**2. Predisposing factors for brain injury**

**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 are restored.

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

function, so following intrapartum insults infants are neurologically abnormal at birth, often require resuscitation to initiate breathing, and cardiovascular support can be needed to stimulate heart function and provide adequate blood pressure and circulation. Tone and behavior usually remain abnormal on admission to the nursery; encephalopathy developing in the hours or days after birth is confirmation that a significant HI insult resulting in brain injury has occurred.

Hypoxic ischemic brain injury is estimated to occur in about 3 out of every 1000 births [8]. Diagnostic features include problems with level of consciousness, tone, respiratory drive, and coordination of sucking and swallowing, and seizure activity which is commonly refractory. In the longer term, the consequences of injury vary between death (15-20%) and complete recovery, with the spectrum of permanent brain injury ranging from mild motor and cognitive defects, to cerebral palsy and severe cognitive disabilities. The pattern and consequences of injury depend on the severity and duration of the insult. The neurovascular and anatomical maturity of the brain relative to the gestational age of the fetus is also a primary factor; corelated elements include the adequacy of metabolic reserves available to the fetus to compensate for oxidative stress, the presence or absence of infection, and preexisting abnormalities in brain growth and development. Different regions of the fetal brain and individual cell lines have gestation specific vulnerability to damage.

**Prematurity**: The 10% of infants born prematurely are at particular risk for brain injury; their neurovascular anatomy has limited development making them vulnerable to fluctuations in brain blood flow and oxygen delivery. In those very immature, the brain lacks both the duplication of blood supply that develops as a fetus matures, and the ability to auto-regulate CBF in response to fluctuations in systemic blood pressure. Vascular complexes in areas such as the germinal matrix are vulnerable to bleeding when blood pressure fluctuates, and perturbations insufficient to cause damage in a more mature fetus may generate injury; bleeding is often related to asphyxial stress, and can result from complications of treatment entities very preterm infants require. Mechanisms underlying this form of injury include: variations in cerebral venous pressure, major cerebral vasodilatation or constriction, altered distribution of CBF, systemic fluctuations in circulating blood volume, and significant changes in either oxygen or carbon dioxide tension [11].

Periventricular leukomalacia (PVL) is predominately a condition affecting the preterm infant. The primary causal mechanism is HI injury, with ischemia being the major component. PVL acquired intrapartum is usually associated with abnormal neurological findings at birth, but may manifest as lower limb weakness evident in the first weeks of life. PVL can be aggravated by, or generated as a result of postnatal events. Neurobiologic research has shown that maturational dependent oligodendroglial precursor cells are a major target in PVL, and these are exquisitely vulnerable to damage by free radicals generated during ischemia and reperfusion. PVL is associated with intraventricular hemorrhage (IVH) in approximately 25% of cases. The pathogenesis of IVH is usually multifactorial, and related to: fluctuating CBF; increased cerebral venous pressure; decreased CBF followed by reperfusion; and disorders of coagulation, platelet function and capillary integrity [11].

The commonest clinical situation where pathogenic factors combine to generate sufficient ischemia to cause PVL is when a sick preterm infant requires mechanical ventilation, and problems occur during 'uncontrolled' intubation, with 'fighting the ventilator,' or when a pneumothorax (air leak) compresses the lung, which raises intrathoracic pressure and disrupts normal blood return to the heart; in turn, this reduces cardiac output and brain blood flow. Vascular factors are also relevant; blood transfusion or rapid IV volume replacement pose potential risk due to the pressure passive nature of the immature cerebral circulation; systemic variations in blood pressure, sequelae of sepsis, and the cerebral effects of hypocarbia can render

**65**

**Table 1.**

*enterocolitis stage 2-3 [3].*

*Pathogenesis and Prevention of Fetal and Neonatal Brain Injury*

an infant symptomatic. Many infants with PVL have a normal neurologic outcome. Those with permanent sequelae exhibit a range of problems with varying degrees of severity; including intellectual and visual deficits, usually superimposed on spastic paresis involving the extremities, where the lower limbs are predominantly affected. In late prematurity (34 weeks to 36 weeks plus 6 days gestation), the vulnerability of the brain to injury, and the pattern of damage commonly seen are different, due to increased structural and functional maturation; at 34 weeks of gestation the brain has 65% of its term volume compared to 13% at 28 weeks, and a fivefold increase in white matter volume occurs between 35 and 41 weeks of gestation. **Low birth weight (LBW)** infants are those born <2500 g. and comprise infants born prematurely but appropriately grown for gestational age, and those who are small because of intrauterine growth retardation (IUGR). LBW is further divided into very low birth weight (<1500 g) and extremely low birth weight (<1000 g). Globally 14.6% of infants born are LBW (5-10% in industrialized countries); UNICEF data indicate that LBW infants have a disproportionate death rate and high intrapartum morbidity. Brain injury is caused by many factors, e.g. placental dysfunction and acute compromise of placental gas exchange, and risks in the newborn period due to the causal factors for their small size. Long-term, neurodevelopmental problems occur. **Extremely low birthweight (ELBW)** infants are often born close to the limit of viability. Many who survive are at risk of brain injury and neurodevelopmental handicaps; however, advances in care have led to a substantial reduction in severe morbidity, with clear benefits evident for ELBW infants of higher gestation [3]. Consequently, gestational age is a factor that continues to drive interventions aimed at prolonging pregnancy. Where such treatment is an option and fetal wellbeing can be sustained, there are clear benefits for the fetus of longer gestation. Data from a national, prospective, population-based cohort study conducted in all maternity and neonatal units in France in 2011 indicate that survival to discharge, and survival

without any severe adverse outcome are both gestation dependent (**Table 1**).

