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 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 differ in pathology, pathophysiology, and potential relationships with intrapartum events. Studies on cerebral palsy are difficult to interpret because of variations in duration of follow-up, birth weight classification, 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 be blamed for cases of cerebral palsy. It is widely believed that an intrapartum reduction in fetal oxygen delivery may cause cerebral palsy, and early primate studies demonstrated that perinatal asphyxia could cause brain injury. Continuous electronic fetal heart rate (FHR) monitoring is believed to prompt delivery of at-risk fetuses and thus reduce asphyxial events, but despite a higher incidence of cesarean delivery, no reduction in the incidence of cerebral palsy has been observed since its widespread implementation 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 compared with intermittent FHR auscultation, and there is little evidence that reassuring FHR tracings exclude the subsequent occurrence of cerebral palsy. A 1993 review of published FHR monitoring studies could not identify FHR patterns that were consistently associated with neurologic injuries and 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 may improve standard clinical care via earlier recognition of nonreassuring FHR tracings. Although use of the algorithm identified more infants with acidemia (base deficit > 12 mol/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.

Despite limitations in the use of intrapartum electronic FHR monitoring, it likely 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 updated the definitions of various types of FHR tracings to simplify interpretation for providers. 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, the most ominous, 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 do not provide sufficient evidence to be classified as either normal or abnormal; these tracings require continued surveillance and reevaluation (see Chapter 8 ).

Although intrapartum events are responsible for some cases of cerebral palsy, 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, and only 13% of infants born at 28 to 33 weeks’ gestation. It was estimated that only 16% of cerebral palsy cases may be preventable by placing a greater focus on earlier changes in FHR progression. 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.

The varying forms of cerebral palsy suggest a multifactorial etiology. The Collaborative Perinatal Project was one of the largest studies of the antecedent factors associated with cerebral palsy. This study evaluated the outcomes of 54,000 pregnancies among patients who delivered at 12 university hospitals between 1959 and 1966 and evaluated more than 400 variables in a univariate analysis ; identified potential risk factors were then subjected to a more rigorous multivariate analysis. Maternal age, parity, socioeconomic status, smoking history, maternal diabetes, duration of labor, and use of anesthesia were not associated with cerebral palsy in the univariate analysis. The factors most strongly associated with cerebral palsy in the multivariate analysis were (1) maternal intellectual disability, (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 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%.

A large epidemiologic Australian study from 1998 noted an incidence of neonatal encephalopathy of 3.8 per 1000 term births and identified preconception and antepartum factors associated with neonatal encephalopathy ( Box 10.2 ). In a 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 operative vaginal delivery were not associated with cerebral palsy. More recently, efforts to create a risk prediction model for cerebral palsy using both demographic and pregnancy factors have been attempted but are still in early stages of development in terms of application to patient care. Evidence suggests that intrapartum factors alone are associated with neonatal encephalopathy in less than 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 to a majority agreement that most cases of cerebral palsy cannot be predicted and that the identification of pregnancy-related conditions contributes minimally to the identification of individuals at risk for cerebral palsy.

In 2000, the ACOG and the American Academy of Pediatrics (AAP) convened the Neonatal Encephalopathy and Cerebral Palsy Task Force. The resulting landmark report, 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 who experienced a sudden and sustained deterioration of the FHR, and who subsequently were found to have cerebral palsy, demonstrated characteristics consistent with the ACOG/AAP Task Force criteria for intrapartum asphyxial injury.

Asphyxia may be defined as insufficient exchange of respiratory gases. However, 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 Virginia Apgar introduced a scoring system for identifying newborn infants in need of resuscitation and assessing 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 between 0 and 3 and 0.2% if the 5-minute Apgar score was greater than or equal to 7. Among infants who weighed less than 2500 g, the incidence of cerebral palsy was 6.7% and 0.8% with Apgar scores of 0 to 3 and greater than or equal to 7, respectively. Among all infants, a higher incidence of cerebral palsy was observed if the Apgar score remained less than or equal to 3 for more 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 attributable to intrapartum insults, intrapartum asphyxia does occur with 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 ≥ 7) conducted between 1977 and 1993, the median umbilical arterial blood gas measurements (2.5th to 97.5th percentiles) were: pH 7.27 (7.10 to 7.38), P o ₂ 17 (6 to 30) mm Hg [2.3 (0.8 to 6.9) kPa], P co ₂ 52 (35 to 74) mm Hg [6.9 (4.7 to 9.9) kPa], and base excess −4 (−11 to 1) 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 < 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; using 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 with umbilical arterial blood pH < 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 umbilical arterial blood pH < 7.00 at delivery, three of whom died during the neonatal period. Umbilical arterial blood base deficit ≥ 16 mmol/L and 5-minute Apgar score < 7 had 79% sensitivity and 81% specificity for predicting adverse neonatal outcomes.

