Complications occurring at any level of foetal oxygen supply will result in hypoxaemia, and this may ultimately lead to hypoxia/acidosis and neurological damage. Hypoxic–ischaemic encephalopathy (HIE) is the short-term neurological dysfunction caused by intrapartum hypoxia/acidosis, and this diagnosis requires the presence of a number of findings, including the confirmation of newborn metabolic acidosis, low Apgar scores, early imaging evidence of cerebral oedema and the appearance of clinical signs of neurological dysfunction in the first 48 h of life. Cerebral palsy (CP) consists of a heterogeneous group of nonprogressive movement and posture disorders, frequently accompanied by cognitive and sensory impairments, epilepsy, nutritional deficiencies and secondary musculoskeletal lesions. Although CP is the most common long-term neurological complication associated with intrapartum hypoxia/acidosis, >80% of cases are caused by other phenomena. Data on minor long-term neurological deficits are scarce, but they suggest that less serious intellectual and motor impairments may result from intrapartum hypoxia/acidosis. This chapter focuses on the existing evidence of neurological damage associated with poor foetal oxygenation during labour.
Highlights
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Hypoxic–ischaemic encephalopathy (HIE) is the short-term neurological dysfunction caused by intrapartum hypoxia.
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Cerebral palsy (CP) is the most common long-term neurological complication of intrapartum hypoxia.
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Intrapartum hypoxia/acidosis accounts for only 10–20% of CP.
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Certain neonatal neuroimaging patterns predict abnormal neurodevelopmental outcome.
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The effect of intrapartum foetal monitoring on the rates of HIE and CP remains inconclusive.
Intrapartum events leading to hypoxia/acidosis
The foetus is totally dependent on the oxygen supply provided by the mother, and any interruption in the flow will result in transient or permanent foetal hypoxaemia. Rhythmic uterine contractions during labour put a particular stress on foetal oxygenation, as they cause reduced blood flow in vessels running inside the myometrium, and they may also compress the umbilical cord. Other intrapartum complications compromising foetal oxygenation include those of maternal origin (sudden maternal hypotension, cardiorespiratory arrest and respiratory or circulatory disorders), mechanical complications of delivery (umbilical cord prolapse, shoulder dystocia and retention of the aftercoming head), major placental abruption, uterine rupture and foetal haemorrhage (ruptured vasa previa or foetal–maternal haemorrhage). The intensity and repetitive nature of foetal hypoxaemia will determine the severity and duration of the resulting hypoxia/acidosis.
Metabolic acidosis is defined as the measurement in umbilical blood, or in the newborn circulation during the first minutes of life, of a pH value below 7.00 and a base deficit (BD) exceeding 12 mmol/l, but there is already an association with adverse short-term outcome when pH values are below 7.05 and BD in the extracellular fluid (BD ecf ) is above 10 mmol/l . Depending on the intensity, duration and repetitive nature of the hypoxic insult, as well as on the individual capacity to cope with the situation, the newborn may recover promptly or may suffer irreparable cell damage. Four distinct patterns of foetal hypoxia have been described: slowly evolving hypoxia, subacute hypoxia, acute hypoxia and pre-existing hypoxia . In a few cases, the hypoxic insult will result in death or in long-term neurological morbidity. Coexisting foetal inflammation may have a synergistic interaction with hypoxia, lowering the threshold for neuronal apoptosis and brain damage.
Hypoxic–ischaemic encephalopathy
Neonatal encephalopathy is reported to occur in 3.0 per 1000 live term births , and it is a major predictor of later neurodevelopmental disability, leading to death in the newborn period in 15–20% of affected infants and permanent neurologic deficits in 25%. Although there is still no universally accepted definition for this entity, it is a clinical syndrome of near-term neonates manifested by a subnormal level of consciousness, seizures, respiratory difficulties and/or a depression of tone and reflexes .