**Small and large for gestational age (SGA/LGA) infants** are those born below the 10th and above the 90th centiles respectively. Hypoxic composite neonatal morbidity is more common among SGA neonates and traumatic–composite neonatal morbidity more common with LGA. In symmetrically growth-retarded SGA infants, brain size and function are affected; long-term deficits in neural connectivity and cognitive problems can result. Fetal glucose is determined by maternal levels, but impaired glucose metabolism occurs with SGA where hepatic glycogen stores are low at birth, and in LGA associated with maternal gestational diabetes [2]. **Placental pathology** underlies many causes of compromised fetal growth and development and intrapartum hypoxia, e.g. decreased maturation of the terminal villi is associated with injury to the white matter/watershed areas and basal ganglia [12]; also, conditions that can cause fetal death (toxemia in pregnancy, twin to twin transfusion syndrome (TTTS), hemorrhage from placenta previa and placental abruption and fetal stroke) [13, 14]. Strokes occur between 14 weeks gestation and delivery. Etiology is often obscure; ischemic, thrombotic or hemorrhagic injury occurs; causes include maternal platelet abnormalities, trauma, TTTS, medication (warfarin and some antiepileptic drugs decrease vitamin K dependent coagulation

Gestation in weeks 23 24 25 26 27-31 32-34 Percentage of survivors 0% 11.6% 30% 47.5% 81.3% 96.8%

*leukomalacia, retinopathy of prematurity stage 3 or higher, severe bronchopulmonary dysplasia, or necrotizing* 

*Gestation-related survival without grade 3/4 intraventricular hemorrhage, cystic periventricular* 

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

#### *Pathogenesis and Prevention of Fetal and Neonatal Brain Injury DOI: http://dx.doi.org/10.5772/intechopen.93840*

*Advancement and New Understanding in Brain Injury*

function, so following intrapartum insults infants are neurologically abnormal at birth, often require resuscitation to initiate breathing, and cardiovascular support can be needed to stimulate heart function and provide adequate blood pressure and circulation. Tone and behavior usually remain abnormal on admission to the nursery; encephalopathy developing in the hours or days after birth is confirmation

Hypoxic ischemic brain injury is estimated to occur in about 3 out of every 1000 births [8]. Diagnostic features include problems with level of consciousness, tone, respiratory drive, and coordination of sucking and swallowing, and seizure activity which is commonly refractory. In the longer term, the consequences of injury vary between death (15-20%) and complete recovery, with the spectrum of permanent brain injury ranging from mild motor and cognitive defects, to cerebral palsy and severe cognitive disabilities. The pattern and consequences of injury depend on the severity and duration of the insult. The neurovascular and anatomical maturity of the brain relative to the gestational age of the fetus is also a primary factor; corelated elements include the adequacy of metabolic reserves available to the fetus to compensate for oxidative stress, the presence or absence of infection, and preexisting abnormalities in brain growth and development. Different regions of the fetal brain and individual cell lines have gestation specific vulnerability to damage. **Prematurity**: The 10% of infants born prematurely are at particular risk for brain injury; their neurovascular anatomy has limited development making them vulnerable to fluctuations in brain blood flow and oxygen delivery. In those very immature, the brain lacks both the duplication of blood supply that develops as a fetus matures, and the ability to auto-regulate CBF in response to fluctuations in systemic blood pressure. Vascular complexes in areas such as the germinal matrix are vulnerable to bleeding when blood pressure fluctuates, and perturbations insufficient to cause damage in a more mature fetus may generate injury; bleeding is often related to asphyxial stress, and can result from complications of treatment entities very preterm infants require. Mechanisms underlying this form of injury include: variations in cerebral venous pressure, major cerebral vasodilatation or constriction, altered distribution of CBF, systemic fluctuations in circulating blood volume, and significant changes in either oxygen or carbon dioxide tension [11]. Periventricular leukomalacia (PVL) is predominately a condition affecting the preterm infant. The primary causal mechanism is HI injury, with ischemia being the major component. PVL acquired intrapartum is usually associated with abnormal neurological findings at birth, but may manifest as lower limb weakness evident in the first weeks of life. PVL can be aggravated by, or generated as a result of postnatal events. Neurobiologic research has shown that maturational dependent oligodendroglial precursor cells are a major target in PVL, and these are exquisitely vulnerable to damage by free radicals generated during ischemia and reperfusion. PVL is associated with intraventricular hemorrhage (IVH) in approximately 25% of cases. The pathogenesis of IVH is usually multifactorial, and related to: fluctuating CBF; increased cerebral venous pressure; decreased CBF followed by reperfusion;

that a significant HI insult resulting in brain injury has occurred.

and disorders of coagulation, platelet function and capillary integrity [11].

