Cerebral palsy (CP) is heterogeneous with different clinical types, comorbidities, brain imaging patterns, causes, and now also heterogeneous underlying genetic variants. Few are solely due to severe hypoxia or ischemia at birth. This common myth has held back research in causation. The cost of litigation has devastating effects on maternity services with unnecessarily high cesarean delivery rates and subsequent maternal morbidity and mortality. CP rates have remained the same for 50 years despite a 6-fold increase in cesarean birth. Epidemiological studies have shown that the origins of most CP are prior to labor. Increased risk is associated with preterm delivery, congenital malformations, intrauterine infection, fetal growth restriction, multiple pregnancy, and placental abnormalities. Hypoxia at birth may be primary or secondary to preexisting pathology and international criteria help to separate the few cases of CP due to acute intrapartum hypoxia. Until recently, 1-2% of CP (mostly familial) had been linked to causative mutations. Recent genetic studies of sporadic CP cases using new-generation exome sequencing show that 14% of cases have likely causative single-gene mutations and up to 31% have clinically relevant copy number variations. The genetic variants are heterogeneous and require function investigations to prove causation. Whole genome sequencing, fine scale copy number variant investigations, and gene expression studies may extend the percentage of cases with a genetic pathway. Clinical risk factors could act as triggers for CP where there is genetic susceptibility. These new findings should refocus research about the causes of these complex and varied neurodevelopmental disorders.
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Two international expert task forces addressed cerebral palsy (CP) causation in 1999 and 2003. In 2014, the American Congress of Obstetricians and Gynecologists and the American Academy of Pediatrics, with many international consultants, updated these reports but chose to focus on neonatal encephalopathy and a variety of neurological outcomes rather than discuss CP causation specifically and did not directly address the ramifications of litigation following a diagnosis of CP. Recent findings published after the 2014 report have identified likely causative genetic variants associated with CP cases and this review contributes to updating clinicians.
CP is a heterogeneous condition with multiple causes; multiple clinical types; multiple patterns of neuropathology on brain imaging; multiple associated developmental pathologies, such as intellectual disability, autism, epilepsy, and visual impairment; and more recently multiple rare pathogenic genetic variations (mutations). CP would be better named “the cerebral palsies” given that within the CP clinical spectrum there are many causal pathways and many types and degrees of disability. These various pathways and etiologies have each resulted in a nonspecific nonprogressive disorder of posture and movement control. Thus, CP should be considered as a descriptive term for affected individuals, with each case receiving adequate consideration of an underlying etiology. There has been little change in the prevalence of this diagnosis throughout the world, where population data are available. It remains around 2-2.5/1000 births. Although there have been small statistical fluctuations in the CP rates among children born preterm, the rates of CP at term remain stable. New interventions such as head or body cooling in selected cases with acute hypoxia have yet to significantly lower overall rates. Only a small percentage of cases are associated solely with acute intrapartum hypoxia. Despite this, many cases are mislabeled as due to birth asphyxia.
Birth asphyxia
“Birth asphyxia” is an outdated term that may wrongly convey that a baby born with signs of fetal and neonatal compromise must have undergone an acute hypoxic event in late labor and/or birth. These clinical signs may also be present when there has been much longer-standing fetal compromise with possible secondary hypoxia near delivery. Similarly, the term “hypoxic ischemic encephalopathy” has been replaced by the term “neonatal encephalopathy” as the large majority of newborn infants showing signs of encephalopathy does not have objective proof of acute hypoxia or ischemia at birth, but have other causes of perinatal compromise such as infectious or genetic. Of note, only 13% of term babies who exhibit neonatal encephalopathy are later diagnosed with CP.
At birth, nonspecific signs of fetal compromise such as meconium-stained amniotic fluid, nonreassuring fetal heart rate patterns, low Apgar scores, and neonatal encephalopathy could all be associated with either acute intrapartum timing or chronic long-standing timing of the pathologies (ie, beginning before labor and during pregnancy). The same signs can be caused by not only hypoxia and/or ischemia, but also by other factors such as infection, placental and umbilical vessel thrombosis, or an altered fetal inflammatory response. Very recent studies suggest that many cases of CP are associated with genetic alterations (mutations) that may either directly cause CP or contribute to susceptibility to CP. As yet, they are not detectable antenatally or preventable.
