Fetal and Neonatal Neurologic Injury


The detection and diagnosis of fetal and neonatal brain injury have been advanced by improvements in functional imaging and the identification of potential biochemical markers. Evidence indicates that inflammatory mediators play an important role in the pathophysiology of fetal brain injury. Maternal administration of magnesium sulfate before anticipated early preterm birth reduces the risk for cerebral palsy in surviving infants. Induced hypothermia is beneficial for the treatment of neonatal hypoxic-ischemic encephalopathy. Of specific concern to anesthesia providers are rodent and nonhuman primate data that suggest that fetal exposure to anesthetic agents may have harmful effects on neurogenesis and synapse formation in the developing brain. Overall, however, little progress has been made in reducing the incidence of neonatal brain injury and cerebral palsy.


Fetal, Neonatal, Neurologic injury, Peripartum asphyxia, Cerebral palsy


  • Chapter Outline

  • Fetal Brain Development, 199

  • Cerebral Palsy, 201

    • History, Definitions, and Significance, 201

    • Epidemiology and Etiology, 202

    • Peripartum Asphyxia and Cerebral Palsy, 203

    • Chorioamnionitis, Fever, and Cerebral Palsy, 204

  • Pathophysiology of Fetal Asphyxia, 205

    • Intrauterine Hypoxemia and the Fetal Brain, 205

    • Maternal Inflammation and Fetal Brain Injury, 205

    • Animal Models of Fetal Asphyxia, 206

    • Neuropathology of Fetal Asphyxia, 208

    • Fetal Adaptive Responses, 209

  • Fetal and Neonatal Assessment, 210

    • Fetal Neurobehavioral Assessment, 210

    • Fetal Neuroimaging Assessment, 210

    • Neonatal Radiologic Diagnosis of Cerebral Injury, 210

  • Anesthesia and Brain Injury, 210

    • Labor Analgesia and the Fetal Brain, 210

    • Maternal Anesthesia and the Fetal Brain, 211

    • Fetal Neuroprotection, 213

  • Neuroprotective Therapies, 214

    • Magnesium Sulfate and Cerebral Palsy, 214

    • Hypothermia, 214

    • Experimental Neuroprotection, 215

The detection and diagnosis of fetal and neonatal brain injury have been advanced by improvements in functional imaging and the identification of potential biochemical markers. Evidence indicates that inflammatory mediators play an important role in the pathophysiology of fetal brain injury. Maternal administration of magnesium sulfate before anticipated early preterm birth reduces the risk for cerebral palsy in surviving infants. Induced hypothermia is beneficial for the treatment of neonatal hypoxic-ischemic encephalopathy. Of specific concern to anesthesia providers are rodent and nonhuman primate data that suggest that fetal exposure to anesthetic agents may have harmful effects on neurogenesis and synapse formation in the developing brain. Overall, however, little progress has been made in reducing the incidence of neonatal brain injury and cerebral palsy.

Fetal Brain Development

Generation of the various cell types that populate the developing brain, and the subsequent layering and organization, is a precisely regulated process encoded by genetic programs and modified by epigenetic influences. Contrary to previous dogma, it is now well established that the brain continuously evolves during ontogeny and that these processes are susceptible to subtle changes in the internal and external milieu. Although such neurodevelopmental processes occur throughout the human lifespan, the process is most robust and dynamic during the perinatal period. Much of our understanding of the processes that drive fetal brain development comes from studies in rodents and nonhuman primates. With recent advances in neuroimaging, it is now possible to study brain anatomy and assess neurobehavioral changes in the human fetus.

When pathways leading to orderly brain development are deconstructed, three major events appear critical to the establishment of functional synapses. Neuronal proliferation, migration, and cellular differentiation occur in a preordained fashion to establish early neural circuitry. These processes often overlap and occur at different rates in different brain regions. Neurogenesis, a term that encompasses both neuronal proliferation and subsequent survival, begins with neural stem/progenitor cells in neurogenic niches such as the subventricular zone and the subgranular zone of the dentate gyrus. These neural progenitor cells undergo mitosis to generate immature neurons that migrate in a radial fashion and laminate the cortex in an “inside-out” fashion. Interneurons, which compose 10% to 15% of the total neuronal cells in the brain, originate from the ganglionic eminences in the developing brain. These newly generated interneurons, which play an indispensable role in circuit inhibition, migrate in a tangential manner to populate distinct brain areas. Both forms of migration are guided by cell-intrinsic mechanisms and by structural scaffolds and humoral mediators such as gamma-aminobutyric acid (GABA) and glutamate.

