Antenatal Exposure to Magnesium Sulfate and Neuroprotection in Preterm Infants

Author: Learning in 10

Good morning, ladies and gentlemen. We're from class of 2015. We're here to present our review paper on antenatal exposure to magnesium sulfate and neuroprotection protection in pre-term infants written them by Costantine and Trevor, published in your Obstetric and Gynecology Clinic of North America in 2011. In this article, neuroprotection on magnesium sulfate is studied using cerebral palsy as the neurological disease model. The disease of the article [INAUDIBLE] also our discussion today has the following objective. First of all, let's just recap what is cerebral palsy. It is the most common cause of motor disabilities in childhood. It is a heterogeneous group of non-progressive clinical syndromes characterized by motor and postural dysfunction.

This picture nicely showed the different subtypes of cerebral palsy-- spastic, dyskinetic, and ataxic, as well as their respective subtypes. As you can also see from the brain illustration on top, the involvement of different area of the brain will have different manifestations just like stroke. But unlike stroke, these are permanent and therefore, it is a devastating condition for the children to have. The current understanding of etiology of cerebral palsy shows it is a result of neuronal insult to the developing brain secondary to inflammatory, hypoxic, excitatory, or oxidative injury in the prenatal or perinatal period. The two biggest perinatal prenatal risk factors are pre-term delivery and low birth weight. The former is associated with 60 times higher risk and later is also associated with 70 times higher risk. Other less significant risk factors also include infection, inflammation, multiple gestation thrombophilia, obstetric hemorrhage, preeclampsia.

A Swedish population based neural imaging study in children with cerebral palsy showed that cerebral malformations originate no later than 20 to 24 weeks gestation. Periventricular atrophy occurs between 24 and 34 weeks gestation and cortical subcortial atrophy goes after 34 weeks. It is possible that silent early third trimester PVL lesions and late third trimester cortical lesions may play a major role in cerebral palsy. In this article, it was mentioned that a population based prevalence study using data from three regions United States showed prevalence of CP in 3.6 per 1000 children.

However, in another study that involved a larger geographical , area 6,000 children with CP from 13 populations in Europe born from 1980 to 1990 is 2.8 per 1000 live births. In summary from other population studies done in the literature, the prevalence in developed versus developing countries is as shown and the incidence amount preterm versus term infants is as shown in the second table. Because the exact cause of CP is not known, various animal models have been used to study the therapeutic effect CP. This includes inflamitory, hypoxic-ischemic and excitatory models the objective of using this animal model is to find out more about the pathogenesis of CP and how magnesium sulfate intervenes in this process to cause a therapeutic effect.

Antenatal Exposure to Magnesium Sulfate and Neuroprotection in Preterm Infants

From various studies, the therapeutic effect of magnesium sulfate was postulated to be in these four areas-- namely, maintaining hemodnamic stability, prevention of excitatory injuries, and enhancing neuronal stabilization and having antioxidant and anti-inflammatory properties. Five prospective randomized controlled trials have examined and reported the long term neurological outcomes of infant exposed antenatally to magnesium sulfate. This study is different in many aspects, including patient characteristics, magnesium protocol, and others. The MagNET trial stands for the Magnesium and Neurological End Point Trial, which was conducted from 1995 to 1997 in the United States in order to investigate adverse pediatric health outcomes in women of preterm labor with administration of magnesium sulfate [INAUDIBLE] on neuroprotective agent. All the recruited women were either a single or twin pregnancy between 24 to 33 three weeks of gestation going into preterm labor. Exclusion criteria includes [INAUDIBLE] fetal heart tracings, preeclampsia, and infection. Magnesium sulfate was given for either your protection or tocolysis based on the maternal cervical dilation [INAUDIBLE] as an entry into the study. Patients with cervical dilation with less than four CM were randomized in the treatment of tocolysis arm to either magnesium sulfate or underlying tocolytic.

Those women with cervical dilation greater than fourCM were controlled-- enrolled in the neuroprotectant arm to either four gram magnesium sulfate bolus or placebo. The primary outcome was to composit of adverse pediatric health outcome, which included neonatal or infant mortality, periventrical [INAUDIBLE] intraventrical hemmorhage, or cerebral palsy. There was no statistically significant differences between both arms.

Despite being statistically not significant, this finding lead to premature termination of the study because of safety concerns of increased pediatric mortality and adverse outcomes. The ACTO magnesium sulfate trial stands for the Australian Collaborative Trial On Magnesium Sulfate which is conducted from 1996 to 2000 in Australia and New Zealand. The primary investigative purpose was to determine the effect of magnesium sulfate on the total pediatric mortality, CP, and a combined outcome of death, or CP.

Patients of less than 30 weeks gestation with expected delivery in less than 24 hours were included. This study excluded patients if they were in the second stage of labor, previously received magnesium sulfate in the current pregnancy, or had other contraindications. A total of 1,062 women were randomized into either magnesium sulfate arm or the placebo arm.

The result showed no difference in the composite neonatal outcome of death or CP or CP alone and total pediatric mortality. However, the secondary outcome of substantial gross motor dysfunction and the combined outcome of death or substantial gross motor dysfunction were decreased in infants exposed in-utero to mangesium sulfate as compared to a placebo. So the Magpie trial stands for the magnesium sulfate for the prevention of eclampsia.

