increased mortality, linking the number of transfusions with death rate [198]. This was further supported by a recent large, multicenter, randomized clinical trial suggesting that significant hemorrhage and death could be prevented by lowering thrombocy-

Platelets are best known for their role in hemostasis. But beyond forming a platelet plug, they are also important in several processes such as recognition and elimination of invading microorganisms, inflammation and interaction with leukocytes, wound healing and tissue repair, angiogenesis, and even tumor growth. These are emerging areas of investigation and there is little to no information on the roles of platelets in such processes in the newborn. Although current understanding suggests that newborn platelets may be somewhat different from adult platelets, they nonetheless protect the healthy newborn adequately. Certain perinatal factors were identified to affect platelet counts and function, but the platelet dysfunctions induced by them are acquired and transitory in nature. Premature neonates are likely at greatest risk for reduced platelet counts and functions, and by extension, at greatest risk of hemorrhage, particularly if prematurity is in combination with antenatal infections or postnatal respiratory disorders. There is, however, still a lot that is not known about platelets in the newborn. Such information is critical to

#### **7.3 Adverse outcomes of platelet transfusions**

A growing number of adverse effects of platelet transfusions are being documented, including but not limited to increased risk of infection, transfusion-related injuries in various organs, alloimmunization, hemolytic reactions, febrile reactions, allergic reactions, anaphylaxis, and NEC [177, 185]. Randomized controlled trials comparing thresholds for platelet transfusion in thrombocytopenic neonates concluded that the frequency of IVH is not reduced by more aggressive thresholds [183]. Additionally, platelet transfusions, themselves, are implicated in increased mortality, linking the number of transfusions with death rate [198]. This was further supported by a recent large, multicenter, randomized clinical trial suggesting that significant hemorrhage and death could be prevented by lowering thrombocytopenia transfusion thresholds from 50,000 to 25,000/μL [193].

### **8. Conclusions**

*Neonatal Medicine*

**7.1 Indications for platelet transfusion**

adequately rigorous scientific basis [179].

**7.2 Clinical guidelines for platelet transfusion in neonates**

Thrombocytopenia may be described by time of onset, where early onset (occurring in the first 72 h of life) is distinguished from late onset (occurring after the first 72 h of life) [179, 184]. In the premature population, the early onset thrombocytopenia is most often mild to moderate, develops gradually, and tends to be related to causes of chronic fetal hypoxia, as seen with intra-uterine growth restriction (IUGR), pregnancy-induced hypertension (PIH), hemolysis, elevated liver enzymes and low platelet count (HELLP) syndrome, or preeclampsia [185]. In term neonates, however, platelet destruction tends to be antibody-mediated [184]. In contrast to early onset, late onset thrombocytopenia tends to be more severe, more acute, and most frequently associated with infections (NEC, sepsis, and viral infections) [184].

Due to limited understanding of neonatal platelet functions, transfusion practice in the newborn is generally extrapolated from what is recognized as beneficial within the pediatric and adult populations. However, neonates are vulnerable to particular illnesses with varying underlying disease processes. Moreover, they tend to have developmental differences in regulation of primary hemostasis [178]. Nevertheless, platelet transfusions are typically given in two distinct clinical scenarios: (a) acutely, as a life-saving procedure and (b) prophylactically, under the presumption that they diminish the risk for hemorrhage. Surprisingly, an overwhelming majority of neonatal transfusions are done prophylactically, accounting for 98% of platelet transfusions [59]. Yet, it is not clear that this practice is beneficial. Prophylactic platelet transfusion in clinically stable neonates with no active bleeding remains controversial at best [186], consistent with the wide range of national and international clinical practices by neonatologists [177]. In this context, the severity of thrombocytopenia does not correlate with increased risk of intraventricular hemorrhage (IVH), and platelet transfusion for mild to moderate thrombocytopenia does not appear to

prevent or reduce the incidence of intracranial hemorrhage [183, 187].

Although adequate quantities of platelets are necessary for hemostasis, increased risk of hemorrhage appears to be dependent on factors other than thrombocytopenia alone. Additional relevant platelet parameters include functional competency, immature platelet fraction, and developmental differences in neonatal thrombopoiesis [49, 188, 189]. Underlying clinical conditions associated with increased risk of hemorrhage include: preterm premature rupture of membranes, low birth weight, sepsis, shock, pulmonary hypertension, respiratory distress, NEC, and premature gestational age [182, 190–192]. Thus, recommendations to transfuse platelets should not be solely based on thrombocytopenia, but also on the presence of such other contributory factors [178, 190]. In spite of such considerations, it appears that management of thrombocytopenia in the newborn still lacks

In the United States, there are currently no national guidelines for neonatal platelet transfusion and only two published randomized controlled trials assessing prophylactic transfusions [183, 193]. Most countries recommend therapeutic transfusion in actively bleeding neonates when platelets fall below 50,000/μL. However, there is no agreement regarding prophylactic transfusions when platelets are anywhere between 20,000 and 90,000/μL [184, 194, 195]. A wide range of thrombocytopenia thresholds are employed, tending to be markedly higher in the United States, between 50,000 and 149,000/µL [187, 196, 197]. Nonetheless, such trends are based on clinical experience and judgment, rather than on reliable and consistent data.

**66**

Platelets are best known for their role in hemostasis. But beyond forming a platelet plug, they are also important in several processes such as recognition and elimination of invading microorganisms, inflammation and interaction with leukocytes, wound healing and tissue repair, angiogenesis, and even tumor growth. These are emerging areas of investigation and there is little to no information on the roles of platelets in such processes in the newborn. Although current understanding suggests that newborn platelets may be somewhat different from adult platelets, they nonetheless protect the healthy newborn adequately. Certain perinatal factors were identified to affect platelet counts and function, but the platelet dysfunctions induced by them are acquired and transitory in nature. Premature neonates are likely at greatest risk for reduced platelet counts and functions, and by extension, at greatest risk of hemorrhage, particularly if prematurity is in combination with antenatal infections or postnatal respiratory disorders. There is, however, still a lot that is not known about platelets in the newborn. Such information is critical to improving the standard of care, intervention, and therapy.

### **Acknowledgements**

This work was supported in part by NIH grant R01 NR011209-08.

### **Conflict of interest**

The authors declare that they have no conflict of interest.

