Few events evoke more apprehension in parents and obstetricians than the specter of “brain injury,” which immediately prompts concerns for disabling cerebral palsy and intellectual disability. Although most brain disorders or injuries are less profound, history has helped to perpetuate the more dismal outlook. In his first edition of this textbook, Williams (1903) limited discussions of brain injury to those sustained from birth trauma. When later editions introduced the concept that asphyxia neonatorum was another cause of cerebral palsy, this too was linked to traumatic birth. Even as brain damage caused by traumatic delivery became uncommon during the ensuing decades, the belief—albeit erroneous—was that intrapartum events caused most neurological disability. This was a major reason for the escalating cesarean delivery rate beginning in the 1970s. Unfortunately, because in most cases the genesis of cerebral palsy occurs long before labor, this did little to mitigate risks for cerebral palsy (O’Callaghan, 2013).
These realizations stimulated scientific investigations to determine the etiopathogenesis of fetal brain disorders, including those leading to cerebral palsy. Seminal observations include those of Nelson and Ellenberg (1984, 1985, 1986a), discussed subsequently. These investigators are appropriately credited with proving that these neurological disorders are due to complex multifactorial processes caused by a combination of genetic, physiological, environmental, and obstetrical factors. Importantly, these studies showed that few neurological disorders were associated with peripartum events. Continuing international interest was garnered to codify the potential role of intrapartum events. In 2000, a task force of the American College of Obstetricians and Gynecologists was appointed to study the vicissitudes of neonatal encephalopathy and cerebral palsy. The multispecialty coalition reviewed contemporaneous data and provided criteria to define various neonatal brain disorders. Their findings were promulgated by the American Academy of Pediatrics and American College of Obstetricians and Gynecologists (2003).
Ten years later, a second task force of these organizations updated the findings (American College of Obstetricians and Gynecologists, 2014c). The 2014 Task Force findings are more circumspect in contrast to the earlier ones. Specifically, more limitations are cited in identifying cause(s) of peripartum hypoxic-ischemic encephalopathy (HIE) compared with other etiologies of neonatal encephalopathy. The 2014 Task Force recommends multidimensional assessment of each affected infant. They add the caveat that no one strategy is infallible, and thus, no single strategy will achieve 100-percent certainty in attributing a cause to neonatal encephalopathy.
The 2014 Task Force defined neonatal encephalopathy as a syndrome of neurological dysfunction identified in the earliest days of life in neonates born at ≥35 weeks’ gestation. It is manifested by subnormal levels of consciousness or seizures and often accompanied by difficulty with initiating and maintaining respiration and by depressed tone and reflexes. The incidence of encephalopathy has been cited to be 0.27 to 1.1 per 1000 term liveborn neonates, and it is much more frequent in preterm newborns (Ensing, 2013; Plevani, 2013; Takenouchi, 2012; Wu, 2011). Although the 2014 Task Force concluded that there are many causes of encephalopathy and cerebral palsy, it focused on HIE and those that were thought to be incurred intrapartum. To identify affected infants, a thorough evaluation is necessary and includes maternal history, obstetrical antecedents, intrapartum factors, placental pathology, and newborn course. These are complemented by laboratory and neuroimaging findings.
There are three clinically defined levels. Mild encephalopathy is characterized by hyperalertness, irritability, jitteriness, and hypertonia and hypotonia. Moderate encephalopathy is manifest by lethargy, severe hypertonia, and occasional seizures. Severe encephalopathy is manifest by coma, multiple seizures, and recurrent apnea.
The 2014 Task Force also concluded that of the several forms of cerebral palsy, only the spastic quadriplegic type can result from acute peripartum ischemia. Other forms—hemiparetic or hemiplegic cerebral palsy, spastic diplegia, and ataxia—are unlikely to result from an intrapartum event. Purely dyskinetic or ataxic cerebral palsy, especially when accompanied by a learning disorder, usually has a genetic origin (Nelson, 1998).
Criteria for Hypoxic-Ischemic Encephalopathy
The 2014 Task Force radically revised its 2003 criteria used to define an acute peripartum event that is consistent with an HIE and neonatal encephalopathy. These are outlined in Table 33-1 and are considered with the following caveats.