An estimated 70% of cases of neonatal encephalopathy are thought to be consequent to events arising before the onset of labour , and <10% to postnatal complications such as severe respiratory distress, sepsis and shock . Most of the remaining cases are due to intrapartum hypoxia/acidosis, but their incidence varies according to health-care settings. Hypoxia/acidosis can also occur before labour and in the postnatal period, and they cause neonatal encephalopathy, but these cases will not display metabolic acidosis at the time of birth.
Hypoxic–ischaemic encephalopathy (HIE) is the short-term neurological dysfunction caused by intrapartum hypoxia/acidosis, and it has an estimated incidence of 1.5 per 1000 live births . As there are multiple non-hypoxic causes of neonatal encephalopathy, this diagnosis requires the confirmation of metabolic acidosis in the umbilical cord blood or in the newborn circulation during the first minutes of life , together with low Apgar scores at 5 and 10 min, and early imaging evidence of cerebral oedema . Multisystem organ failure may coexist, involving the renal, hepatic, haematologic, cardiac, metabolic and gastrointestinal systems, but the severity of neurological injury does not necessarily correlate with this.
HIE occurs in the first 48 h of life, and it can be classified as mild, moderate or severe, according to the criteria described by Sarnat and Sarnat (grades 1, 2 and 3, respectively). Grade 1 is characterised by hyperalertness, irritability, jitteriness and a normal electroencephalogram. Grade 2 is characterised by obtundation, hypotonia, strong distal flexion and occasional multifocal seizures, and it has a 20–30% risk of death or major neurological sequelae such as cerebral palsy (CP). Grade 3 is associated with coma, and in the majority of cases neonatal death or long-term neurological sequelae such as CP occur . Permanent neurological damage is rare in cases with mild HIE, whereas moderate encephalopathy consists of a more heterogeneous group, with varying rates of disabilities. In a recent systematic review of studies evaluating the long-term consequences of HIE, 14.5% of all cases were reported to develop CP .
The occurrence of a clinical sentinel event during labour may help to differentiate between a prenatal and an intrapartum cause of hypoxia/acidosis, particularly when there is documentation of prolonged maternal hypotension, uterine rupture, umbilical cord prolapse, etc. However, recent studies have documented that sentinel events on their own are poorly predictive of neonatal encephalopathy . A continuous cardiotocography (CTG) tracing acquired in the beginning of labour may also help to determine the timing of damage. Some foetal heart rate (FHR) patterns suggest an acute intrapartum event, whereas the documentation of reduced variability and absent accelerations from the start of labour suggests a previously damaged foetus.
Nucleated red blood cells and lymphocyte counts are frequently increased in the neonate’s circulation in response to hypoxia or haemorrhage, and the quantification of these cells has been proposed as a measure of hypoxia. However, most studies are underpowered to evaluate the discriminative capacity of this biomarker in the prediction of HIE, especially in infants undergoing therapeutic hypothermia .
Hypoxic–ischaemic encephalopathy
Neonatal encephalopathy is reported to occur in 3.0 per 1000 live term births , and it is a major predictor of later neurodevelopmental disability, leading to death in the newborn period in 15–20% of affected infants and permanent neurologic deficits in 25%. Although there is still no universally accepted definition for this entity, it is a clinical syndrome of near-term neonates manifested by a subnormal level of consciousness, seizures, respiratory difficulties and/or a depression of tone and reflexes .
An estimated 70% of cases of neonatal encephalopathy are thought to be consequent to events arising before the onset of labour , and <10% to postnatal complications such as severe respiratory distress, sepsis and shock . Most of the remaining cases are due to intrapartum hypoxia/acidosis, but their incidence varies according to health-care settings. Hypoxia/acidosis can also occur before labour and in the postnatal period, and they cause neonatal encephalopathy, but these cases will not display metabolic acidosis at the time of birth.