### **Author details**

Ijeoma Esiaba1,2, Iman Mousselli3 , Giulia M. Faison4 , Danilyn M. Angeles3 and Danilo S. Boskovic1,5\*

1 Department of Earth and Biological Sciences, School of Medicine, Loma Linda University, Loma Linda, CA, United States

2 Department of Biochemistry, School of Medicine, Babcock University, Ilishan-Remo, Ogun State, Nigeria

3 Division of Physiology, Department of Basic Sciences, School of Medicine, Loma Linda University, Loma Linda, CA, United States

4 Division of Neonatology, Department of Pediatrics, School of Medicine, Loma Linda University, Loma Linda, CA, United States

5 Division of Biochemistry, Department of Basic Sciences, School of Medicine, Loma Linda University, Loma Linda, CA, United States

\*Address all correspondence to: dboskovic@llu.edu

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**69**

*Platelets in the Newborn*

10.1016/j.blre.2004.05.002

science.328.5978.562

cnm.2623

[2] Leslie M. Beyond clotting: The powers of platelets. Science. 2010;**328**(5978):562-564. DOI: 10.1126/

[3] Storti F, Kempen THS, Vosse FN. A continuum model for platelet plug formation and growth. International Journal of Numerical Methods in Biomedical Engineering. 2014;**30**(6):634-658. DOI: 10.1002/

[4] Hou Y, Carrim N, Wang Y, Gallant RC, Marshall A, Ni H. Platelets in hemostasis and thrombosis: Novel mechanisms of fibrinogen-independent platelet aggregation and fibronectin-mediated protein wave of hemostasis. Journal of Biomedical Research. 2015;**29**(6): 437-444. DOI: 10.7555/JBR.29.20150121

[5] Muthard RW, Welsh JD, Brass LF, Diamond SL. Fibrin, γ'-fibrinogen, and trans-clot pressure gradient control hemostatic clot growth during human blood flow over a collagen/ tissue factor wound. Arteriosclerosis, Thrombosis, and Vascular Biology. 2015;**35**(3):645-654. DOI: 10.1161/

[6] Colace T, Muthard R, Diamond SL. Thrombus growth and embolism on tissue factor-bearing collagen surfaces under flow: Role of thrombin with and without fibrin. Arteriosclerosis, Thrombosis, and Vascular Biology. 2012;**32**(6):1466-1476. DOI: 10.1161/

[7] Manco-Johnson MJ. Development of hemostasis in the fetus and neonate. Thrombosis Research. 2007;**119**:S4-S5. DOI: 10.1016/s0049-3848(07)70004-x

[8] Haley KM, Recht M, McCarty OJT. Neonatal platelets: Mediators of

ATVBAHA.114.305054

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*Neonatal Medicine*

**Author details**

Ijeoma Esiaba1,2, Iman Mousselli3

Ilishan-Remo, Ogun State, Nigeria

University, Loma Linda, CA, United States

Loma Linda University, Loma Linda, CA, United States

Loma Linda University, Loma Linda, CA, United States

\*Address all correspondence to: dboskovic@llu.edu

provided the original work is properly cited.

Linda University, Loma Linda, CA, United States

and Danilo S. Boskovic1,5\*

, Giulia M. Faison4

1 Department of Earth and Biological Sciences, School of Medicine, Loma Linda

2 Department of Biochemistry, School of Medicine, Babcock University,

3 Division of Physiology, Department of Basic Sciences, School of Medicine,

4 Division of Neonatology, Department of Pediatrics, School of Medicine, Loma

5 Division of Biochemistry, Department of Basic Sciences, School of Medicine,

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

, Danilyn M. Angeles3

**68**

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[2] Leslie M. Beyond clotting: The powers of platelets. Science. 2010;**328**(5978):562-564. DOI: 10.1126/ science.328.5978.562

[3] Storti F, Kempen THS, Vosse FN. A continuum model for platelet plug formation and growth. International Journal of Numerical Methods in Biomedical Engineering. 2014;**30**(6):634-658. DOI: 10.1002/ cnm.2623

[4] Hou Y, Carrim N, Wang Y, Gallant RC, Marshall A, Ni H. Platelets in hemostasis and thrombosis: Novel mechanisms of fibrinogen-independent platelet aggregation and fibronectin-mediated protein wave of hemostasis. Journal of Biomedical Research. 2015;**29**(6): 437-444. DOI: 10.7555/JBR.29.20150121

[5] Muthard RW, Welsh JD, Brass LF, Diamond SL. Fibrin, γ'-fibrinogen, and trans-clot pressure gradient control hemostatic clot growth during human blood flow over a collagen/ tissue factor wound. Arteriosclerosis, Thrombosis, and Vascular Biology. 2015;**35**(3):645-654. DOI: 10.1161/ ATVBAHA.114.305054

[6] Colace T, Muthard R, Diamond SL. Thrombus growth and embolism on tissue factor-bearing collagen surfaces under flow: Role of thrombin with and without fibrin. Arteriosclerosis, Thrombosis, and Vascular Biology. 2012;**32**(6):1466-1476. DOI: 10.1161/ ATVBAHA.112.249789

[7] Manco-Johnson MJ. Development of hemostasis in the fetus and neonate. Thrombosis Research. 2007;**119**:S4-S5. DOI: 10.1016/s0049-3848(07)70004-x

[8] Haley KM, Recht M, McCarty OJT. Neonatal platelets: Mediators of

primary hemostasis in the developing hemostatic system. Pediatric Research. 2014;**76**(3):230-237. DOI: 10.1038/ pr.2014.87

[9] Boulaftali Y, Hess PR, Getz TM, Cholka A, Stolla M, Mackman N, et al. Platelet ITAM signaling is critical for vascular integrity in inflammation. Journal of Clinical Investigation. 2013;**123**(2):908-916. DOI: 10.1172/ jci65154

[10] Kollmann TR, Kampmann B, Mazmanian SK, Marchant A, Levy O. Protecting the newborn and young infant from infectious diseases: Lessons from immune ontogeny. Immunity. 2017;**46**(3):350-363. DOI: 10.1016/j. immuni.2017.03.009

[11] Hallevi H, Walker KC, Kasam M, Bornstein N, Grotta JC, Savitz SI. Inflammatory response to intraventricular hemorrhage: Time course, magnitude and effect of t-PA. Journal of the Neurological Sciences. 2012;**315**(1-2):93-95. DOI: 10.1016/j.jns.2011.11.019

[12] Dani C, Cecchi A, Bertini G. Role of oxidative stress as physiopathologic factor in the preterm infant. Minerva Pediatrica. 2004;**56**(4):381-394