TABLE 33-1Findings Consistent with an Acute Peripartum or Intrapartum Event Leading to Hypoxic-Ischemic Encephalopathy ||Download (.pdf) TABLE 33-1 Findings Consistent with an Acute Peripartum or Intrapartum Event Leading to Hypoxic-Ischemic Encephalopathy
|Neonatal Findings |
| Apgar score: <5 at 5 and 10 minutes |
| Umbilical arterial acidemia: pH <7.0 and/or base deficit ≥12 mmol/L |
| Neuroimaging evidence of acute brain injury: MR imaging or MRS consistent with HIE |
| Multisystem involvement consistent with HIE |
|Type and Timing of Contributing Factors |
| Sentinel hypoxic or ischemic event occurring immediately before or during delivery |
| Fetal heart rate monitor patterns consistent with an acute peripartum or intrapartum event |
First, Apgar Scores that are low at 5 and 10 minutes are associated with greater risk for neurological impairment. Low scores stem from many causes, and most of these infants will not develop cerebral palsy. With a 5-minute Apgar ≥7, it is unlikely that peripartum HIE caused cerebral palsy.
Acid-base study results define a second HIE criterion. Low pH and base deficit levels raise the likelihood that neonatal encephalopathy was caused by HIE. Decreasing levels form a continuum of increasing risk, but most acidemic neonates will be neurologically normal (Wayock, 2013). A cord artery pH ≥7.2 is very unlikely to be associated with HIE.
Magnetic resonance (MR) imaging or MR spectroscopy (MRS) is the best modality with which to visualize findings consistent with HIE. The 2014 Task Force concludes that cranial sonography and computed tomography (CT) lack sensitivity in the term newborn. Normal imaging findings after the first 24 hours of life, however, effectively exclude a hypoxic-ischemic cause of encephalopathy. MR imaging between 24 and 96 hours may be more sensitive for the timing of peripartum cerebral injury, and MR imaging at 7 to 21 days following birth is the best technique to delineate the full extent of cerebral injury.
Last, multisystem involvement of injury is consistent with HIE. These include renal, gastrointestinal, hepatic, or cardiac injury; hematological abnormalities; or combinations of these. The severity of neurological injury does not necessarily correlate with injuries to these other systems.
The 2014 Task Force also found that certain contributing factors may be consistent with an acute peripartum event. Of these, sentinel events are considered adverse obstetrical events that may lead to catastrophic clinical outcomes. Examples include ruptured uterus, severe placental abruption, cord prolapse, and amnionic fluid embolism. Martinez-Biarge and associates (2012) studied almost 58,000 deliveries and identified 192 cases with one of these sentinel events. Of these 192 fetus/newborns, 6 percent died intrapartum or in the early neonatal period, and 10 percent developed neonatal encephalopathy. Other risk factors for neonatal acidosis include prior or emergent cesarean delivery, maternal age ≥35 years, thick meconium, chorioamnionitis, and general anesthesia (Ahlin, 2016; Johnson, 2014; Nelson, 2014).
Differentiating an abnormal fetal heart rate (FHR) tracing on presentation versus one that develops subsequently was also emphasized by the 2014 Task Force. A category 1 or 2 FHR tracing associated with Apgar scores ≥7 at 5 minutes, normal cord gases (±1 SD), or both are not consistent with an acute HIE event (Graham, 2014). An FHR pattern at the time of presentation with persistently minimal or absent variability and lacking accelerations, with duration ≥60 minutes, and even without decelerations is suggestive of an already compromised fetus (Chap. 24, Cardiac Arrhythmia). The 2014 Task Force further recommended that if fetal well-being cannot be established with these findings present, the woman should be evaluated for the method and timing of delivery.
