**Abstract**

Recent advances in the clinical management of at-risk pregnancy and care of the newborn have reduced morbidity and mortality among sick neonates, and improved our knowledge of factors that influence the risks of brain injury. In parallel, the refinement of imaging techniques has added to the ability of clinicians to define the etiology, timing and location of pathologic changes with diagnostic and prognostic relevance to the developing fetus and newborn infant. Abnormalities of brain growth, or injury to the developing brain can occur during pregnancy; during labor and delivery, hypoxia, acidosis and ischemia pose major risks to the fetus. Defined practices for the management of pregnancy and delivery, and evidence-based strategies for care in the newborn period are influencing outcome. However, newborn infants, especially those born prematurely, remain at risk from situations that can cause or worsen brain injury. The literature reviewed here explains the mechanisms and timing of injury, and the importance of hypoxia, ischemia, hypotension and infection; describes current diagnostic strategies, neuroimaging technologies and care entities available; and outlines approaches that can be used to prevent or mitigate brain injury. Some show particular promise, and all are relevant to lowering the incidence and severity of brain damage.

**Keywords:** encephalopathy, hypoxia, ischemia, magnetic resonance imaging, prematurity, ultrasound, umbilical cord blood gases

## **1. Introduction**

*"This work must begin with the conception of man, and describe the nature of the womb and how the foetus lives in it, up to what stage it resides there, and in what way it quickens into life and feeds. Also, its growth and what interval there is between one stage of growth and another. What it is that forces it out from the body of the mother, and for what reasons it sometimes comes out of the mother's womb before the due time."—Leonardo da Vinci (1452-1519) [1].*

In a prior review (2012), literature describing the etiology of fetal brain injury, and its presentation, evolution and management in the neonate was summarized [2]. However, recent advances have considerably increased our knowledge of the nature and prognosis of brain injury, and what can be done to treat and prevent it.

The importance of maternal and fetal health throughout the nine months of intrauterine life remains. But the vulnerability of the fetus to adverse events related to labor and delivery is better understood, and more readily anticipated. Substantial progress has also been made in the care of neonates, our

understanding of the pathogenesis of injury, and protective strategies which can help to prevent or mitigate permanent injury. It is now clear that acute brain injury is a continuum; hypoxia and ischemia in particular generate a sequence of physiologic consequences where the acute phase of injury is followed by a period of latency, and then brain cells undergo secondary energy failure where a cascade of disruptive events occurs which leads ultimately to programmed cell death. This understanding is particularly valuable, as it now guides investigation linked to both the diagnosis and prognosis of injury, and provides critical opportunities for novel care strategies.

The birth and care of infants born prematurely remains challenging. The inherent immaturity of their organ systems and complex therapies they require makes them vulnerable physiologically to a spectrum of potentially adverse events; the result is a significant incidence of long-term cognitive and motor deficits. In spite of advances in obstetric and neonatal care lowering the overall prevalence of complications, the incidence of cerebral palsy has not reduced significantly. But it is clear now that a strong relationship exists between gestational age at delivery and the probability of both survival and discharge without major handicap, with every additional week in utero tending to improve the chances of a good outcome [3].

Fetal and neonatal brain injury, and the long-term neurodevelopmental handicap caused, is an extremely important problem, and especially so in premature infants, because of the large absolute number born. Research documents that infants born very prematurely (<32 weeks gestation), and those with an extremely low birth weight (<1000 g), are at increased risk for neurobehavioral impairments (cerebral palsy, blindness, deafness), lower general intelligence, specific cognitive defects, learning disabilities, and behavioral and emotional problems [2, 3]. Modern neonatal care does now enable an increasing number of these infants to survive and escape significant handicaps. Survival of extremely preterm infants (<25 weeks gestation) remains rare, but in Europe and the USA 75-90% of infants who weigh <1500 g at birth now survive, however 5-10% of them develop cerebral palsy subsequently, and many have cognitive, behavioral, attention-related or socialization deficits.

Normal fetal growth is a continuum that must be appreciated in order to fully understand the causes, evolution, and consequences of abnormalities in brain development. Key factors have been reviewed previously [2]. Genetic anomalies are the principal cause of fetal loss, and structural abnormalities are commonly evident at a macroscopic and microscopic level. Advances in genetic screening and analysis have led to genetic studies becoming an integral part of the workup of an increasing number of infants. Genetic counseling is central to prevention in situations where there is a family history of a genetic brain abnormality, birth of a prior infant with an anomaly, or predisposition to a genetic problem due to racial or age-related factors. An autopsy and placental pathology are important after fetal loss.