[13] Nurden AT. Platelets, inflammation and tissue regeneration. Thrombosis and Haemostasis. 2011;**105**(99):S13-S33. DOI: 10.1160/THS10-11-0720

[14] Kaushansky K. Historical review: Megakaryopoiesis and thrombopoiesis. Blood. 2008;**111**(3):981-986. DOI: 10.1182/blood-2007-05-088500

[15] Andres O, Schulze H, Speer CP. Platelets in neonates: Central mediators in haemostasis, antimicrobial defence and inflammation. Thrombosis and Haemostasis. 2015;**113**(1):3-12. DOI: 10.1160/TH14-05-0476

[16] Liu Z-J, Hoffmeister KM, Hu Z, Mager DE, Ait-Oudhia S, Debrincat MA, et al. Expansion of the neonatal platelet mass is achieved via an extension of platelet lifespan. Blood. 2014;**123**(22):3381-3389. DOI: 10.1182/ blood-2013-06-508200

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[18] Murray NA, Watts TL, Roberts IA. Thrombopoietin in the fetus and neonate. Early Human Development. 2000;**59**(1):1-12. DOI: 10.1016/ S0378-3782(00)00078-5

[19] Del Vecchio A, Motta M, Romagnoli C. Neonatal platelet function. Clinics in Perinatology. 2015;**42**(3):625-638. DOI: 10.1016/j.clp.2015.04.015

[20] Brass L. Understanding and evaluating platelet function. Hematology. American Society of Hematology. Education Program. 2010;**2010**(1):387-396. DOI: 10.1182/ asheducation-2010.1.387

[21] Weyrich AS, Dixon DA, Pabla R, Elstad MR, McIntyre TM, Prescott SM, et al. Signal-dependent translation of a regulatory protein, Bcl-3, in activated human platelets. Proceedings of the National Academy of Sciences of the United States of America. 1998;**95**(10):5556-5561. DOI: 10.1073/ pnas.95.10.5556

[22] Golebiewska EM, Poole AW. Platelet secretion: From haemostasis to wound healing and beyond. Blood Reviews. 2015;**29**(3):153-162. DOI: 10.1016/j. blre.2014.10.003

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2007;**21**(2):99-111. DOI: 10.1016/j. blre.2006.06.001

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[27] Cox D, Kerrigan SW, Watson SP. Platelets and the innate immune system: Mechanisms of bacterialinduced platelet activation. Journal of Thrombosis and Haemostasis. 2011;**9**(6):1097-1107. DOI: 10.1111/j.1538-7836.2011.04264.x

[28] Lentz BR. Exposure of platelet membrane phosphatidylserine regulates blood coagulation. Progress in Lipid Research. 2003;**42**(5):423-438. DOI: 10.1016/S0163-7827(03)00025-0

[29] George JN. Platelets. Lancet. 2000;**355**(9214):1531-1539. DOI: 10.1016/S0140-6736(00)02175-9

[30] Kuhle S, Male C, Mitchell L. Developmental hemostasis: Proand anticoagulant systems during childhood. Seminars in Thrombosis and Hemostasis. 2003;**29**(4):329-337. DOI: 10.1055/s-2003-42584

[31] Brass LF. Thrombin and platelet activation. Chest. 2003;**124**(3 Suppl): 18S-25S. DOI: 10.1378/chest.124.3\_ suppl.18S

[32] Mann K, Brummel-Ziedins K. Normal Coagulation: DTIC Document.2014

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[42] Etulain J, Negrotto S, Carestia A, Pozner RG, Romaniuk MA, D'Atri LP, et al. Acidosis downregulates platelet haemostatic functions and promotes neutrophil proinflammatory responses mediated by platelets. Thrombosis and Haemostasis. 2012;**107**(1):99-110. DOI:

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[44] Polanowska-Grabowska R, Wallace K, Field JJ, Chen L, Marshall MA, Figler R, et al. P-selectin–mediated plateletneutrophil aggregate formation activates

neutrophils in mouse and human sickle cell disease. Arteriosclerosis, Thrombosis, and Vascular Biology. 2010;**30**(12):2392-2399. DOI: 10.1161/

[45] Zuchtriegel G, Uhl B, Puhr-Westerheide D, Pörnbacher M, Lauber K, Krombach F, et al. Platelets guide leukocytes to their sites of extravasation. PLoS Biology. 2016;**14**(5):e1002459. DOI: 10.1371/

[46] Kornerup KN, Salmon GP, Pitchford SC, Liu WL, Page CP. Circulating platelet-neutrophil complexes are important for subsequent

neutrophil activation and migration. Journal of Applied Physiology. 2010;**109**(3):758-767. DOI: 10.1152/

jlb.3TA0315-082R

10.1160/th11-06-0443

10.1161/01.cir.98.9.873

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journal.pbio.1002459

japplphysiol.01086.2009

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[36] Bambace NM, Holmes CE. The platelet contribution to cancer

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Mechanisms of Development. 2015;**138**(Pt 1):43-49. DOI: 10.1016/j.

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10.1046/j.1365-2141.2000.01992.x

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s40348-016-0063-5

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progression. Journal of Thrombosis and Haemostasis. 2011;**9**(2):237-249. DOI: 10.1111/j.1538-7836.2010.04131.x

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The functional role of platelets in the regulation of angiogenesis. Platelets. 2015;**26**(3):199-211. DOI: 10.3109/09537104.2014.909022

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*Neonatal Medicine*

blood-2013-06-508200

[16] Liu Z-J, Hoffmeister KM, Hu Z, Mager DE, Ait-Oudhia S, Debrincat MA, et al. Expansion of the neonatal platelet mass is achieved via an extension of platelet lifespan. Blood. 2014;**123**(22):3381-3389. DOI: 10.1182/ 2007;**21**(2):99-111. DOI: 10.1016/j.