In humans, neurogenesis starts and peaks at 5 and 25 weeks’ gestation, respectively, while neuronal migration is completed between 30 and 36 weeks’ gestation. Between 20 and 40 weeks’ gestation, these processes are followed by the generation of an array of supporting glial cells, such as astrocytes and oligodendrocytes. Concurrently, synapse formation begins as early as the 10th week of gestation and continues to increase gradually at a rate of approximately 4% per week until the end of the second trimester. After this phase, a robust and exponential increase in synapse formation (almost 40,000 synapses/min) occurs between 28 weeks’ and term gestation. These processes, in conjunction with the onset of myelination, result in a fivefold increase in brain volume and the appearance of morphologic features of the mature brain such as sulci and gyri. By 24 weeks’ gestation, the fetus has all the neural machinery necessary to perceive pain. Many clinicians recommend that appropriate measures should be taken to provide fetal analgesia during fetal surgical procedures from this point onward.

Although the ontogeny of neurotransmitter systems is less well studied, a wealth of animal and human data indicates that these systems appear very early in life, before the phase of active synaptogenesis. The presence of these neuromodulatory substances before synapse formation lends credence to the view that they serve a trophic role during early brain development, a role that is distinct from their predominant role of facilitating synaptic neurotransmission in the mature brain. Among these neurotransmitters, GABA remains the most widely studied ( Fig. 10.1 ). Although GABA has an inhibitory action in the mature brain, GABA serves an excitatory role during fetal brain development. The major mechanism for this role reversal is the differential expression of chloride ion transporters NKCC1 and KCC2; these transporters increase the intracellular concentration of chloride in developing neurons. On stimulation of GABA receptors that are expressed in neural progenitor cells and immature neurons, chloride ions are actively extruded, causing membrane depolarization rather than the hyperpolarization seen in mature neurons. This depolarizing effect of GABA decreases DNA synthesis and inhibits proliferation of neural progenitor cells, causes concentration- and time-dependent effects on neuronal migration, and plays a major role in activity-dependent synapse formation.

Fig. 10.1

Gamma-aminobutyric acid’s (GABA) role in regulating embryonic cortical development. During corticogenesis, interneurons migrating in the subventricular zone (SVZ) can release GABA and activate GABAergic receptors on the radial glia, depolarizing these progenitors and decreasing their proliferation. Radial glia generate immature pyramidal neurons through asymmetric division, and the migration of these immature neurons along the radial fibers is decreased by GABA signaling. As young neurons assume their position in the cortex and begin to mature, GABA-mediated depolarization by the interneurons is required for the development of dendritic arbors and excitatory synaptic inputs from other pyramidal neurons. MZ, marginal zone; VZ, ventricular zone; SVZ, subventricular zone; CP, cortical plate.

(From Wang DD, Kriegstein AR. Defining the role of GABA in cortical development. J Physiol. 2009;587:1873–1879.)

The N -methyl- d -aspartate ( NMDA)-subtype glutamate receptors originate later than the GABA receptors and remain functionally silent because of magnesium ion–induced channel blockade; thus, they play a limited role during early brain development. Dopaminergic, cholinergic, and serotonergic systems develop concomitantly and appear fully functional by the second trimester. Pharmacologic interventions (e.g., ethanol, antiepileptic drugs) that act directly or indirectly on these powerful neuromodulator systems induce long-lasting impairment of fetal brain development, mainly owing to impaired neurogenesis and/or altered neuronal migration. Alteration of this excitation-inhibition balance is purported to be responsible for an array of childhood neurodevelopmental disorders.

Experimental studies reveal that the fetal blood-brain barrier is morphologically well developed and functionally competent at term. Convincing evidence confirms that the endothelial tight junctions of the blood-brain barrier are as effective in the term fetus as in the adult, although the exact time that blood-brain barrier competency is established in the human fetus is unknown. In rodents, data suggest that the fetal blood-brain barrier is established between embryonic days 11 and 17 (term gestation is 22 days), a time period that corresponds to approximately the late second and early third trimesters in humans.