The commonest clinical situation where pathogenic factors combine to generate sufficient ischemia to cause PVL is when a sick preterm infant requires mechanical ventilation, and problems occur during 'uncontrolled' intubation, with 'fighting the ventilator,' or when a pneumothorax (air leak) compresses the lung, which raises intrathoracic pressure and disrupts normal blood return to the heart; in turn, this reduces cardiac output and brain blood flow. Vascular factors are also relevant; blood transfusion or rapid IV volume replacement pose potential risk due to the pressure passive nature of the immature cerebral circulation; systemic variations in blood pressure, sequelae of sepsis, and the cerebral effects of hypocarbia can render

**64**

an infant symptomatic. Many infants with PVL have a normal neurologic outcome. Those with permanent sequelae exhibit a range of problems with varying degrees of severity; including intellectual and visual deficits, usually superimposed on spastic paresis involving the extremities, where the lower limbs are predominantly affected.

In late prematurity (34 weeks to 36 weeks plus 6 days gestation), the vulnerability of the brain to injury, and the pattern of damage commonly seen are different, due to increased structural and functional maturation; at 34 weeks of gestation the brain has 65% of its term volume compared to 13% at 28 weeks, and a fivefold increase in white matter volume occurs between 35 and 41 weeks of gestation.

**Low birth weight (LBW)** infants are those born <2500 g. and comprise infants born prematurely but appropriately grown for gestational age, and those who are small because of intrauterine growth retardation (IUGR). LBW is further divided into very low birth weight (<1500 g) and extremely low birth weight (<1000 g). Globally 14.6% of infants born are LBW (5-10% in industrialized countries); UNICEF data indicate that LBW infants have a disproportionate death rate and high intrapartum morbidity. Brain injury is caused by many factors, e.g. placental dysfunction and acute compromise of placental gas exchange, and risks in the newborn period due to the causal factors for their small size. Long-term, neurodevelopmental problems occur.

**Extremely low birthweight (ELBW)** infants are often born close to the limit of viability. Many who survive are at risk of brain injury and neurodevelopmental handicaps; however, advances in care have led to a substantial reduction in severe morbidity, with clear benefits evident for ELBW infants of higher gestation [3]. Consequently, gestational age is a factor that continues to drive interventions aimed at prolonging pregnancy. Where such treatment is an option and fetal wellbeing can be sustained, there are clear benefits for the fetus of longer gestation. Data from a national, prospective, population-based cohort study conducted in all maternity and neonatal units in France in 2011 indicate that survival to discharge, and survival without any severe adverse outcome are both gestation dependent (**Table 1**).

**Small and large for gestational age (SGA/LGA) infants** are those born below the 10th and above the 90th centiles respectively. Hypoxic composite neonatal morbidity is more common among SGA neonates and traumatic–composite neonatal morbidity more common with LGA. In symmetrically growth-retarded SGA infants, brain size and function are affected; long-term deficits in neural connectivity and cognitive problems can result. Fetal glucose is determined by maternal levels, but impaired glucose metabolism occurs with SGA where hepatic glycogen stores are low at birth, and in LGA associated with maternal gestational diabetes [2].

**Placental pathology** underlies many causes of compromised fetal growth and development and intrapartum hypoxia, e.g. decreased maturation of the terminal villi is associated with injury to the white matter/watershed areas and basal ganglia [12]; also, conditions that can cause fetal death (toxemia in pregnancy, twin to twin transfusion syndrome (TTTS), hemorrhage from placenta previa and placental abruption and fetal stroke) [13, 14]. Strokes occur between 14 weeks gestation and delivery. Etiology is often obscure; ischemic, thrombotic or hemorrhagic injury occurs; causes include maternal platelet abnormalities, trauma, TTTS, medication (warfarin and some antiepileptic drugs decrease vitamin K dependent coagulation


**Table 1.**

*Gestation-related survival without grade 3/4 intraventricular hemorrhage, cystic periventricular leukomalacia, retinopathy of prematurity stage 3 or higher, severe bronchopulmonary dysplasia, or necrotizing enterocolitis stage 2-3 [3].*

factors), parvovirus B19 and cytomegalovirus infections, and protein C deficiency [15, 16]. Diagnosis in utero can be made by ultrasound (US); magnetic resonance imaging (MRI) is the optimal imaging modality [16].

**Twin to twin transfusion syndrome (TTTS)** occurs in up to 1:4 monochorionic diamniotic twin pregnancies; nearly 100% have placental vascular anastomoses; most are hemodynamically balanced, but severe complications result when there is a chronic net transfusion imbalance between fetuses. Hemodynamically significant shunts classically manifest in the mid trimester; while subtle initially, cardiovascular effects do impact both recipient and donor twins and are an important factor contributing to morbidity and mortality [13, 17]; 70% of recipient twins show echocardiographic evidence of cardiac compromise [18]. Protocols for frequent US of at-risk twins are the mainstay of management; these monitor onset/progression of complications through defined stages of evolution (Quintero stages 1–5), quantify the adverse effects of the altered hemodynamics on each twin, and allow perinatal management interventions that have the potential to improve fetal morbidity and mortality. US provides assessment of amniotic fluid status, measurements of fetal structures, and fetal weight estimates which identify growth disparity, and are predictive of birth weight discordance [19]. As the transfusion of blood from one twin to the other increases, the donor twin becomes oliguric due to decreased renal perfusion, with virtual absence of amniotic fluid; this can be so marked it prevents fetal movement giving rise to the term 'stuck' twin. In contrast, the recipient develops polyhydramnios due to increased urine production. Without intervention to treat TTTS, increasing polyhydramnios will ultimately result in preterm labor, due to the mechanical forces generated by overdistention of the uterus; overall, polyhydramnios is complicated by preterm labor in up to 26% of cases, and premature rupture of the membranes (PROM) in up to 19% of cases.