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 metaanalysis, 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.

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. Elevated maternal temperature is a sign of chorioamnionitis, but alone 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 discussion below). A 2000 metaanalysis reported that both clinical and histologic chorioamnionitis were strongly associated with increased risk for cerebral palsy and periventricular leukomalacia in both preterm and term infants. Similarly, in a 2010 metaanalysis, 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 found to be significantly associated with cerebral palsy. Preterm infants are particularly at risk, as up to 50% of cases of brain abnormalities in this population have been attributed to direct effect of moderate to severe acute histologic chorioamnionitis.

Maternal temperature increases after administration of epidural labor analgesia in some women (see Chapter 24 ). Although uncertain, the mechanism for this may be inflammatory. Epidural analgesia has been blamed for antibiotic administration to mothers with fever but no other evidence of chorioamnionitis, which may lead to unnecessary neonatal sepsis evaluations and antibiotic exposure. Rather than treat all women with pyrexia for presumed chorioamnionitis, Mayer et al. recommended that physicians make an effort to differentiate true chorioamnionitis from incidental maternal fever; they 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.

The fetus is exclusively dependent on the placenta for oxygen and nutrients; thus, acute and chronic conditions that affect the placenta or the umbilical cord can deprive the fetus of these vital resources. Evidence from experimental animal models and humans suggests that both hypoxemic and inflammatory pathways interact and augment fetal brain damage.

The spectrum of neurologic injury in neonates depends on the duration and gestational age at hypoxemic-ischemic insult. Acute hypoxemia during the early- to mid-gestational period in sheep affects the predominant neurodevelopmental events such as neurogenesis and neuronal migration. Such hypoxemia causes the death of cerebellar Purkinje cells and hippocampal pyramidal neurons, and impaired neuronal migration. In contrast, acute hypoxemia in late gestation appears to spare the hippocampus and cerebellum but causes neuronal death in the cerebral cortex and striatum. Furthermore, acute perinatal anoxia causes long-term changes in dendritic arborization and synaptic connectivity.

Experimental models of chronic hypoxemia, based on restriction of placental mass or blood flow, have demonstrated an array of completely different effects on the fetal brain. Chronic placental insufficiency relatively spares the fetal brain compared with other organ systems, although it results in reduced fetal brain weight. Overall, neurons appear to survive chronic and mild hypoxemia; even minor behavioral changes appear to resolve fully by adulthood in animal models. It is not known whether these effects are mediated by hypoxemia per se , or by other accompanying conditions such as chronic reduction of fetal nutrient supply or altered maternal-fetal endocrine status.

Dysregulation of neuronal calcium transport appears to be the initial pathway by which cerebral hypoxemia causes perinatal neuronal injury. Hypoxia-induced changes in the NMDA receptor increase cellular permeability to calcium, triggering a variety of downstream effects, ultimately resulting in the generation of free radicals, peroxidation of lipid membranes, and nuclear fragmentation. It has long been recognized that developing oligodendroglia are highly vulnerable to excitotoxic injury in preterm infants. Altered maturation or premature oligodendrocyte death can occur in areas of severe hypoxia-ischemia as a result of upregulation of inflammatory cytokines by activated microglia, elevated glutamate levels, or depleted levels of the antioxidant glutathione. It is highly likely that a combination of these mechanisms, modified by the nature and duration of insults and gestational age, determines the ultimate neurobehavioral phenotype.

Although the development of the fetal brain is encoded by genetic programming, this is highly susceptible to environmentally induced epigenetic modifications and appears closely intertwined with maternal immune and endocrine systems. Experimental and epidemiologic studies reveal that maternal infection and inflammation early in pregnancy can cause an array of neurodevelopmental abnormalities in offspring such as schizophrenia and autism. Among maternal infections, chorioamnionitis is the best characterized and investigated model of perinatal neuroinflammation. Human registry studies have confirmed an association between histological chorioamnionitis and cerebral palsy. Although the exact contribution of maternal inflammation to perinatal brain injury is obscured because of the association of chorioamnionitis with preterm delivery and hypoxic-ischemic encephalopathy, inflammatory experimental models have revealed much information on cytokine induction, their transport across the placenta and amniotic fluid, and subsequent activation of the fetal immune system.