[25] Ogedegbe HO. An overview of hemostasis. Laboratory Medicine. 2002;**33**(12):948-953. DOI: 10.1092/

[26] Heemskerk JW, Bevers EM, Lindhout T. Platelet activation and blood coagulation. Thrombosis and Haemostasis. 2002;**88**(2):186-193. DOI:

[27] Cox D, Kerrigan SW, Watson SP. Platelets and the innate immune system: Mechanisms of bacterialinduced platelet activation. Journal of Thrombosis and Haemostasis. 2011;**9**(6):1097-1107. DOI: 10.1111/j.1538-7836.2011.04264.x

[28] Lentz BR. Exposure of platelet membrane phosphatidylserine regulates blood coagulation. Progress in Lipid Research. 2003;**42**(5):423-438. DOI: 10.1016/S0163-7827(03)00025-0

[29] George JN. Platelets. Lancet. 2000;**355**(9214):1531-1539. DOI: 10.1016/S0140-6736(00)02175-9

[30] Kuhle S, Male C, Mitchell L. Developmental hemostasis: Proand anticoagulant systems during childhood. Seminars in Thrombosis and Hemostasis. 2003;**29**(4):329-337. DOI:

[31] Brass LF. Thrombin and platelet activation. Chest. 2003;**124**(3 Suppl): 18S-25S. DOI: 10.1378/chest.124.3\_

[32] Mann K, Brummel-Ziedins K. Normal Coagulation: DTIC

10.1055/s-2003-42584

suppl.18S

Document.2014

[24] Rondina MT, Weyrich AS, Zimmerman GA. Platelets as cellular effectors of inflammation in vascular diseases. Circulation Research. 2013;**112**(11):1506-1519. DOI: 10.1161/

blre.2006.06.001

circresaha.113.300512

QWJQLR8ELGL6X32H

10.1055/s-0037-1613209

[17] Watts TL, Murray NA, Roberts IAG.

production in preterm babies. Pediatric Research. 1999;**46**(1):28-32. DOI: 10.1203/00006450-199907000-00005

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10.1016/j.clp.2015.04.015

asheducation-2010.1.387

pnas.95.10.5556

blre.2014.10.003

[20] Brass L. Understanding and evaluating platelet function. Hematology. American Society of Hematology. Education Program. 2010;**2010**(1):387-396. DOI: 10.1182/

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[22] Golebiewska EM, Poole AW. Platelet secretion: From haemostasis to wound healing and beyond. Blood Reviews. 2015;**29**(3):153-162. DOI: 10.1016/j.

[23] Zarbock A, Polanowska-Grabowska

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[34] Walsh TG, Metharom P, Berndt MC. The functional role of platelets in the regulation of angiogenesis. Platelets. 2015;**26**(3):199-211. DOI: 10.3109/09537104.2014.909022

[35] Italiano JE, Richardson JL, Patel-Hett S, Battinelli E, Zaslavsky A, Short S, et al. Angiogenesis is regulated by a novel mechanism: Pro- and antiangiogenic proteins are organized into separate platelet α granules and differentially released. Blood. 2008;**111**(3):1227-1233. DOI: 10.1182/ blood-2007-09-113837

[36] Bambace NM, Holmes CE. The platelet contribution to cancer progression. Journal of Thrombosis and Haemostasis. 2011;**9**(2):237-249. DOI: 10.1111/j.1538-7836.2010.04131.x

[37] Lacoste B, Gu C. Control of cerebrovascular patterning by neural activity during postnatal development. Mechanisms of Development. 2015;**138**(Pt 1):43-49. DOI: 10.1016/j. mod.2015.06.003

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[41] Mauler M, Seyfert J, Haenel D, Seeba H, Guenther J, Stallmann D, et al. Platelet-neutrophil complex formation—A detailed in vitro analysis of murine and human blood samples. Journal of Leukocyte Biology. 2016;**99**(5):781-789. DOI: 10.1189/ jlb.3TA0315-082R

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S164-S167

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AOG.0000000000000118

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10.1155/2010/401323

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fn.88.5.F359

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[155] Crowther MA, Cook DJ, Meade MO, Griffith LE, Guyatt GH, Arnold DM, et al. Thrombocytopenia in medical-surgical critically ill patients: Prevalence, incidence, and risk factors. Journal of Critical Care. 2005;**20**(4):348-353. DOI: 10.1016/j. jcrc.2005.09.008

[156] Williamson DR, Albert M, Heels-Ansdell D, Arnold DM, Lauzier F, Zarychanski R, et al. Thrombocytopenia in critically ill patients receiving thromboprophylaxis: Frequency, risk factors, and outcomes. Chest. 2013;**144**(4):1207-1215. DOI: 10.1378/ chest.13-0121

[157] Abrams D, Baldwin MR, Champion M, Agerstrand C, Eisenberger A, Bacchetta M, et al. Thrombocytopenia and extracorporeal membrane oxygenation in adults with acute respiratory failure: A cohort study. Intensive Care Medicine. 2016;**42**(5):844-852. DOI: 10.1007/ s00134-016-4312-9

[158] Lieberman L, Bercovitz RS, Sholapur NS, Heddle NM, Stanworth SJ, Arnold DM. Platelet transfusions for critically ill patients with thrombocytopenia. Blood. 2014;**123**(8):1146-1151. DOI: 10.1182/ blood-2013-02-435693

[159] Bembea MM, Annich G, Rycus P, Oldenburg G, Berkowitz I, Pronovost P. Variability in anticoagulation management of patients on extracorporeal membrane oxygenation: An international survey. Pediatric Critical Care Medicine. 2013;**14**(2):E77-E84. DOI: 10.1097/ PCC.0b013e31827127e4

[160] Faraoni D, Levy JH. Algorithmbased management of bleeding in patients with extracorporeal membrane oxygenation. Critical Care. 2013;**17**(3):432. DOI: 10.1186/cc12682

[161] Nair P, Hoechter DJ, Buscher H, Venkatesh K, Whittam S, Joseph J, et al. Prospective observational study of hemostatic alterations during adult extracorporeal membrane oxygenation (ECMO) using pointof-care thromboelastometry and platelet aggregometry. Journal of Cardiothoracic and Vascular Anesthesia. 2015;**29**(2):288-296. DOI: 10.1053/j. jvca.2014.06.006

[162] Young G, Yonekawa KE, Nakagawa P, Nugent DJ. Argatroban as an alternative to heparin in extracorporeal membrane oxygenation circuits. Perfusion. 2004;**19**(5):283-288. DOI: 10.1191/0267659104pf759oa

[163] Jyoti A, Maheshwari A, Daniel E, Motihar A, Bhathiwal RS, Sharma D. Bivalirudin in venovenous extracorporeal membrane oxygenation. The Journal of Extra-Corporeal Technology. 2014;**46**(1):94-97

[164] Gray B, Rintoul N. ELSO Guidelines for Cardiopulmonary Extracorporeal Life Support. Version 1.4. Extracorporeal Life Support Organization: Ann Arbor, MI, USA; 2017

[165] Cuker A. Clinical and laboratory diagnosis of heparin-induced thrombocytopenia: An integrated approach. Seminars in Thrombosis and Hemostasis. 2014;**40**(1):106-114. DOI: 10.1055/s-0033-1363461

