**5. Adjuncts to comprehensive care**

**Fetal ultrasound (US):** Endovaginal ultrasonography has become the standard imaging measure in pregnancy. US uses pulsed high-frequency sound to produce images and employs terminology and standardized interpretations based on defined criteria to ensure safe maternal examination, and prevent inadvertent harm to early normal pregnancy [79]. US provides routine confirmation of gestational age/due date, detects fetal anomalies, oligo or polyhydramnios, and provides assessment of fetal growth parameters in early pregnancy [80]. Protocols also exist for the management of specific clinical scenarios that pose a risk for the fetus and require increased fetal surveillance; these allow for appropriate referral when complications are suspected, e.g. for intrauterine growth retardation, and monochorionic dichorionic twin gestation where there is a high risk of twin-to-twin transfusion syndrome developing [81].

**Fetal scalp blood sampling:** can assess the evolution of hypoxia and acidosis via blood gas measurement or lactate analysis, once the membranes have ruptured and the fetal head has descended into the birth canal during the later stages of labor.

**Fetal heart rate monitoring (EFM):** The physiologic perturbations in fetal oxygenation and hemodynamics that changes in fetal heart rate (FHR) reflect, provide the rationale for FHR measurement and EFM intrapartum [56]. With onset of hypoxia, physiological effects on the fetus usually generate detectable changes in fetal heart rate pattern, as the myocardium is sensitive to reduced oxygen tension, elevated carbon dioxide, and progressive evolution of acidosis. From a preventive standpoint the importance of EFM is that clinically relevant FHR changes are usually evident before the brain is affected sufficiently for permanent damage to begin.

**Assessment at birth:** Transition to extra-uterine life is physiologically complex. Where needed, resuscitation must mitigate any residual effects of compromised organ function or intrapartum events that have depressed or damaged the brain. A key element in reducing morbidity is the immediate availability of skilled personnel able to provide the well-established neonatal life support (NALS) priorities for resuscitation [68], assess the history, intrapartum events and clinical status of the

infant, and order the level of care and specific diagnostic and treatment entities required.

**Apgar score:** Named for Virginia Apgar, this is intended as an objective index to evaluate the condition of a newborn infant based on a rating of 0, 1 or 2 for each of the five components: color, heart rate, response to stimulation of the sole of the foot, muscle tone, and respiration. Scores are determined by observing/examining the newborn infant in real time at 1, 5 and 10 minutes of age. Scores principally gauge progress in response to resuscitation; persistently low scores equate with failure to respond, and imply the newborn has significant physiologic problems. Apgars were not meant to be an outcome parameter. Also, retrospectively estimated scores are problematic when they do not match contemporaneous event descriptors in the resuscitation record. Care with interpretation is also required where an infant is premature due to an associated degree of physical immaturity, and where active life support (e.g. assisted ventilation) is generating the improvements observed.

**Umbilical cord blood gas analysis:** Fetal oxygenation and acid base status can be assessed from paired blood samples collected from the umbilical vein (UV) and arteries (UA) at birth; this is an integral part of monitoring high-risk deliveries [82], but an understanding of fetal placental perfusion and how specific conditions affect values are necessary for accurate interpretation. Cord compression, for example, is associated with normal values when acute and complete, in spite of the infant being profoundly acidotic systemically, as they reflect fetal status when cord flow ceased. In contrast, partial restriction causes UA and UV values to progressively widen, and with impaired maternal placental perfusion UA/UV differences are small [82, 83].

Normally, oxygenated blood from the placenta flows through the UV and preferentially supplies the fetal brain and heart via shunts that bypass the liver; repeated uterine contractions during labor exert a significant, but manageable metabolic stress on the fetus. But when labor is precipitous, or contractions are abnormally frequent or prolonged, uterine artery blood flow becomes restricted, and intercontraction restoration of placental perfusion is delayed as it is dependent on uterine relaxation; in this and similar scenarios maternal to fetal oxygen transfer via the UV can suffer sufficiently for HI injury to occur. Where blood return through the UA is also affected, normal removal of carbon dioxide from the fetus is reduced.