Most prophylactic measures for neonatal encephalopathy have been evaluated in preterm infants (Chap. 42, Magnesium Sulfate for Neuroprotection). One of these—postnatally induced hypothermia—may prevent death and mitigate moderate to severe neurological disability in term newborns (Garfinkle, 2015; Nelson, 2014; Shankaran, 2012). MR imaging studies have demonstrated a slowing of diffusional abnormalities and fewer infarctions with hypothermia (Bednarek, 2012; Natarajan, 2016b). Most randomized trials have shown improved outcomes with induced hypothermia in those born at 36 weeks’ gestation or older (Azzopardi, 2014; Guillet, 2012; Jacobs, 2011). In a metaanalysis of more than 1200 newborns, Tagin and colleagues (2012) concluded that hypothermia improves survival rates and neurodevelopment. Clinical trials to evaluate concomitant neonatal erythropoietin therapy for neuroprophylaxis have reported conflicting results (Fauchère, 2015; Malla, 2017). Preliminary data from one multicenter trial of maternal allopurinol therapy indicate some mitigation of cerebral damage caused by hypoxia and ischemia (Kaandorp, 2013).
This term refers to a group of nonprogressive disorders of movement or posture caused by abnormal development or damage to brain centers for motor control. Cerebral palsy is further classified by the type of neurological dysfunction—spastic, dyskinetic, or ataxic—and by the number and distribution of limbs involved—quadriplegia, diplegia, hemiplegia, or monoplegia. Together, the major types are spastic quadriplegia—the most common—which has a strong association with mental retardation and seizure disorders; diplegia, which is common in preterm or low-birthweight infants; hemiplegia; choreoathetoid types; and mixed varieties. Although epilepsy and mental retardation frequently accompany cerebral palsy, these two disorders seldom are associated with perinatal asphyxia in the absence of cerebral palsy.
Incidence and Epidemiological Correlates
According to Nelson and coworkers (2015), the prevalence of cerebral palsy in the United States averages 2 of every 1000 children. It is crucial to emphasize that this rate is derived from all children—including those born preterm. Because of the remarkably greater survival rates of the latter currently, and despite the elevated cesarean delivery rate, the overall rate of cerebral palsy has remained essentially unchanged (Fig. 33-1). For example, follow-up studies of more than 900,000 Norwegian nonanomalous term infants cite an incidence of 1 per 1000, but the incidence was 91 per 1000 for those born at 23 to 27 weeks (Moster, 2008). Similar findings have been reported for Australian births (Smithers-Sheedy, 2016). In absolute numbers, term newborns comprise half of cerebral palsy cases because there are proportionately far fewer preterm births. It is again emphasized that most studies of cerebral palsy rates have not made distinctions between term and preterm infants.
Elective and emergency cesarean deliveries and live births with cerebral palsy. (Reproduced with permission from Nelson KB, Blair E: Prenatal factors in singletons with cerebral palsy born at or near term, N Engl J Med. 2015 Sep 3;373(10):946–953.)
As noted earlier, Nelson and Ellenberg (1984, 1985, 1986a) made many fundamental observations concerning cerebral palsy. Their initial studies emanated from data from the Collaborative Perinatal Project. This included children from almost 54,000 pregnancies who were followed until age 7. They found that the most frequently associated risk factors for cerebral palsy were: (1) evidence of genetic abnormalities such as maternal mental retardation or fetal congenital malformations; (2) birthweight <2000 g; (3) birth before 32 weeks; and (4) perinatal infection. They also found that obstetrical complications were not strongly predictive, and only a fifth of affected children had markers of perinatal asphyxia. For the first time, there was solid evidence that the cause of most cases of cerebral palsy was unknown, and importantly, only a small proportion was caused by neonatal HIE. Equally importantly, there was no foreseeable single intervention that would likely prevent a large proportion of cases.