[166] Schmugge M, Risch L, Huber AR, Benn A, Fischer JE. Heparin-induced thrombocytopenia-associated thrombosis in pediatric intensive care patients. Pediatrics. 2002;**109**(1):E10. DOI: 10.1542/peds.109.1.e10

[167] Klenner AF, Lubenow N, Raschke R, Greinacher A. Heparin-induced thrombocytopenia in children: 12 new cases and review of the literature. Thrombosis and Haemostasis. 2004;**91**(4):719-724. DOI: 10.1160/ TH03-09-0571

[168] Risch L, Fischer JE, Herklotz R, Huber AR. Heparin-induced thrombocytopenia in paediatrics: Clinical characteristics, therapy and outcomes. Intensive Care Medicine. 2004;**30**(8):1615-1624. DOI: 10.1007/ s00134-004-2315-4

[169] Severin T, Sutor AH. Heparininduced thrombocytopenia in pediatrics. Seminars in Thrombosis and

**81**

*Platelets in the Newborn*

10.1055/s-2001-15259

*DOI: http://dx.doi.org/10.5772/intechopen.86715*

Hemostasis. 2001;**27**(3):293-299. DOI:

American Journal of Perinatology. 2016;**33**(11):1079-1084. DOI: 10.1055/s-0036-1586106

[178] Sola-Visner M, Bercovitz RS. Neonatal platelet transfusions and future areas of research. Transfusion Medicine Reviews. 2016;**30**4 SI:183-188.

DOI: 10.1016/j.tmrv.2016.05.009

Seminars in Fetal and Neonatal Medicine. 2016;**21**(1):10-18. DOI:

[180] Castle V, Andrew M, Kelton J, Giron D, Johnston M, Carter C.

[181] Mehta P, Vasa R, Neumann L, Karpatkin M. Thrombocytopenia in the high-risk infant. The Journal of Pediatrics. 1980;**97**(5):791-794. DOI: 10.1016/S0022-3476(80)80272-1

[182] Christensen RD, Henry E, Wiedmeier SE, Stoddard RA, Sola-Visner MC, Lambert DK, et al. Thrombocytopenia among extremely low birth weight neonates: Data from a multihospital healthcare system. Journal of Perinatology. 2006;**26**(6):348-353.

DOI: 10.1038/sj.jp.7211509

S0022-3476(05)81705-6

[183] Andrew M, Vegh P, Caco C, Kirpalani H, Jefferies A, Ohlsson A, et al. A randomized, controlled trial of platelet transfusions in thrombocytopenic premautre infants. The Journal of Pediatrics. 1993;**123**(2):285-291. DOI: 10.1016/

[184] Gunnink SF, Vlug R, Fijnvandraat K, van der Bom JG, Stanworth SJ,

Lopriore E. Neonatal thrombocytopenia: Etiology, management and outcome. Expert Review of Hematology.

Frequency and mechanism of neonatal thrombocytopenia. The Journal of Pediatrics. 1986;**108**(5):749-755. DOI: 10.1016/S0022-3476(86)81059-9

10.1016/j.siny.2015.11.001

[179] Cremer M, Sallmon H, Kling PJ, Buhrer C, Dame C. Thrombocytopenia and platelet transfusion in the neonate.

[170] Pollak U, Yacobobich J, Tamary H, Dagan O, Manor-Shulman O. Heparininduced thrombocytopenia and

extracorporeal membrane oxygenation:

[171] Lee GM, Arepally GM. Heparin-

[172] Warkentin TE. HIT paradigms and paradoxes. Journal of Thrombosis and Haemostasis. 2011;**9**(Suppl 1):105-117. DOI: 10.1111/j.1538-7836.2011.04322.x

[173] Crowther M, Cook D, Guyatt G, Zytaruk N, McDonald E, Williamson D, et al. Heparin-induced thrombocytopenia in the critically ill: Interpreting the 4Ts test in a randomized trial. Journal of Critical Care. 2014;**29**(3):470.e7. DOI:

A case report and review of the literature. The Journal of Extra-Corporeal Technology. 2011;**43**(1):5-12

induced thrombocytopenia. Hematology. American Society of Hematology. Education Program. 2013;**2013**(1):668-674. DOI: 10.1182/

asheducation-2013.1.668

10.1016/j.jcrc.2014.02.004

Organization; 2014

1999;**4**(1):5-16

[174] Beiderlinden M, Treschan T, Görlinger K, Peters J. Argatroban in extracorporeal membrane oxygenation. Artificial Organs. 2007;**31**(6):461-465. DOI: 10.1111/j.1525-1594.2007.00388.x

[176] Ramasethu J, Luban N. Red blood cell transfusions in the newborn. Seminars in Neonatology.

[177] Del Vecchio A, Franco C, Petrillo F, D'Amato G. Neonatal

transfusion practice: When do neonates need red blood cells or platelets?

[175] Lequier L, Annich G, Al-Ibrahim O, Bembea M, Brodie D, Brogan T. ELSO Anticoagulation Guidelines. Ann Arbor, MI: Extracorporeal Life Support

*Platelets in the Newborn DOI: http://dx.doi.org/10.5772/intechopen.86715*

*Neonatal Medicine*

chest.13-0121

s00134-016-4312-9

blood-2013-02-435693

Oldenburg G, Berkowitz I, Pronovost P. Variability in anticoagulation management of patients on extracorporeal membrane oxygenation: An international survey. Pediatric Critical Care Medicine. 2013;**14**(2):E77-E84. DOI: 10.1097/

PCC.0b013e31827127e4

[156] Williamson DR, Albert M, Heels-Ansdell D, Arnold DM, Lauzier F, Zarychanski R, et al. Thrombocytopenia [162] Young G, Yonekawa KE, Nakagawa

alternative to heparin in extracorporeal membrane oxygenation circuits. Perfusion. 2004;**19**(5):283-288. DOI:

[163] Jyoti A, Maheshwari A, Daniel E, Motihar A, Bhathiwal RS, Sharma D.

extracorporeal membrane oxygenation.

Organization: Ann Arbor, MI, USA; 2017

[165] Cuker A. Clinical and laboratory

[166] Schmugge M, Risch L, Huber AR, Benn A, Fischer JE. Heparin-induced thrombocytopenia-associated

thrombosis in pediatric intensive care patients. Pediatrics. 2002;**109**(1):E10.