Acidosis occurs as a consequence of cellular hypoxia (inadequate oxygenation), tissue ischemia (inadequate blood flow) and retention of carbon dioxide; the unit of measurement, pH, is on a logarithmic scale, so small differences represent a major change in the degree of acidosis. Bicarbonate naturally buffers acid production; as reserves are depleted, base deficit increases. With resolution of acidosis, PCO2 values are restored first, followed by bicarbonate and pH; base deficit remains abnormal longest. Normal cell metabolism only occurs when pH is held within a narrow range, beyond these limits, cells progressively lose their ability to sustain normal function and maintain their metabolic integrity, and organs begin to fail.

Blood gas data are compared to the reference range of the testing laboratory. Significant, recent HI stress usually manifests with low oxygen, elevated PCO2, low pH, low bicarbonate and high base deficit, with UA values most affected. However, it is most relevant clinically to define pathological acidosis as the threshold at which the incidence of adverse events starts to correlate strongly [83]. Criteria to define an acute intrapartum event as sufficient to cause cerebral palsy include UA pH <7.00 and base deficit of >12; infants with a pH <7.0 who are not vigorous are at high risk of adverse outcome [84], and the threshold for moderate or severe newborn complications is defined as a UA base deficit of >12 [85]. With worsening acidosis progression of adverse sequelae rises sharply; in one reported series, HIE occurred in 12% of infants with cord pH <7.0, in 33% with pH <6.9, and in 80% with pH

**75**

are identified.

management.

*Pathogenesis and Prevention of Fetal and Neonatal Brain Injury*

<6.7; a pH <6.8 equated with the probability of neonatal death [86]. Persisting lactic acidosis is associated with severe encephalopathy [82]. Identifying those at risk is

**Hematology:** White blood cell (wbc) counts can be strongly indicative (but not always diagnostic) of the presence of infection. Elevated total wbc numbers, a high proportion of neutrophils (granulocytes), and elevated primitive (band) cells indicate that stimulation of the bone marrow by inflammatory cytokines has occurred; very low counts often indicate inability to mount an effective immune response. Elevation of band cells is the earliest change in response to inflammatory stimuli, although hypoxia can also result in an increase in band cell number [87]. Hemoglobin concentration and hematocrit are used to identify anemia and polycythemia where too few or too many red cells are circulating respectively. Both circumstances compromise oxygen delivery; anemia by limiting the amount of oxygen that can be transported, and polycythemia by reducing the ease with which blood flows, which also increases the risk of blood vessel occlusion (thrombosis), and is one of the mechanisms underlying stroke. Also, by following serial measurements from birth, situations can be identified where bleeding occurred while the fetus was in utero. After significant blood loss, the volume of the blood in the circulation is reduced, but the hemoglobin concentration remains the same initially, then, as physiological compensation for the blood lost occurs, fluid is drawn into the circulation to restore blood volume and, as a consequence, hemoglobin concen-

especially important now, since neuroprotection strategies are available.

tration and the number of red cells per unit of volume (hematocrit) fall.

**Blood chemistry:** Electrolyte and glucose measurements, in parallel with blood gas analysis of pH, oxygen and carbon dioxide tension, bicarbonate and base deficit, plasma lactate, serum calcium and liver transaminases are the mainstays of clinical monitoring in brain injured infants, particularly when multisystem involvement complicates the course of neonatal encephalopathy. A small but complex group of congenital metabolic abnormalities causing neonatal encephalopathy exist [58]; these require expert assessment, comprehensive investigation and

