Babies born preterm have a higher chance of dying in the first few weeks of life than those born at term [1
]. Babies who survive have a greater risk of neurologic impairments, such as cerebral palsy, blindness, deafness, or cognitive dysfunction, and a greater risk of substantial disability as a result of these neurologic impairments [2
]. The social and economic long-term costs are considerable [5
Cerebral palsy is a term which includes a number of different diseases or conditions that can arise at any time during brain development. It involves a disorder of movement or posture, or both, and a disorder of motor function that is permanent but may change over time [6
]. The cerebral palsies remain the most frequent cause of severe motor disability in childhood with a background prevalence of two per thousand live births [6
]. Most affected children (92%) survive to 20 years or later, yielding a substantial burden of illness into adulthood [7
Very preterm birth (less than 34 weeks) is the principal risk factor for cerebral palsy [8
], responsible for 17% to 32% of all cases of cerebral palsy. The latest Australian Cerebral Palsy Register Report (2009) shows that approximately 45% of all cases of cerebral palsy are associated with preterm birth [10
]. Whilst the highest risks are for extremely preterm infants [3
], babies born between 30 and 33 completed weeks’ gestation still have significant risks [11
] with the risk of cerebral palsy being up to eight times more likely than babies born at term [4
]. Moderate prematurity is responsible for as many cases of cerebral palsy as extreme prematurity [10
At present there is no cure for cerebral palsy, which makes effective preventative interventions of paramount importance. Prevention of cerebral palsy has been identified by consumers, clinicians and researchers as a top priority for research by the Australian Cerebral Palsy Institute [12
]. To reduce the impact of cerebral palsy from preterm birth, efforts must be focused on primary prevention.
Observational studies on the effect of antenatal magnesium sulphate on neurodevelopment
A landmark case–control study 15 years ago described the association of exposure to antenatal magnesium sulphate with a dramatic reduction in the risk of cerebral palsy (odds ratio (OR) 0.14; 95% confidence interval (CI) 0.05 to 0.51) [13
]. Other observational studies support a reduction in cerebral palsy in preterm babies after antenatal magnesium sulphate [14
] and some a reduction in the risk of intraventricular hemorrhage (IVH) [16
] and perinatal mortality [18
]. However, not all studies report benefit for antenatal magnesium sulphate on the risk of IVH [19
], cerebral palsy [20
] or perinatal mortality [19
Biological plausibility for use of magnesium sulphate for fetal and infant neuroprotection
In humans, magnesium is essential for key cellular processes, including glycolysis, oxidative phosphorylation, protein synthesis, DNA and RNA aggregation and maintenance of plasma membrane integrity [24
]. Magnesium favourably affects mechanisms implicated in cell death by decreasing proinflammatory cytokines or free radicals produced during hypoxic-ischaemic reperfusion and inflammatory diseases of pregnancy [26
]. Magnesium prevents excitotoxic calcium-induced injury [28
], by a non-competitive voltage-dependent inhibition of the N-methyl-D-aspartate receptor to glutamate reducing calcium entry into the cell [29
]. The fetal and neonatal brain seems more susceptible to glutamate damage. Consequently, blocking glutamate receptors through agents such as magnesium sulphate may reduce the risk of injury in the perinatal period. Magnesium has some beneficial haemodynamic effects including stabilising blood pressure during the first two days of life in preterm neonates [30
], and may increase cerebral blood flow by reducing constriction of the cerebral arteries [31
]. Transplacental transfer of magnesium is rapid with magnesium concentrations increased in fetal serum within one hour of maternal intravenous administration [32
Maternal and neonatal adverse effects and side effects of magnesium sulphate
The best available evidence about potential maternal harms from antenatal magnesium sulphate administration comes from the four Cochrane reviews that compare magnesium sulphate with placebo or no treatment [33
]. Magnesium sulphate, by its peripheral vasodilator effects when infused intravenously, produces a sensation of warmth and flushing. Reported maternal side-effects, related to dosage and speed of infusion, include nausea, vomiting, headache and palpitations. Hypotension and respiratory depression are more severe recognised risks. Magnesium sulphate acts as a neuromuscular blocking agent that causes abolition of tendon reflexes [37
]. Magnesium could aggravate the cardiovascular or neuromuscular side-effects of other drugs such as betamimetics, calcium-channel blockers and gentamicin [38
]. Infusion to concentrations above the recommended therapeutic range can have life threatening consequences for the women that include respiratory arrest and cardiac arrest leading to death [40
]. For the neonate, hypermagnesaemia can lead to hyporeflexia, poor sucking, and, rarely, respiratory depression needing assisted ventilation [41
How antenatal magnesium sulphate can reduce the burden of being born preterm
Systematic review of randomized trials of magnesium sulphate for neonatal neuroprotection
The updated Cochrane systematic review to assess the use of antenatal magnesium sulphate for women at risk of preterm birth [33
] included four trials (4446 babies) where magnesium sulphate had been given specifically for neuroprotection of the fetus; two from the US; the MagNet Trial [43
] and the BEAM Trial [44
], one from Australia and New Zealand; the ACTOMgSO4
], one from France; the PreMag Trial [46
]. There was diversity in the inclusion and exclusion criteria for the four included trials with wide variation in gestational age, reasons women were at risk of preterm birth and time of treatment prior to expected preterm birth [33
]. All trials used intravenous magnesium sulphate although the dose used, whether a maintenance infusion was given and whether treatment could be repeated varied between trials.