[167] Klenner AF, Lubenow N, Raschke R, Greinacher A. Heparin-induced thrombocytopenia in children: 12 new cases and review of the literature. Thrombosis and Haemostasis. 2004;**91**(4):719-724. DOI: 10.1160/

[168] Risch L, Fischer JE, Herklotz R,

[169] Severin T, Sutor AH. Heparininduced thrombocytopenia in

pediatrics. Seminars in Thrombosis and

Huber AR. Heparin-induced thrombocytopenia in paediatrics: Clinical characteristics, therapy and outcomes. Intensive Care Medicine. 2004;**30**(8):1615-1624. DOI: 10.1007/

P, Nugent DJ. Argatroban as an

10.1191/0267659104pf759oa

Bivalirudin in venovenous

The Journal of Extra-Corporeal Technology. 2014;**46**(1):94-97

[164] Gray B, Rintoul N. ELSO Guidelines for Cardiopulmonary Extracorporeal Life Support. Version 1.4. Extracorporeal Life Support

diagnosis of heparin-induced thrombocytopenia: An integrated approach. Seminars in Thrombosis and Hemostasis. 2014;**40**(1):106-114. DOI:

10.1055/s-0033-1363461

DOI: 10.1542/peds.109.1.e10

TH03-09-0571

s00134-004-2315-4

in critically ill patients receiving thromboprophylaxis: Frequency, risk factors, and outcomes. Chest. 2013;**144**(4):1207-1215. DOI: 10.1378/

[157] Abrams D, Baldwin MR, Champion M, Agerstrand C, Eisenberger A, Bacchetta M, et al. Thrombocytopenia and extracorporeal membrane oxygenation in adults with acute respiratory failure: A cohort study. Intensive Care Medicine. 2016;**42**(5):844-852. DOI: 10.1007/

[158] Lieberman L, Bercovitz RS, Sholapur NS, Heddle NM,

Stanworth SJ, Arnold DM. Platelet transfusions for critically ill patients with thrombocytopenia. Blood. 2014;**123**(8):1146-1151. DOI: 10.1182/

[159] Bembea MM, Annich G, Rycus P,

[160] Faraoni D, Levy JH. Algorithmbased management of bleeding in patients with extracorporeal

membrane oxygenation. Critical Care. 2013;**17**(3):432. DOI: 10.1186/cc12682

[161] Nair P, Hoechter DJ, Buscher H, Venkatesh K, Whittam S, Joseph J, et al. Prospective observational study of hemostatic alterations during adult extracorporeal membrane oxygenation (ECMO) using pointof-care thromboelastometry and platelet aggregometry. Journal of

Cardiothoracic and Vascular Anesthesia. 2015;**29**(2):288-296. DOI: 10.1053/j.

**80**

jvca.2014.06.006

Hemostasis. 2001;**27**(3):293-299. DOI: 10.1055/s-2001-15259

[170] Pollak U, Yacobobich J, Tamary H, Dagan O, Manor-Shulman O. Heparininduced thrombocytopenia and extracorporeal membrane oxygenation: A case report and review of the literature. The Journal of Extra-Corporeal Technology. 2011;**43**(1):5-12

[171] Lee GM, Arepally GM. Heparininduced thrombocytopenia. Hematology. American Society of Hematology. Education Program. 2013;**2013**(1):668-674. DOI: 10.1182/ asheducation-2013.1.668

[172] Warkentin TE. HIT paradigms and paradoxes. Journal of Thrombosis and Haemostasis. 2011;**9**(Suppl 1):105-117. DOI: 10.1111/j.1538-7836.2011.04322.x

[173] Crowther M, Cook D, Guyatt G, Zytaruk N, McDonald E, Williamson D, et al. Heparin-induced thrombocytopenia in the critically ill: Interpreting the 4Ts test in a randomized trial. Journal of Critical Care. 2014;**29**(3):470.e7. DOI: 10.1016/j.jcrc.2014.02.004

[174] Beiderlinden M, Treschan T, Görlinger K, Peters J. Argatroban in extracorporeal membrane oxygenation. Artificial Organs. 2007;**31**(6):461-465. DOI: 10.1111/j.1525-1594.2007.00388.x

[175] Lequier L, Annich G, Al-Ibrahim O, Bembea M, Brodie D, Brogan T. ELSO Anticoagulation Guidelines. Ann Arbor, MI: Extracorporeal Life Support Organization; 2014

[176] Ramasethu J, Luban N. Red blood cell transfusions in the newborn. Seminars in Neonatology. 1999;**4**(1):5-16

[177] Del Vecchio A, Franco C, Petrillo F, D'Amato G. Neonatal transfusion practice: When do neonates need red blood cells or platelets?

American Journal of Perinatology. 2016;**33**(11):1079-1084. DOI: 10.1055/s-0036-1586106

[178] Sola-Visner M, Bercovitz RS. Neonatal platelet transfusions and future areas of research. Transfusion Medicine Reviews. 2016;**30**4 SI:183-188. DOI: 10.1016/j.tmrv.2016.05.009

[179] Cremer M, Sallmon H, Kling PJ, Buhrer C, Dame C. Thrombocytopenia and platelet transfusion in the neonate. Seminars in Fetal and Neonatal Medicine. 2016;**21**(1):10-18. DOI: 10.1016/j.siny.2015.11.001

[180] Castle V, Andrew M, Kelton J, Giron D, Johnston M, Carter C. Frequency and mechanism of neonatal thrombocytopenia. The Journal of Pediatrics. 1986;**108**(5):749-755. DOI: 10.1016/S0022-3476(86)81059-9

[181] Mehta P, Vasa R, Neumann L, Karpatkin M. Thrombocytopenia in the high-risk infant. The Journal of Pediatrics. 1980;**97**(5):791-794. DOI: 10.1016/S0022-3476(80)80272-1

[182] Christensen RD, Henry E, Wiedmeier SE, Stoddard RA, Sola-Visner MC, Lambert DK, et al. Thrombocytopenia among extremely low birth weight neonates: Data from a multihospital healthcare system. Journal of Perinatology. 2006;**26**(6):348-353. DOI: 10.1038/sj.jp.7211509

[183] Andrew M, Vegh P, Caco C, Kirpalani H, Jefferies A, Ohlsson A, et al. A randomized, controlled trial of platelet transfusions in thrombocytopenic premautre infants. The Journal of Pediatrics. 1993;**123**(2):285-291. DOI: 10.1016/ S0022-3476(05)81705-6

[184] Gunnink SF, Vlug R, Fijnvandraat K, van der Bom JG, Stanworth SJ, Lopriore E. Neonatal thrombocytopenia: Etiology, management and outcome. Expert Review of Hematology.