**Neuroimaging:** Modalities include ultrasound, computerized tomography and magnetic resonance imaging [55, 88]. US provided the initial method for imaging brain structures and is still clinically attractive because of the ability to study sick pre-term infants in the nursery. The advent of CT greatly advanced knowledge of brain development and injury. But MRI is now the imaging modality of choice, in spite of cost, due to the lack of ionizing radiation and its superior sensitivity and specificity in detecting brain abnormalities. CT remains relevant for infants too sick for MRI. MR image interpretation needs to be as sophisticated as the technology. **Magnetic resonance imaging** (MRI) is now invaluable in assessing the neonatal brain following suspected perinatal injury. Imaging during the first week of life is prognostic and can aid management decisions. MR imaging is an excellent predictor of outcome following perinatal brain injury; characteristic lesions and patterns of changes are at their most obvious on conventional imaging between 1 and 2 weeks from birth [7]. Diffusion-weighted imaging (MRI sensitive to water diffusion) allows early identification of ischemic tissue; associated restricted diffusion on day 3 of life implies injury was acquired around the time of birth, and is not the late manifestation of remote in utero injury sustained during the third trimester [6]. However, DWI may underestimate the final extent of injury, particularly in basal ganglia and thalamic lesions. The outstanding contrast resolution of MRI, superimposed on the ability to image in any plane, means even subtle brain malformations

Like US and CT, MRI scans are best done at defined intervals after birth (3-5 and 10-14 days of life) for accurate diagnosis, timing and evolution of injury [55, 57].

*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*

required.

are small [82, 83].

infant, and order the level of care and specific diagnostic and treatment entities

**Apgar score:** Named for Virginia Apgar, this is intended as an objective index to evaluate the condition of a newborn infant based on a rating of 0, 1 or 2 for each of the five components: color, heart rate, response to stimulation of the sole of the foot, muscle tone, and respiration. Scores are determined by observing/examining the newborn infant in real time at 1, 5 and 10 minutes of age. Scores principally gauge progress in response to resuscitation; persistently low scores equate with failure to respond, and imply the newborn has significant physiologic problems. Apgars were not meant to be an outcome parameter. Also, retrospectively estimated scores are problematic when they do not match contemporaneous event descriptors in the resuscitation record. Care with interpretation is also required where an infant is premature due to an associated degree of physical immaturity, and where active life support (e.g. assisted ventilation) is generating the improvements observed. **Umbilical cord blood gas analysis:** Fetal oxygenation and acid base status can be assessed from paired blood samples collected from the umbilical vein (UV) and arteries (UA) at birth; this is an integral part of monitoring high-risk deliveries [82], but an understanding of fetal placental perfusion and how specific conditions affect values are necessary for accurate interpretation. Cord compression, for example, is associated with normal values when acute and complete, in spite of the infant being profoundly acidotic systemically, as they reflect fetal status when cord flow ceased. In contrast, partial restriction causes UA and UV values to progressively widen, and with impaired maternal placental perfusion UA/UV differences

Normally, oxygenated blood from the placenta flows through the UV and preferentially supplies the fetal brain and heart via shunts that bypass the liver; repeated uterine contractions during labor exert a significant, but manageable metabolic stress on the fetus. But when labor is precipitous, or contractions are abnormally frequent or prolonged, uterine artery blood flow becomes restricted, and intercontraction restoration of placental perfusion is delayed as it is dependent on uterine relaxation; in this and similar scenarios maternal to fetal oxygen transfer via the UV can suffer sufficiently for HI injury to occur. Where blood return through the UA is

Acidosis occurs as a consequence of cellular hypoxia (inadequate oxygenation), tissue ischemia (inadequate blood flow) and retention of carbon dioxide; the unit of measurement, pH, is on a logarithmic scale, so small differences represent a major change in the degree of acidosis. Bicarbonate naturally buffers acid production; as reserves are depleted, base deficit increases. With resolution of acidosis, PCO2 values are restored first, followed by bicarbonate and pH; base deficit remains abnormal longest. Normal cell metabolism only occurs when pH is held within a narrow range, beyond these limits, cells progressively lose their ability to sustain normal function and maintain their metabolic integrity, and organs begin to fail. Blood gas data are compared to the reference range of the testing laboratory. Significant, recent HI stress usually manifests with low oxygen, elevated PCO2, low pH, low bicarbonate and high base deficit, with UA values most affected. However, it is most relevant clinically to define pathological acidosis as the threshold at which the incidence of adverse events starts to correlate strongly [83]. Criteria to define an acute intrapartum event as sufficient to cause cerebral palsy include UA pH <7.00 and base deficit of >12; infants with a pH <7.0 who are not vigorous are at high risk of adverse outcome [84], and the threshold for moderate or severe newborn complications is defined as a UA base deficit of >12 [85]. With worsening acidosis progression of adverse sequelae rises sharply; in one reported series, HIE occurred in 12% of infants with cord pH <7.0, in 33% with pH <6.9, and in 80% with pH

also affected, normal removal of carbon dioxide from the fetus is reduced.

