**4. Multisystem involvement secondary to hypoxia**

The effects of hypoxia extend beyond the brain [9, 11, 67, 68], associated injury to other organs principally occurs due to compensatory redistribution of blood during partial and prolonged insults, but can follow profound, near total episodes; 60-80% of affected neonates exhibit single or multiple organ injury [68].

The fetus often passes meconium (fetal bowel contents) in utero due to hypoxia; a combination of gut ischemia and reduced sphincter tone secondary to neurological depression is the likely mechanism, hence, the presence of meconium is a marker for probable HI. Following a recent event, meconium seen is usually thick and green; after a remote event, because mixing with amniotic fluid disperses and thins the meconium, the liquor is evenly discolored, and the fetal skin may be stained green.

In the neonate, multiple organs can show varying effects from hypoxia.

**The lungs** can be injured directly and indirectly; inhaled meconium, surfactant depletion, pulmonary hypertension and left ventricular failure can all result in impaired gas exchange and the need for assisted ventilation. The risks of brain injury increase where such effects are superimposed on the poorly compliant lungs of a preterm infant. A pneumothorax (air leak into the pleural space) causing lung compression and elevated intrathoracic pressure is less common with modern ventilation techniques, but when it occurs, major disturbances in cerebral perfusion pressure result that increase the risk of brain ischemia and hemorrhage.

**The heart** can suffer functional and structural damage; acidosis seriously impairs myocardial function, myocardial ischemia further compromises conduction and mechanical contractile efficiency; affected neonates often require fluid resuscitation at birth and inotropic agents (dobutamine/dopamine) to maintain their circulation. Abnormalities on ECG and echocardiogram, and elevated cardiac enzymes (creatine kinase–MB fraction/troponin T levels) reflect heart dysfunction and damage.

**The kidneys**: Absent or significantly reduced urine output in the 24 hours following HI is common, associated hematuria indicates renal tubular damage. Renal injury is the best systemic marker of potential brain injury when oliguria (urine output <1 ml/kg/h) is associated with an abnormal neurological exam [68]. Blood urea and serum creatinine rise progressively and peak in the days following injury. Inappropriate secretion of antidiuretic hormone (ADH) causes hyponatremia; hypoxia stimulates the carotid body chemoreceptors to secrete ADH which causes fluid retention, and a secondary fall in serum sodium concentration.

**The liver:** Elevated enzymes reflect hepatic cellular damage; lactate dehydrogenase (LDH) is the best hepatic predictor of HIE (sensitivity 100% and specificity 97%), and also of long-term outcome after HIE [71]; blood glucose concentration can fluctuate, with hypoglycemia being most common [72].

**Bone marrow:** Increased release of nucleated (immature) red blood cells (NRBC) and reduction in platelet numbers (thrombocytopenia) reflect hemopoietic effects. After HI, platelets numbers fall by 12 hours, with the nadir at 2-3 days [2], while NRBCs peak in the hours after birth and fall by 50% after 12 hours [73]; distinct patterns relate to timing of HI [74]. Hypoxic events likely induce exaggerated erythropoiesis as a compensatory response, with release of NRBCs into the fetal circulation. Elevated NRBCs are associated with intrapartum fetal distress and acidemia at birth secondary to hypoxia, with a direct correlation reported between decreasing UA pH and NRBC elevation in the term human fetus. Newborns with elevated NRBCs suffer a significant increase in both short-term morbidity and mortality and long-term disability [75]. NRBC counts are best given as an absolute number per unit volume rather than relative to 100 white blood cells as this avoids misleadingly low

**73**

*Pathogenesis and Prevention of Fetal and Neonatal Brain Injury*

values when wbc counts are high; published values indicate normal counts decrease with advancing gestation and increasing birth weight [73, 74]. A value >1000/mm3 (or > 10-20/100 wbc) in the first hours of life is considered elevated [73]; A prospective case-controlled study identified that a NRBC count of >13/100 leukocytes had a sensitivity of 81.3% and a specificity of 94.4% in predicting adverse outcomes [76]. In

within

neonates subsequently cooled, those with absolute NRBC counts >1324/mm3

6 hours of birth had high risks of abnormal MRIs and adverse 2-year outcomes; the combination of NRBC count and other early markers, such as lactate levels and EEG, could increase the overall predictive ability [77]. The magnitude of increase in NRBCs is a function of the severity and duration of asphyxia, and a reliable index of

**Metabolic markers:** Plasma lactate is an important marker for recent tissue hypoxia; lactate is a metabolite in aerobic metabolism, and measurements in arterial blood at 30 minutes of life show lactate to be as equally valuable as base deficit in assessing the severity of birth asphyxia; elevated concentrations >9 mmol/l are associated with moderate or severe encephalopathy and PVL (sensitivity 84% and specificity 67%) [78]. Low serum calcium and elevation of bilirubin can also occur. **Gastrointestinal tract:** abnormal peristalsis underlies feeding intolerance after hypoxia, and the risk of necrotizing enterocolitis is increased [68]. Infants also feed poorly due to an impaired rooting reflex, reduced tone, diminished coordination and drowsiness; associated cranial nerve and brain stem lesions contribute.

**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

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

perinatal brain damage [73–77].