The mechanism by which maternal inflammation triggers a fetal immune response is likely multifactorial ( Fig. 10.2 ). Despite the presence of circulating immune cells as early as 7 weeks’ gestation in humans, antigen presentation is suboptimal because of reduced expression of the major histocompatibility complex class II on antigen-presenting cells. Furthermore, the T cells are relatively immature. Therefore, maternally derived humoral mediators seem credible candidates to initiate and perpetuate an inflammatory cascade across the placenta. This idea has gained traction with the identification of maternal interleukin-6 (IL-6) in the fetal circulation as early as the second trimester, suggesting the possibility of transplacental transfer of proinflammatory cytokines. Proinflammatory mediators such as IL-6 cause significant impairment of placental blood flow and fetal hypoxemia in animal models, dysregulate the barrier function of both the placenta and the immature fetal blood-brain barrier, trigger production of acute-phase proteins from the fetal liver, promote T-cell entry into the immature brain parenchyma, and disrupt the orderly patterning of the fetal cerebral cortex. The role of inflammatory mediators in this phenomenon is reinforced by the direct correlation between plasma levels of IL-6 and the severity of functional deficits in offspring. In addition to IL-6, cytokines such as IL-1β, IL-7, and IL-13 are upregulated in the fetal brain after a prenatal immune insult, which suggests collective activation of the innate fetal immune response.

Probable Mechanisms of Fetal Brain Injury With In Utero Exposure to Maternal Inflammation. ELGAN , Extremely low gestational age neonate; IL , interleukin; LBWI , low-birth-weight infant; TNF , tissue necrosis factor.

From Burd I, Balakrishnan B, Kannan S. Models of fetal brain injury, intrauterine inflammation, and preterm birth. Am J Reprod Immunol . 2012;67:287–294.

Both microglia (the major resident macrophages in the developing brain) and the complement system have been implicated as amplifiers of this immune response. During normal fetal development, microglia invade and colonize the fetal brain during the first and second trimesters and are readily activated by proinflammatory mediators such as IL-1β. Activated microglial cells either cause a direct cytotoxic effect on oligodendrocytes and impair myelination or produce long-lasting alterations in neuronal-glial crosstalk, resulting in impaired synaptic function and subsequent neurodevelopmental disorders.

At the cellular level, numerous mechanisms are involved in propagating the prenatal immune response. Intrauterine inflammation is linked to the metabolic demand of the fetal brain; in infants born before 30 weeks’ gestation, chorioamnionitis was associated with increased total carotid artery blood flow (92 versus 63 mL/kg/min) and oxygen delivery (13.7 versus 10.1 mL/kg/min) compared with a control cohort without chorioamnionitis. Whether the increase in oxygen delivery contributes to, or is a consequence of, fetal brain injury is unclear, but evidence suggests an enhanced susceptibility of the developing brain to oxidative stress.

Collectively, robust experimental evidence suggests that prenatal inflammation alters fetal brain development at the molecular, cellular, and circuit levels. These findings are reinforced by epidemiologic studies that show a strong correlation between maternal infection/inflammation and neurodevelopmental disorders such as schizophrenia and autism. Likewise, a study of placental histopathology of infants admitted to the neonatal intensive care unit (NICU) with hypoxic ischemic encephalopathy found that acute inflammation, including fetal inflammatory reaction, was higher in the moderate-severe hypoxic ischemic encephalopathy group than in the mild group.

Much of our knowledge of the fetal response to insufficient exchange of respiratory gases comes from animal models, which have limitations. Raju reviewed the various animal models of fetal brain injury. At birth, sheep and guinea pig brains are much closer to maturity than the human brain. In this regard, rat pup and human brains are more similar to each other because they both undergo significant extrauterine development ( Fig. 10.3 ). Nonetheless, the importance of this distinction has been challenged. Previously, investigators relied mainly on morphologic milestones (e.g., the brain growth spurt) to compare species at different stages of development. A computerized method attempted to more accurately compare observations among 10 species (including humans) by evaluating the mathematical relationships of more than 100 developmental events and factors (e.g., evolutionary, genetic, neurochemical, neuroanatomic). Although all events have not been cataloged for any one species, the iterative process allows information to be added to improve the theoretic model and is freely available online. This method is not completely understood or accepted but may explain some of the variability in various models of developmental brain injury.