Ischemia is the principal mechanism underlying brain damage; lesions include white matter infarction, intra-ventricular hemorrhage, hydranencephaly, and porencephaly. In up to 58% of TTTS affected pregnancies combined US evidence is reported of antenatally acquired brain abnormalities and IVH, and periventricular echogenicity assumed to be perinatally acquired [20]. Fetal MRI can identify CNS injury; findings range from ischemic or hemorrhagic lesions in the brain to marked dilation of the cerebral venous sinuses secondary to central venous hypertension.

US can also evaluate flow in the umbilical vein (UV) and ductus venosus (DV). Normally, the UV blood flow velocity waveform has an even non-pulsating pattern, since the pulse waves caused by atrial contractions are not propagated backwards through the narrow ductus venosus. However, if the DV widens, the pulse waves propagate into the UV and result in a pulsating pattern. UV pulsations were first described in fetuses in imminent danger of asphyxia, then in those hydropic due to heart failure. In fetuses exposed to chronic hypoxia, UV pulsations predict poor outcome [21]. The presence of absent or reversed flow in the DV during atrial systole (defined as absent/reversed a-wave) is associated with poor perinatal outcomes because of compromise to mechanisms that normally preferentially supply the fetal brain with well oxygenated blood. The function of the DV is to shunt a portion of the oxygenated blood arriving from the placenta directly to the inferior vena cava, allowing oxygenated blood to bypass the liver. Consequently, DV flow plays a critical role in preferentially supplying oxygen to the fetal brain, in parallel with the other fetal shunts (foramen ovale and ductus arteriosus). And so, US evidence of an absent or reversed a-wave in the DV identifies those fetuses who are at the highest risk of hypoxic brain injury in utero [13, 22, 23].

The expectation of maternal treatment, even for severe TTTS, is for improvement, with probable resolution in utero [24], including regression of fetal cardiovascular pathology and improved myocardial performance. Recovery may take

**67**

controlled [11].

*Pathogenesis and Prevention of Fetal and Neonatal Brain Injury*

longer in more severely affected pregnancies, but this is not the case in all series. Survival, particularly for the recipient twin, is likely to be compromised if treatment is delayed [25] hence the relevance of US surveillance and early diagnosis [17]. **Maternal Illness during pregnancy:** Some are specific to pregnancy such as gestational diabetes; others pre-exist; many have the potential to cause damage, or predispose the fetus to independent risks for neurological morbidity [2]. Some have well known associations with brain injury; rubella and the TORCH group of viruses are examples; TORCH viruses are also a potent cause of perinatal death and a particular burden in developing countries; some are amenable to treatment; early recognition, including maternal prenatal screening, is a key aspect in management [26]. Common upper respiratory tract infections and gastroenteritis, although often of concern to pregnant women, are not usually associated with brain injury [27]. **Fetal inflammatory response syndrome (FIRS):** Inflammatory mediators are known to precipitate premature rupture of the membranes (PROM) and preterm labor, inflame and cross the placenta, and have been linked to increased risk of fetal brain injury and cerebral palsy [28]. In FIRS, maternal systemic inflammation occurs with activation of the innate fetal immune system and elevation of fetal plasma cytokines. Cytokine production usually generates a normal immune response, but in the immature fetus and premature infant born after FIRS, the complex effects of cytokine activity have been linked to increased infant morbidity and mortality, perhaps because the balance of these agents is imperfectly

Many cytokines are vasoactive, so in the immature brain, focal variations in brain perfusion could result in local ischemia followed by reperfusion; such perturbations may cause cumulative injury to brain white matter due to the primitive neuro-vascular architecture, immature autoregulatory control mechanisms, and sensitivity of maturational dependent cells to free radical damage. The germinal matrix is also particularly vulnerable to variations in brain blood flow and blood pressure [11]; consequently, it has been hypothesized that periventricular hemor-

The initial literature supported a role for inflammatory mediators in premature labor and delivery; linked maternal infection and pro-inflammatory mediators in the neonatal systemic circulation with increased risk of periventricular leukomalacia and/or spastic diplegia; emphasized the synergistic role of inflammation and hypoxia and ischemia when they occur together; and reported a higher incidence of HI brain damage where fetal exposure to maternal inflammation/infection occurred [2]. This literature also states: "For the premature fetus, once clinical chorioamnionitis occurs, rates of sepsis, pneumonia, respiratory distress syndrome and death are all increased by 2-4-fold and long-term neurologic injury is substantially more likely to occur" [29]. Strategies can be used to down-regulate the inflammatory response and treat mothers with signs and symptoms of infection; some antibiotic therapies reduce cytokine production; because of the independent association of elevated maternal temperature with worse fetal outcome, appropriate management

rhage would be more likely to occur in the preterm fetus exposed to FIRS.

to control fever is also cited as a treatment of potential benefit [30, 31].