Numerous studies have since confirmed many of these findings and identified an imposing list of other risk factors that are shown in Table 33-2. As expected, preterm birth continues to be the single most important risk factor (Nelson, 2015; Thorngren-Jerneck, 2006). Small-for-gestational-age neonates are also at higher risk. Stoknes and associates (2012) showed that in more than 90 percent of growth-restricted newborns, cerebral palsy was due to antepartum factors. Many other placental and neonatal risk factors have been correlated with neurodevelopmental abnormalities (Ahlin, 2013; Avagliano, 2010; Blair, 2011; Redline, 2008). Some placental factors are discussed further in Chapter 6 (Normal Placenta). One example is the substantively greater risk from chorioamnionitis (Gilbert, 2010; Shatrov, 2010). An example of a neonatal cause is arterial ischemic stroke, which may be associated with inherited fetal thrombophilias (Harteman, 2013; Kirton, 2011). Also, newborns with isolated congenital heart lesions have an elevated risk for microcephaly, possibly due to chronic fetal hypoxemia (Barbu, 2009). Other miscellaneous etiologies of cerebral palsy include fetal anemia, twin-twin transfusion syndrome, intrauterine transfusions, and fetal alcohol syndrome (DeJong, 2012; Lindenburg, 2013; O’Leary, 2012; Rossi, 2011; Spruijt, 2012).
TABLE 33-2Perinatal Risk Factors Reported to Be Increased in Children with Cerebral Palsy ||Download (.pdf) TABLE 33-2 Perinatal Risk Factors Reported to Be Increased in Children with Cerebral Palsy
|Risk Factors ||Risk Ratio ||95% CI |
|Hydramnios ||6.9 ||1.0–49.3 |
|Placental abruption ||7.6 ||2.7–21.1 |
|Interval between pregnancies <3 mo or >3 yr ||3.7 ||1.0–4.4 |
|Spontaneous preterm labor ||3.4 ||1.7–6.7 |
|Preterm delivery at 23–27 weeks ||78.9 ||56.5–110 |
|Breech or face presentation, transverse lie ||3.8 ||1.6–9.1 |
|Severe birth defect ||5.6 ||8.1–30.0 |
|Nonsevere birth defect ||6.1 ||3.1–11.8 |
|Time to cry >5 minutes ||9.0 ||4.3–18.8 |
|Obesity ||1.2–2 ||1.1–2.8 |
|Low placental weight ||3.6 ||1.5–8.4 |
|Placental infarction |
|2.5 ||1.2–5.3 |
| Clinical |
Apart from these causes, intrapartum hypoxemia was linked to only a minority of cerebral palsy cases by the National Collaborative Perinatal Project. However, because the study was carried out in the 1960s, there were inconsistent criteria to accurately assign cause. The contribution of HIE to subsequent neurological disorders is discussed in detail in Neonatal Encephalopathy. The 2003 Task Force applied these criteria to more contemporaneous outcomes and determined that only 1.6 cases of cerebral palsy per 10,000 deliveries are attributable solely to intrapartum hypoxia. This finding is supported by a study from Western Australia that spanned from 1975 to 1980 (Stanley, 1991). Other studies concluded that very few cases were due to intrapartum events and therefore preventable (Phelan, 1996; Strijbis, 2006).
Intrapartum Fetal Heart Rate Monitoring
Despite persistent attempts to validate continuous intrapartum electronic fetal monitoring as effective to prevent adverse perinatal outcomes, evidence does not support its ability to predict or reduce cerebral palsy risk (Clark, 2003; Thacker, 1995). Importantly, no specific fetal heart rate patterns predict cerebral palsy. Further, no relationship has been found between the clinician’s response to abnormal patterns and neurological outcome. And, efforts using assisted computer analysis of fetal heart tracings have not enhanced predictability (Alfirevic, 2017; INFANT Collaborative Group, 2017). Indeed, an abnormal heart rate pattern in fetuses that ultimately develop cerebral palsy may reflect a preexisting neurological abnormality (Phelan, 1994). Because of these studies, the American College of Obstetricians and Gynecologists (2017a,d) has concluded that electronic fetal monitoring does not reduce the incidence of long-term neurological impairment. This is discussed further in Chapter 24 (Benefits of Electronic Fetal Heart Rate Monitoring).
In general, 1- and 5-minute Apgar scores are poor predictors of long-term neurological impairment (American College of Obstetricians and Gynecologists, 2017e). When the 5-minute Apgar score is ≤3, however, neonatal death or the risk of neurological sequelae rises substantially (Dijxhoorn, 1986; Nelson, 1984). In a Swedish study, 5 percent of such children subsequently required special schooling (Stuart, 2011). In a Norwegian study, the incidence of these low Apgar scores was 0.1 percent in more than 235,000 newborns. Almost a fourth of those with such scores died, and 10 percent of survivors developed cerebral palsy (Moster, 2001).