**74**

<6.7; a pH <6.8 equated with the probability of neonatal death [86]. Persisting lactic acidosis is associated with severe encephalopathy [82]. Identifying those at risk is especially important now, since neuroprotection strategies are available.

**Hematology:** White blood cell (wbc) counts can be strongly indicative (but not always diagnostic) of the presence of infection. Elevated total wbc numbers, a high proportion of neutrophils (granulocytes), and elevated primitive (band) cells indicate that stimulation of the bone marrow by inflammatory cytokines has occurred; very low counts often indicate inability to mount an effective immune response. Elevation of band cells is the earliest change in response to inflammatory stimuli, although hypoxia can also result in an increase in band cell number [87].

Hemoglobin concentration and hematocrit are used to identify anemia and polycythemia where too few or too many red cells are circulating respectively. Both circumstances compromise oxygen delivery; anemia by limiting the amount of oxygen that can be transported, and polycythemia by reducing the ease with which blood flows, which also increases the risk of blood vessel occlusion (thrombosis), and is one of the mechanisms underlying stroke. Also, by following serial measurements from birth, situations can be identified where bleeding occurred while the fetus was in utero. After significant blood loss, the volume of the blood in the circulation is reduced, but the hemoglobin concentration remains the same initially, then, as physiological compensation for the blood lost occurs, fluid is drawn into the circulation to restore blood volume and, as a consequence, hemoglobin concentration and the number of red cells per unit of volume (hematocrit) fall.

**Blood chemistry:** Electrolyte and glucose measurements, in parallel with blood gas analysis of pH, oxygen and carbon dioxide tension, bicarbonate and base deficit, plasma lactate, serum calcium and liver transaminases are the mainstays of clinical monitoring in brain injured infants, particularly when multisystem involvement complicates the course of neonatal encephalopathy. A small but complex group of congenital metabolic abnormalities causing neonatal encephalopathy exist [58]; these require expert assessment, comprehensive investigation and management.

**Neuroimaging:** Modalities include ultrasound, computerized tomography and magnetic resonance imaging [55, 88]. US provided the initial method for imaging brain structures and is still clinically attractive because of the ability to study sick pre-term infants in the nursery. The advent of CT greatly advanced knowledge of brain development and injury. But MRI is now the imaging modality of choice, in spite of cost, due to the lack of ionizing radiation and its superior sensitivity and specificity in detecting brain abnormalities. CT remains relevant for infants too sick for MRI. MR image interpretation needs to be as sophisticated as the technology.

**Magnetic resonance imaging** (MRI) is now invaluable in assessing the neonatal brain following suspected perinatal injury. Imaging during the first week of life is prognostic and can aid management decisions. MR imaging is an excellent predictor of outcome following perinatal brain injury; characteristic lesions and patterns of changes are at their most obvious on conventional imaging between 1 and 2 weeks from birth [7]. Diffusion-weighted imaging (MRI sensitive to water diffusion) allows early identification of ischemic tissue; associated restricted diffusion on day 3 of life implies injury was acquired around the time of birth, and is not the late manifestation of remote in utero injury sustained during the third trimester [6]. However, DWI may underestimate the final extent of injury, particularly in basal ganglia and thalamic lesions. The outstanding contrast resolution of MRI, superimposed on the ability to image in any plane, means even subtle brain malformations are identified.

Like US and CT, MRI scans are best done at defined intervals after birth (3-5 and 10-14 days of life) for accurate diagnosis, timing and evolution of injury [55, 57].

Pathology identified includes structural developmental abnormalities, edema, hemorrhage, early ischemic damage, localization of the predominant injury to either cortical tissue or deep brain structures, the evolution and end stages of scarring, and, onset and progression of hydrocephalus or microcephaly. Importantly, intrapartum and late antepartum HI damage can be distinguished from congenital structural effects or lesions due to acquired causes that occurred well prior to birth, so MRI scans can identify damage caused to an otherwise normal and pristine brain.