2014;**7**(3):387-395. DOI: 10.1586/17474086.2014.902301

[185] Resch E, Hinkas O, Urlesberger B, Resch B. Neonatal thrombocytopeniacauses and outcomes following platelet transfusions. European Journal of Pediatrics. 2018;**177**(7):1045-1052. DOI: 10.1007/s00431-018-3153-7

[186] Venkatesh V, Khan R, Curley A, New H, Stanworth S. How we decide when a neonate needs a transfusion. British Journal of Haematology. 2013;**160**(4): 421-433. DOI: 10.1111/bjh.12095

[187] Sparger KA, Assmann SF, Granger S, Winston A, Christensen RD, Widness JA, et al. Platelet transfusion practices among very-low-birth-weight infants. JAMA Pediatrics. 2016;**170**(7):687-694. DOI: 10.1001/jamapediatrics.2016.0507

[188] Cremer M, Weimann A, Schmalisch G, Hammer H, Buhrer C, Dame C. Immature platelet values indicate impaired megakaryopoietic activity in neonatal early-onset thrombocytopenia. Thrombosis and Haemostasis. 2010;**103**(5 SI):1016-1021. DOI: 10.1160/TH09-03-0148

[189] MacQueen BC, Christensen RD, Henry E, Romrell AM, Pysher TJ, Bennett ST, et al. The immature platelet fraction: Creating neonatal reference intervals and using these to categorize neonatal thrombocytopenias. Journal of Perinatology. 2017;**37**(7):834-838. DOI: 10.1038/jp.2017.48

[190] Sparger K, Deschmann E, Sola-Visner M. Platelet transfusions in the neonatal intensive care unit. Clinics in Perinatology. 2015;**42**(3):613-623. DOI: 10.1016/j.clp.2015.04.009

[191] Wiedmeier SE, Henry E, Sola-Visner MC, Christensen RD. Platelet reference ranges for neonates, defined using data from over 47,000 patients in a multihospital healthcare system. Journal of Perinatology. 2009;**29**(2):130-136. DOI: 10.1038/jp.2008.141

[192] Poryo M, Boeckh JC, Gortner L, Zemlin M, Duppre P, Ebrahimi-Fakhari D, et al. Ante-, peri- and postnatal factors associated with intraventricular hemorrhage in very premature infants. Early Human Development. 2018;**116**:1-8. DOI: 10.1016/j. earlhumdev.2017.08.010

[193] Curley A, Stanworth SJ, Willoughby K, Fustolo-Gunnink SF, Venkatesh V, Hudson C, et al. Randomized trial of platelet-transfusion thresholds in neonates. The New England Journal of Medicine. 2019;**380**(3):242-251. DOI: 10.1056/NEJMoa1807320

[194] New HV, Berryman J, Bolton-Maggs PH, Cantwell C, Chalmers EA, Davies T, et al. Guidelines on transfusion for fetuses, neonates and older children. British Journal of Haematology. 2016;**175**(5):784-828. DOI: 10.1111/bjh.14233

[195] Liumbruno G, Bennardello F, Lattanzio A, Piccoli P, Rossetti G, et al. Recommendations for the transfusion of plasma and platelets. Blood Transfusion. 2009;**7**(2):132-150. DOI: 10.2450/2009.0005-09

[196] Cremer M, Sola-Visner M, Roll S, J osephson CD, Yilmaz Z, Buhrer C, et al. Platelet transfusions in neonates: Practices in the United States vary significantly from those in Austria, Germany, and Switzerland. Transfusion. 2011;**51**(12):2634-2641. DOI: 10.1111/j.1537-2995.2011.03208.x

[197] Josephson CD, Su LL, Christensen RD, Hillyer CD, Castillejo MI, Emory MR, et al. Platelet transfusion practices among neonatologists in the United States and Canada: Results of a survey. Pediatrics. 2009;**123**(1):278-285. DOI: 10.1542/peds.2007-2850

[198] Baer VL, Lambert DK, Henry E, Snow GL, Sola-Visner MC, Christensen RD. Do platelet transfusions in the NICU adversely affect survival? Analysis of 1600 thrombocytopenic

**83**

*Platelets in the Newborn*

Effect of temperature on

archdischild-2013-305763

10.1159/000329818

[201] Christensen RD, Sheffield MJ, Lambert DK, Baer VL. Effect of therapeutic hypothermia in neonates with hypoxic-ischemic encephalopathy on platelet function. Neonatology. 2012;**101**(2):91-94. DOI:

10.1038/pr.2014.19

sj.jp.7211833

*DOI: http://dx.doi.org/10.5772/intechopen.86715*

neonates in a multihospital healthcare system. Journal of Perinatology. 2007;**27**(12):790-796. DOI: 10.1038/

[199] Forman KR, Wong E, Gallagher M, McCarter R, Luban NLC, Massaro AN.

thromboelastography and implications for clinical use in newborns undergoing therapeutic hypothermia. Pediatric Research. 2014;**75**(5):663-669. DOI:

[200] Chakkarapani E, Davis J, Thoresen M. Therapeutic hypothermia delays the C-reactive protein response and suppresses white blood cell and platelet count in infants with neonatal encephalopathy. Archives of Disease in Childhood. Fetal and Neonatal Edition. 2014;**99**(6):F485-F463. DOI: 10.1136/

*Platelets in the Newborn DOI: http://dx.doi.org/10.5772/intechopen.86715*

*Neonatal Medicine*

2014;**7**(3):387-395. DOI: 10.1586/17474086.2014.902301

10.1007/s00431-018-3153-7

[185] Resch E, Hinkas O, Urlesberger B, Resch B. Neonatal thrombocytopeniacauses and outcomes following platelet transfusions. European Journal of Pediatrics. 2018;**177**(7):1045-1052. DOI: [192] Poryo M, Boeckh JC, Gortner L, Zemlin M, Duppre P, Ebrahimi-Fakhari D, et al. Ante-, peri- and postnatal factors associated with intraventricular

[193] Curley A, Stanworth SJ, Willoughby K, Fustolo-Gunnink SF, Venkatesh V, Hudson C, et al. Randomized trial of platelet-transfusion thresholds in neonates. The New England Journal of Medicine. 2019;**380**(3):242-251. DOI:

hemorrhage in very premature infants. Early Human Development.