Brain growth spurts of seven mammalian species expressed as first-order velocity curves of the increase in weight with age. The units of time for each species are as follows: guinea pig d); rhesus monkey (4 d); sheep (5 d); pig (w); human (mo); rabbit (2 d); rat (d). Rates are expressed as a percentage of adult weight for each unit of time.

Modified from Dobbing J, Sands S. Comparative aspects of the brain growth spurt. Early Hum Dev . 1979;3:79–83.

The chronically instrumented fetal lamb is similar in size to the human fetus, which facilitates placement of electrodes and vascular catheters in both the fetus and the mother. Investigators may obtain measurements while the mother (and fetus) remains anesthetized, or from awake animals that have recovered from surgery. Studies of animals with continuous instrumentation allow the assessment of fetal breathing movements, gross body movements, brain electrical activity (electroencephalogram), and blood gas and pH measurements. Blood concentrations of glucose, lactate, and various hormones can also be determined. Microdialysis techniques have been used to evaluate neurotransmitter release within the fetal brain in vivo , in acute, exteriorized, and chronic preparations. Other studies have measured fetal cerebral blood flow in vivo during episodes of hypoxemia and during maternal infusion of ethanol. These studies have enhanced understanding of the fetal brain response to pathophysiologic insults in utero , which ultimately may lead to improved diagnoses, treatment, and prevention of fetal brain injury.

Various methods have been used to produce fetal hypoxemia and acidemia in fetal lambs. Each method attempts to mimic one or more clinically relevant situation(s), including (1) decreased concentration of maternal inspired oxygen for several hours or days ; (2) decreased uterine blood flow, which may be accomplished by placement of an adjustable clamp on the common iliac artery ; (3) decreased umbilical blood flow, either by total obstruction or by means of a slow, progressive obstruction ; (4) selective uteroplacental embolization ; (5) maternal hemorrhage ; and (6) a combination of two insults, such as hypoxemia plus hypotension.

Care must be exercised in the application of knowledge gained from hypoxia-ischemia studies conducted on nonfetal models (e.g., rat pups) to the problem of insufficient intrauterine gas exchange. The fetus and the fetal brain exist in a relatively hypoxemic environment. Despite preferential streaming of the most highly oxygenated blood to the brain and heart, the average P o ₂ measured in the carotid artery of fetal lambs at term is approximately 22 mm Hg (2.9 kPa). Further, unlike adult conditions in which global anoxia (i.e., cardiac arrest) or focal ischemia (i.e., stroke) is the clinical correlate, fetal asphyxia typically involves diminution, but not absence, of oxygen delivery, with variable degrees of respiratory or metabolic acidosis. A complete loss of cerebral blood flow rarely occurs, except as a terminal event. Of course, prolonged hypoxemia and decreased oxygen delivery can lead to acidemia and myocardial failure, followed by ischemia and rapid fetal demise. Fetal hypoxemia may result from the compromise of any or all of the steps involved in maternal-fetal oxygen transport ( Box 10.3 ). The impact of repeated hypoxic-ischemic insults, which may occur from various causes (e.g., repetitive umbilical cord occlusion, chronic abruption), should not be underestimated. Moreover, repeated brief insults may be harmful, as demonstrated in adult rats and in fetal lambs.

The neuropathology of intrauterine asphyxia depends, to some extent, on gestational age. In fetal lambs exposed to sustained hypoxemia with developing acidemia, immature fetuses demonstrated a predominantly periventricular injury, whereas mature fetuses had a primarily cortical injury, although there was some overlap ( Fig. 10.4 ). This finding is consistent with injury patterns in humans. Matsuda et al. observed that the development of metabolic acidemia, reduced fetal breathing and body movements, and an altered sleep state were much less pronounced in mid-gestational fetal lambs subjected to hypoxemia than in fetal lambs at term.

Composite diagram showing distribution of hypoxic injury in mid-gestational (top) and near-term (bottom) fetal lambs at 3 d after 8 h of arterial hypoxemia. Hypoxemia was produced by placing the pregnant ewe in a chamber with reduced ambient oxygen. Each shading pattern represents an individual animal. The severity of injury is not indicated in this diagram.

From Penning DH, Grafe MR, Hammond R, et al. Neuropathology of the near-term and midgestation ovine fetal brain after sustained in utero hypoxemia. Am J Obstet Gynecol . 1994;170:1425–1432.

