November 2007 Fact Sheet
Sex and the Pathogenesis of Cerebral Palsy*

Basic research into the causes of cerebral palsy has revealed that gender may influence the pathogenesis of developmental brain injury.  Sex differences in the immature brain appear to be strongly influenced by intrinsic differences between male and female cells due to their distinct chromosomal complements. These cellular differences could be associated with the different patterns of brain injury observed in males and females and might be important for designing future trials of neuroprotective agents.

Males have a higher incidence than females of several brain-based developmental disabilities including mental retardation, autism, attention deficit hyperactivity disorder and cerebral palsy.  A recent analysis of a European database of 4500 children with cerebral palsy found that the incidence of CP was 30% higher in males than females. This same study showed that the risk of cerebral palsy for male babies is 16 times higher than females for those with birth weights are below the 3rd percentile and 4 times higher for those with birth weights over the 97th percentile. In another recent study of the incidence of neurological and developmental disability after extremely preterm birth, males had significantly increased incidence of severe disability, cerebral palsy, and low scores of cognitive function at 6 years of age compared with females. Further evidence of greater biological vulnerability in the male infant versus the female infant includes a higher incidence of preterm birth, mortality due to prematurity, stillbirth and intraventricular hemorrhage (neo-natal stroke). 

Studies have reported gender-based brain structure differences in children born very prematurely.  Premature males have significantly less white matter than age/sex-matched controls while there is no difference in white matter volume between premature females and age/sex-matched controls. In contrast, premature females who had an intraventricular hemorrhage (IVH) had less grey matter than controls while males with IVH did not. This suggests that the adverse effects of preterm birth and IVH on the developing brain are strongly influenced by their interaction with sex-specific differences in normal brain development.

Evidence is accumulating to suggest the cellular pathways leading to neuronal death after an infant brain injury are different in males and females and that this is influenced by the sex chromosomes, not sex hormones as it may be later in life. Thus, an intervention found to be efficacious in preventing neuronal damage after an insult in infant males may not confer the same protection in infant females.  For example, a recent study showed that the clinically approved glutamate antagonist dextromethorphan is protective against ischemia in male but not female infant rats, while another study showed that erythropoietin is more effective in female than in male pups subjected to hypoxia-ischemia. Thus, it is prudent when designing future pre-clinical and clinical trials of neuroprotective agents that study subjects be stratified by sex so as not to mask a potential beneficial effect. 

* Johnston, MV and Hagberg, H. Sex and the pathogenesis of cerebral palsy. Dev. Med. & Child Neurol. 2007, 49:74-78