Cerebral Palsy

History, Definitions, and Significance

In 1861, John Little, an orthopedic surgeon, first described cerebral palsy in a report to the Obstetrical Society of London. Described as a neonatal neurologic disorder associated with difficult labor or birth trauma, the disorder was known as Little’s disease until William Osler coined the term cerebral palsy in 1888. A precise definition and classification of cerebral palsy has proved elusive. In the foreword to the “Report on the Definition and Classification of Cerebral Palsy,” published in 2007 in Developmental Medicine and Child Neurology, Peter Baxter wrote, “This [supplement] illustrates the difficulties inherent in trying to agree what we mean by the terms we use and that a classification that suits one purpose, such as a diagnostic approach, may not always be ideal for others, such as therapy issues. Defining and classifying cerebral palsy is far from easy. We do need a consensus that can be used in all aspects of day-to-day care and for future research on cerebral palsy.”

Today, cerebral palsy is defined as a nonprogressive disorder of the central nervous system (CNS) present since birth that includes some impairment of motor function or posture. Intellectual disability (formerly known as mental retardation ) may be present but is not an essential diagnostic criterion. Various forms of cerebral palsy exist, with differences in pathology, pathophysiology, and potential relationships with intrapartum events. The literature on cerebral palsy is difficult to review and understand. Data from individual studies are difficult to compare because of variations in the duration of follow-up, birth weight classifications, inclusion criteria for congenital abnormalities, and exclusion criteria for various causes of death. Terms such as hypoxic-ischemic encephalopathy of the newborn, newborn asphyxia, birth asphyxia, and asphyxia neonatorum are difficult to distinguish. Some authorities, including the American College of Obstetricians and Gynecologists (ACOG), have argued that the term birth asphyxia should be abandoned.

Intrapartum events continue to receive the blame for some cases of cerebral palsy. It is a widely believed theory that an intrapartum reduction in fetal oxygen delivery may cause cerebral palsy, and early reports in primates demonstrated that perinatal asphyxia could cause brain injury. Continuous electronic fetal heart rate (FHR) monitoring, which has largely replaced intermittent FHR auscultation during labor, is believed to prompt the delivery of at-risk fetuses and thus reduce asphyxial events. However, despite a higher incidence of cesarean delivery, no reduction in the incidence of cerebral palsy has been observed since the widespread implementation of continuous electronic FHR monitoring during labor. Further, among patients with new-onset late FHR decelerations, an estimated 99% of tracings would be false positive “if used as an indicator for subsequent development of cerebral palsy.”

Large randomized trials have not demonstrated better fetal and neonatal outcomes with continuous electronic FHR monitoring than with intermittent FHR auscultation. In an editorial citing observations made by Schifrin and Dame, Friedman opined, “The absence of either suggestive or overtly ominous fetal heart rate patterns is reliably reassuring.” Unfortunately, there is little objective evidence that reassuring FHR tracings exclude the subsequent occurrence of cerebral palsy. In a 1993 review of published FHR monitoring studies, Rosen and Dickinson could not identify FHR patterns that were consistently associated with neurologic injuries. These investigators concluded, “We do not advocate the abandonment of the use of electronic fetal monitoring, but we do believe that it is yet to be proved to be of value in predicting or preventing neurologic morbidity.” A more focused application of FHR monitoring may ultimately be found useful. For example, fetal inflammatory changes, which can be associated with neurologic injury, may be associated with characteristic FHR findings.

More recently, research has focused on whether expert, algorithm-assisted FHR interpretation has the potential to improve standard clinical care by leading to earlier recognition of nonreassuring FHR tracings. Although use of the algorithm identified more infants with acidemia (base deficit > 12 mM/L) than standard monitoring (46% versus 30%), less than 50% of the acidemic infants were identified. Thus, the current application of electronic FHR monitoring provides incomplete data that should be evaluated in the clinical context in which it is used.

Despite significant limitations in the use of intrapartum electronic FHR monitoring, there is no doubt that it will continue to be used for the foreseeable future. In a review of medicolegal issues in FHR monitoring, Schifrin and Cohen noted that despite its limitations, “Monitoring deserves credit for reducing intrapartum death, one of the original rationales for its development.”