Recent literature reappraises prior FIRS-related research. Isolated cytokinemediated injury is not reported in term infants [11], and in the premature newborn, newer studies have found the relationship between chorioamnionitis and brain injury to be attenuated; this difference may result from heterogeneity of the studies, or possibly improved neonatal intensive care [32]. Current literature does conflict on whether or not histopathological chorioamnionitis is linked to an increased risk of white matter injury and intraventricular hemorrhage, or with abnormalities of brain development identifiable via MRI (e.g. variations in cortical thickness). But research continues to emphasize that postnatal complications from infections,

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

#### *Pathogenesis and Prevention of Fetal and Neonatal Brain Injury DOI: http://dx.doi.org/10.5772/intechopen.93840*

*Advancement and New Understanding in Brain Injury*

imaging (MRI) is the optimal imaging modality [16].

factors), parvovirus B19 and cytomegalovirus infections, and protein C deficiency [15, 16]. Diagnosis in utero can be made by ultrasound (US); magnetic resonance

**Twin to twin transfusion syndrome (TTTS)** occurs in up to 1:4 monochorionic diamniotic twin pregnancies; nearly 100% have placental vascular anastomoses; most are hemodynamically balanced, but severe complications result when there is a chronic net transfusion imbalance between fetuses. Hemodynamically significant shunts classically manifest in the mid trimester; while subtle initially, cardiovascular effects do impact both recipient and donor twins and are an important factor contributing to morbidity and mortality [13, 17]; 70% of recipient twins show echocardiographic evidence of cardiac compromise [18]. Protocols for frequent US of at-risk twins are the mainstay of management; these monitor onset/progression of complications through defined stages of evolution (Quintero stages 1–5), quantify the adverse effects of the altered hemodynamics on each twin, and allow perinatal management interventions that have the potential to improve fetal morbidity and mortality. US provides assessment of amniotic fluid status, measurements of fetal structures, and fetal weight estimates which identify growth disparity, and are predictive of birth weight discordance [19]. As the transfusion of blood from one twin to the other increases, the donor twin becomes oliguric due to decreased renal perfusion, with virtual absence of amniotic fluid; this can be so marked it prevents fetal movement giving rise to the term 'stuck' twin. In contrast, the recipient develops polyhydramnios due to increased urine production. Without intervention to treat TTTS, increasing polyhydramnios will ultimately result in preterm labor, due to the mechanical forces generated by overdistention of the uterus; overall, polyhydramnios is complicated by preterm labor in up to 26% of cases, and

premature rupture of the membranes (PROM) in up to 19% of cases.

risk of hypoxic brain injury in utero [13, 22, 23].

Ischemia is the principal mechanism underlying brain damage; lesions include white matter infarction, intra-ventricular hemorrhage, hydranencephaly, and porencephaly. In up to 58% of TTTS affected pregnancies combined US evidence is reported of antenatally acquired brain abnormalities and IVH, and periventricular echogenicity assumed to be perinatally acquired [20]. Fetal MRI can identify CNS injury; findings range from ischemic or hemorrhagic lesions in the brain to marked dilation of the cerebral venous sinuses secondary to central venous hypertension. US can also evaluate flow in the umbilical vein (UV) and ductus venosus (DV). Normally, the UV blood flow velocity waveform has an even non-pulsating pattern, since the pulse waves caused by atrial contractions are not propagated backwards through the narrow ductus venosus. However, if the DV widens, the pulse waves propagate into the UV and result in a pulsating pattern. UV pulsations were first described in fetuses in imminent danger of asphyxia, then in those hydropic due to heart failure. In fetuses exposed to chronic hypoxia, UV pulsations predict poor outcome [21]. The presence of absent or reversed flow in the DV during atrial systole (defined as absent/reversed a-wave) is associated with poor perinatal outcomes because of compromise to mechanisms that normally preferentially supply the fetal brain with well oxygenated blood. The function of the DV is to shunt a portion of the oxygenated blood arriving from the placenta directly to the inferior vena cava, allowing oxygenated blood to bypass the liver. Consequently, DV flow plays a critical role in preferentially supplying oxygen to the fetal brain, in parallel with the other fetal shunts (foramen ovale and ductus arteriosus). And so, US evidence of an absent or reversed a-wave in the DV identifies those fetuses who are at the highest

The expectation of maternal treatment, even for severe TTTS, is for improvement, with probable resolution in utero [24], including regression of fetal cardiovascular pathology and improved myocardial performance. Recovery may take

**66**

longer in more severely affected pregnancies, but this is not the case in all series. Survival, particularly for the recipient twin, is likely to be compromised if treatment is delayed [25] hence the relevance of US surveillance and early diagnosis [17].

**Maternal Illness during pregnancy:** Some are specific to pregnancy such as gestational diabetes; others pre-exist; many have the potential to cause damage, or predispose the fetus to independent risks for neurological morbidity [2]. Some have well known associations with brain injury; rubella and the TORCH group of viruses are examples; TORCH viruses are also a potent cause of perinatal death and a particular burden in developing countries; some are amenable to treatment; early recognition, including maternal prenatal screening, is a key aspect in management [26]. Common upper respiratory tract infections and gastroenteritis, although often of concern to pregnant women, are not usually associated with brain injury [27].