**5. Adjuncts to comprehensive care**

*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*

stained green.

and damage.

**4. Multisystem involvement secondary to hypoxia**

The effects of hypoxia extend beyond the brain [9, 11, 67, 68], associated injury to other organs principally occurs due to compensatory redistribution of blood during partial and prolonged insults, but can follow profound, near total episodes;

The fetus often passes meconium (fetal bowel contents) in utero due to hypoxia;

**The lungs** can be injured directly and indirectly; inhaled meconium, surfactant

60-80% of affected neonates exhibit single or multiple organ injury [68].

a combination of gut ischemia and reduced sphincter tone secondary to neurological depression is the likely mechanism, hence, the presence of meconium is a marker for probable HI. Following a recent event, meconium seen is usually thick and green; after a remote event, because mixing with amniotic fluid disperses and thins the meconium, the liquor is evenly discolored, and the fetal skin may be

In the neonate, multiple organs can show varying effects from hypoxia.

depletion, pulmonary hypertension and left ventricular failure can all result in impaired gas exchange and the need for assisted ventilation. The risks of brain injury increase where such effects are superimposed on the poorly compliant lungs of a preterm infant. A pneumothorax (air leak into the pleural space) causing lung compression and elevated intrathoracic pressure is less common with modern ventilation techniques, but when it occurs, major disturbances in cerebral perfusion

**The heart** can suffer functional and structural damage; acidosis seriously impairs myocardial function, myocardial ischemia further compromises conduction and mechanical contractile efficiency; affected neonates often require fluid resuscitation at birth and inotropic agents (dobutamine/dopamine) to maintain their circulation. Abnormalities on ECG and echocardiogram, and elevated cardiac enzymes (creatine kinase–MB fraction/troponin T levels) reflect heart dysfunction

**The kidneys**: Absent or significantly reduced urine output in the 24 hours following HI is common, associated hematuria indicates renal tubular damage. Renal injury is the best systemic marker of potential brain injury when oliguria (urine output <1 ml/kg/h) is associated with an abnormal neurological exam [68]. Blood urea and serum creatinine rise progressively and peak in the days following injury. Inappropriate secretion of antidiuretic hormone (ADH) causes hyponatremia; hypoxia stimulates the carotid body chemoreceptors to secrete ADH which causes fluid retention, and a secondary fall in serum sodium concentration.

**The liver:** Elevated enzymes reflect hepatic cellular damage; lactate dehydrogenase (LDH) is the best hepatic predictor of HIE (sensitivity 100% and specificity 97%), and also of long-term outcome after HIE [71]; blood glucose concentration

**Bone marrow:** Increased release of nucleated (immature) red blood cells (NRBC) and reduction in platelet numbers (thrombocytopenia) reflect hemopoietic effects. After HI, platelets numbers fall by 12 hours, with the nadir at 2-3 days [2], while NRBCs peak in the hours after birth and fall by 50% after 12 hours [73]; distinct patterns relate to timing of HI [74]. Hypoxic events likely induce exaggerated erythropoiesis as a compensatory response, with release of NRBCs into the fetal circulation. Elevated NRBCs are associated with intrapartum fetal distress and acidemia at birth secondary to hypoxia, with a direct correlation reported between decreasing UA pH and NRBC elevation in the term human fetus. Newborns with elevated NRBCs suffer a significant increase in both short-term morbidity and mortality and long-term disability [75]. NRBC counts are best given as an absolute number per unit volume rather than relative to 100 white blood cells as this avoids misleadingly low

can fluctuate, with hypoglycemia being most common [72].

pressure result that increase the risk of brain ischemia and hemorrhage.

**72**

values when wbc counts are high; published values indicate normal counts decrease with advancing gestation and increasing birth weight [73, 74]. A value >1000/mm3 (or > 10-20/100 wbc) in the first hours of life is considered elevated [73]; A prospective case-controlled study identified that a NRBC count of >13/100 leukocytes had a sensitivity of 81.3% and a specificity of 94.4% in predicting adverse outcomes [76]. In neonates subsequently cooled, those with absolute NRBC counts >1324/mm3 within 6 hours of birth had high risks of abnormal MRIs and adverse 2-year outcomes; the combination of NRBC count and other early markers, such as lactate levels and EEG, could increase the overall predictive ability [77]. The magnitude of increase in NRBCs is a function of the severity and duration of asphyxia, and a reliable index of perinatal brain damage [73–77].

**Metabolic markers:** Plasma lactate is an important marker for recent tissue hypoxia; lactate is a metabolite in aerobic metabolism, and measurements in arterial blood at 30 minutes of life show lactate to be as equally valuable as base deficit in assessing the severity of birth asphyxia; elevated concentrations >9 mmol/l are associated with moderate or severe encephalopathy and PVL (sensitivity 84% and specificity 67%) [78]. Low serum calcium and elevation of bilirubin can also occur.

**Gastrointestinal tract:** abnormal peristalsis underlies feeding intolerance after hypoxia, and the risk of necrotizing enterocolitis is increased [68]. Infants also feed poorly due to an impaired rooting reflex, reduced tone, diminished coordination and drowsiness; associated cranial nerve and brain stem lesions contribute.