The mechanism and timing of an asphyxial insult can affect the resulting fetal or neonatal pathology. Acute, complete asphyxia must be distinguished from incomplete, brief, or intermittent asphyxia or chronic hypoxemia. Complete asphyxia may occur in the setting of total placental abruption or umbilical cord occlusion (e.g., uterine rupture or umbilical cord prolapse), which if not treated rapidly leads to fetal demise. Incomplete asphyxia may occur whenever oxygen delivery to the fetus is inadequate to meet all of its needs (e.g., brief and/or repeated episodes of partial umbilical cord occlusion, placental embolization, or incomplete placental abruption). This latter category of asphyxia presumably contributes to the largest proportion of cases of cerebral palsy attributed to antepartum events. In these cases, the insult is not severe enough to lead to immediate fetal death but can profoundly affect fetal brain growth and development. Ongoing studies are attempting to determine whether there is a period in utero when the fetus is especially vulnerable to neurologic injury.

Using a primate model to perform seminal research on perinatal brain injury, Myers identified two patterns of injury based on whether the fetus suffered complete or partial asphyxia. True complete asphyxia was demonstrated in fetal monkeys at term subjected to varying durations (0 to 25 minutes) of complete asphyxia. These fetuses were resuscitated when possible, a procedure that often required the use of cardiac massage and epinephrine (adrenaline), and postmortem examinations revealed extensive pathology in brainstem areas. In humans, such a severe intrauterine insult would most likely be incompatible with extrauterine survival. If survival did occur, the infant would show obvious encephalopathy and multiorgan system dysfunction at birth. The second pattern (i.e., partial asphyxia) is more relevant to the discussion of human cerebral palsy. In studies of fetal monkeys subjected to partial asphyxia, some animals demonstrated cortical necrosis, subcortical white matter damage, and basal ganglia damage. Although these two studies form the core of our knowledge of perinatal brain injury in primates, there were relatively few animals in each experimental group, and considerable variation in response occurred. Some animals suffered no injury, whereas others could not be resuscitated. Volpe emphasized that the variation in neuropathology after intrauterine asphyxia depends on fetal gestational age and proposed a framework for these variations. He reported that the principal sites of injury in preterm fetuses are the white matter (especially periventricular white matter) and the basal ganglia, while older fetuses demonstrate injury primarily in the gray matter of the cortex and cerebellum. However, a 2023 study found that basal ganglia-thalamus injury accounted for three-fourths of cases of cerebral palsy in term or near-term infants.

Cerebral white matter injury is a term that encompasses the full spectrum of periventricular leukomalacia. Diffuse noncystic white matter injury is currently the predominant form of brain injury in children born prematurely. The incidence of cystic necrotic white matter injury has declined markedly in the past several decades. The primary reason for white matter injury in preterm infants is the vulnerability of premyelinating oligodendrocytes to hypoxia-ischemia and inflammation. Preterm infants have impaired cerebral blood flow autoregulation, particularly in vascular end zones and border zones. Premyelinating oligodendrocytes are more susceptible to oxidative stress than mature cells because they lack antioxidant enzymes.

Approximately one-third of preterm infants born between 24 and 32 weeks’ gestation have evidence of diffuse white matter injury on magnetic resonance imaging (MRI). These lesions cause disrupted white matter maturation and associated long-term neurodevelopmental consequences as these children grow.

The fetus has several adaptive responses for survival and growth in the relatively hypoxemic intrauterine environment; these adaptive changes to intrauterine hypoxemia vary between immature and mature fetuses. Fetal responses to asphyxia may be categorized as an alteration of fetal metabolism or maximization of fetal oxygen transport ( Box 10.4 ). Richardson defined the oxygen margin of safety as the extent to which fractional oxygen extraction can increase and fetal arterial P o ₂ can decrease before tissue oxygen supplies are inadequate. Regardless of the etiology of decreased oxygen delivery to the fetus, fetal oxygen consumption is maintained by increasing oxygen extraction until oxygen delivery is approximately 50% of normal. Lower levels of tissue oxygen tension result in progressive metabolic acidemia and a terminal decrease in oxygen consumption.