**Fetal inflammatory response syndrome (FIRS):** Inflammatory mediators are known to precipitate premature rupture of the membranes (PROM) and preterm labor, inflame and cross the placenta, and have been linked to increased risk of fetal brain injury and cerebral palsy [28]. In FIRS, maternal systemic inflammation occurs with activation of the innate fetal immune system and elevation of fetal plasma cytokines. Cytokine production usually generates a normal immune response, but in the immature fetus and premature infant born after FIRS, the complex effects of cytokine activity have been linked to increased infant morbidity and mortality, perhaps because the balance of these agents is imperfectly controlled [11].

Many cytokines are vasoactive, so in the immature brain, focal variations in brain perfusion could result in local ischemia followed by reperfusion; such perturbations may cause cumulative injury to brain white matter due to the primitive neuro-vascular architecture, immature autoregulatory control mechanisms, and sensitivity of maturational dependent cells to free radical damage. The germinal matrix is also particularly vulnerable to variations in brain blood flow and blood pressure [11]; consequently, it has been hypothesized that periventricular hemorrhage would be more likely to occur in the preterm fetus exposed to FIRS.

The initial literature supported a role for inflammatory mediators in premature labor and delivery; linked maternal infection and pro-inflammatory mediators in the neonatal systemic circulation with increased risk of periventricular leukomalacia and/or spastic diplegia; emphasized the synergistic role of inflammation and hypoxia and ischemia when they occur together; and reported a higher incidence of HI brain damage where fetal exposure to maternal inflammation/infection occurred [2]. This literature also states: "For the premature fetus, once clinical chorioamnionitis occurs, rates of sepsis, pneumonia, respiratory distress syndrome and death are all increased by 2-4-fold and long-term neurologic injury is substantially more likely to occur" [29]. Strategies can be used to down-regulate the inflammatory response and treat mothers with signs and symptoms of infection; some antibiotic therapies reduce cytokine production; because of the independent association of elevated maternal temperature with worse fetal outcome, appropriate management to control fever is also cited as a treatment of potential benefit [30, 31].

Recent literature reappraises prior FIRS-related research. Isolated cytokinemediated injury is not reported in term infants [11], and in the premature newborn, newer studies have found the relationship between chorioamnionitis and brain injury to be attenuated; this difference may result from heterogeneity of the studies, or possibly improved neonatal intensive care [32]. Current literature does conflict on whether or not histopathological chorioamnionitis is linked to an increased risk of white matter injury and intraventricular hemorrhage, or with abnormalities of brain development identifiable via MRI (e.g. variations in cortical thickness). But research continues to emphasize that postnatal complications from infections,

particularly when associated with hypotension in the premature newborn, are associated with an increased risk of white matter injury [33, 34].

**Fetal and neonatal Infection** significantly increases the risk of brain injury. Mechanisms promoting sepsis include PROM; the risk of fetal infection from membrane rupture beyond 18 hours increases (10-fold), as does the occurrence of perinatal asphyxia, maternal urinary tract infection and colonization with group B Streptococcus [35]. Maternal treatment and prophylactic antibiotics given in anticipation of sepsis to the infant at birth are essential, as by the time confirmatory tests (bacterial cultures) are positive, the risks of infection having disseminated into the blood stream (septicemia) or spread to the meninges (meningitis) are high. Hypotension secondary to sepsis can profoundly compromise brain perfusion and oxygen delivery, and dramatically increases morbidity; once present, it is often refractory to treatment as the underlying mechanisms are multifactorial, including the generation of cytokines, and release of toxic metabolites by bacteria.

**Hypoglycemia:** During transition to extrauterine life, fetal adaptation normally enables alternative fuels to be metabolized (lactate, ketone bodies, fatty acids) which ensures energy supply to vital organs when blood glucose concentration falls. But once born, this ability is down-regulated, especially by oral feeding [2], and transitional hypoglycemia can occur. While no single glucose value can define hypoglycemia, fully ensure an infant's safety or limit morbidity, management guidelines exist as hypoglycemia can have neurologic consequences [36–38], especially when accompanied by seizures, including: motor and/or psychodevelopmental delay, microcephaly, seizures, visual impairment, and spastic quadriplegia and hemiplegia.

Population data indicate that blood glucose levels as low as 2.0 mmol/L (or even 1.8 mmol/L at 1 hour of age) are not uncommon in healthy newborns. However, various syndromes and metabolic conditions cause or contribute to hypoglycemia. Importantly, HI injury can disrupt normal metabolic adaptation, as anaerobic glycolysis depletes hepatic glycogen and hyperinsulinism can also occur; there is a correlation between lower serum glucose levels and higher Sarnat stages in hypoxic ischemic encephalopathy (HIE).

For at-risk infants, outcome data support raising the intervention threshold from conventional levels. Current screening and management guidelines are that neonates with hypoglycemia persisting beyond the first 72 should be investigated further when levels remain ≤2.8 mmol/L, and ≥ 3.3 mmol/L should be the therapeutic glucose target level in symptomatic/at risk infants. Also, before discharge, those experiencing persistent hypoglycemia should have a 5-6 hour fast, while maintaining blood glucose levels ≥3.3 mmol/L, to ensure safety at home [39].