Hypoxic–ischaemic encephalopathy (HIE) is the short-term neurological dysfunction caused by intrapartum hypoxia/acidosis, and it has an estimated incidence of 1.5 per 1000 live births . As there are multiple non-hypoxic causes of neonatal encephalopathy, this diagnosis requires the confirmation of metabolic acidosis in the umbilical cord blood or in the newborn circulation during the first minutes of life , together with low Apgar scores at 5 and 10 min, and early imaging evidence of cerebral oedema . Multisystem organ failure may coexist, involving the renal, hepatic, haematologic, cardiac, metabolic and gastrointestinal systems, but the severity of neurological injury does not necessarily correlate with this.
HIE occurs in the first 48 h of life, and it can be classified as mild, moderate or severe, according to the criteria described by Sarnat and Sarnat (grades 1, 2 and 3, respectively). Grade 1 is characterised by hyperalertness, irritability, jitteriness and a normal electroencephalogram. Grade 2 is characterised by obtundation, hypotonia, strong distal flexion and occasional multifocal seizures, and it has a 20–30% risk of death or major neurological sequelae such as cerebral palsy (CP). Grade 3 is associated with coma, and in the majority of cases neonatal death or long-term neurological sequelae such as CP occur . Permanent neurological damage is rare in cases with mild HIE, whereas moderate encephalopathy consists of a more heterogeneous group, with varying rates of disabilities. In a recent systematic review of studies evaluating the long-term consequences of HIE, 14.5% of all cases were reported to develop CP .
The occurrence of a clinical sentinel event during labour may help to differentiate between a prenatal and an intrapartum cause of hypoxia/acidosis, particularly when there is documentation of prolonged maternal hypotension, uterine rupture, umbilical cord prolapse, etc. However, recent studies have documented that sentinel events on their own are poorly predictive of neonatal encephalopathy . A continuous cardiotocography (CTG) tracing acquired in the beginning of labour may also help to determine the timing of damage. Some foetal heart rate (FHR) patterns suggest an acute intrapartum event, whereas the documentation of reduced variability and absent accelerations from the start of labour suggests a previously damaged foetus.
Nucleated red blood cells and lymphocyte counts are frequently increased in the neonate’s circulation in response to hypoxia or haemorrhage, and the quantification of these cells has been proposed as a measure of hypoxia. However, most studies are underpowered to evaluate the discriminative capacity of this biomarker in the prediction of HIE, especially in infants undergoing therapeutic hypothermia .
Cerebral palsy
CP is the most common physical disability of childhood, and it consists of a heterogeneous group of nonprogressive movement and posture disorders, frequently accompanied by cognitive and sensory impairments, epilepsy, nutritional deficiencies and secondary musculoskeletal lesions. The worldwide prevalence of CP has remained stable at two to three per 1000 live births for more than four decades, despite remarkable improvements in obstetric and neonatal care . Although in developing countries, circa 50% of cases are related to prematurity, in industrialised countries, the prevalence of CP appears to be decreasing among prematures, but it has remained stable in full-term neonates. The latter account for 50–65% of cases, and these tend to be more severely impaired .
CP of the ‘spastic quadriplegic’ and ‘dyskinetic’ types is the long-term neurological complications most strongly associated with intrapartum hypoxia/acidosis. ‘Spastic quadriplegic’ is one of the most severe forms of CP, affecting the ability to relax the muscles of all the limbs. Described in circa 90% of cases in very low birthweight children, it is associated with parasagittal brain injury to the periventricular and subcortical white matter (periventricular leukomalacia), arising from intermittent reductions in foetal oxygenation occurring over a period of at least 1 h. ‘Dyskinetic CP’ typically affects term infants, and it arises from an acute and severe reduction in foetal oxygenation (as occurs with umbilical cord prolapse, major placental abruption, maternal cardiovascular collapse or uterine rupture). This disorder is consequent to selective neuronal necrosis of the hippocampus, thalamus, basal ganglia, reticular formation and Purkinje cells of the cerebellum, leading to marble-like lesions known as ‘status marmoratus’ on neonatal magnetic resonance imaging (MRI) .
