Karin B. Nelson and Taeun Chang
                        Current Opinion in Neurology 2008, 21:129-135

Introduction: The causes of cerebral palsy, and thus approaches to prevention, differ by gestational age group and by clinical subtype. In premature infants, the most common CP subtype is spastic diplegia (hypertonia and spasticity of the legs, hips and pelvis) with the underlying pathology being white matter damage associated with either a hypoxic-ischemic event, inflammatory conditions and exposure to cytokines, or a combination of both. In term infants, quadriplegic CP (spasticity in all four limbs) with dyskinesia, is most often associated with acute asphyxia during the process of birth. Other potential causes of dyskinetic CP include hyperbilirubinemia.

Etiological Factors and their Preventability
1. Birth Asphyxia
Electric Fetal Monitoring – Controlled studies in defined populations over two decades confirm that severe birth asphyxia is not a common cause of CP. However, in the past, many thought it to be the primary cause of CP, and electric fetal monitoring was introduced in the 1970’s in the belief and that it could alert caregivers of impending asphyxia and thus prevent neurologic injury. Subsequent randomized clinical trials showed that use of the EFM did not result in a decline in the occurrence of CP.
Therapeutic Hypothermia – A recent meta-analysis of 8 randomized controlled clinical trials have demonstrated a significant reduction in infant mortality and major neurodevelopmental disability after administration of therapeutic hypothermia to term infants with moderate encephalopathy as a result of birth asphyxia. It appears that therapeutic hypothermia can be neuroprotective if administered early enough after injury and maintained long enough with a gradual rewarming.

2. Prematurity
Prematurity is a major risk factor for CP. The rate of preterm birth in the US is now 12.7% and rising. Causes of preterm birth include infection, congenital maldevelopment and genetic factors. Strategies to prevent premature birth have not been consistently successful in decreasing the frequency of preterm birth.
Nitric Oxide – A systematic review of 11 randomized trials of nitric oxide administration to premature infants concluded that inhaled nitric oxide may decrease serious brain injury in mildly, but not in severely ill preterm infants. In term infants, nitric oxide was not associated with less disability later on.
Magnesium Sulfate – Animal data and an observational clinical study suggested that administration of magnesium sulfate to women in preterm labor may provide neuroprotection for the infant and a lower rate of motor handicap. However, in a review of four additional clinical trials, a diagnosis of CP was only marginally significantly reduced.

3. Intrauterine exposure to infection/inflammation
To date there is no-evidence based approach to prevention of CP or other adverse long-term neurological outcomes due to infection/inflammation of the placenta other than that related to meningitis or encephalitis.

4. Perinatal Stroke
Perinatal ischemic stroke has in recent years been recognized to be a common cause of CP, especially in term infants. About half of infants with stroke have thrombophilias. However, perinatal stroke rarely repeats in siblings thus indicating that environmental factors are important. It is likely that it is a combination of thrombophillic risk factors and environmental factors that determines whether a perinatal stroke will occur. Identification of factors leading to thrombosis in fetal or neonatal stroke is still a work in progress. No study has yet tried to establish selective criteria for women to receive anti-coagulation therapy in pregnancy for women to purpose of avoiding stroke in the infant and none has examined whether stroke is more or less frequent in infants following anti-coagulation of the mother for maternal or pregnancy complications.

5. Multiple Gestation
Twins and higher order multiple births have a higher rate of CP, accounted for in part by the commonly associated prematurity, but also by death of a co-twin. Advanced maternal age and assistive reproductive technologies are associated with a higher rate of multiple births and prematurity which may account for much or all of the increased risk of CP in babies born of assistive reproductive techniques.

6. Genes
The occurrence of CP has been observed to run in families with high consanguinity and a Swedish national database indicates familial risk for CP. Inherited thrombophilias occur in greater numbers of children with perinatal stroke than in the general population, very preterm infants with CP, and in CP overall. A genetic variant of an imflammatory cytokine is associated with CP risk as is an apoliprotein E genotype.
There are genetic components of a number of risk factors for CP, including preterm birth, abruption of placenta, chorioamnionitis and preeclampsia. Research into the interaction of genetic susceptibilities with environmental factors has only recently started and may provide a fruitful avenue for prevention.

The Future of Research into CP Prevention

Advancements in information technology, such as electronic medical records, will help to create large and representative databases of newborns of all gestational ages that will allow for studies of uncommon maternal and pregnancy conditions resulting in a diagnosis of CP to further elucidate risk factors. Also improvements in and greater access to neuroimaging technology for infants and children along with improvements in remote digital technology will enable multicenter trials of treatment and preventive measures. Development of consensus on methodology and interpretation of placental pathology, and incorporation of placental investigation into studies in obstetrics and neonatology are likely to add important information.