Description of the condition
Fetal brain injury: causes and consequences
The developing fetal brain is extremely vulnerable, and thus a compromised intrauterine environment increases the risk of brain injury (and/or abnormal brain development) for both the preterm (before 37 weeks' gestation) and term fetus (Rees 2011). Fetal brain injury is a major contributor to perinatal mortality and morbidity worldwide (Jensen 2003), with such injury being associated with a spectrum of life-long functional and behavioural disorders.
While a number of causes of fetal brain injury have been recognised (such as intrauterine infection, placental insufficiency, and chronic fetal hypoxia leading to metabolic derangement), episodes of cerebral hypoxia-ischaemia (reduced oxygen in the blood combined with reduced blood flow to the brain) appear to be important in a great number of cases (whether being acute, chronic, associated with inflammation, or as an antecedent of preterm birth) (du Plessis 2002; Rees 2011; Volpe 2001). Following cerebral hypoxia and ischaemia, it is believed that a sequence of pathophysiological events ultimately leading to cell death (via necrosis or apoptosis) are triggered, involving for example, the overstimulation of N-methyl-D-aspartate type glutamate receptors, the accumulation of calcium in cells, and the activation of deleterious events mediated by calcium (including the stimulation of enzymes such as nitric oxide synthase, and the production of oxygen free radicals) (Jensen 2003; Johnston 2000; Rees 2011). Studies of the developing fetal brain have shown that the nature and severity of insult, and gestational age at the time of injury, can greatly influence the subsequent neuropathology. An important common feature of the fetal brain in all such situations, however, is the depletion of cellular energy. While it has been shown that neuronal cell injury predominates in term infants, and cerebral white matter injury predominates in premature infants (Volpe 2001), recent evidence has suggested that the same white matter injury in preterm infants can be sustained and is important in term infants also; and recent studies have additionally highlighted the importance of grey matter injury as a component of preterm brain damage (Rees 2011).
Injury to both the preterm and term developing brain is known to be associated with life-long and devastating sequelae, such as hearing, sight and speech disorders, seizures, intellectual disabilities, and motor impairments that may manifest as cerebral palsy (Vexler 2001). Cerebral palsy is an umbrella term, describing "a group of disorders of the development of movement and posture, causing activity limitations, which are attributed to non progressive disturbances that occurred in the developing fetal or infant brain” (Bax 2005). Cerebral palsy is a complex neurological condition, and is often found alongside cognitive, communication, sight and hearing impairments, or epilepsy, pain, behaviour and sleep disorders (Novak 2012). It is the most common physical disability in childhood, and the most severe physical disability within the spectrum of developmental delay. While for a small number of individuals, a brain injury after birth may lead to the development of cerebral palsy, for the vast majority (94%), the injury leading to cerebral palsy occurs to the fetus in utero, or before one month of age (ACPR Group 2009).
A great number of potential predisposing factors and causal pathways for cerebral palsy and associated impairments and disabilities have been identified. While preterm birth has been recognised as one of the most important risk factors for cerebral palsy (Blair 2006; Jacobsson 2002; McIntyre 2013) (with preterm infants being at an increased risk of white matter injury such as periventricular leukomalacia, and of intraventricular haemorrhage (Larroque 2003)), approximately 60% of all children with cerebral palsy are born at term (ACPR Group 2009; McIntyre 2013; Wu 2003). For infants born at term, antenatal or intrapartum risk factors for cerebral palsy consistently identified in the literature have included small-for-gestational age, low birthweight, and placental abnormalities (Blair 2006; McIntyre 2013). Maternal bleeding in the second and third trimesters (McIntyre 2013), hypertension in pregnancy (McIntyre 2013), pre-eclampsia (Blair 2006; McIntyre 2013), perinatal infection (such as chorioamnionitis) (Blair 2006; McIntyre 2013; Wu 2003), and increasing plurality (Blair 2006), have been shown to increase the risk of cerebral palsy and associated neurosensory disorders across all gestational ages. For term infants, intrapartum birth asphyxia (a condition resulting from deprivation of oxygen to a newborn, lasting long enough to cause physical harm) has also been shown to be an important predictor of brain injury and later disability (Dilenge 2001; McIntyre 2013).
To date, there is minimal knowledge regarding effective strategies to prevent, reduce or remove the risk of antenatally-acquired fetal brain injury, and accordingly, to prevent the potentially devastating life-long consequences associated with such brain injury for the infant, child and adult. Magnesium sulphate, when given to the mother immediately prior to very preterm birth, is one of the first antenatal interventions shown to be effective in reducing the risk of death and cerebral palsy for the infant (Doyle 2009). Following major advances in understanding the mechanisms of fetal brain injury and in identifying predisposing factors for such brain injury, further promise has been raised for the development of primary preventative strategies, based on preventing the complex sequence of pathophysiological and biochemical events that induce irreversible injury.
Description of the intervention
Creatine is a simple guanidine compound, which may be synthesised endogenously from the amino acids arginine, glycine, and methionine, in the liver, kidney and pancreas (Adcock 2002). Creatine may also be ingested, through the consumption of dairy, fish and meat, and is found throughout the human body, including in the brain (Rees 2011). Creatine is taken up into tissues via the creatine transporter and stored as creatine or phosphocreatine. Phosphocreatine is readily converted to creatine via creatine kinase in a reversible reaction which yields a high energy phosphate allowing the conversion of adenosine diphosphate (ADP) to adenosine triphosphate (ATP) (Wallimann 1992).