Results of the meta-analysis of the Cochrane systematic review
The combined outcome of death or cerebral palsy or cerebral palsy alone showed significant reductions where women who were at risk of preterm birth were given magnesium sulphate antenatally with the intent of providing neuroprotection (Table ). The review showed that 63 babies (95% CI 44 to 155) need to be treated with magnesium sulphate for one baby to avoid cerebral palsy. The corresponding number needed to treat to benefit (NNTB) for combined death or cerebral palsy was 42 babies, 95% CI 24 to 346.
Table 1 Magnesium sulphate vs placebo/no treatment: primary outcomes
Is there clinical evidence for the role of antenatal magnesium sulphate for neuroprotection of the fetus, infant and child prior to preterm birth at 30 to 34 weeks gestation?
The Australian and New Zealand Bi-national Clinical Practice Guidelines on the use of antenatal magnesium sulphate prior to preterm birth for neuroprotection of the fetus, infant and child summarise the evidence available from the four individual neuroprotective intent trials within the Doyle 2009 Cochrane Review [33
] that consider gestational age at trial entry and effect of antenatal magnesium sulphate [47
]. All women in the four included trials were given magnesium sulphate before 34 weeks’ gestation. In Rouse 2008, all women were less than 32 weeks at trial entry with the majority (68% of trial participants) less than 30 weeks gestation [44
]. Subgroup analyses for women at different gestational ages were possible for women with a gestational age of less than 34 weeks, less than 33 weeks, less than 32 weeks and less than 30 weeks. However there was only one trial within each subgroup available for analysis and the results are inconclusive due to small sample sizes (Table ).
Table 2 Results of primary outcomes by gestational age subgroup
Summary of CPG evidence statement judgements for gestational age subgroup
The subgroup analyses are from trials with low risk of bias, with results between trials fairly consistent. While the evidence is applicable to the Australian and New Zealand context, generalisability was reduced as the majority of the women (87%) in the largest trial [44
] had PPROM and so represent a limited subset of women at risk of preterm birth. Overall clinical impact was judged to be very large (Table ) but any differences in death and cerebral palsy by gestational age are unclear at present. To minimise the number of women exposed, the Australian and New Zealand clinic practice guideline panel felt it would be prudent to restrict magnesium sulphate administration to the subgroup containing the lowest gestational age (less than 30 weeks).
Recommendations made by the Australian and New Zealand Bi-National CPG panel for use of antenatal magnesium sulphate
The main clinical recommendation is to use magnesium sulphate for neuroprotection of the fetus, infant and child “in women at risk of early preterm (gestational age is less than 30 weeks), imminent birth (when early preterm birth is planned or definitely expected within 24 hours)” [47
In recognition of the need for further research, the guideline panel specifically recommended that further randomised trials were needed, comparing antenatal magnesium sulphate with placebo when given to women at risk of preterm birth at 30 weeks’ gestation or more, that assess mortality, cerebral palsy and combined death and cerebral palsy [47
Preventative strategies that may reduce the risk of cerebral palsy need appropriate evaluation prior to introduction into clinical practice. Given the magnitude of the protective effect in the systematic review, the ongoing uncertainty about benefits at later gestational ages, the serious health and cost consequences of this condition for the child, family and society a trial of magnesium sulphate for women at risk of preterm birth between 30 to 34 weeks’ gestation is both justifiable and needed.
Aims and objectives of this trial
The aim of this randomised controlled trial is to assess whether giving magnesium sulphate compared with placebo to women immediately prior to preterm birth between 30 and 34 weeks’ gestation reduces the risk of death or cerebral palsy in their children at two years’ corrected age.
The primary hypothesis is that antenatal magnesium sulphate compared with placebo given to women at risk of preterm birth between 30 and 34 weeks’ gestation when birth is imminent (defined as planned or definitely expected in the next 24 hours) reduces the risk of death or cerebral palsy in their children at two years’ corrected age.
The secondary hypotheses are that antenatal magnesium sulphate compared with placebo given to women at risk of preterm birth between 30 and 34 weeks’ gestation when birth is imminent (defined as planned or definitely expected in the next 24 hours) above has benefits relating to the infant/child: including individual components of the primary outcome (mortality and cerebral palsy), and neonatal and childhood morbidity (including IVH and the other neurosensory disabilities at two years’ corrected age of blindness, deafness or developmental delay). At the same time, it is hypothesized that the intervention does not harm the mother: no clinically important effect on mode of birth or maternal morbidity as measured by risk of serious adverse cardiovascular effects of the infusion, side effects of the infusion and postpartum haemorrhage.