Cerebral palsy: Epidemiology, etiology, and prevention

INTRODUCTION — Cerebral palsy (CP) refers to a heterogeneous group of conditions involving permanent motor dysfunction that affects muscle tone, posture, and/or movement. These conditions are due to abnormalities of the developing fetal or infant brain resulting from a variety of non-progressive causes. Although the disorder itself is not neurodegenerative, the clinical expression may change over time as the central nervous system matures. The motor impairment results in limitations in functional abilities and activity, which can vary in severity. Multiple additional symptoms often accompany the primary motor abnormalities, including altered sensation or perception, intellectual disability, communication and behavioral difficulties, seizures, and musculoskeletal complications [1].

The epidemiology, etiology, and prevention of CP are reviewed here. The classification, clinical features, evaluation, diagnosis, management, and prognosis of CP are discussed separately:

●(See "Cerebral palsy: Classification and clinical features".)

●(See "Cerebral palsy: Evaluation and diagnosis".)

●(See "Cerebral palsy: Overview of management and prognosis".)

●(See "Cerebral palsy: Treatment of spasticity, dystonia, and associated orthopedic issues".)

EPIDEMIOLOGY

Prevalence — The overall prevalence of CP is approximately 2 per 1000 live births in the United States but may be up to 3to 4 per 1000 live births in other parts of the world [2-9].

The prevalence of CP is far higher in preterm compared with term infants and increases with decreasing gestational age (GA) and birth weight (BW), as discussed below. (See 'Prematurity' below.)

Although infants born preterm are at higher risk of developing CP, preterm infants account for less than one-half of cases of CP. In large epidemiologic studies of children with CP in high-income countries, approximately 25 percent were very preterm (GA <32 weeks), 10 to 20 percent were moderately preterm or late preterm (GA 32 to 36 weeks), and 60 percent were born at term (GA >36 weeks) [3,10].

In other parts of the world, postnatal etiologies like infection may be more common causes, perhaps due to reduced survival of children born preterm [7,8]. (See 'Specific causes and risk factors' below.)

Trends over time — In the 1960s through 1980s, the rate of CP and the extent of disability among preterm infants increased as survival improved for the most premature [11]. During the 1980s and 1990s, there was a reversal in this trend, most likely because of improvements in perinatal care. In one study, the prevalence of CP among very low birth weight (VLBW; <1500 g) infants declined from 6 percent in the early 1980s to 4 by the mid-1990s [12]. This improvement occurred despite overall increases in survival and multiple births and decreases in mean BW among this group. In another study, the prevalence of CP among preterm infants (GA 20 to 27 weeks) decreased from 16 percent in the early 1990s to 2 percent by the early 2000s [13]. This was in the setting of stable or decreasing mortality during the same time period.

Among term and late preterm infants, the prevalence of CP remained stable during the 1980s and 1990s [14]. An analysis of registry data from Europe and Australia found the prevalence of CP declined in infants born from 1995 to 2015, perhaps due to improvements in perinatal care [9].

SPECIFIC CAUSES AND RISK FACTORS — The etiology of CP is often multifactorial and can include anything with a negative impact on the developing fetal or neonatal brain. Numerous antenatal and perinatal risk factors have been reported (table 1), though for many of these risk factors, a causal relationship has not been established [3,10,15-21]. Potentially modifiable prenatal factors that may contribute to CP risk include heavy maternal alcohol consumption, maternal smoking, maternal obesity, and infections during pregnancy [21-28]. Prematurity is the most common association; however, in many cases, no specific cause is identified [29].