Embryonic development progresses rapidly after conception, so that a large proportion of the brain's structure is already formed by the time many women become aware that they are pregnant. By the end of the first trimester (3 months of gestation), all the main structures of the central nervous system are formed and so brain growth alone follows between this time and fetal maturity (40 weeks). Hence the relevance of more people understanding the concepts currently articulated in the developmental origins of health and disease (DOHaD) [4] and the importance of:


**63**

are restored.

shows particular promise.

**2. Predisposing factors for brain injury**

*Pathogenesis and Prevention of Fetal and Neonatal Brain Injury*

• the beneficial effects of a maternal diet that provides essential nutrients

to treatment. Neuroimaging protocols help to define both the timing and geographic location of injury, and document the evolution of neuronal changes through defined phases over time [6, 7]. In the acute phase, damage follows decreased cerebral blood flow and reduced oxygen and glucose delivery and resulting ischemia and acidosis. A period of latency follows with transient recovery of energy metabolism. Then an 'excito-oxidative' cascade leads to cerebral energy failure and progression to cell death [8–10]. In this phase, reduced adenosine triphosphate (ATP) production affects membrane integrity; intracellular accumulation of sodium and water follows, and brain cell injury is caused by neuronal depolarization, glutamate release, an influx of calcium, and release of toxic nitric oxide free radicals. The 'therapeutic window' offered by the 'latent phase' now allows interventions to ameliorate the effects of HI injury, and hypothermia initiated within 6 hours of age

**Hypoxia** is central to the genesis of much of the brain injury that occurs in the fetus. Compromised oxygen delivery is a particular risk during labor and delivery, but the fetus is at risk whenever brain ischemia occurs due to impaired cerebral blood flow (CBF). After ischemic injury, reperfusion can potentially cause additional injury or complicate recovery, as can any situations that compromise normal brain perfusion further, including disturbance of oxygen delivery and/or carbon dioxide transport, acid base status, or the supply of energy and metabolites required for normal brain function. Resuscitation of a newborn neurologically depressed by intrapartum asphyxia is such a situation, and ongoing brain injury will occur until effective cardiac output, cerebral perfusion and oxygen transport

Clinical effects of hypoxia include a disturbance of acid base status. An unrelieved hypoxic event in the fetus causes progressive acidosis which leads to systemic organ dysfunction, including cardiac depression, where compromised contractility and filling reduce cardiac output leading to a reduction in CBF and high risk of brain insult when cerebral hypoxia and ischemia occur. Importantly, cardiac functional impairment can precede depression of fetal heart rate. Hypoxic insults depress brain

• maternal nutrition and weight gain that avoids fetal stunting or overweight

Impaired fetal growth secondary to poor maternal nutrition or placental insufficiency can be associated with reduced brain development; growth retarded infants are at increased risk of hypoxic stress and hypoxic ischemic (HI) brain injury due to altered placental blood flow and sub-optimal fetal oxygenation, particularly at the time of delivery. Suboptimal nutrition also poses the risk of hypoglycemic brain injury immediately after birth; the impact of this form of brain injury can now be defined through neuroimaging [5]. At the opposite end of the spectrum, being large for gestational age, post mature, or the product of a multiple pregnancy poses unique challenges, and increases the risk of HI injury [2]. In addition, surviving infants born small or large for gestational age are at increased risk of developing adult-onset chronic diseases (e.g. hypertension, cardiovascular disease, stroke, type 2 diabetes, obesity); the current epidemic of non-communicable diseases has been shown to be linked to early stunting of growth and excessive infant weight gain [4]. Importantly many of the causes of brain damage are now avoidable or amenable

*DOI: http://dx.doi.org/10.5772/intechopen.93840*

*Advancement and New Understanding in Brain Injury*

novel care strategies.

socialization deficits.

understanding of the pathogenesis of injury, and protective strategies which can help to prevent or mitigate permanent injury. It is now clear that acute brain injury is a continuum; hypoxia and ischemia in particular generate a sequence of physiologic consequences where the acute phase of injury is followed by a period of latency, and then brain cells undergo secondary energy failure where a cascade of disruptive events occurs which leads ultimately to programmed cell death. This understanding is particularly valuable, as it now guides investigation linked to both the diagnosis and prognosis of injury, and provides critical opportunities for