International consensus criteria to identify severe acute intrapartum hypoxia
There is now increasing evidence that babies given a “birth asphyxia” label due to clinical signs such as low Apgar scores often do not have primary asphyxia. Many such babies are in ill health due to longer-standing problems. Acute or chronic hypoxia can cause a metabolic acidosis in the blood of the newborn and this has to be objectively measured in umbilical arterial blood gases at birth to ascertain if clinically severe hypoxia is contributing to the poor condition of the newborn. When metabolic acidosis is proven to be present, this is evidence of either acute hypoxia beginning in labor or chronic hypoxia (ie, long-standing compromise in pregnancy beginning before labor). Secondary asphyxia in labor is not necessarily the initial cause of the brain injury but may be a subsequent result of the established neuropathological process. International consensus criteria have been published and refined to help define cases where neuropathology may have become established only in labor and birth. These 9 criteria have helped recognize the few cases of severe de novo acute intrapartum hypoxia ( Table 1 ). These criteria, as a group, have been well verified. The first 4 essential criteria have a high but not individually perfect correlation (94-100%) in acutely asphyxiated neonates. The 5 nonspecific timing criteria were individually less predictive, but were to be assessed together, and their consensus helps understand the likely timing of the neuropathology. In 2014, a third consensus statement similarly examined neonatal encephalopathy, rather than CP, and largely supported the criteria that define a causative intrapartum neuropathological event.
Essential criteria to show presence of hypoxia at birth are:
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| Five nonspecific criteria collectively point toward acute or chronic causes of hypoxia. If most are met they suggest timing of neuropathology near delivery. If most are not met they suggest longer-standing pathological process. These criteria are:
|
International consensus criteria to identify severe acute intrapartum hypoxia
There is now increasing evidence that babies given a “birth asphyxia” label due to clinical signs such as low Apgar scores often do not have primary asphyxia. Many such babies are in ill health due to longer-standing problems. Acute or chronic hypoxia can cause a metabolic acidosis in the blood of the newborn and this has to be objectively measured in umbilical arterial blood gases at birth to ascertain if clinically severe hypoxia is contributing to the poor condition of the newborn. When metabolic acidosis is proven to be present, this is evidence of either acute hypoxia beginning in labor or chronic hypoxia (ie, long-standing compromise in pregnancy beginning before labor). Secondary asphyxia in labor is not necessarily the initial cause of the brain injury but may be a subsequent result of the established neuropathological process. International consensus criteria have been published and refined to help define cases where neuropathology may have become established only in labor and birth. These 9 criteria have helped recognize the few cases of severe de novo acute intrapartum hypoxia ( Table 1 ). These criteria, as a group, have been well verified. The first 4 essential criteria have a high but not individually perfect correlation (94-100%) in acutely asphyxiated neonates. The 5 nonspecific timing criteria were individually less predictive, but were to be assessed together, and their consensus helps understand the likely timing of the neuropathology. In 2014, a third consensus statement similarly examined neonatal encephalopathy, rather than CP, and largely supported the criteria that define a causative intrapartum neuropathological event.
Essential criteria to show presence of hypoxia at birth are:
|
| Five nonspecific criteria collectively point toward acute or chronic causes of hypoxia. If most are met they suggest timing of neuropathology near delivery. If most are not met they suggest longer-standing pathological process. These criteria are:
|
Intrapartum cardiotocography
It is important to understand the great limitations of intrapartum electronic fetal heart rate monitoring, and in particular its inability to reduce or prevent CP. Cochrane systematic reviews of relevant randomized controlled trials of electronic fetal heart rate monitoring show no reduction in CP rates with its use compared to intermittent auscultation of the fetal heart. Continuous electronic fetal heart rate monitoring was introduced in the 1960s, without prior testing in randomized controlled trials, partly in the belief that it would allow early recognition of acute fetal compromise and in particular hypoxia. It was hoped that this would reduce intrapartum brain injury, because of the long-standing assumption and belief that many cases of CP were due to preventable acute hypoxia beginning in labor. However, fetal heart rate is a very indirect and poor measure of past and present fetal brain function and damage.
Intrapartum cardiotocography has a very high false-positive rate and with the pressures of obstetric litigation in many countries, birth attendants and especially individuals giving private care, who cannot be in continuous attendance, often opt for cesarean delivery. Defensive obstetrics, often in response to uncertain cardiotocographic interpretation, has contributed to a large increase in cesarean delivery rates without a change in CP rates ( Figure 1 ). The quantum of claims following CP is very high in countries such as the United States, Australia, and the United Kingdom. English health trusts paid £482 million for “maternity negligence” coverage in 2012 through 2013 equating to a fifth of all spending on maternity services. A small group of expert witnesses for the plaintiff regularly opine that the cause of the CP was birth asphyxia that was recognizable in labor and preventable by earlier delivery. To challenge such nonevidence-based opinion, it is time for obstetric colleges and academic scientific societies in this field to spell out that cardiotocography: (1) cannot detect the timing of the onset of neuropathology; (2) cannot determine a time when it would be reversible and then irreversible; and (3) cannot be used to determine that earlier delivery by cesarean delivery “on the balance of probabilities” would have prevented the CP outcome. Courts should find that junk science is inadmissible in determining CP causation and prevention.