Individuals with CP, particularly in its most severe forms, frequently have other associated neurological abnormalities, namely intellectual disabilities in circa 50% of cases, epilepsy in 25–45%, speech and language disorders in 40%, visual deficits in 40% and hearing impairments in 10–20% . Neurodevelopmental disorders are also common, and features of the autism spectrum disorder may appear in up to 7% of children. Other organs and systems that may be affected are the somatosensory (stereognosis and proprioception impairments), genito-urinary (dysfunctional voiding and a high rate of urinary infections), gastrointestinal (dysphagia, oesophageal and bowel dismotility), endocrine (growth failure and osteopaenia) and musculoskeletal (subluxation, progressive dysplasia of the hip, foot deformities and scoliosis). Chronic pulmonary disease is a leading cause of death, due to recurrent pneumonia caused by gastroesophageal reflux, palatopharyngeal incoordination and aspiration of gastric content, as well as to restrictive lung disease related to scoliosis.
A definitive diagnosis of CP usually requires repeated observations, and it should be deferred until later in infancy, particularly in preterm infants. Isolated abnormalities may resolve progressively after 9 months of age, spasticity may not be apparent until 6 months of age and dyskinetic patterns are typically identified only after 18 months. Despite some disagreement as to the age required for an accurate diagnosis, 36 months usually allows a reliable assessment of motor capacity, in contrast to the false-positive diagnoses that may occur before 18 months of age .
The complex aetiology of CP comprises a wide range of antenatal, intrapartum and postnatal factors that presumably act along the common pathogenic pathways of hypoxia/acidosis, inflammation and neurodevelopmental abnormalities. Prematurity, low birthweight, intrapartum hypoxia/acidosis, chorioamnionitis, central nervous system malformations, intrapartum fever, multiple gestations, coagulation disorders, ischaemic stroke, maternal thyroid disease, obesity and placental pathology are the most commonly reported risk factors .
Intrapartum hypoxia/acidosis is perhaps the most extensively studied risk factor for CP, with the clear limitation that an agreed set of criteria to define the former entity has not existed for many years. Nevertheless, even with previously existing markers, several large population-based studies, conducted over different time frames and in different populations, have led to the widely accepted conclusion that intrapartum hypoxia/acidosis accounts for only 10–20% of CP cases .
Many intrapartum events have been statistically associated with CP, including instrumental vaginal delivery, caesarean section and breech delivery . Other related factors are meconium-stained amniotic fluid, meconium aspiration, severe placental vascular lesions, placental abruption and cord prolapse. On the other hand, a recent meta-analysis including a total of 3810 participants found no association between the use of elective caesarean delivery and CP. An increased risk of CP (odds ratio (OR): 2.17; 95% confidence interval (CI): 1.58–2.98) was found in emergency caesarean sections, although the indication leading to surgery is a very likely confounder . Low 5-min Apgar scores, seizures, respiratory distress syndrome, hypoglycaemia, jaundice, hyperbilirubinaemia, neonatal sepsis and meningitis have all been reported as neonatal risk factors for CP . Perinatal stroke has been the focus of many studies, and it is correlated with other antenatal and perinatal risk factors for CP, such as intrauterine growth restriction, pre-eclampsia, infection and thrombophilia, although the evidence regarding the latter remains controversial .
A consensus statement was published in 1999 by the multidisciplinary International Cerebral Palsy Task Force defining the criteria needed to establish a link between intrapartum acidosis and CP . The subject was revised in 2003 by the American College of Obstetricians and Gynecologists (ACOG) and the American Academy of Pediatricians (AAP). More recently, Fédération Internationale de Gynécologie et d’Obstétrique (FIGO) published a revised consensus document on intrapartum foetal monitoring, where the causal relationship between hypoxia/acidosis and CP is evaluated . There is general agreement on a number of findings necessary to implicate intrapartum hypoxia/acidosis as the possible cause of CP in term infants ( Table 1 ).