Alterations in substrate use may affect the fetal response to insufficient exchange of respiratory gases. Unlike in adults, the fetal brain can use ketone bodies and lactate as alternative energy sources. In gravid ewes, a reduction in uterine blood flow results in reduced fetal glucose consumption. Current opinion holds that hyperglycemia should be avoided in adult humans at risk for ischemia. Hyperglycemia may exacerbate metabolic acidosis by providing substrate for anaerobic metabolism, which increases lactic acid production. However, Vannucci and Mujsce, citing experiments in neonatal rat pups, suggested that the immature brain may respond differently and that glucose administration may actually reduce hypoxic-ischemic brain injury. These investigators did not consider earlier work by Blomstrand et al., who studied the effects of hypoxia in the anesthetized, exteriorized fetal lamb and found that hyperglycemia accelerated the loss of somatosensory-evoked potentials, the onset of metabolic acidosis, and the reduction of cerebral oxygen consumption. Until these different observations are reconciled, the maintenance of normoglycemia in utero appears prudent.

During chronic hypoxemia, the fetus may also restrict the use of energy derived from oxidative metabolism to maintain essential cellular processes. This may lead to decreased somatic growth and fetal growth restriction. Using an ovine model of asphyxia, Hooper detected decreased incorporation of tritiated [ ³ H]-thymidine (which reflects decreased DNA turnover and, presumably, decreased cell division) in fetal tissue. The decrease in incorporation of tritiated [ ³ H]-thymidine was not uniform in all tissues. The rates of DNA synthesis were maintained in most fetal tissues (including the fetal brain) but were greatly reduced in the lung, the skeletal muscle, and the thymus gland.

The fetus can conserve additional energy by decreasing breathing and gross body movements. Rurak and Gruber demonstrated a 17% reduction in oxygen consumption in fetal lambs paralyzed by neuromuscular blockers. Perceptible fetal movements represent an index of fetal health. Many obstetric providers instruct their patients to count episodes of fetal activity for specified periods and to consult them if fetal movements are decreased or absent (see Chapter 6 ). Fetal hypoxemia results in decreases in both activity and rapid eye movement (REM) sleep in fetal lambs. REM sleep states are associated with an increased cerebral metabolic rate for oxygen (CMR o ₂ ). Thus, during periods of fetal stress, reductions in fetal body movements or REM sleep lead to a significant decline in fetal energy expenditure.

Oxygen deprivation typically results in a change in and/or redistribution of fetal cardiac output, the magnitude of which depends on the mechanism and severity of oxygen deprivation. Sheldon et al. demonstrated that fetal hypoxemia produced by decreasing maternal inspired oxygen concentration resulted in greater blood flow to the brain, myocardium, and adrenal glands. In fetal lambs, a brief (4-minute) complete arrest of uterine and ovarian blood flow resulted in a decrease in blood flow to all organs except the myocardium and adrenal glands.

With advances in the understanding of prenatal brain development and imaging technology, there is considerable interest in monitoring and codifying fetal neurologic development and behavior to predict postnatal neurodevelopment. The driving principle is that fetal behavioral patterns reflect complex interactions between the maternal environment and primitive neuronal network generators in the developing brain. It is widely agreed that most neurodevelopmental disorders have an intrauterine origin and that there is extensive neurobehavioral continuity from the fetal to the neonatal period.

Although the assessment of high-risk pregnancies has included an analysis of certain aspects of fetal behavior, until recently there have been no unified scales for assessment of fetal neurobehavior. Current fetal neurobehavioral scales assess a variety of behaviors that can be categorized into the four main domains described by DiPietro : (1) heart rate, (2) motor activity, (3) existing behavioral state, and (4) responsiveness to external stimuli. The Fetal Neurobehavioral Coding System (FENS) incorporates most elements of fetal behavior. Using ultrasonography, FENS analysis can identify specific behaviors in fetuses with growth restriction; compared with normally developing fetuses, fetuses with growth restriction demonstrate a delayed appearance of behavioral states, longer behavioral state transitions, and disorganized behavioral patterns. These tests have been validated in other paradigms, including pregnancies that were complicated by maternal diabetes, substance abuse, and cigarette smoking.

A more comprehensive scale is the Kurjak Antenatal Neurodevelopmental Test, which includes an assessment of eight fetal parameters related to fetal behavior, general movements, and other physical signs (e.g., head circumference, presence or absence of overlapping cranial sutures, finger movements). However, these fetal assessment studies are time-consuming and require specific training to codify behaviors. Moreover, because the brain structures driving such behaviors have not been clearly identified, it is difficult to understand the significance of any differences in behavior.

In vivo MRI provides details of the architecture of the developing brain beginning in the 18th gestational week and can quantify brain growth and structural abnormalities. Other techniques, such as magnetic resonance (MR) tractography and functional fetal MRI, may enhance our understanding of normal brain development and thus facilitate identification of abnormal development. Until controlled trials demonstrate adequate sensitivity, specificity, and positive predictive power, these tests have limited clinical potential; any advantages will need to be balanced against possible detrimental effects of ultrasonography and MRI on fetal neuronal development and migration.