The multifactorial etiology of CP was illustrated in a series of 213 children diagnosed with CP in Australia, of whom 98 percent had contributing causes other than intrapartum hypoxia [30]. The relative frequencies of different contributing factors were as follows (many children had more than one contributing factor):

●Prematurity (78 percent)

●Intrauterine growth restriction (34 percent)

●Intrauterine infection (28 percent)

●Antepartum hemorrhage (27 percent)

●Severe placental pathology (21 percent)

●Multiple pregnancy (20 percent)

In a large case-control study using multivariable logistic regression modeling to identify pre- and perinatal factors associated with increased risk of CP, the strongest independent predictors were 5-minute Apgar score, maternal intrauterine infection, and maternal drug use [21]. Other important predictors included maternal tobacco use, prolonged rupture of membranes, maternal diabetes, preeclampsia, preterm birth, low birthweight, male sex, and history of prior miscarriages. Infants with ≥2 of these risk factors were at substantially higher risk.

Postnatal events may also be common contributing causes of CP. In a large epidemiological study in Uganda, postnatal causes including cerebral malaria and seizures were attributed to 25 percent of CP cases [8].

Common causes of CP are described below. The associated causes and risk factors differ somewhat based upon the subtype of CP (table 2) [20].

Prematurity — The prevalence of CP is far higher in preterm compared with term infants. CP develops in approximately 5 to 10 percent of surviving preterm very low birth weight (VLBW; BW <1500 g) infants [2,31]. The risk of CP increases with decreasing gestational age (GA) and birth weight (BW) [2]:

●GA:

•GA <28 weeks – 82 per 1000 live births

•GA 28 to 31 weeks – 43 per 1000 live births

•GA 32 to 36 weeks – 7 per 1000 live births

•GA >36 weeks – 1.4 per 1000 live births

●BW:

•<1500 g – 59 per 1000 live births

•1500 to 2499 g – 10 per 1000 live births

•>2500 g – 1.3 per 1000 live births

In preterm infants, CP is often associated with the following conditions [32]:

●Periventricular leukomalacia (PVL) – PVL refers to injury of cerebral white matter that occurs in a characteristic distribution affecting white matter tracts responsible for leg motor control more so than tracts controlling the arms. PVL consists of periventricular focal necrosis, with subsequent cystic formation, and more diffuse cerebral white matter injury. PVL is the major form of brain white matter injury that affects premature infants. (See "Germinal matrix and intraventricular hemorrhage (GMH-IVH) in the newborn: Risk factors, clinical features, screening, and diagnosis", section on 'White matter injury'.)

●Intraventricular hemorrhage (IVH) – Severe IVH, periventricular hemorrhagic infarction, and posthemorrhagic hydrocephalus (a potential complication of IVH) may lead to CP [33]. (See "Germinal matrix and intraventricular hemorrhage (GMH-IVH) in the newborn: Risk factors, clinical features, screening, and diagnosis" and "Germinal matrix and intraventricular hemorrhage (GMH-IVH) in the newborn: Management and outcome".)

●Bronchopulmonary dysplasia (BPD) – The risk of motor impairment is greater in preterm infants affected by BPD [34]. The mechanism is not known but may involve the use of corticosteroids to improve lung disease. This issue is discussed in greater detail separately. (See "Postnatal use of glucocorticoids for prevention of bronchopulmonary dysplasia (BPD) in preterm infants" and "Bronchopulmonary dysplasia (BPD): Management and outcome", section on 'Neurodevelopmental outcomes'.)

Perinatal hypoxic-ischemic injury — Perinatal hypoxia and/or ischemia accounts for a minority of cases of CP [35,36]. Reports of the proportion of CP cases caused by birth asphyxia vary from <3 to >50 percent depending on the definition of birth asphyxia used [35]. In a study using the criteria set forth by the American College of Obstetricians and Gynecologists (ACOG) and the International Cerebral Palsy Task Force (table 3), an acute intrapartum hypoxic event was identified in only 1 percent (2 of 213 infants) of children with CP [30,37]. (See "Etiology and pathogenesis of neonatal encephalopathy", section on 'Acute events'.)

When severely damaging perinatal hypoxia occurs, it presents as neonatal encephalopathy, which is a heterogeneous, clinically defined syndrome characterized by disturbed neurologic function in the earliest days of life in an infant born at term, manifested by a subnormal level of consciousness or seizures, often accompanied by difficulty with initiating and maintaining respiration and depression of tone and reflexes [37]. (See "Clinical features, diagnosis, and treatment of neonatal encephalopathy".)

