Risk factors for cerebral palsy

While we don't know what exactly causes cerebral palsy, several risk factors have been identified. Bear in mind, however, that cerebral palsy is an incredibly heterogenous disorder, so any given case of cerebral palsy could have one, some or all of these risk factors, or maybe even some novel risk factors that we haven't identified yet.

Hypoxaemia

For a long time, it was thought that hypoxaemia at the time of birth was a major risk factor for cerebral palsy. However, further studies have found that hypoxaemia is implicated in only around 8-10% of cases.

Chorioamnionitis

Chorioamnionitis, as the name suggests, is inflammation of the amnion and chorion (fetal tissues). It is usually caused by an ascending bacterial infection. Chorioamnionitis is associated with prolonged labour and an increase in the risk of cerebral palsy.

Periventricular leukomalacia (PVL)

Periventricular leukomalacia (PVL) is a cerebral lesion characterised by foci of necrosis in the white matter near the lateral ventricles. The presence of brain lesions in the white matter, which can be detected by sonography and appear prior to the onset of PVL, is one of the most important identifiable risk factors for cerebral palsy. The risk of PVL, in turn, may be increased by factors such as prematurity, asphyxia, respiratory distress and infection. For example, PVL is more likely to be seen in neonates with documented sepsis, purulent amniotic fluid, chorioamnionitis or high concentrations of IL-6. There is evidence to suggest that PVL can be initiated before birth, so prevention of cerebral palsy may need to start in utero.

Funisitis

Funisitis, which may be caused by a fetal inflammatory response, is inflammation of the connective tissue of the umbilical cord. It is typically preceded by vasculitis of the umbilical artery and/or veins. Funisitis may be caused by chorioamnionitis and is also a risk factor for cerebral palsy.

Prematurity

Premature birth, along with PVL, is one of the leading risk factors for cerebral palsy. It is estimated that over 25% of preterm deliveries are associated with subclinical intrauterine infection: the fetal (rather than maternal) systemic inflammatory response may contribute to the early onset of labour and an increased risk of cerebral palsy. One proposed mechanism is that intrauterine infection increases levels of IL-6 and other cytokines, leading to PVL and preterm labour. TNF (tumour necrosis factor) may also contribute to PVL (and thus increase the risk of CP) in the following ways:

1. Induces fetal hypotension and brain ischaemia
2. Stimulates production of tissue factors that can contirbute to the coagulation necrosis of white matter
3. Induces the release of platelet-activating factor, which damages brain cells by acting as a "membrane detergent"
4. Directly toxic to oligodendrocytes, which make up the myelin sheath of CNS neurons

Summary of the inflammatory response

I'll wrap up this post with a summary of the proposed mechanism by which an inflammatory response may contribute to cerebral palsy. Firstly, when microorganisms gain access to the fetus, mononuclear cells produce cytokines such as IL-1 and TNF, increasing blood-brain barrier permeability. Increased BBB permeability allows microbial products (as well as cytokines) to enter the brain. Microbial products then stimulate fetal microglia (basically the CNS equivalent of macrophages) to produce IL-1 and TNF. These cytokines increase astrocyte proliferation, as well as further increase TNF levels, leading to oligodendrocyte damage.

It's important to note, however, that none of this is the be-all and end-all. Most cases of intrauterine infection do not result in cerebral palsy. Yup, unfortunately we still have a lot to learn.

References

Yoon, BH, Park, C-W, Chaiworapongsa, T 2003, 'Intrauterine infection and the development of cerebral palsy', BJOG: An International Journal of Obstetrics and Gynaecology, vol. 110, supplement 20, pp. 124-127