MRI is useful for diagnosis of neonatal brain injury. MRI can assist in the diagnosis of hypoxic-ischemic encephalopathy in newborn infants, provide three-dimensional evaluations to determine the volume of gray matter and the extent of white matter myelination (thus providing valuable insights into normal and abnormal brain development), and estimate the timing of the brain injury in patients with cerebral palsy. Newer techniques, such as diffusion tensor imaging and MR spectroscopy, may offer advantages over conventional MRI when performed early (i.e., hours) after a hypoxic-ischemic insult. Diffusion tensor imaging detects the microscopic movement of water particles in brain tissue. MR spectroscopy analyzes the signal of protons attached to molecules such as glutamate, glutamine, and lactate, among others. These methods detect acute chemical changes in brain tissue and may accurately predict motor outcome in preterm infants. Injury patterns detected with these methods are present for several days and resolve over the next week, when the chronic injury becomes visible with conventional MRI. Identification of injuries with these techniques shortly after birth can support the hypothesis that injury occurred within days of delivery. Thus, MR spectroscopy and diffusion tensor imaging are powerful new tools for timing the occurrence and understanding the pathophysiology of perinatal brain injury. Cerebral ultrasonography remains a useful technique in the early neurologic neonatal assessment, especially for the critically ill infant who might not be a candidate for transfer to an MRI facility.

Local anesthetic agents are given in lower concentrations for longer durations during labor analgesia than during surgery. Despite widespread use, there has been little attention to the neurodevelopmental consequences of antepartum and intrapartum fetal exposure to these drugs. Because neurodevelopmental events at term are quite different from those that occur during the second trimester, there is a need for experimental studies to investigate the effects of analgesic techniques and drugs administered during the third trimester of pregnancy.

Many pregnant women continue to require general anesthesia for either pregnancy-related or nonobstetric surgical procedures. Commonly used anesthetic agents freely cross the placenta and reach the fetal brain, causing fetal sleep or sedation. Obstetric anesthesia research has focused primarily on the teratogenic effects of anesthetic agents administered during the first trimester (see Chapter 18 ) and the effects of anesthetic agents on neonatal behavior when administered during cesarean delivery. Historically, the second trimester was assumed to be a safe period for surgery and anesthesia, primarily because of a lack of targeted studies. However, extensive subsequent animal research has shown that anesthetic agents administered during the phase of synaptogenesis can induce a profound neurodegenerative response in the developing brain and cause functional impairment in offspring. Human epidemiologic studies appear to support an association between early childhood exposure to anesthetic agents and subsequent functional impairment. However, it is unclear whether these outcomes result from the underlying disease, surgery, or anesthesia, or a combination of these factors.

Because human synaptogenesis appears to begin during the third trimester, there is serious concern that intrauterine fetal exposure to anesthetic agents may result in similar functional impairment. Because there is no precise way to monitor human fetal brain development in utero , the potential long-term effects of maternal anesthesia on the fetal brain must be investigated in animal models. However, given the considerable differences in neural maturation among species (see Fig. 10.3 and Fig. 10.5 ), and the relative duration of anesthesia exposure in relation to the life span of the organism, these results should be interpreted with caution.

Time Lines of Major Neurodevelopmental Events In Utero in Rodents, Nonhuman Primates, and Humans. Events are as marked in the figure legend ( d , days; w , weeks; y , years). Synaptogenesis is predominantly a postnatal event in rodents, unlike that in primates and humans.

From Palanisamy A. Maternal anesthesia and fetal neurodevelopment. Int J Obstet Anesth . 2012;21:152–162.

The exact mechanisms by which anesthetic agents impair early brain development remain under investigation. Anesthetic agent interactions with GABA and the NMDA-subtype of glutamate receptors decrease activity-dependent synapse formation and cause apoptotic neurodegeneration in multiple areas of the developing brain. These histopathologic changes have been well investigated, especially in the hippocampal formation, an area that is crucial for memory. Early exposure to anesthetic agents affects long-term potentiation in the hippocampus and affects spatial working memory in animal models. These changes do not appear to be caused by direct cytotoxicity but rather by a combination of effects on both neuronal and nonneuronal cells in the developing brain ( Box 10.5 ).