Neonates with severe intrapartum hypoxia-ischemia may have seizures, encephalopathy, hypotonia, dysfunction of other organ systems, a persistently low Apgar score, and evidence of profound metabolic acidosis. On magnetic resonance imaging (MRI), the two most typical patterns of hypoxic-ischemic injury are basal ganglia/thalamic-predominant pattern and a watershed-predominant pattern (image 1) [38].

Antenatal infection or injury

●Intrauterine infection – Congenital infections with organisms such as cytomegalovirus, syphilis, Zika virus, varicella virus, and toxoplasmosis are associated with increased risk of CP [39]. Bacterial infections are also associated with CP. (See "Overview of TORCH infections" and "Congenital cytomegalovirus infection: Clinical features and diagnosis" and "Congenital Zika virus infection: Clinical features, evaluation, and management of the neonate" and "Clinical features, evaluation, and diagnosis of sepsis in term and late preterm neonates".)

Maternal intraamniotic infection (IAI; also called clinical chorioamnionitis) is associated with an increased risk of CP in the offspring [40-43]. A meta-analysis of 12 observational studies demonstrated a strong association between IAI and cerebral palsy (pooled odds ratio [OR] 2.42, 95% CI 1.5-3.8) [40]. Another case-control study found that any maternal infection during pregnancy was associated with increased risk of CP (OR 2.9, 95% CI 1.7-4.8) and that neonatal infection was a strong independent predictor of CP (OR 14.7, 95% CI 1.7-126.5) [44]. (See "Clinical chorioamnionitis", section on 'Perinatal outcome'.)

In preterm infants, perinatal infection appears to play a key role in the pathogenesis of cystic encephalomalacia, PVL, and subsequent CP [45]. (See 'Prematurity' above.)

●Maternal trauma during pregnancy – Severe trauma during pregnancy can have adverse effects on the developing fetus and may increase the risk of long-term disabilities, including CP. In a population-based longitudinal cohort study that included >2,000,000 children, those with in utero exposure to maternal injury that required emergency department or inpatient care had a higher prevalence of CP compared with unexposed children (3.6 versus 2.5 per 1000 children) [46]. Maternal injuries of greater severity (eg, those resulting in hospitalization) were associated with higher CP risk in the offspring. The association remained statistically significant after adjusting for maternal sociodemographic and clinical characteristics (hazard ratio 1.33, 95% CI 1.18-1.50). These findings highlight the importance of prevention efforts to reduce the risk of severe injury during pregnancy (eg, correct use of seat belts and airbags). (See "Prenatal care: Patient education, health promotion, and safety of commonly used drugs", section on 'Use of seat belts and air bags'.)

Congenital abnormalities — Congenital abnormalities, both structural central nervous system (CNS) abnormalities and abnormalities outside of the CNS, are more common in children with than without CP [15,47-51]. Congenital abnormalities are noted in approximately 15 percent of children with CP and are more common in term than preterm infants [15,50]. In one registry study, the most common CNS anomalies were microcephaly and congenital hydrocephalus [50]. Non-CNS anomalies included cardiac, urinary, and skeletal malformations.

Intrapartum events may be influenced by a preexisting abnormality [52,53]. In one report, congenital anomalies (mostly non-CNS anomalies) occurred more often in term infants with neonatal encephalopathy than in controls (28 versus 4 percent) [54]. The congenital anomaly was considered the cause of the encephalopathy in approximately one-third of affected infants. Infants with congenital anomalies who had encephalopathy were three times more likely to have CP than those without.

