Magnesium for neuroprophylaxis: fact or fiction?

doi:10.1016/j.ajog.2009.04.003

American Journal of Obstetrics and Gynecology

Volume 200, Issue 6, June 2009, Pages 590-594

https://doi.org/10.1016/j.ajog.2009.04.003 Get rights and content

The use of magnesium for prevention of cerebral palsy in preterm infants has been a pressing clinical question for some time. This issue was recently brought to the forefront again after the completion of a large trial conducted by the Maternal-Fetal Medicine Units Network and published by Rouse et al in August, 2008 in the New England Journal of Medicine. After review of the complex body of literature on this topic, and the recent addition of this important piece of evidence, we discussed the “pros” and “cons” of the evidence-based use of magnesium for prevention of cerebral palsy at the annual meeting for the Society of Maternal-Fetal Medicine as a luncheon roundtable.

The evidence currently available does not make the clinical decision of whether or not to use magnesium for the prevention of cerebral palsy as clear as we would hope. It appears that despite well-designed and executed studies on this critically important topic in obstetrics, the answer to the question of whether evidence-based medicine supports the use of magnesium for neuroprophylaxis in preterm infants remains unclear.

Section snippets

MagNET

The first study to be completed and published, the Magnesium and Neurologic Endpoints Trial (MagNET), was performed by Mittendorf et al.⁸ It was conducted at 16 centers in Chicago, IL, from 1995 to 1997. The study population included women who were either experiencing preterm labor or preterm premature rupture of membranes (PPROM); each was carrying a singleton or twins at less than 34 weeks' gestation. There were 2 protocols: 1 examined MgSO₄ use for tocolysis, and the other examined its use

ACTOMgSO4

Data from the Australasian Collaborative Trial of Magnesium Sulphate (ACTOMgSO4) Collaborative Group were published in 2003.⁹ The population, recruited from 16 centers in Australia or New Zealand, consisted specifically of women who were likely to deliver within 24 hours (eg, they had advanced cervical dilation, severe preeclampsia, or intrauterine growth retardation [IUGR] with worrisome Doppler findings). Participants were randomized to infusions of MgSO₄ or normal saline; MgSO₄ was

MAGPIE

A secondary analysis of the MAGnesium Sulphate for the Prevention of Eclampsia (MAGPIE) trial is the next relevant study.¹⁰ The original MAGPIE study demonstrated that the risk of seizures (eclampsia) among preeclamptic women was 58% lower among those randomized to MgSO₄.¹¹ Conducted at 175 hospitals in 33 countries from 1998 to 2001, it included women with preeclampsia, only 24% of whom were at less than 33 weeks' gestation. The protocol involved randomization to a 4 g bolus of MgSO₄ followed

PREMAG

In 2008, Marret et al¹² published a letter to the editor of the journal Pediatrics, describing follow-up data from an RCT of MgSO₄ vs placebo. Their original study was conducted at 13 centers in France from 1997 to 2003.¹³ Like Crowther et al⁹ did in the ACTOMgSO4, the PREMAG Trial Collaborative Group randomized women who were believed likely to deliver within 24 hours. Subjects received a 4 g bolus of MgSO₄ followed by continuous infusion of 1 g/h or normal saline. A total of 564 women were

BEAM

Finally, in 2008 Rouse et al¹⁴ published results from the Beneficial Effects of Antenatal Magnesium Sulfate Trial (BEAM) in the New England Journal of Medicine. This large, multicenter trial was conducted by the Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network at 20 centers from 1997 to 2004. It included women at less than 32 weeks' gestation, and 87% of the participants had PPROM. Women were randomized to a 6 g bolus of MgSO₄

Pro

Once the BEAM results are added to the existing data, particularly those pertaining to the question of MgSO₄'s potential benefit in neuroprophylaxis, it appears that we should consider using MgSO₄ to prevent neurologic complications of pregnancy in the neonate.