The birth and care of infants born prematurely remains challenging. The inherent immaturity of their organ systems and complex therapies they require makes them vulnerable physiologically to a spectrum of potentially adverse events; the result is a significant incidence of long-term cognitive and motor deficits. In spite of advances in obstetric and neonatal care lowering the overall prevalence of complications, the incidence of cerebral palsy has not reduced significantly. But it is clear now that a strong relationship exists between gestational age at delivery and the probability of both survival and discharge without major handicap, with every additional week in utero tending to improve the chances of a good outcome [3]. Fetal and neonatal brain injury, and the long-term neurodevelopmental handicap caused, is an extremely important problem, and especially so in premature infants, because of the large absolute number born. Research documents that infants born very prematurely (<32 weeks gestation), and those with an extremely low birth weight (<1000 g), are at increased risk for neurobehavioral impairments (cerebral palsy, blindness, deafness), lower general intelligence, specific cognitive defects, learning disabilities, and behavioral and emotional problems [2, 3]. Modern neonatal care does now enable an increasing number of these infants to survive and escape significant handicaps. Survival of extremely preterm infants (<25 weeks gestation) remains rare, but in Europe and the USA 75-90% of infants who weigh <1500 g at birth now survive, however 5-10% of them develop cerebral palsy subsequently, and many have cognitive, behavioral, attention-related or

Normal fetal growth is a continuum that must be appreciated in order to fully understand the causes, evolution, and consequences of abnormalities in brain development. Key factors have been reviewed previously [2]. Genetic anomalies are the principal cause of fetal loss, and structural abnormalities are commonly evident at a macroscopic and microscopic level. Advances in genetic screening and analysis have led to genetic studies becoming an integral part of the workup of an increasing number of infants. Genetic counseling is central to prevention in situations where there is a family history of a genetic brain abnormality, birth of a prior infant with an anomaly, or predisposition to a genetic problem due to racial or age-related factors.

Embryonic development progresses rapidly after conception, so that a large proportion of the brain's structure is already formed by the time many women become aware that they are pregnant. By the end of the first trimester (3 months of gestation), all the main structures of the central nervous system are formed and so brain growth alone follows between this time and fetal maturity (40 weeks). Hence the relevance of more people understanding the concepts currently articulated in the developmental origins of health and disease (DOHaD) [4] and the importance of:

An autopsy and placental pathology are important after fetal loss.

• health at the time of conception (both paternal and maternal);

• the detrimental effects on the fetal brain of drugs, alcohol and nicotine;

**62**


Impaired fetal growth secondary to poor maternal nutrition or placental insufficiency can be associated with reduced brain development; growth retarded infants are at increased risk of hypoxic stress and hypoxic ischemic (HI) brain injury due to altered placental blood flow and sub-optimal fetal oxygenation, particularly at the time of delivery. Suboptimal nutrition also poses the risk of hypoglycemic brain injury immediately after birth; the impact of this form of brain injury can now be defined through neuroimaging [5]. At the opposite end of the spectrum, being large for gestational age, post mature, or the product of a multiple pregnancy poses unique challenges, and increases the risk of HI injury [2]. In addition, surviving infants born small or large for gestational age are at increased risk of developing adult-onset chronic diseases (e.g. hypertension, cardiovascular disease, stroke, type 2 diabetes, obesity); the current epidemic of non-communicable diseases has been shown to be linked to early stunting of growth and excessive infant weight gain [4].

Importantly many of the causes of brain damage are now avoidable or amenable to treatment. Neuroimaging protocols help to define both the timing and geographic location of injury, and document the evolution of neuronal changes through defined phases over time [6, 7]. In the acute phase, damage follows decreased cerebral blood flow and reduced oxygen and glucose delivery and resulting ischemia and acidosis. A period of latency follows with transient recovery of energy metabolism. Then an 'excito-oxidative' cascade leads to cerebral energy failure and progression to cell death [8–10]. In this phase, reduced adenosine triphosphate (ATP) production affects membrane integrity; intracellular accumulation of sodium and water follows, and brain cell injury is caused by neuronal depolarization, glutamate release, an influx of calcium, and release of toxic nitric oxide free radicals. The 'therapeutic window' offered by the 'latent phase' now allows interventions to ameliorate the effects of HI injury, and hypothermia initiated within 6 hours of age shows particular promise.