Persistence past 5 minutes of these extremely low scores correlates strongly with a higher risk for neurological morbidity and death (Grünebaum, 2013). This of course is not absolute, and the 2003 Task Force cited a 10-percent risk for cerebral palsy for infants with 10-minute scores of 0 to 3. For 15-minute scores ≤2, there is a 53-percent mortality rate and a 36-percent cerebral palsy rate. For 20-minute scores ≤2, mortality rate is 60 percent, and a cerebral palsy rate is 57 percent. Some outcomes in the Norwegian Study of infants with these low 5-minute Apgar scores are shown in Table 33-3. Survivors who had Apgar scores of 0 at 10 minutes have even worse outcomes. In a review of 94 such newborns, 78 died, and all survivors assessed had long-term disabilities (Harrington, 2007).
TABLE 33-3Comparison of Mortality and Morbidity in Norwegian Infants Weighing >2500 g According to 5-Minute Apgar Scores ||Download (.pdf) TABLE 33-3 Comparison of Mortality and Morbidity in Norwegian Infants Weighing >2500 g According to 5-Minute Apgar Scores
|Outcome ||Apgar 0–3 (%) ||Apgar 7–10 (%) ||Relative Risk (95% CI) |
|Number ||292 ||233, 500 || |
|Mortality rates || || || |
|Neonatal ||16.5 ||0.05 ||386 (270–552) |
|Infant ||19.2 ||0.3 || 76 (56–103) |
|1–8 yr ||3 ||0.2 || 18 (8–39) |
|Morbidity rates || || || |
|Cerebral palsy ||6.8 ||0.09 || 81 (48–128) |
|Mental retardation ||1.3 ||0.1 || 9 (3–29) |
|Other neurological ||4.2 ||0.5 || 9 (5–17) |
|Non-neurological ||3.4 ||2.0 || 2 (0.8–5.5) |
Umbilical Cord Blood Gas Studies
As outlined in Neonatal Encephalopathy, objective evidence for metabolic acidosis—cord arterial blood pH <7.0 and base deficit ≥12 mmol/L—is a risk factor for encephalopathy and for cerebral palsy. The risk accrues as acidosis worsens. From their review of 51 studies, Malin and coworkers (2010) found that low cord arterial pH correlates with greater risk for neonatal encephalopathy and cerebral palsy. When used alone, however, these determinations are not accurate in predicting long-term neurological sequelae (Dijxhoorn, 1986; Yeh, 2012).
Data from several studies corroborate that a pH <7.0 is the threshold for clinically significant acidemia (Gilstrap, 1989; Goldaber, 1991). The likelihood of neonatal death grows as the cord artery pH falls to 7.0 or less. Casey and colleagues (2001) reported that when the pH was ≤6.8, the neonatal mortality rate rose 1400-fold. When the cord pH was ≤7.0 and the 5-minute Apgar score was 0 to 3, the risk of neonatal death was increased 3200-fold.
In the study from Oxford, adverse neurological outcomes were 0.36 percent with pH <7.1 and 3 percent with pH <7.0 (Yeh, 2012). As mentioned, newborn complication rates rise coincident with increasing severity of acidemia at birth. In a Swedish study, researchers observed that cord blood lactate levels may prove to be superior to base deficit for prognostication of neurological disorders (Wiberg, 2010).
Nucleated Red Blood Cells and Lymphocytes
Both immature red cells and lymphocytes enter the circulation of term newborns in response to hypoxia or hemorrhage. During the past two decades, quantification of these cells has been proposed as a measure of hypoxia, but most studies do not support this premise (Boskabadi, 2017; Silva, 2006; Walsh, 2011, 2013).