A number of studies have demonstrated that creatine has neuroprotective and antioxidant properties, suggesting benefits for neurodegenerative diseases, including amyotrophic lateral sclerosis and Parkinson's disease, traumatic brain disease, and adult stroke; conditions encompassing hypoxia and excitotoxic-mediated brain injury (Sullivan 2000; Zhu 2004). A Cochrane review that included three trials assessing creatine for improving amyotrophic lateral sclerosis survival, or for slowing progression, found no clear evidence to support meaningful improvements. Importantly, however, creatine was found to be well-tolerated, with no serious adverse effects observed (Pastula 2010). A new Cochrane review will assess the efficacy and safety of creatine when used alone, or as an adjunctive treatment, for Parkinson's disease (Wang 2012).
How the intervention might work
Creatine for fetal neuroprotection
There is currently increasing support for the use of creatine as a therapy for protecting tissues against injury; particularly, there is growing evidence of creatine's potential to act as a neuroprotective agent (Wallimann 2011). One of the primary mechanisms of injury arising from severe hypoxia at birth (particularly for the brain) involves mitochondrial dysfunction, leading to impaired energy metabolism and oxidative stress (Calvert 2005; Wyss 2002). It has been suggested that preservation of ATP through increase of the intracellular pool of creatine and phosphocreatine can protect the brain from such injuries (Beal 2011; Wallimann 1992). In addition to its role as an 'energy buffer' (providing energy in the absence of oxygen), creatine appears to have antioxidant properties, scavenging free radicals (Lawler 2002; Sestili 2006). Creatine has also been shown to improve the recovery of cerebral blood flow following the cessation of a hypoxic episode (Prass 2006).
Hypoxic-ischaemic models of neonatal brain damage in rodents have provided support for the neuroprotective effects of creatine. Subcutaneous injections of creatine given to neonatal rodents prior to transient severe hypoxia-ischaemia have been shown to reduce brain oedema (Adcock 2002). Recently, the supplementation of the maternal diet with creatine, from mid-pregnancy until term, has been shown to not only increase the concentration of creatine and phosphocreatine in rodent fetal tissues, but also to improve survival and postnatal growth of the offspring after an acute hypoxic episode at birth (Ireland 2008). Maternal creatine supplementation during pregnancy has been shown to prevent lipid peroxidation and apoptosis in the brains of rodent offspring following intrapartum hypoxia (Ireland 2011). It has been proposed that creatine's ability to protect mitochondrial function may account for this observed neuroprotective effect (Ireland 2011).
In addition to offering neuroprotection, maternal creatine supplementation has been shown to protect the newborn diaphragm from intrapartum hypoxia-induced damage (Cannata 2010). Rodent offspring born to mothers who received creatine supplementation from mid-pregnancy, have been shown to be less likely to incur diaphragmatic damage (including muscular atrophy and contractile dysfunction) following hypoxia, as compared with control offspring (Cannata 2010). Most recently, maternal creatine supplementation has been shown to protect the newborn kidney from intrapartum hypoxia-induced damage. Specifically, creatine given to the mother throughout the second half of pregnancy, has been shown to be able to prevent structural damage to the glomeruli and tubules of the kidney of the newborn spiny mouse (Ellery 2013).
Importantly, with any intervention during pregnancy, the impact for the mother must be considered, along with the impact on the normal development of the fetus. Walker, Dickinson and colleagues have recently assessed the impact of maternal creatine supplementation from mid-gestation on the capacity for creatine synthesis and transport in the newborn spiny mouse; encouragingly, long-term supplementation was not shown to impact on the normal development of these pathways (Dickinson 2013). Similarly, to date, no effects of maternal creatine supplementation on maternal body composition have been observed when creatine-fed pregnant spiny mice have been compared with control-fed spiny mice (unpublished observations). While there has been some concern over possible deleterious effects on long-term, high-dose creatine supplementation on kidney function, recent work, measuring chromium-ethylenediamine tetraacetic acid (51-Cr-EDTA) clearance, has indicated no negative impact of creatine supplementation on kidney function in human type 2 diabetic patients (Gualano 2011). Studies measuring urine creatinine (as compared with 51-Cr-EDTA), as a marker of kidney function, should be interpreted with caution, given that creatinine is a breakdown product of creatine phosphate in muscle; thus the presence of high urine creatinine would be expected during periods of high creatine consumption, and is not necessarily indicative of kidney damage (Gualano 2011).
In light of the current evidence, it is considered plausible, therefore, that creatine could protect the human fetal brain against injury associated with hypoxia-ischaemia, excitotoxicity or oxidative stress, without causing harm to the fetus or the mother. It is important to assess whether maternally administered creatine (at time of known, suspected, or potential fetal compromise) may offer fetal neuroprotection and may accordingly reduce the risk of cerebral palsy and associated impairments and disabilities arising from fetal brain injury.
Why it is important to do this review
Creatine has been shown to have neuroprotective properties (such as providing cellular energy in the absence of oxygen (Beal 2011; Wallimann 1992), demonstrating antioxidant effects (Lawler 2002; Sestili 2006), and improving cerebral blood flow following hypoxia (Prass 2006)). Animal studies have supported a fetal neuroprotective role for creatine when administered maternally (Ireland 2008; Ireland 2011). It is important to assess whether creatine, when given to pregnant women, can reduce the risk of neurological impairments and disabilities (including cerebral palsy) associated with fetal brain injury, and death, for the preterm or term fetus.
This review will complement the Cochrane review 'Melatonin for women in pregnancy for neuroprotection of the fetus' (Wilkinson 2013), that is assessing melatonin as a novel agent for preterm and/or term fetal neuroprotection.