Trial was conducted in 1998 to 2001 in around 125 countries in order to evaluate the effectiveness of magnesium sulfate as an anti-convulsant for pre-eclamptic patients. The Magpie trial result showed that magnesium sulfate halves the risk of pre-eclampsia and reduces the risk of maternal death and there do not appear to be substantial harmful effect to mother or baby in the short term until discharge. In the full op trial on the outcome of children born to pre-eclamptic mothers from the Magpie trial, and assessment of long term effect of in-utero exposure to magnesium sulfate at 18 months of age while compare with placebo was done and the mean outcome measures were either death on neurosensory disabilities at age of 18 months. It was found that there was no substantial differences in death rate or in the risk of neurological impairment between the magnesium sulfate and placebo group. So in conclusion, the lower risk of eclampsia followed prophylaxis with magnesium sulfate was not associated with a clear difference in the risk of death or disability for children at 18 months. The PREMAG trial was conducted in France in 1997 to 2003. Woman with singleton or multiple gestation at less than three weeks gestation with anticipated delivery in 24 hours were included. Women were randomized to IV magnesium sulfate 4 gram insusion bolus of saline as placebo.

The primary outcome was severe white matter injury, infant death before hospital discharge, or the combined outcome. A two year full lab of this infant would [INAUDIBLE] evaluate the long term outcome, including CP, pediatric mortality, and combined outcome. There was no difference in the primary outcome between those exposed to magnesium sulfate or placebo respectively. At the two year follow up of 606 infants, perinatal mortality and death or CP were also similar between those exposed to magnesium sulfate or placebo, respectively. The beneficial effects of anti-natal magnesium sulfate trial was conducted at 20 centers in the United States from 1997 to 2004. The study randomized women at imminent risk of delivery between 24 and 31 weeks gestation. The study allowed retreatment if the patient did not deliver after 12 hours.

A total of 2241 women were randomized and teh neonates were followed up and assessed at two years of age. The primary outcome was a composite of moderate to severe CP or death. There was no difference in the primary outcomes between those exposed to magnesium sulfate versus placebo. There was also no difference in the risk of perinatal mortalities. However, moderate or severe CP was significantly less likely to occur among children exposed to magnesium sulfate compared with placebo as well as overall cerebral palsy. After the publication of the BIM trial, several systematic reviews and meta-analyses were published. This review showed similarly that magnesium reduces the rate of CP by approximately 30% and moderate to severe CP by 40% to 45% without increasing the rate of death in 6,145 infants.

After pooling all studies designed for neuroprotection, it was shown that antenatal exposure to magnesium sulfate was associated with reduction in the following- combined outcome of CP or dath, outcome of death alone, and outcome of moderate to severe CP. Four major limitations were identified in this paper. They was the heterogeneity of participants, regimens, and outcomes as well as the concomitant used to tocolysis. The studies are clinically heterogeneous in patient selection and characteristics. All patients in the Magpie trial were enrolled with a diagnosis of pre-eclampsia. All patients of the neck trial is preterm labor.

87% of patients in the BIM trial had PPROM and 63% of those in ACTOM magnesium sulfate had preterm labor. Different maternal diseases and intraenvironmental leading to preterm delivery examples such as premature rupture of membrane, intrauterine infection, and inflamation have been shown to modify the risk of cerebral palsy. It is possible that the impact of magnesium sulfate neuroprotection may be different according to the indications for pre-term birth. The magnesium regimen used and the actual dosage received varied between different studies and between patients within individual studies as shown here.

Moreover, although most of the studies included women with anticipated delivery within 24 hours, not all patients delivered within that time frame, which raises the issue of the timing of magnesium sulfate infusion for fetal neuroprotection. Plus, the appropriate dosage and theraputic window for neuroprotection is not knowing. The use of a composite outcome of death or cerebral palsy in these studies may be due to logistic reasons such as sample size and feasibility issues. However, death and cerebral palsy are competing outcomes. If the infant dies, he or she cannot be evaluated for diagnosis of CP. The results from all the RCTs were negative for a primary outcome. Only the meta-analysis of neuroprotective trials demonstrate a reduction in the composite outcome with magnesium sulfate. Another important question in the [INAUDIBLE] use of tocolytic with magnesium sulfate given the setting of neuroprotection-- the BIM trial included patients who were not candidates for tocalysis, PPROM, advanced cervical dilation, or indicated delivery.

The combination of both may have serious adverse effect. Magnesium sulfate has been used extensively either as a tocalytic or for pre-eclampsia prevention and treatment. Now, based on the following reasons, magnesium sulfate should be considered for use as a neuroprotectant in the setting up anticipated preterm birth after discussing the risks and benefits with a patient and obtaining her approval.

Based on the available data from meta-analysis, 46 to 56 patients would need to be exposed to magnesium sulfate in Europe before 30 or 32 weeks of gestation respectively to prevent one case of cerebral palsy. The number needed to treat to prevent one case of CP appeared justifiable and comparable or better with those for eclampsia prevention. The relative safety of magnesium sulfate for the mother, the lack of evidence of risk regarding infant mortality, and the familiarity of most obstetricians with its use. Cerebral palsy is permanent, can result in severe sequellae infant, and can significantly affect the family and society as a whole. Significant questions remain unanswered, in particular the ideal candidate and the dosage and timing of magnesium sulfate. Until then, it's just preferable to follow a specific protocol that should be decided upon at the institution level.

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