Of specific concern are the effects of anesthetic agents on neurogenesis and synapse formation in the fetal brain. Human neural ontogeny suggests that the second trimester is a period of active fetal brain development, with neuroblast proliferation peaking between the 5th and 25th postmenstrual weeks. Because GABA and glutamate play a crucial role in these processes, there is concern that prolonged and nonphysiologic modulation of the fetal GABA and glutamatergic systems (e.g., during second-trimester maternal anesthesia) might affect neurogenesis, neuronal migration, and/or synapse formation.

In one of the first studies to simulate a clinically relevant scenario, a single exposure to 1.4% isoflurane (1 MAC [minimum anesthetic concentration]) for 4 hours during the second trimester caused long-lasting impairment of spatial working memory in rodent offspring. Although the exact mechanisms behind these behavioral disturbances are unclear, other studies suggest that mid-gestational exposure to isoflurane upregulates the proapoptotic protein caspase-12, decreases overall synapse numbers in the fetal hippocampus, and downregulates the plasticity-associated protein GAP-43. Similar results have been reported in pregnant guinea pigs and macaques, suggesting that the fetal brain remains highly susceptible to maternal mid-trimester anesthesia. Furthermore, isoflurane suppresses neurogenesis in rodents both in vitro and in vivo , causing a depletion of the neural stem cell pool. At least in vitro , this phenomenon appears to be dose-dependent. At present, the impact of reduced neurogenesis on behavioral deficits and the effect of anesthetic agents on neuronal migration remain unknown.

Extension of these studies to the third trimester has yielded mixed results. In one rodent study, third-trimester maternal administration of 1.3% isoflurane for 6 hours had no effect on offspring neurodevelopment. However, another dose-response study in term rodents found that maternal administration of 3% isoflurane, but not 1.3% isoflurane, for 1 hour caused fetal brain hippocampal neurodegeneration. No neurodegenerative changes were observed after third-trimester exposure in guinea pigs. Thus, in rodent models, it appears that the fetal brain is less vulnerable to the adverse effects of anesthetic agents during the third trimester. This could be caused by the stage of neurodevelopment, or more likely, by an increase in the levels of neuroprotective hormones such as estrogen, progesterone, neurosteroids, and oxytocin during the third trimester. Work from nonhuman primate models, however, shows that even a 5-hour exposure to either isoflurane (1% to 1.5%) or ketamine and propofol during the late second and early third trimester can cause a 2.5- to 5-fold increase in neuronal apoptosis in the fetal brain.

Few studies have examined offspring neurodevelopmental effects after shorter-duration maternal anesthesia exposure. This knowledge gap is important because surgical anesthesia exposure in pregnant women is usually short. The relative safety of short exposures was supported by a population-based birth cohort study that sought to determine the incidence of learning disabilities in children after maternal administration of general or neuraxial anesthesia during cesarean or vaginal delivery. Children exposed to general anesthesia during cesarean delivery were not more likely to develop learning disabilities compared with those born vaginally with no exposure to general anesthesia. Although the study was retrospective and used data from 1976 to 1982, it is reassuring that even the children whose mothers required emergency general anesthesia did not have a higher incidence of learning disability. In contrast, a human study using data from the US Medicaid database (1999 to 2013) identified an association between maternal exposure to anesthesia during nonobstetric surgery and disruptive or internalizing behavior disorder in offspring. Again, it is difficult to separate the possible adverse effects of anesthetic agents from the effects of surgery and the underlying illness.

Newer studies have explored the association between general anesthesia during the third trimester and ASDs in offspring, with inconclusive results. Using a propensity score-matched technique to adjust for underlying risk factors in a population-based data set derived from national registries in Taiwan, Chien et al. reported that general anesthesia during cesarean delivery was associated with a 52% higher risk for developing autism than vaginal delivery. By contrast, a population-based sibling cohort study from Puerto Rico found no evidence for an association, although in this study both exposures during pregnancy and the first 2 years of life were included. Further epidemiologic work is required to ascertain the effects of maternal anesthesia during nonobstetric surgery in the second trimester.

The wealth of anesthetic neurotoxicity studies prompted the US Food and Drug Administration (FDA) to issue an updated Drug Safety Communication in late 2016, warning that repeated or lengthy use of general anesthetic or sedative drugs during the third trimester of pregnancy or the first 3 years of life may have consequences for early brain development. However, the results of recent prospective clinical trials suggest that short-duration exposure to anesthesia in children younger than 3 years of age does not have a detrimental effect on cognitive development.