Differing patterns of damage now help to distinguish hypoglycemic from HI brain injury [5, 40, 41]; the combination on MRI of selective edema in the posterior white matter and pulvinar appears specific even in absence of hypoglycemic laboratory values. In neonates with concurrent hypoglycemia and HIE, injury is synergistic, and the imaging features of both HI injury and hypoglycemia may be detected [5].

**Hyperglycemia:** A blood glucose concentration > 125 mg/dL (6.9 mmol/L) is a common metabolic abnormality encountered in preterm and critically ill newborns [42]. Management varies; often iatrogenic, hyperglycemia can cause or aggravate brain damage, principally because of the hyperosmolar state that ensues [43].

**Hyponatremia** in the premature can cause sensorineural hearing loss, cerebral palsy, intracranial hemorrhage, and increase mortality following asphyxia [44, 45].

**Hypernatremia**/**hyperbilirubinemia** when extreme are neurotoxic. Inadequate fluid intake in immature infants and those primarily breast fed is contributory [46, 47]. Kernicterus selectively damages the globus pallidus and subthalamic nuclei [8, 48]; hazardous hyperbilirubinemia is often preventable; health care professional

**69**

*Pathogenesis and Prevention of Fetal and Neonatal Brain Injury*

compliance with best practices for screening, phototherapy and related treatment is

As the physiologist Haldane said: "Hypoxia not only stops the machine it wrecks the machinery" [2]. A healthy fetus can respond to, and tolerate, the early effects of hypoxia, and the degree of acidosis that occurs initially in response to the associated retention of carbon dioxide. Acute hypoxia promotes adenosine release, which reduces fetal cerebral oxygen consumption via action on neuronal A1 receptors on the cerebral arteries, and initiates vasodilatation through activation of A2 receptors; release of nitric oxide and opioids and direct effects of hypoxia on the vascular endothelium also contribute [53]. As a result, while fetal vascular resistance can decrease up to 50%, the net effect is to maintain CBF with only minimal reduction in oxygen delivery; but normal or elevated mean arterial blood pressure is critical in parallel, and once

With moderate HI stress and evolving acidosis, the fetus also has the physiologic ability to preferentially perfuse the deep structures of the brain that have higher metabolic rates (brainstem, cerebellum, basal ganglia). However, this compensatory redistribution of blood from the anterior to the posterior circulation results in the brain's cortical areas being less well perfused, and hence, if ongoing hypoxia remains unrecognized and unrelieved over the course of an hour or more, the end result is damage to cortical white matter, and the watershed areas of the cerebral hemispheres. In contrast to this partial prolonged pattern of injury, situations occur where the HI event is near total in nature and the effect profound. With such insults, acidosis develops relatively abruptly, and little or no compensatory redistribution of blood to the deep brain structures occurs, because there is no time for effective redistribution of CBF to maintain their perfusion. Hence it is the basal ganglia and thalami that are predominantly injured, and damage happens over a much shorter time frame [9, 54–56]. In the premature, mild to moderate HI injury results in periventricular leukomalacia and germinal matrix bleeds, and in full term

hypotension ensues the brain suffers from the resulting ischemia.

**Seizures:** Major causes include brain malformation or structural injury, hypoxia, infection and reversible metabolic disorders. Clinical signs vary from subtle movement disorders to focal or generalized, brief or sustained convulsive activity. Abnormal movement often involves the eyes (blinking, staring, horizontal tonic deviation), mouth (lip smacking or sucking, tongue thrusting), and extremities ('bicycling', 'rowing' or jerking movement). Respiratory (apnea) and cardiac effects (tachycardia or bradycardia) occur, often with color change and significant oxygen desaturation. Focal clonic seizures may indicate brain damage due to arterial or venous infarction. Clinical signs suggesting seizures require confirmatory EEG. MRI can distinguish between seizures due to HI events and other causes. Preventable or reversible causes include hypoglycemia, hypocalcemia, hyponatremia, hypoxemia and acidosis. Seizures do not always imply poor neurodevelopmental outcome for affected infants. But the severity of seizures in human newborns with perinatal asphyxia is independently associated with brain injury, and not limited to structural damage detectable by MRI [51]. In term newborns, the predominant pattern of watershed and basal nuclei injury after hypoxic ischemic encephalopathy is a valuable predictor for later epilepsy; injury to the motor cortex, hippocampus and occipital lobe are also independent risk factors, and the severity of brain injury and recurrent neonatal seizures elevate risk [52]. Delayed treatment likely increases the probability of residual consequences, because of the stresses placed on the brain by the high oxygen and substrate requirements implicit when seizures are prolonged.

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

required [49, 50].