2018;**116**:1-8. DOI: 10.1016/j. earlhumdev.2017.08.010

10.1056/NEJMoa1807320

DOI: 10.1111/bjh.14233

10.2450/2009.0005-09

10.1542/peds.2007-2850

[194] New HV, Berryman J, Bolton-Maggs PH, Cantwell C, Chalmers EA,

[195] Liumbruno G, Bennardello F, Lattanzio A, Piccoli P, Rossetti G, et al. Recommendations for the transfusion

Transfusion. 2009;**7**(2):132-150. DOI:

[196] Cremer M, Sola-Visner M, Roll S, J osephson CD, Yilmaz Z, Buhrer C, et al. Platelet transfusions in neonates: Practices in the United States vary significantly from those in Austria, Germany, and Switzerland. Transfusion. 2011;**51**(12):2634-2641. DOI: 10.1111/j.1537-2995.2011.03208.x

[197] Josephson CD, Su LL, Christensen RD, Hillyer CD, Castillejo MI, Emory MR, et al. Platelet transfusion practices among neonatologists in the United States and Canada: Results of a survey. Pediatrics. 2009;**123**(1):278-285. DOI:

[198] Baer VL, Lambert DK, Henry E, Snow GL, Sola-Visner MC, Christensen RD. Do platelet transfusions in the NICU adversely affect survival? Analysis of 1600 thrombocytopenic

of plasma and platelets. Blood

Davies T, et al. Guidelines on transfusion for fetuses, neonates and older children. British Journal of Haematology. 2016;**175**(5):784-828.

[186] Venkatesh V, Khan R, Curley A, New H, Stanworth S. How we decide when a neonate needs a transfusion. British Journal of Haematology. 2013;**160**(4): 421-433. DOI: 10.1111/bjh.12095

[187] Sparger KA, Assmann SF, Granger S, Winston A, Christensen RD, Widness JA, et al. Platelet transfusion practices among very-low-birth-weight infants. JAMA Pediatrics. 2016;**170**(7):687-694. DOI: 10.1001/jamapediatrics.2016.0507

[188] Cremer M, Weimann A,

DOI: 10.1160/TH09-03-0148

10.1038/jp.2017.48

10.1016/j.clp.2015.04.009

DOI: 10.1038/jp.2008.141

Schmalisch G, Hammer H, Buhrer C, Dame C. Immature platelet values indicate impaired megakaryopoietic activity in neonatal early-onset thrombocytopenia. Thrombosis and Haemostasis. 2010;**103**(5 SI):1016-1021.

[189] MacQueen BC, Christensen RD, Henry E, Romrell AM, Pysher TJ, Bennett ST, et al. The immature platelet fraction: Creating neonatal reference intervals and using these to categorize neonatal thrombocytopenias. Journal of Perinatology. 2017;**37**(7):834-838. DOI:

[190] Sparger K, Deschmann E, Sola-Visner M. Platelet transfusions in the neonatal intensive care unit. Clinics in Perinatology. 2015;**42**(3):613-623. DOI:

[191] Wiedmeier SE, Henry E, Sola-Visner MC, Christensen RD. Platelet reference ranges for neonates, defined using data from over 47,000 patients in a multihospital healthcare system. Journal of Perinatology. 2009;**29**(2):130-136.

**82**

neonates in a multihospital healthcare system. Journal of Perinatology. 2007;**27**(12):790-796. DOI: 10.1038/ sj.jp.7211833

[199] Forman KR, Wong E, Gallagher M, McCarter R, Luban NLC, Massaro AN. Effect of temperature on thromboelastography and implications for clinical use in newborns undergoing therapeutic hypothermia. Pediatric Research. 2014;**75**(5):663-669. DOI: 10.1038/pr.2014.19

[200] Chakkarapani E, Davis J, Thoresen M. Therapeutic hypothermia delays the C-reactive protein response and suppresses white blood cell and platelet count in infants with neonatal encephalopathy. Archives of Disease in Childhood. Fetal and Neonatal Edition. 2014;**99**(6):F485-F463. DOI: 10.1136/ archdischild-2013-305763

[201] Christensen RD, Sheffield MJ, Lambert DK, Baer VL. Effect of therapeutic hypothermia in neonates with hypoxic-ischemic encephalopathy on platelet function. Neonatology. 2012;**101**(2):91-94. DOI: 10.1159/000329818

**85**

(WHO) [1].

**Chapter 5**

**Abstract**

*Simona Delia Nicoară*

local side effects in our series.

and with low birth weights (BWs) [1, 2].

**1. Introduction**

Therapeutic Options in

Retinopathy of Prematurity

Preterm babies may develop retinopathy of prematurity (ROP) in various stages.

Most of them regress spontaneously without treatment, and a small proportion develops severe ROP that can lead to visual loss if not treated promptly. Less than 10% of the ROP cases require treatment worldwide. Before 1980, the only treatment for ROP was vitreoretinal surgery for retinal detachment in advanced stages of the disease. Around this time, cryotherapy started to be used in order to ablate the peripheral retina and interrupt the pathogenic chain in ROP, but there were no indications correlated with the severity of the disease. Few years later, cryotherapy was replaced by indirect laser photocoagulation of the nonvascular retina that became the golden standard of treatment for ROP. During the last years, efforts have been made in order to find therapeutic methods to induce the regression of new vessels with minimal side effects. Among these, intravitreal injections of anti-vascular endothelial growth factor (VEGF) became increasingly popular in the treatment of ROP worldwide. Personal experience in treating aggressive posterior ROP (APROP) with laser versus intravitreal anti-VEGF is presented. Intravitreal anti-VEGF proved its superiority in treating APROP as compared to laser, with no systemic and/or

**Keywords:** retinopathy of prematurity, laser, bevacizumab, cryotherapy, blindness

birth which is induced either due to maternal factors or fetal factors. Moreover, theoretically there could be more instances where retinopathy of prematurity (ROP) can develop because there has been a lot of development as well as success in management of preterm babies. Progress in neonatal care was associated with higher survival rates of low birth weight and low gestational age newborns.

All high-risk pregnancies are on the rise, and most of them result in a premature

Retinopathy of prematurity (ROP) is an important threat for the vision of the premature infants, especially for those born at low postconceptional ages (PCAs)

Following progress in neonatal care, the prevalence of ROP is increasing in the developing world, justifying the identification of ROP as a leading cause of visual impairment in children in the developing world, by the World Health Organization

In the developed countries, ROP accounts for 4% of childhood blindness,

whereas in the developing ones, ROP generates 40% of it [1].

#### **Chapter 5**