A 2008 workshop (sponsored by the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the ACOG, and the Society for Maternal-Fetal Medicine [SMFM]) updated the definitions of various types of FHR tracings to simplify interpretation for providers. As a result, a three-category system was developed. Category I FHR tracings provide reassuring evidence of fetal well-being and strongly predict normal fetal acid-base status at the time of observation. Category III tracings are the most ominous; these tracings predict abnormal fetal acid-base status at the time of observation and require prompt evaluation. Most FHR tracings are category II (indeterminate). Category II tracings are not predictive of abnormal fetal acid-base status, but they do not provide sufficient evidence to be classified as either normal or abnormal; these tracings require continued surveillance and reevaluation (see Chapter 8 ).

Intrapartum events are responsible for some cases of cerebral palsy ; however, these cases are few. After exclusion of infants with significant congenital anomalies, intrapartum events—including asphyxial insults—likely account for only 5% to 8% of all cases of cerebral palsy at all gestational ages. In 1999, the International Task Force on Cerebral Palsy published a consensus statement summarizing criteria that are necessary and suggestive of an intrapartum etiology for neurologic abnormalities ( Box 10.1 ). In 2010, a proposed evidence-based neonatal workup to confirm or refute allegations of intrapartum asphyxia was published.

Box 10.1

Criteria to Define an Acute Intrapartum Hypoxic Event as Sufficient to Cause Cerebral Palsy

Essential Criteria (All Four Must Be Met)

  • 1.

    Evidence of metabolic acidosis in fetal umbilical cord arterial blood obtained at delivery (pH < 7 and base deficit ≥ 12 mmol/L) a

    a Buffer base is defined as the amount of buffer in blood available to combine with nonvolatile acids. A buffer base of 34 mmol/L is equivalent to a whole blood base deficit of 12 mmol/L.

  • 2.

    Early onset of severe or moderate neonatal encephalopathy in infants born at 34 or more weeks’ gestation

  • 3.

    Cerebral palsy of the spastic quadriplegic or dyskinetic type b

    b Spastic quadriplegia and, less commonly, dyskinetic cerebral palsy are the only types of cerebral palsy associated with acute hypoxic intrapartum events. Spastic quadriplegia is not specific to intrapartum hypoxia. Hemiparetic cerebral palsy, hemiplegic cerebral palsy, spastic diplegia, and ataxia are unlikely to result from acute intrapartum hypoxia.

  • 4.

    Exclusion of other identifiable etiologies, such as trauma, coagulation disorders, infectious conditions, and genetic disorders

Criteria That Collectively Suggest an Intrapartum Event—within Close Proximity to Labor and Delivery (e.g., 0 to 48 hours)—but Are Nonspecific to Asphyxial Insults

  • 1.

    A sentinel (signal) hypoxic event occurring immediately before or during labor

  • 2.

    A sudden and sustained fetal bradycardia or the absence of fetal heart rate variability in the presence of persistent, late, or variable decelerations, usually after a hypoxic sentinel event when the pattern was previously normal

  • 3.

    Apgar scores of 0 to 3 beyond 5 minutes

  • 4.

    Onset of multisystem involvement within 72 hours of birth

  • 5.

    Early imaging study showing evidence of acute nonfocal cerebral abnormality

From Nelson KB, Grether JK. Potentially asphyxiating conditions and spastic cerebral palsy in infants of normal birth weight. Am J Obstet Gynecol. 1998;179:507–513.

Epidemiology and Etiology

The causes of cerebral palsy are not known, but the varying forms suggest a multifactorial etiology. The Collaborative Perinatal Project still represents one of the largest studies of the antecedent factors associated with cerebral palsy. The investigators in this study evaluated the outcomes of 54,000 pregnancies among patients who delivered at 12 university hospitals between 1959 and 1966. They evaluated more than 400 variables in a univariate analysis, which identified potential risk factors that were then subjected to a more rigorous multivariate analysis. Maternal age, parity, socioeconomic status, smoking history, maternal diabetes, duration of labor, or use of anesthesia was not associated with cerebral palsy in the univariate analysis. The factors most strongly associated with cerebral palsy in the multivariate analysis were (1) maternal mental retardation, (2) birth weight ≤ 2000 g, and (3) fetal malformations. Other factors associated with cerebral palsy included (1) breech presentation (but not vaginal breech delivery), (2) severe proteinuria (> 5 g/24 h) during the second half of pregnancy, (3) third-trimester bleeding, and (4) gestational age ≤ 32 weeks. There was a slight association between cerebral palsy and fetal bradycardia, chorioamnionitis, and low placental weight. However, only 37% of the cases of cerebral palsy occurred in patients with one or more of these identified risk factors.