Clinical risk factors for CP during pregnancy
There is increasing scientific evidence that CP is usually associated with long-standing intrauterine pathology like genetic mutations and probable environmental triggers such as bacterial and viral intrauterine infection, intrauterine growth restriction (IUGR), antepartum hemorrhage, tight nuchal cord, and threatened miscarriage. It can be difficult to pinpoint adverse pregnancy factors in retrospect, many years after birth, that individually or together might have triggered the pathways to the neuropathology.
Preterm delivery
Preterm delivery is a major risk factor for CP and is seen in approximately 35% of all cases, and the risk increases the lower the viable gestational age. The risk of subsequent CP <33 weeks’ gestation is 30 times higher than among those born at term and is approximately 70/1000 deliveries. The prevalence of CP is highest in children born <28 weeks’ gestational age (111.8/1000 neonatal survivors; 82.25/1000 live births) and declines with increasing gestational age, being 43.15/1000 live births between 28-31 weeks, 6.75/1000 between 32-36 weeks, and 1.35/1000 for those born >36 weeks. The mechanisms and pathways to the neuropathology of CP may differ from term babies, although associated risk factors such as infection, genetic variations, and growth restriction are likely to contribute.
Coexisting congenital anomalies
The prevalence of congenital anomalies in children with CP is much higher than in the general population and most are cerebral, such as schizencephaly and hydrocephaly. Noncerebral malformations are also increased, such as cardiac, musculoskeletal, and urinary. In a case-control study of 494 singleton infants with CP born >35 weeks’ gestation included on the Western Australian Register of Developmental Anomalies and 508 matched controls, birth defects (42.3%) and fetal growth restriction (16.5%) were more strongly associated with CP than potentially asphyxial birth events (8.5%) and inflammation (4.8%). Birth defects had the largest association with CP in that study in both term and preterm babies. Growth-restricted babies with birth defects were at special risk of CP. The strong association with congenital abnormalities suggests possible genetic factors although congenital infections, nutritional disorders, and teratogenic influences all contribute to maldevelopment.
Intrauterine infection
There are many probable antenatal causes of white-matter damage and risk factors for CP ( Table 2 ). Some of these causes include damage acquired following perinatal infection (ie, maternal infection that affects the fetus and its brain during pregnancy and/or labor or in the neonatal period). Viral or bacterial infections may be relatively silent during pregnancy and not recognized clinically at the time and the placenta is often discarded without histological examination for inflammatory pathology. Maternal reports of fever or infection during pregnancy are significantly associated with an increased risk of CP in our recent large Australian case-control study. Evidence of intrauterine infection, evidenced by histological chorioamnionitis in the placenta and membranes or intrapartum pyrexia, is associated with a 4-fold increase in CP (odds ratio 3.8; 95% confidence interval, 1.5–10.1) in term infants.
| Preterm delivery Coexisting congenital anomaly (maldevelopment) Probable genetic causes Bacterial and viral intrauterine infection Altered fetal inflammatory or thrombophilic response (perinatal stroke) Fetal growth restriction Higher-order pregnancy, risk greater with monozygosity and in vitro fertilization Tight nuchal umbilical cord Prolonged shoulder dystocia Placental pathology, eg, chorioamnionitis, funisitis, villitis Inborn errors of metabolism Male:female ratio 1.3:1 |
Abnormal fetal inflammatory response and thrombophilia
Another possible related cause and mechanism of CP is an abnormal inflammatory response in the fetus and the neonate. An excessive or abnormal rise in cytokines (due to genetic predisposition or mutations) following infection and an inflammatory response, which is part of the body’s normal defense mechanism against infection or toxins, may cause an autoimmune type of attack on the fetal or neonatal developing nerve cells. The prematurely delivered baby’s immature brain is even more vulnerable to these proinflammatory cytokines. In previous genetic association studies, hereditary thrombophilia (the methylenetetrahydrofolate reductase cC677T mutation and the prothrombin gene c20210G>A variant) and some cytokine polymorphisms (interleukin-6, interleukin-8, tumor necrosis factor, and mannose binding lectin) were associated with an increased risk of CP.
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