MRI, magnetic resonance spectroscopy, and diffusion-weighted MRI have identified the patterns of brain injury that evolve after HI insults. Studies also define the severity of the insult and can indicate the age at which it probably occurred. Injury evolves over days, if not weeks before the final stage with scarring is evident. The anatomical regions of the brain affected define the mechanism of injury. Distinction can be made between an insult that involved a relatively short period of total or near total hypoxia/ischemia (profound hypotension), or one occurring over a more prolonged period where HI was partial in degree (moderate hypotension).

In near total insults, the most metabolically active brain structures are damaged; the lentiform nuclei, especially the posterior putamina, the ventrolateral thalami, the Rolandic cortex and the hippocampi are predominantly injured, while there is little or no involvement of the remainder of the cerebral cortex.

In contrast, in partial and prolonged hypoxia, cortical white matter integrity is compromised, and there is relative preservation of the basal ganglia and thalami. In severe cases the whole cortex may be involved, while with milder injury, the principal areas damaged are the interfaces between the perfusion zones of the anterior, middle and posterior cerebral arteries. An excellent schematic derived from a medicolegal database of MR images of term neonates with partial-prolonged HI injury illustrates the geography of the inter-arterial watershed zone [89].

While these are the two distinctive and predominant patterns of HI brain injury seen, in reality, the type, pattern, duration and variability in severity of HI are a continuum, so there is a spectrum of MRI findings, and mixed patterns of damage are seen, with changes of varying degree in both the basal ganglia thalami and cortical regions [55, 57]. Very severe injury from moderate or profound hypotension can also cause global brain involvement, and extend to include the brainstem [66].

MRI detectable changes take time to evolve; the first abnormality seen is diffusion restriction which peaks at about 72 hours [57]; brain edema, identified as T2 hyperintensity, reflects the progression of energy failure that follows brain cell damage, and precedes cell death due to the apoptosis necrosis continuum. Where there is significant involvement of the cortex, abnormal T1 hyperintensity is evident from about 1 week following the HI event; this can persist for several weeks. T1 hyperintensity due to basal ganglia damage is visualized over a similar time frame. The end result of injury is permanent scaring (gliosis), and compensatory enlargement of the ventricles (ventriculomegaly) [7, 55, 57].

Destructive lesions characterized by periventricular hyperintensity, focal defects in the germinal matrix, and areas of abnormal signal intensity occur in developing white matter. In encephalopathic term newborns, non-cystic white matter injury is a distinct and common pattern. A helpful sign in those >37 weeks gestation is loss of normal signal intensity in the posterior limb of the internal capsule. Hemorrhage is associated with hypointense areas; signal intensity depends on degree of evolution.

Periventricular leukomalacia can develop during fetal life and in the newborn period. Imaging predominantly identifies PVL in preterm infants, but importantly, lesions also occur in term and late preterm infants (those born between 34 weeks and 0 days and 36 weeks plus 6 days gestation) [90].

Fetal MR imaging is a technique that complements prenatal sonography as it has higher contrast resolution and allows direct visualization of the fetal brain, and

**77**

conception.