Con

Whereas numerous strengths can be cited in the BEAM study, the results could also be interpreted as negative.¹⁴ It can be instinctive to conclude that the reason investigators choose a composite as the primary outcome of a study

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Association between the use of antenatal magnesium sulfate in preterm labor and adverse health outcomes in infants
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Metaanalysis vs large clinical trials: which should guide our management?
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Causes of cerebral palsy
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Incidence and prediction of periventricular-intraventricular hemorrhage in very preterm infants
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Maternal toxemia and neonatal germinal matrix hemorrhage in intubated infants less than 1751 g
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Cited by (28)

Magnesium sulfate and risk of postpartum uterine atony and hemorrhage: A meta-analysis
2021, European Journal of Obstetrics and Gynecology and Reproductive Biology
Citation Excerpt :
The exact mechanism of its action in obstetrics is still not well known but according to our understanding of intracellular physiology it is proposed to act by changing the balance between calcium and Mg and thus their antagonist interaction with other molecules [3,5]. Magnesium sulfate has been also widely used a neuroprotective agent during the last years as it has been proposed that the inhibition of NMDA receptors in the brain prevents the possible cell damage from their activation by hypoxic stress [6,7]. Besides this, MgSO4 also decreases Acetylholine (Ach) in the neuromuscular junction, interferes with actin-myosin, blocks NMDA receptors and depresses selected catecholamines.
Magnesium sulfate (MgSO₄) is among the most commonly used medications in labor and delivery units. It has been used as a mean to protect against eclampsia and a neuroprotective agent for fetuses at risk of preterm birth. In the present study we investigated its impact in the occurrence of postpartum uterine atony and hemorrhage.
We searched the Medline, Scopus, EMBASE, Cochrane Central Register of Controlled Trials CENTRAL, Clinicaltrials.gov and Google Scholar databases for randomized trials and observational studies. Statistical analysis was performed with the Hartung-Knapp-Sidik-Jonkman model in RStudio using the meta package.
Twelve studies fitted the predetermined criteria and these involved 41,190 women of whom 10,565 (25.6 %) received MgSO_4. The meta-analysis revealed that the risk of postpartum uterine atony was similar among patients that received MgSO₄ and those that did not (OR 1.93, 95 % CI 0.78, 4.81). Estimated blood loss (SMD 0.04, 95 % CI -0.10, 0.18) as well as the risk of postpartum hemorrhage (OR 1.82, 95 % CI 0.99, 3.35) also did not differ. Subgroup analysis revealed that evidence drawn from observational studies indicates a significant effect of MgSO₄ on the odds of postpartum uterine atony and hemorrhage; however, randomized trials do not support this.
The results of our meta-analysis suggest that it is reasonable to consider MgSO4 in women at risk of delivering before the completion of its elimination half-life. However, physicians should be vigilant in cases at risk of postpartum hemorrhage as current data are very heterogeneous and should not be considered as definitive.
PREVENTING NEURONAL DAMAGE IN EXTREMELY PRETERM
2016, Revista Medica Clinica Las Condes
La prevención del parto prematuro es uno de los desafíos de la obstetricia en el siglo XXI. Los prematuros tienen riesgo de morbimortalidad perinatal, sobre todos los nacidos antes de las 30 semanas, tienen mayor riesgo de lesiones neurológicas generalmente secundarias a isquemia o infección intrauterina ascendente. Existen estrategias para prevenir el daño neurológico fetal en el trabajo de parto prematuro. La administración de sulfato de magnesio endovenoso reduce en forma significativa la probabilidad de desarrollar parálisis cerebral y disfunciones motoras. También se ha mostrado la utilidad del pinzamiento tardío del cordón umbilical y la administración antenatal y postnatal de N-acetilcisteína. En estudios animales se ha observado un potencial efecto neuroprotector de stem cells mesenquimáticas, estradiol y progesterona, melatonina y creatina.
The prevention of preterm birth represents one of the most significant challenges to the field of obstetrics in the 21^st century. Preterm infants have risk of perinatal mortality and morbidity. Preterm infants born before the 30^th week of pregnancy are especially at risk of perinatal brain damage which is usually a result of cerebral ischemia or an ascending intrauterine infection. The prophylaxis against fetal neuronal injury during threatened preterm labor. It has been shown that administering magnesium intravenously leads to a significant reduction in the likelihood of the infant developing cerebral palsy and motor skill dysfunction. It has also been demonstrated utility that delayed clamping of the umbilical cord after birth and administration antenatal and postnatal N-acetylcysteine. In addition, mesenchymal stem cells, estradiol and progesterone, melatonin and creatine seem to have significant neuroprotective potential in animal experiments.
The Changing Role of Magnesium in Obstetric Practice
2013, Anesthesiology Clinics
Citation Excerpt :
Over many years, anecdotal evidence has shown a relationship between maternal magnesium sulfate therapy in obstetrics and decreased neurologic morbidity in preterm infants.1 As a result, several multicenter trials have been conducted to better evaluate this relationship.2 Cerebral palsy is a group of chronic, debilitating neurologic disorders and the most common motor disability present in childhood.
Magnesium sulfate therapy for the prevention of cerebral palsy in preterm infants: A decision-analytic and economic analysis
2011, American Journal of Obstetrics and Gynecology
Citation Excerpt :
Additionally, in multivariable iterative analyses, the magnesium strategy compared with none was chosen 100% of the time for the subgroups of women with PPROM and those at risk for delivery <28 weeks; for all women at risk for preterm delivery, it was only the preferred strategy 86.7% of the time, reflective of both the poor correlation between the diagnosis of PTL and subsequent preterm birth as well as the published data regarding magnesium for neuroprophylaxis. Since the body of evidence regarding magnesium for neuroprophylaxis is challenging to interpret, as many authors have illustrated,43-46 and the extrapolation into clinical practice complex, several investigators have used the technique of metaanalysis to formally pool the results from the primary trials and better estimate the effect of magnesium on risk for CP and neonatal death.8,47 However, one criticism that has been made with regard to interpretation of these metaanalyses is that the patient populations studied in each of the 4 trials varied significantly.
We sought to estimate the cost-effectiveness of magnesium neuroprophylaxis for all women at risk for preterm birth <32 weeks.
A decision analytic and cost-effectiveness model was designed to compare use of magnesium for neuroprophylaxis vs no treatment for women at risk for preterm birth <32 weeks due to preterm premature rupture of membranes or preterm labor from 24-32 weeks. Outcomes included neonatal death and moderate-severe cerebral palsy. Effectiveness was reported in quality-adjusted life years.
Magnesium for neuroprophylaxis led to lower costs ($1739 vs $1917) and better outcomes (56.684 vs 56.678 quality-adjusted life years). However, sensitivity analysis revealed the model to be sensitive to estimates of effect of magnesium on risk of moderate or severe cerebral palsy as well as neonatal death.
Based on currently published evidence for efficacy, magnesium for neuroprophylaxis in women at risk to deliver preterm is cost-effective.
Antenatal Exposure to Magnesium Sulfate and Neuroprotection in Preterm Infants
2011, Obstetrics and Gynecology Clinics of North America
Citation Excerpt :
Only the meta-analysis of neuroprotective trials demonstrates a reduction in the composite outcome with MgSO4. This finding has reignited the debate on the appropriate use of meta-analytical studies of well-designed and powered individual RCTs.54 Other questions that are not answered in these studies involve the concomitant use of tocolytics with MgSO4 given in the setting of neuroprotection.
MgSO<inf>4</inf> neuroprophylaxis: going from evidence to recommendation
2010, American Journal of Obstetrics and Gynecology