Rosen and Dickinson reviewed studies from Europe, Australia, and the United States that were published between 1985 and 1990 and included data from 1959 to 1982. The incidence of cerebral palsy ranged from 1.8 to 4.9 (composite rate of 2.7) cases per 1000 live births. The incidence of certain conditions in infants with cerebral palsy was as follows: birth weight < 2500 g, 26%; diplegia, 34%; hemiplegia, 30%; quadriplegia, 20%; and extrapyramidal forms, 16%.

Two more recent studies from Australia reexamined the risk factors for cerebral palsy. A large epidemiologic study from 1998 noted an incidence of neonatal encephalopathy of 3.8 per 1000 term births. The investigators identified preconception and antepartum factors that were associated with neonatal encephalopathy ( Box 10.2 ). In the second study from 2011, the greatest risks for cerebral palsy included (1) preterm birth, (2) fetal growth restriction, (3) perinatal infection, and (4) multiple gestation. Upper respiratory tract and gastrointestinal infections during pregnancy and instrumental (forceps or vacuum) vaginal delivery were not associated with cerebral palsy. Evidence suggests that intrapartum factors alone are associated with neonatal encephalopathy in < 5% of cases. These data, along with the recognition that most patients with identified risk factors do not have children with cerebral palsy, have led the majority of investigators to agree that most cases of cerebral palsy cannot be predicted and that the identification of pregnancy-related conditions contributes minimally to the identification of patients at risk for having a child with cerebral palsy.

Box 10.2

Risk Factors for Neonatal Encephalopathy

Preconception Factors

  • Increasing maternal age

  • Mother unemployed, unskilled laborer, or stay-at-home

  • No private health insurance

  • Family history of seizures

  • Family history of neurologic disorders

  • Infertility treatment

Antepartum Factors

  • Maternal thyroid disease

  • Severe preeclampsia

  • Bleeding in pregnancy

  • Viral illness in pregnancy

  • Postdates pregnancy

  • Fetal growth restriction

  • Placental abnormalities

Information compiled from Badawi N, Kurinczuk JJ, Keogh JM, et al. Antepartum risk factors for neonatal encephalopathy: the Western Australia case-control study. BMJ. 1998;317:1549–1553.

In 2000, the ACOG and the American Academy of Pediatrics (AAP) convened the Neonatal Encephalopathy and Cerebral Palsy Task Force. The resulting landmark report, which was released in 2003, was reviewed and endorsed by many groups. The Task Force extended the earlier international consensus statement regarding the requirements for establishing a causal relationship between intrapartum events and cerebral palsy (see Box 10.1 ). The consensus statement led to several medicolegal conclusions :

  • 1.

    The only types of cerebral palsy associated with intrapartum hypoxia are spastic quadriplegia and, less commonly, dyskinesia.

  • 2.

    Intellectual disability, learning disorders, and epilepsy should not be ascribed to birth asphyxia unless accompanied by spastic quadriplegia.

  • 3.

    No statements about severity should be made before an affected child is 3 to 4 years of age, because mild cases may improve and dyskinesia may not be evident until then.

  • 4.

    Intrapartum hypoxia sufficient to cause cerebral palsy is always accompanied by neonatal encephalopathy and seizures.

Phelan et al. subsequently confirmed that fetuses that experienced a sudden and sustained deterioration of the FHR, and that subsequently were found to have cerebral palsy, demonstrated characteristics consistent with the ACOG/AAP Task Force criteria for intrapartum asphyxial injury.

Peripartum Asphyxia and Cerebral Palsy

Asphyxia may be defined as insufficient exchange of respiratory gases. Although accurate, this definition does not include an index of severity or have any predictive value. Unfortunately, most studies have not used a uniform definition of birth asphyxia.