In children with CP due to brain malformations, the biologic basis is usually unknown. Some result from abnormalities that occur during brain development and affect cell proliferation, migration, differentiation, survival, or synaptogenesis. Disorders of development occasionally result from exposure to radiation, toxins, or infectious agents during a critical period of gestation [55-58]. Some disorders (eg, schizencephaly) are genetic and follow Mendelian inheritance patterns [59-63]. Certain cerebral malformations can also be associated with chromosomal abnormalities (eg, holoprosencephaly is associated with both trisomy 13 and 18). Some neurocutaneous syndromes are associated with brain malformations (eg, hemimegalencephaly and hypomelanosis of Ito or the linear sebaceous nevus syndrome) [64]. (See "Prenatal diagnosis of CNS anomalies other than neural tube defects and ventriculomegaly", section on 'Schizencephaly' and "Prenatal diagnosis of CNS anomalies other than neural tube defects and ventriculomegaly", section on 'Holoprosencephaly' and "Congenital cytogenetic abnormalities", section on 'Trisomy 13 syndrome' and "Congenital cytogenetic abnormalities", section on 'Trisomy 18 syndrome' and "The genodermatoses: An overview", section on 'Neurocutaneous syndromes'.)

Genetic susceptibility — A genetic contribution to CP risk was identified by the aggregation of CP in groups with high consanguinity and observations of increased familial risk for CP [65-67]. These disorders were historically thought to be uncommon causes of CP, but with the advent of next-generation genetic testing techniques, they are increasingly recognized as playing an important role in the etiology of CP [68-70]. Genetic factors have been identified in 8 to higher than 30 percent of people with CP [71-77]. In a meta-analysis of 13 studies that included more than 2600 patients with CP who underwent exome or genome testing, the diagnostic yield was 31 percent [78]. In a report of 1345 children with CP (mean age 8.8 years) who were referred for diagnostic exome sequencing at one clinical genetics laboratory, 33 percent were found to have pathogenic or likely pathogenic variants involving >200 distinct genes [76]. The genes most frequently identified were CTNNB1 (n = 18), KIF1A (n = 8), COL4A1 (n = 7), GNAO1 (n = 7), KCNQ2 (n = 7), and STXBP1 (n = 7). The diagnostic yield was highest when testing was performed concurrently in the proband and both parents (ie, trio testing). Among trios with positive diagnostic results (n = 357), 72 percent had de novo variants, 20 percent were inherited in an autosomal recessive manner, 5 percent were inherited in an autosomal dominant manner, and 3 percent were X-linked.

Several genetic polymorphisms have been reported to be associated with susceptibility for CP, including apolipoprotein E [79,80], genes associated with thrombophilia (eg, prothrombin G20210A pathologic variant) [81,82], and genes involved with inflammation (eg, inducible nitric oxide synthetase, lymphotoxin alpha, and certain cytokines) [83,84]. However, only the association with prothrombin G20210A pathologic variant was confirmed by a subsequent large study [82]. (See "Prothrombin G20210A".)

However, identifying a genetic cause of CP generally does not replace the diagnosis of CP since some patients with a genetic disorder may have CP due instead or additionally to other causes [85]. Up to 11 percent of those with acquired risk factors for CP have additional genetic findings that may have contributed to their CP phenotype [68,69].

In addition, numerous genetic disorders can present with findings consistent with CP (table 4). Some inborn errors of metabolism and other progressive disorders may initially mimic CP [86,87]. Genetic testing can sometimes identify these conditions, some of which may be potentially treatable. (See "Inborn errors of metabolism: Epidemiology, pathogenesis, and clinical features".)

Hereditary spastic paraplegia (HSP), a mimicker of spastic diplegic CP, is a diverse group of neurologic disorders that range in phenotype and inheritance pattern [88,89]. HSP is characterized by progressive lower extremity spasticity; however, progression may be slow, particularly in infantile-onset HSP, making it difficult to distinguish HSP from CP clinically. Corresponding genes that have been linked to HSP are summarized in the table (table 5). HSP is discussed in greater detail separately. (See "Hereditary spastic paraplegia".)

Multiple births — The risk of CP is increased among multiple births [90-95]. Causes that may contribute to this risk include low BW, prematurity, congenital anomalies, cord entanglement, and abnormal vascular connections [96]. In a study of births in Western Australia from 1980 to 1989, the prevalence of CP was 1.6, 7.3, and 28 per 1000 survivors to one year of age in singletons, twins, and triplets, respectively [90]. In this report, the increased rates of CP in multiples were limited to infants of normal BW, although multiples were more likely to have low BW.