*Pathogenesis and Prevention of Fetal and Neonatal Brain Injury*

hence more readily identifies both cerebral malformations and destructive lesions, including agenesis of the corpus callosum, cerebellar dysplasia, germinal matrix hemorrhage, IVH, multicystic encephalomalacia, periventricular leukomalacia, periventricular nodular heterotopias, porencephaly, and sulcation anomalies. For post-natal studies, diffusion-weighted MR imaging and proton MR spectroscopy are the most sensitive modalities for diagnosis in the early hours following injury. Future advances in MRI hardware and software will likely enable neuroimaging technologies to contribute more by further delineating the site(s), progression and extent of injury; this will aid evaluation of causation and timing, and advance care strategies able to reverse or mitigate the long-term effects of perinatal brain injury. **Electroencephalogram (EEG):** Patterns of brain waves obtained allow the location and relative severity of various brain pathologies to be identified. Seizure activity occurring in the brain but not visible clinically is detected. Patterns of depression of cortical brain activity on EEG have been defined that are associated with varying stages and severity of HIE [69]. Serial measurements document the evolution of, and recovery from, abnormal brain function and the effect of therapy. **Placental pathology:** Examination of the placenta is an integral part of investigation of fetal brain injury and neonatal encephalopathy [67]. Pathology provides key information related to the fetus, and causal mechanisms underlying intrapartum events [91] e.g. fetal distress, chorioamnionitis and hemorrhage; and to maternal conditions that affect placental function and fetal oxygenation e.g. hypertension and diabetes. Evidence of placental insufficiency links to fetal growth retardation and increased risk of fetal distress. Any significant disturbance of placental gas exchange and fetal perfusion poses risks of brain injury; examples include pre-eclamptic toxemia, hemorrhage from placenta previa, uterine tachysystole, cord compression and placental abruption [92–94]; abruption is the commonest identifiable antecedent factor for injury in preterm infants with HIE. Examination can also identify causal pathology in the absence of a 'sentinel event' [67] and in circumstances where the umbilical cord is vulnerable e.g. abnormal insertion, tearing, true knots, prolapse, occlusion, and entrapment, each of which causes recognized adverse consequences for fetal oxygenation. Decreased placental maturation is associated with increased risk of white matter/watershed injury with or without basal ganglia/thalami involvement, and chronic villitis with basal ganglia/thalami

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

injury irrespective of white matter injury [93].

Prevention of brain damage requires knowledge of the etiologies underlying injury, awareness of the availability of preventive measures, and timely employment of them to address the underlying cause. In addition, situations that may aggravate existing or evolving brain injury need to be anticipated, recognized, and appropriate evidence-based care provided that is capable of improving outcome. **Maternal and paternal medical history and lifestyle:** Maternal nutrition and trace element status, the health and age of both parents at conception, and other factors related to current developmental origins of health and disease (DOHaD) concepts are all relevant to prevention [4, 95]. The risk of fetal brain injury is decreased where mothers maintain a good diet, add folic acid and iron plus required prenatal supplements (vit. D, calcium), avoid smoking and the detrimental effects of alcohol and drugs, and exposure to TORCH infections is prevented. There are benefits to becoming a mother earlier rather than later in life, and from both parents having lifestyles that promote physical health and mental wellness especially at

**6. Prevention of 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*

Pathology identified includes structural developmental abnormalities, edema, hemorrhage, early ischemic damage, localization of the predominant injury to either cortical tissue or deep brain structures, the evolution and end stages of scarring, and, onset and progression of hydrocephalus or microcephaly. Importantly, intrapartum and late antepartum HI damage can be distinguished from congenital structural effects or lesions due to acquired causes that occurred well prior to birth, so MRI scans can

MRI, magnetic resonance spectroscopy, and diffusion-weighted MRI have identified the patterns of brain injury that evolve after HI insults. Studies also define the severity of the insult and can indicate the age at which it probably occurred. Injury evolves over days, if not weeks before the final stage with scarring is evident. The anatomical regions of the brain affected define the mechanism of injury. Distinction can be made between an insult that involved a relatively short period of total or near total hypoxia/ischemia (profound hypotension), or one occurring over a more

In near total insults, the most metabolically active brain structures are damaged; the lentiform nuclei, especially the posterior putamina, the ventrolateral thalami, the Rolandic cortex and the hippocampi are predominantly injured, while there is

In contrast, in partial and prolonged hypoxia, cortical white matter integrity is compromised, and there is relative preservation of the basal ganglia and thalami. In severe cases the whole cortex may be involved, while with milder injury, the principal areas damaged are the interfaces between the perfusion zones of the anterior, middle and posterior cerebral arteries. An excellent schematic derived from a medicolegal database of MR images of term neonates with partial-prolonged

While these are the two distinctive and predominant patterns of HI brain injury seen, in reality, the type, pattern, duration and variability in severity of HI are a continuum, so there is a spectrum of MRI findings, and mixed patterns of damage are seen, with changes of varying degree in both the basal ganglia thalami and cortical regions [55, 57]. Very severe injury from moderate or profound hypotension can also