In 1953, Dr. Virginia Apgar, an anesthesiologist, introduced her scoring system to identify newborn infants in need of resuscitation and to assess the adequacy of subsequent resuscitation efforts. Although the Apgar score has also been used to identify infants at risk for cerebral palsy, only a weak association has been found. In the Collaborative Perinatal Project, only 1.7% of children with a 1-minute Apgar score ≤ 3 developed cerebral palsy. Among infants who weighed more than 2500 g at delivery, the incidence of cerebral palsy was 4.7% if the 5-minute Apgar score was 0 to 3 and 0.2% if the 5-minute Apgar score was at least 7. Among infants who weighed < 2500 g with the same 5-minute Apgar scores, the incidence of cerebral palsy was 6.7% and 0.8%, respectively. Among all infants, a higher incidence of cerebral palsy was observed if the Apgar score remained ≤ 3 for longer than 5 minutes. The incidence of early neonatal death increased among those infants with prolonged neonatal depression.

Most infants who subsequently manifest evidence of cerebral palsy have a normal 5-minute Apgar score. In the Collaborative Perinatal Project, only 15% of the infants in whom cerebral palsy later developed had a 5-minute Apgar score ≤ 3. It should also be noted that preterm delivery is independently associated with a low Apgar score.

Although most cases of cerebral palsy are not attributed to intrapartum insults, intrapartum asphyxia does occur and can have serious consequences. However, the degree of asphyxia necessary to produce irreversible CNS injury is unclear. In some cases, an intrapartum insult that might have otherwise been innocuous might be superimposed on subclinical chronic fetal compromise and result in permanent injury.

Umbilical cord blood gas measurements are often used to diagnose suspected asphyxia. However, the definition of normal umbilical cord blood gas and pH measurements remains unclear. In one study of 15,073 vigorous neonates (arbitrarily defined as having a 5-minute Apgar score of ≥ 7) conducted between 1977 and 1993, the median umbilical arterial blood gas measurements (with the 2.5th percentile in parentheses) were as follows: pH 7.26 (7.10), P o 2 17 (6) mm Hg, P co 2 52 (74) mm Hg, and base excess –4 (–11) mmol/L. Only small differences in median pH and other measurements were present when infants were grouped according to gestational age. These data suggest that umbilical arterial blood pH in vigorous neonates can be as low as 7.10, and base excess may be as low as –11 mmol/L.

Although intrapartum events are most likely associated with a minority of cerebral palsy cases, clinical studies have attempted to define the associated extent and duration of perinatal asphyxia. Fee et al. defined asphyxia as an umbilical arterial blood pH of < 7.05 with a base deficit > 10 mmol/L; they concluded that this threshold was a poor predictor of adverse neurologic outcomes. Goodwin et al. defined asphyxia as an umbilical arterial blood pH < 7.00; with the use of this definition, hypoxic-ischemic encephalopathy and abnormal neurologic outcome were associated with acidemia. Goldaber et al. also observed greater neonatal morbidity and mortality among term infants (birth weight > 2500 g) with an umbilical arterial blood pH < 7.00.

Low et al. also studied complications of intrapartum asphyxia in term and preterm infants. They developed a complication score that expressed the magnitude of neonatal complications. Among term infants, the frequency and severity of newborn complications increased with the severity and duration of metabolic acidosis at birth. Importantly, respiratory acidosis at birth did not predict complications in newborns. Similar results were noted for preterm infants delivered between 32 and 36 weeks’ gestation. In contrast, in infants delivered before 32 weeks’ gestation, complications were similar in the control and asphyxia (defined as umbilical arterial blood buffer base < 30 mmol/L) groups. When this scoring system was used in term infants, the threshold for moderate or severe newborn complications was an umbilical arterial blood base deficit of 12 mmol/L.

Relatively few studies have followed neurodevelopmental examinations for a sufficient duration to make meaningful conclusions about peripartum predictors of neurologic injury. Nagel et al. performed such examinations in 30 children in whom umbilical arterial blood pH was < 7.00 at delivery, 28 of whom survived the neonatal period. Evaluation at 1 to 3 years of age detected three children who had experienced an episode of hypertonia. Most of the children exhibited no major problems, with only one child displaying mild motor developmental delay. Another study examined neonatal complications (neonatal death, grade 3 or 4 intraventricular hemorrhage, gastrointestinal dysfunction, and neonatal seizures) in 35 newborns with an umbilical arterial blood pH < 7.00 at delivery, three of whom died during the neonatal period. An umbilical arterial blood base deficit ≥ 16 mmol/L and a 5-minute Apgar score < 7 had a sensitivity and specificity for predicting adverse neonatal outcomes of 79% and 81%, respectively.