Death of a co-twin greatly increases the risk of CP. In the report from Western Australia, the risk of CP among twins was greater when one twin died in utero (96 versus 12 per 1000 twin pairs) compared with both surviving [90]. The mechanism may include release of thromboplastin and emboli from the dead twin, causing injury to the survivor. It is possible that some cases of CP in apparent singletons may be due to an unrecognized fetal death of a co-twin [97].

Postnatal death also increases the risk of CP in the surviving co-twin, and monozygosity appears to influence this risk. In a study that analyzed birth and death certificate data (1993 to 1995) for different sex (dizygotic) and same sex (dizygotic and monozygotic) twins, and assessed disability in surviving twins after neonatal death of the co-twin using questionnaires sent to clinicians, the risk of CP was greater in same-sex compared with different-sex twin survivors (167 versus 21 per 1000) for infants of BW 1000 to 1999 g, although the difference was only marginal for infants of BW <1000 g (224 versus 200 per 1000) [98].

Stroke — Stroke in the perinatal period contributes to CP, especially unilateral spasticity [99]. Thromboembolism and prothrombotic disorders contribute to the etiology of this disorder. Lesions typically are identified by cranial imaging studies following a neonatal seizure. However, some newborns with stroke appear asymptomatic until hemiparesis or other abnormalities become more apparent as developmental milestones are assessed over time. (See "Cerebral palsy: Classification and clinical features", section on 'Early signs of cerebral palsy'.)

Prenatal causes include hypercoagulable states, vasculopathies, abnormal development of blood vessels, and emboli secondary to disorders affecting the placenta or fetus [100]. Stroke that occurs during early infancy may be caused by sepsis, disseminated intravascular coagulation, venous sinus thrombosis, emboli, and congenital heart disease [101,102]. Some cases are caused by periventricular atrophy or cerebral dysgenesis. Affected patients with nondiagnostic neuroimaging may have maldevelopment at a microscopic level [103,104]. However, risk factors for stroke in the neonatal period are unique, and detailed vasculopathy and hypercoagulability evaluations do not predict risk of recurrence [105]. (See "Stroke in the newborn: Classification, manifestations, and diagnosis".)

Intracranial hemorrhage — Intracranial hemorrhage (ICH) in term infants is unusual but frequently results in neuromotor abnormalities. Most are recognized because of the sudden and dramatic onset of symptoms, including seizures, abnormal movements, apnea, lethargy, irritability, vomiting, and bulging fontanelle. Diagnosis is made by cranial imaging.

The incidence depends in part upon the method of ascertainment. In one series of 33 term infants with symptomatic ICH, the regional incidence was estimated to be 0.27 per 1000 live births [106]. Approximately one-third of cases were related to coagulopathies. In another report, ICH was diagnosed by ultrasound scan in 54 of 2019 term infants (2.7 percent) treated in a newborn intensive care unit from 1989 to 1999 [107]. Neurologic impairment developed in 28 percent.

Thalamic hemorrhage with residual germinal matrix hemorrhage is a common source of ICH in this population. When no source is apparent, the ICH is thought to originate from the choroid plexus. In one report, thalamic hemorrhage was identified in 12 of 19 term infants younger than one month of age with ICH diagnosed by computed tomography (CT) [108]. Thalamic hemorrhage typically occurred in infants with uneventful birth histories and presentation after one week of age. Many had predisposing factors for cerebral vein thrombosis (eg, sepsis, congenital heart disease, coagulopathy, electrolyte disturbance). At 18 months of age, the majority had CP, predominantly hemiplegia, and other neurologic abnormalities such as hydrocephalus and seizures.