MRI detectable changes take time to evolve; the first abnormality seen is diffusion restriction which peaks at about 72 hours [57]; brain edema, identified as T2 hyperintensity, reflects the progression of energy failure that follows brain cell damage, and precedes cell death due to the apoptosis necrosis continuum. Where there is significant involvement of the cortex, abnormal T1 hyperintensity is evident from about 1 week following the HI event; this can persist for several weeks. T1 hyperintensity due to basal ganglia damage is visualized over a similar time frame. The end result of injury is permanent scaring (gliosis), and compensatory enlargement of the

Destructive lesions characterized by periventricular hyperintensity, focal defects in the germinal matrix, and areas of abnormal signal intensity occur in developing white matter. In encephalopathic term newborns, non-cystic white matter injury is a distinct and common pattern. A helpful sign in those >37 weeks gestation is loss of normal signal intensity in the posterior limb of the internal capsule. Hemorrhage is associated with hypointense areas; signal intensity depends on degree of evolution. Periventricular leukomalacia can develop during fetal life and in the newborn period. Imaging predominantly identifies PVL in preterm infants, but importantly, lesions also occur in term and late preterm infants (those born between 34 weeks

Fetal MR imaging is a technique that complements prenatal sonography as it has higher contrast resolution and allows direct visualization of the fetal brain, and

identify damage caused to an otherwise normal and pristine brain.

little or no involvement of the remainder of the cerebral cortex.

prolonged period where HI was partial in degree (moderate hypotension).

HI injury illustrates the geography of the inter-arterial watershed zone [89].

cause global brain involvement, and extend to include the brainstem [66].

ventricles (ventriculomegaly) [7, 55, 57].

and 0 days and 36 weeks plus 6 days gestation) [90].

**76**

hence more readily identifies both cerebral malformations and destructive lesions, including agenesis of the corpus callosum, cerebellar dysplasia, germinal matrix hemorrhage, IVH, multicystic encephalomalacia, periventricular leukomalacia, periventricular nodular heterotopias, porencephaly, and sulcation anomalies. For post-natal studies, diffusion-weighted MR imaging and proton MR spectroscopy are the most sensitive modalities for diagnosis in the early hours following injury.

Future advances in MRI hardware and software will likely enable neuroimaging technologies to contribute more by further delineating the site(s), progression and extent of injury; this will aid evaluation of causation and timing, and advance care strategies able to reverse or mitigate the long-term effects of perinatal brain injury.

**Electroencephalogram (EEG):** Patterns of brain waves obtained allow the location and relative severity of various brain pathologies to be identified. Seizure activity occurring in the brain but not visible clinically is detected. Patterns of depression of cortical brain activity on EEG have been defined that are associated with varying stages and severity of HIE [69]. Serial measurements document the evolution of, and recovery from, abnormal brain function and the effect of therapy.

**Placental pathology:** Examination of the placenta is an integral part of investigation of fetal brain injury and neonatal encephalopathy [67]. Pathology provides key information related to the fetus, and causal mechanisms underlying intrapartum events [91] e.g. fetal distress, chorioamnionitis and hemorrhage; and to maternal conditions that affect placental function and fetal oxygenation e.g. hypertension and diabetes. Evidence of placental insufficiency links to fetal growth retardation and increased risk of fetal distress. Any significant disturbance of placental gas exchange and fetal perfusion poses risks of brain injury; examples include pre-eclamptic toxemia, hemorrhage from placenta previa, uterine tachysystole, cord compression and placental abruption [92–94]; abruption is the commonest identifiable antecedent factor for injury in preterm infants with HIE. Examination can also identify causal pathology in the absence of a 'sentinel event' [67] and in circumstances where the umbilical cord is vulnerable e.g. abnormal insertion, tearing, true knots, prolapse, occlusion, and entrapment, each of which causes recognized adverse consequences for fetal oxygenation. Decreased placental maturation is associated with increased risk of white matter/watershed injury with or without basal ganglia/thalami involvement, and chronic villitis with basal ganglia/thalami injury irrespective of white matter injury [93].
