Description of the condition
Fetal brain injury: risk factors and consequences
Injury to the fetal brain is a major contributor to morbidity and mortality in infants and children born preterm (at less than 37 weeks' gestation) and at term (at 37 weeks' gestation and later) (Vexler 2001; Volpe 2000). The pathogenesis of brain injury is known to be complex and multifactorial, with a number of interrelated pathways contributing to central nervous system cellular dysfunction and death, including the accumulation of reactive oxygen species, the release of excitatory amino acids, energy depletion and apoptosis (Inder 2000; Vexler 2001). While there are known to be multiple causes of such brain injury, including hypoxia-ischaemia (characterised by a reduction of oxygen in the blood combined with reduced blood flow to the brain), haemorrhage, infection and metabolic derangement, hypoxia-ischaemia is believed to be an important cause of brain injury in a large number of cases (Volpe 2000). Brain hypoxia (deficiency of oxygen) and ischaemia (insufficient blood supply) may lead to different neuropathology in infants born prematurely and at term, with neuronal cell injury predominating in term infants, and cerebral white matter injury predominating in premature infants (Volpe 2000). Injury to the developing brain is known to be associated with a number of long-term sequelae for the infant and child, including hearing, sight and speech disorders, seizures, intellectual disabilities, and motor impairments, such as cerebral palsy (Vexler 2001).
Cerebral palsy is a broad term, encompassing non-progressive (but not unchanging) permanent physical disorders of movement or posture acquired in early life, resulting from complications in brain development (interferences, lesions or abnormalities) (ACPR Group 2009; Blair 2006). Cerebral palsy is the most frequent cause of childhood motor disability, affecting approximately two per 1000 live births in high-income countries (ACPR Group 2009). It is estimated that in approximately 94% of cases (13 in 14), the brain injury leading to cerebral palsy occurs to the fetus in utero, or before one month of age (ACPR Group 2009). Other neurologic impairments and neurosensory disabilities frequently associated with cerebral palsy include hearing, sight and speech disorders, intellectual disability and epilepsy.
Preterm birth is one of the principal risk factors for cerebral palsy and associated neurologic impairments and neurosensory disabilities (Blair 2006; Drummond 2002; Himpens 2008). The degree of prematurity is associated with vulnerability of cerebral white matter, and is predictive of an increasing risk of white matter injury such as periventricular leukomalacia, and of intraventricular haemorrhage (Larroque 2003) - established risk factors for the development of cerebral palsy and associated neurosensory disabilities (Saliba 2001). Although preterm birth is acknowledged as a major risk factor for cerebral palsy (ACPR Group 2009), accounting for approximately 40% of all cases, most children with cerebral palsy are in fact born at term (ACPR Group 2009; Wu 2003).
Along with very preterm birth, low birthweight is an independent, important risk factor for cerebral palsy and associated neurosensory disabilities, particularly in infants born at term or moderately preterm (Blair 1990). A number of studies have revealed high risks of neurosensory impairments and disabilities (including cerebral palsy, blindness, deafness and intellectual impairment) for very low birthweight (less than 1500 g) and extremely low birthweight (less than 1000 g) infants, when compared to normal birthweight controls (Doyle 2001). Intrauterine growth restriction and being small-for-gestational age at birth have additionally been shown to be important risk factors for neurologic injury and long-term sequale for both preterm and term fetuses (Jacobsson 2008; Leitner 2000; Low 1992; O’Keeffe 2003). For term infants, perinatal asphyxia (a condition resulting from deprivation of oxygen to a newborn infant, lasting long enough to cause physical harm) has been shown to be an important cause of brain injury and later neurodevelopmental disabilities (Dilenge 2001; Greenwood 2005).
Though conflicting evidence exists, further suggested risk factors for neurologic injury and associated longer-term consequences (including cerebral palsy) include increasing plurality (with pregnancies of higher plurality being more likely to be of shorter gestation and associated with slower uterine growth) (Blair 2006), infection such as chorioamnionitis (Blair 2006; Greenwood 2005; Wu 2003), and pre-eclampsia (Blair 2006; Greenwood 2005).
While a great number of potential risk factors for neurosensory disabilities have been identified, their commonality is that separately, or in combination, they may lead to fetal brain injury. The aim of primary preventative strategies, therefore, is to target early stages in the multifactorial, interrelated pathways before brain injury becomes irreversible.
Description of the intervention
Melatonin (N-acetyl-5-methoxytryptamin) is a small lipid-soluble molecule that is primarily synthesised and secreted by the pineal gland at night, under normal environmental conditions (Claustrat 2005); it has recently been recognised as a "ubiquitously distributed and functionally diverse molecule" (Reiter 2010). The key physiological functions of melatonin include mediating seasonality and circadian rhythm (Claustrat 2005). The endogenous rhythm of melatonin secretion is related to the light-dark cycle, however, the regulating system of secretion is complex, following both central and autonomic pathways (Claustrat 2005). There are thus many pathophysiological situations where melatonin secretion can be disturbed, and alterations of regulation can increase predisposition to disease, and modify the courses and outcomes of disorders (Claustrat 2005; Reiter 2010).