Acquired postnatal causes — Though CP in high-income countries is most commonly due to prenatal or perinatal factors, CP can also result from insults to the developing brain acquired during infancy and early childhood, which may be more common causes of CP globally. Approximately 10 to 25 percent of cases of CP are acquired after the neonatal period. Most of these patients have spastic CP. Common causes of postnatally acquired CP include:

●Stroke − Stroke is uncommon in infants and children and is usually associated with an underlying disorder (eg, congenital heart disease, prothrombotic disorder, sickle cell disease, vasculopathy, or metabolic disorder). Stroke typically results in unilateral spasticity. (See "Stroke in the newborn: Classification, manifestations, and diagnosis" and "Ischemic stroke in children and young adults: Epidemiology, etiology, and risk factors".)

●Trauma − (See "Child abuse: Evaluation and diagnosis of abusive head trauma in infants and children".)

●Severe hypoxic events such as near-drowning − (See "Drowning (submersion injuries)", section on 'Neurologic'.)

●Sepsis or meningitis − (See "Clinical features, evaluation, and diagnosis of sepsis in term and late preterm neonates" and "Bacterial meningitis in the neonate: Neurologic complications".)

●Kernicterus − Infants with severe hyperbilirubinemia are at risk for kernicterus, permanent neurologic sequelae of bilirubin-induced neurotoxicity that manifests itself as a type of CP characterized by choreoathetosis, with gaze abnormalities and sensorineural hearing loss. The disorder results when unconjugated bilirubin enters the brain and causes focal necrosis of neurons and glia. The regions most often affected include the basal ganglia and the brainstem nuclei for oculomotor and auditory function, accounting for the clinical features of this condition. (See "Unconjugated hyperbilirubinemia in neonates: Risk factors, clinical manifestations, and neurologic complications", section on 'Chronic bilirubin encephalopathy (kernicterus)'.)

●Other causes of encephalopathy − (See "Etiology and pathogenesis of neonatal encephalopathy" and "Acute toxic-metabolic encephalopathy in children", section on 'Specific etiologies of encephalopathy'.)

PREVENTION

Antenatal measures — Antenatal measures to reduce the likelihood of CP include provision of routine prenatal care, including measures to reduce the likelihood of preterm birth. These issues are discussed separately. (See "Prenatal care: Initial assessment" and "Prenatal care: Second and third trimesters" and "Spontaneous preterm birth: Overview of risk factors and prognosis".)

Magnesium sulfate — There is evidence from clinical trials that antenatal administration of magnesium sulfate to females at risk for preterm birth decreases the incidence and severity of CP in their offspring without affecting mortality. This issue is discussed in greater detail separately. (See "Neuroprotective effects of in utero exposure to magnesium sulfate".)

Intrapartum measures — In vigorous preterm infants, delaying umbilical cord clamping for at least 30 seconds after birth may reduce the risk of intraventricular hemorrhage. This issue is discussed in greater detail separately. (See "Labor and delivery: Management of the normal third stage after vaginal birth", section on 'Early versus delayed cord clamping'.)

Postnatal measures

Supportive measures — Supportive, neuroprotective measures for neonates at risk of neurologic injury (ie, preterm very low birth weight [VLBW] infants and infants with neonatal asphyxia and/or encephalopathy) are aimed at reducing the likelihood of long-term neurodevelopmental sequelae and include (see "Clinical features, diagnosis, and treatment of neonatal encephalopathy", section on 'Supportive management'):

●Maintaining adequate ventilation (see "Overview of mechanical ventilation in neonates")

●Maintaining sufficient cerebral perfusion (see "Neonatal shock: Etiology, clinical manifestations, and evaluation")

●Maintaining normal metabolic status (see "Fluid and electrolyte therapy in newborns" and "Management and outcome of neonatal hypoglycemia" and "Neonatal hyperglycemia", section on 'Management')

●Controlling seizures (see "Treatment of neonatal seizures")

●Treating any underlying causes for encephalopathy (eg, infection or metabolic derangements) (see "Management and outcome of sepsis in term and late preterm neonates" and "Treatment and prevention of bacterial sepsis in preterm infants <34 weeks gestation" and "Metabolic emergencies in suspected inborn errors of metabolism: Presentation, evaluation, and management")

Therapeutic hypothermia — For infants with neonatal asphyxia and/or encephalopathy, therapeutic hypothermia improves survival and neurodevelopmental outcome at 18 months. (See "Clinical features, diagnosis, and treatment of neonatal encephalopathy", section on 'Therapeutic hypothermia'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Cerebral palsy".)