**3. Hypoxic brain injury**

*Pathogenesis and Prevention of Fetal and Neonatal Brain Injury DOI: http://dx.doi.org/10.5772/intechopen.93840*

*Advancement and New Understanding in Brain Injury*

particularly when associated with hypotension in the premature newborn, are

the generation of cytokines, and release of toxic metabolites by bacteria.

enables alternative fuels to be metabolized (lactate, ketone bodies, fatty acids) which ensures energy supply to vital organs when blood glucose concentration falls. But once born, this ability is down-regulated, especially by oral feeding [2], and transitional hypoglycemia can occur. While no single glucose value can define hypoglycemia, fully ensure an infant's safety or limit morbidity, management guidelines exist as hypoglycemia can have neurologic consequences [36–38], especially when accompanied by seizures, including: motor and/or psychodevelopmental delay, microcephaly, seizures, visual impairment, and spastic quadriplegia

**Hypoglycemia:** During transition to extrauterine life, fetal adaptation normally

Population data indicate that blood glucose levels as low as 2.0 mmol/L (or even 1.8 mmol/L at 1 hour of age) are not uncommon in healthy newborns. However, various syndromes and metabolic conditions cause or contribute to hypoglycemia. Importantly, HI injury can disrupt normal metabolic adaptation, as anaerobic glycolysis depletes hepatic glycogen and hyperinsulinism can also occur; there is a correlation between lower serum glucose levels and higher Sarnat stages in hypoxic

For at-risk infants, outcome data support raising the intervention threshold from conventional levels. Current screening and management guidelines are that neonates with hypoglycemia persisting beyond the first 72 should be investigated further when levels remain ≤2.8 mmol/L, and ≥ 3.3 mmol/L should be the therapeutic glucose target level in symptomatic/at risk infants. Also, before discharge, those experiencing persistent hypoglycemia should have a 5-6 hour fast, while maintain-

Differing patterns of damage now help to distinguish hypoglycemic from HI brain injury [5, 40, 41]; the combination on MRI of selective edema in the posterior white matter and pulvinar appears specific even in absence of hypoglycemic laboratory values. In neonates with concurrent hypoglycemia and HIE, injury is synergistic, and

**Hyperglycemia:** A blood glucose concentration > 125 mg/dL (6.9 mmol/L) is a common metabolic abnormality encountered in preterm and critically ill newborns [42]. Management varies; often iatrogenic, hyperglycemia can cause or aggravate brain damage, principally because of the hyperosmolar state that ensues [43].

**Hyponatremia** in the premature can cause sensorineural hearing loss, cerebral palsy, intracranial hemorrhage, and increase mortality following asphyxia [44, 45]. **Hypernatremia**/**hyperbilirubinemia** when extreme are neurotoxic. Inadequate

fluid intake in immature infants and those primarily breast fed is contributory [46, 47]. Kernicterus selectively damages the globus pallidus and subthalamic nuclei [8, 48]; hazardous hyperbilirubinemia is often preventable; health care professional

ing blood glucose levels ≥3.3 mmol/L, to ensure safety at home [39].

the imaging features of both HI injury and hypoglycemia may be detected [5].

**Fetal and neonatal Infection** significantly increases the risk of brain injury. Mechanisms promoting sepsis include PROM; the risk of fetal infection from membrane rupture beyond 18 hours increases (10-fold), as does the occurrence of perinatal asphyxia, maternal urinary tract infection and colonization with group B Streptococcus [35]. Maternal treatment and prophylactic antibiotics given in anticipation of sepsis to the infant at birth are essential, as by the time confirmatory tests (bacterial cultures) are positive, the risks of infection having disseminated into the blood stream (septicemia) or spread to the meninges (meningitis) are high. Hypotension secondary to sepsis can profoundly compromise brain perfusion and oxygen delivery, and dramatically increases morbidity; once present, it is often refractory to treatment as the underlying mechanisms are multifactorial, including

associated with an increased risk of white matter injury [33, 34].

**68**

and hemiplegia.

ischemic encephalopathy (HIE).

compliance with best practices for screening, phototherapy and related treatment is required [49, 50].

**Seizures:** Major causes include brain malformation or structural injury, hypoxia, infection and reversible metabolic disorders. Clinical signs vary from subtle movement disorders to focal or generalized, brief or sustained convulsive activity. Abnormal movement often involves the eyes (blinking, staring, horizontal tonic deviation), mouth (lip smacking or sucking, tongue thrusting), and extremities ('bicycling', 'rowing' or jerking movement). Respiratory (apnea) and cardiac effects (tachycardia or bradycardia) occur, often with color change and significant oxygen desaturation. Focal clonic seizures may indicate brain damage due to arterial or venous infarction. Clinical signs suggesting seizures require confirmatory EEG. MRI can distinguish between seizures due to HI events and other causes. Preventable or reversible causes include hypoglycemia, hypocalcemia, hyponatremia, hypoxemia and acidosis. Seizures do not always imply poor neurodevelopmental outcome for affected infants. But the severity of seizures in human newborns with perinatal asphyxia is independently associated with brain injury, and not limited to structural damage detectable by MRI [51]. In term newborns, the predominant pattern of watershed and basal nuclei injury after hypoxic ischemic encephalopathy is a valuable predictor for later epilepsy; injury to the motor cortex, hippocampus and occipital lobe are also independent risk factors, and the severity of brain injury and recurrent neonatal seizures elevate risk [52]. Delayed treatment likely increases the probability of residual consequences, because of the stresses placed on the brain by the high oxygen and substrate requirements implicit when seizures are prolonged.