A feature that characterises melatonin is the variety of mechanisms that it employs to modulate the physiology and molecular biology of cells (Reiter 2010). In addition to mediating action through well-characterised G-protein coupled melatonin receptors in cellular membranes, melatonin is able to detoxify oxygen free radicals and related oxygen derivatives, and thus can also influence cellular physiology via receptor-indepedent means (Reiter 2010). The complexities of such processes have made it at times difficult to determine how melatonin functions to exert particular actions (Reiter 2010). Despite this, melatonin has been regarded as a molecule with "virtual absence of toxicity" (Reiter 2010), with great potential for application in human medicine, due to its ability to contribute to improved cellular physiology.
Clinically, melatonin has been shown to be effective in preventing and reducing jet lag (Herxheimer 2002), and some benefits have been seen when it is given for dementia, with a reduction in dementia-related psychopathologic behaviour disturbances observed (Jansen 2006). Melatonin has also been used to treat non-respiratory related sleep disorders in children, though benefits for this indication are currently undetermined (Khan 2011; Khan 2011b). Melatonin has been shown to reduce oxidative stress in human newborns with septicaemia, and lead to improved clinical outcomes (Gitto 2001). It has, in addition, been shown to reduce products associated with oxidative stress and damage in the blood of asphyxiated human newborns (Fulia 2001).
How the intervention might work
Melatonin for fetal neuroprotection
While the pathogenesis of white matter brain injury (such as periventricular leukomalacia), associated with perinatal mortality and long-term neurosensory disabilities, is complex and multifactorial, free radical-induced oxidative damage and infection or inflammatory-induced damage appear to be important. Free radical-induced damage also appears to be important in neonatal haemorrhagic brain injury (such as intraventricular haemorrhage) (Lekic 2011), which may subsequently lead to neurosensory disabilities, including cerebral palsy.
In adult animals, melatonin has been shown to be neuroprotective in models of focal cerebral ischaemia (stroke) (Macleod 2005), and in neonatal mice, melatonin has been shown to attenuate the development of white matter cysts following acute excitotoxic brain injury (Husson 2002). More recently, the neuroprotective effects of melatonin in the fetal brain have been assessed. Following intrauterine asphyxia (via umbilical cord occlusion), melatonin administration to both preterm and near-term fetal sheep has been shown to reduce oxidative stress (Miller 2005) and attenuate cell death (including apoptosis) in the fetal brain, in association with a reduced inflammatory response (Welin 2007). Systemic administration of melatonin following acute neonatal haemorrhagic brain injury in rats, has additionally been shown to protect against post-haemorrhagic consequences of brain atrophy, splenomegaly and cardiac hypertrophy (Lekic 2011). Importantly, melatonin has been shown to improve functional outcomes following such brain injury - ameliorating cognitive and sensorimotor dysfunction in the juvenile rat (Lekic 2011).
In addition to the direct fetal and neonatal administration of melatonin being associated with neuroprotective effects, the maternal administration of melatonin has been shown to lead to benefits for the offspring. The prophylactic administration of melatonin to pregnant rats immediately prior to an acute ischaemic episode (Watanabe 2004) and regularly throughout pregnancy (Watanabe 2011), has been shown to reduce ischaemia-reperfusion-induced oxidative damage in the premature fetal rat brain (Watanabe 2004; Watanabe 2011). Maternal administration of melatonin one hour after an ischaemic episode has also been shown to prevent against ischaemia-reperfusion-induced oxidative brain damage and degeneration in neonatal rats (Hamada 2010). At three to 12 hours post reperfusion however, melatonin has failed to protect against oxidative brain injury in neonatal rats (Hamada 2010), suggesting that there may be a critical window of time to administer melatonin, after which the molecule no longer has therapeutic benefit.
In view of the evidence from such studies, it is plausible that melatonin, an antioxidant agent with apparent anti-inflammatory and anti-apoptotic effects (Cheung 2003), may protect the human fetal brain against free radical-induced brain damage occurring during times of increased oxidative stress in pregnancy (such as in pregnancies complicated by pre-eclampsia, intrauterine growth restriction, infection, and preterm delivery) when administered fetally or maternally.
Why it is important to do this review
Melatonin is an antioxidant agent with anti-inflammatory and anti-apoptotic effects. Animal studies have supported a fetal neuroprotective role for melatonin when administered maternally. It is important to assess whether melatonin, when given to the mother, may reduce the risk of neurosensory disabilities (including cerebral palsy) and death, for the preterm or term compromised fetus.