Because metabolic acidosis may be a predictor of complications in newborns, the severity of intrapartum acidosis could be an important variable. Gull et al. studied a small cohort of 27 patients with terminal bradycardia who were delivered vaginally. Not surprisingly, the umbilical arterial blood base deficit was greater in infants with end-stage bradycardia than in controls. The loss of short-term FHR variability for more than 4 minutes during terminal bradycardia correlated with the development of metabolic acidosis.

The relationship between umbilical arterial blood base excess values and the timing of hypoxic injury has been estimated in human and animal studies. In a 2010 systematic review and meta-analysis, an umbilical cord arterial blood pH < 7.00 was significantly associated with important, biologically plausible, adverse neonatal outcomes (i.e., neonatal mortality, hypoxic ischemic encephalopathy, intraventricular hemorrhage, periventricular leukomalacia, cerebral palsy). Unfortunately, this relationship does not consider the role of previous or repetitive hypoxic episodes before the episode in question and therefore cannot accurately pinpoint the time of injury. Fortunately, the human fetus is quite robust, and episodes of intrauterine asphyxia usually yield a normal neonate. Blumenthal concluded that there is a fine threshold between normality and death from asphyxia.

The increased presence of nucleated red blood cells in the umbilical circulation at delivery has been proposed as a marker of the occurrence and timing of intrauterine asphyxia. However, data from these investigations demonstrated considerable variability and were influenced by birth weight and gestational age. In 2014, the ACOG concluded that biomarkers predictive of long-term outcome after a hypoxic insult have not been identified, and that it is likely that a battery of such markers, in conjunction with clinical and imaging findings, rather than a single biomarker, would better predict outcome.

Chorioamnionitis, Fever, and Cerebral Palsy

An association between cerebral palsy and chorioamnionitis has been demonstrated in preterm and term infants. Intra-amniotic infection and inflammation show direct evidence of causality between the intrauterine process and white matter injury. An elevated maternal temperature is one sign of chorioamnionitis, but alone it is insufficient for the diagnosis. Other signs include, but are not limited to, maternal and fetal tachycardia, foul-smelling amniotic fluid, uterine tenderness, and maternal leukocytosis. The diagnosis remains unproven until confirmed by placental culture or histologic examination.

The mechanism by which chorioamnionitis is associated with cerebral palsy is unclear; however, inflammatory cytokines may play a role (see later discussion). A landmark meta-analysis published in 2000 reported that both clinical and histologic chorioamnionitis were strongly associated with an increased risk for cerebral palsy and periventricular leukomalacia in both preterm and term infants. In a 2010 meta-analysis, both histologic (pooled odds ratio [OR], 1.83; 95% confidence interval [CI], 1.17 to 2.89) and clinical chorioamnionitis (OR, 2.42; 95% CI, 1.52 to 3.84) were again found to be significantly associated with cerebral palsy.

Several studies have demonstrated a tendency for maternal temperature to rise after administration of epidural analgesia during labor (see Chapter 23 ). The mechanism of epidural analgesia–associated maternal pyrexia remains unclear but appears to be inflammatory in nature. Epidural analgesia has been blamed for the common obstetric practice of antibiotic administration to mothers with fever but no other evidence of chorioamnionitis. This practice may lead to unnecessary neonatal sepsis evaluations and antibiotic exposure. Rather than treat all women with pyrexia for presumed chorioamnionitis, Mayer et al. correctly noted that physicians should make an effort to differentiate true chorioamnionitis from incidental maternal fever. These investigators found that additional signs of chorioamnionitis were present in all cases in which the diagnosis was later confirmed by culture or pathologic examination. Neuraxial anesthesia is not a risk factor for cerebral palsy.

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Jun 12, 2019 | Posted by in ANESTHESIA | Comments Off on Fetal and Neonatal Neurologic Injury
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