View all citing articles on Scopus

: Reprints not available from the authors.

: This study was supported in part by the Robert Wood Johnson Foundation (to A.B.C. as a Physician Faculty Scholar).

: This article summarizes a debate that was conducted during a luncheon roundtable at the 29th Annual Meeting of the Society for Maternal-Fetal Medicine, San Diego, CA, Jan. 30, 2009. The information and opinions presented herein reflect solely the views of the debaters and not the Society for Maternal-Fetal Medicine.

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ReviewObstetricsMagnesium for neuroprophylaxis: fact or fiction?

Section snippets

MagNET

ACTOMgSO4

MAGPIE

PREMAG

BEAM

Pro

Con

Obstet Gynecol

Am J Obstet Gynecol

Am J Obstet Gynecol

Causes of cerebral palsy

Curr Opin Pediatr

Incidence and prediction of periventricular-intraventricular hemorrhage in very preterm infants

J Perinat Med

Maternal toxemia and neonatal germinal matrix hemorrhage in intubated infants less than 1751 g

Obstet Gynecol

Maternal toxemia is associated with reduced incidence of germinal matrix hemorrhage in premature babies

J Child Neurol

Can magnesium sulfate reduce the risk of cerebral palsy in very low birthweight infants?

Pediatrics

Review
Obstetrics
Magnesium for neuroprophylaxis: fact or fiction?