SUMMARY AND RECOMMENDATIONS

●Epidemiology – The prevalence of cerebral palsy (CP) is approximately 2 to 3.4 cases per 1000 children. The risk is markedly increased among preterm infants with low birth weight (BW). (See 'Epidemiology' above.)

●Etiology – The etiology of CP is multifactorial (table 1). In many cases, CP is thought to be due to prenatal factors. (See 'Specific causes and risk factors' above.)

•Prematurity and/or low BW are the most commonly identified prenatal risk factors for CP. CP develops in approximately 5 to 15 percent of surviving very low birth weight (VLBW) infants. In this population, CP is often associated with the periventricular leukomalacia (PVL), intraventricular hemorrhage (IVH), and/or bronchopulmonary dysplasia (BPD). (See 'Prematurity' above.)

•Perinatal hypoxia and/or ischemia likely accounts for a minority of cases of CP. Infants with CP caused by an acute intrapartum hypoxic-ischemic event are more likely to have spastic quadriparesis or dyskinetic CP than other CP subtypes. (See 'Perinatal hypoxic-ischemic injury' above.)

•Intrauterine infections and maternal trauma during pregnancy are risk factors for CP. Congenital infections associated with CP include bacterial infections, cytomegalovirus, syphilis, Zika virus, varicella virus, and toxoplasmosis. (See 'Antenatal infection or injury' above.)

•Genetic causes may account for up to one-third of all cases of CP. Numerous genetic disorders can present with findings of CP (table 4). (See 'Genetic susceptibility' above.)

•Multiple births are associated with an increased risk of CP due to associated risks of low BW, prematurity, congenital anomalies, cord entanglement, and abnormal vascular connections. (See 'Multiple births' above.)

•Stroke in the perinatal period may cause CP and is typically manifested as unilateral spasticity. (See 'Stroke' above and 'Intracranial hemorrhage' above and "Stroke in the newborn: Classification, manifestations, and diagnosis".)

•Insults to the developing brain acquired during infancy and early childhood may cause CP. These include stroke, traumatic or hypoxic injury, sepsis, kernicterus, and other sources of encephalopathy in children. (See 'Acquired postnatal causes' above.)

●Prevention – Preventive measures to reduce the likelihood of CP include (see 'Prevention' above):

•Antenatal measures – Provision of routine prenatal care, including measures to reduce the likelihood of preterm birth (see "Prenatal care: Initial assessment" and "Prenatal care: Second and third trimesters" and "Spontaneous preterm birth: Overview of risk factors and prognosis")

Antenatal administration of magnesium sulfate for females at risk for preterm delivery is discussed separately. (See "Neuroprotective effects of in utero exposure to magnesium sulfate".)

•Intrapartum measures – In vigorous preterm infants, delaying umbilical cord clamping for at least 30 seconds after birth may reduce the risk of IVH. This issue is discussed separately. (See "Labor and delivery: Management of the normal third stage after vaginal birth", section on 'Early versus delayed cord clamping'.)

•Postnatal measures – Supportive neuroprotective measures for neonates at risk of neurologic injury (ie, preterm VLBW infants and infants with neonatal asphyxia and/or encephalopathy) (see "Clinical features, diagnosis, and treatment of neonatal encephalopathy", section on 'Supportive management')

Therapeutic hypothermia for infants with neonatal asphyxia and/or encephalopathy (see "Clinical features, diagnosis, and treatment of neonatal encephalopathy", section on 'Therapeutic hypothermia')

ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges Geoffrey Miller, MD and Laurie Glader, MD, who contributed to earlier versions of this topic review.