Neuroimaging Studies in Encephalopathy and Cerebral Palsy
Various neuroimaging techniques have provided important insight into the etiology and evolution of perinatal HIE and later cerebral palsy (Neonatal Encephalopathy). Importantly, findings are highly dependent on fetal age. The preterm neonatal brain responds quite differently to an ischemic episode compared with that of a term newborn. Other factors include insult severity and duration as well as restoration of cerebrovascular hypoperfusion. Thus, precise timing of an injury with neuroimaging studies is not a realistic goal. Moreover, the grade of neonatal encephalopathy, that is, mild, moderate, or severe, does not correlate with MR imaging findings (Walsh, 2017).
Neuroimaging in Neonatal Period
Regarding early use, the 2014 Task Force concluded that these imaging techniques provide the following information:
Sonographic studies are generally normal on the day of birth. With injury, increasing echogenicity in the thalami and basal ganglia is seen beginning at approximately 24 hours. This progresses over 2 to 3 days and persists for 5 to 7 days.
Computed tomography scans are usually normal the first day in term infants. With injury, decreased density in the thalami or basal ganglia is seen beginning at about 24 hours and persists for 5 to 7 days.
Magnetic resonance imaging will detect some abnormalities on the first day. Within 24 hours, MR imaging may show restricted water diffusion that peaks at approximately 5 days and disappears within 2 weeks. Acquisitions with T1- and T2-weighted images show variable abnormalities, which have an onset from less than 24 hours to several days. In a study of 175 term neonates with acute encephalopathy, it was reported that MR imaging showing basal ganglia lesions accurately predicted motor impairment at 2 years of age (Martinez-Biarge, 2012).
The 2014 Task Force concluded that for term newborns, imaging studies are helpful in timing an injury, but they provide only a window in time that is imprecise. In one study, the optimal range was 3 to 10 days (Lee, 2017).
Neuroimaging in Older Children with Cerebral Palsy
Imaging studies performed in children diagnosed with cerebral palsy frequently show abnormal findings. Wu and associates (2006) used CT or MR imaging to study 273 children who were born after 36 weeks’ gestation and who were diagnosed later in childhood with cerebral palsy. Although a third of these studies were normal, focal arterial infarction was seen in 22 percent; brain malformations in 14 percent; and periventricular white-matter injuries in 12 percent. In another study of 351 children with cerebral palsy—approximately half were born near term—MR imaging findings were abnormal in 88 percent (Bax, 2006). Similar findings were reported in an Australian study (Robinson, 2008).
CT and MR imaging techniques have also been used in older children to help define the timing of fetal or perinatal cerebral injury. Wiklund and coworkers (1991a,b) studied 83 children between ages 5 and 16 years who were born at term and who developed hemiplegic cerebral palsy. Nearly 75 percent had abnormal CT findings, and these investigators concluded that more than half had CT changes that suggested a prenatal injury. Approximately 20 percent were attributed to a perinatal injury. In a similar study, Robinson and associates (2008) used MR imaging. They reported pathological findings in 84 percent of children with spastic quadriplegia. Remember, this is the neurological lesion that the 2014 Task Force concluded correlated with neonatal encephalopathy.
Intellectual Disability and Seizure Disorders
The term intellectual disability describes a spectrum of disabilities and seizure disorders that frequently accompany cerebral palsy. But, when either of these manifests alone, they are seldom caused by perinatal hypoxia (Nelson, 1984, 1986a,b). Severe mental disability has a prevalence of 3 per 1000 children, and its most frequent causes are chromosomal, gene mutation, and other congenital malformations. Finally, preterm birth is a common association for these (Moster, 2008).
The major predictors of seizure disorders are fetal malformations—cerebral and noncerebral; family history of seizures; and neonatal seizures (Nelson, 1986b). Neonatal encephalopathy causes a small proportion of seizure disorders. Reports from the Neonatal Research Network and other studies concluded that increasing severity of encephalopathy correlates best with seizures (Glass, 2011; Kwon, 2011).
Autism Spectrum Disorders
According to the Centers for Disease Control and Prevention, the frequency of autism spectrum disorders is 14.6 per 1000 in 8-year-old children (Christensen, 2016). Although these may be associated with maternal metabolic conditions, none has been linked convincingly to peripartum events (Krakowiak, 2012).