The small molecule that is making a big difference.

As molecules go, magnesium sulphate (MgSO4) had a pretty glamorous start. The story goes that early in the 17th century in the district of Epsom in England, a local farmer found that his cattle were refusing to drink from his well. The farmer tried the water himself, noted that it was bitter and found that the springs all around the Epsom region shared this bitter taste. However, Epsom spring waters were thought to possess healing powers and the town became a spa town. Chemist Nehemiah Grew found that boiling down the spa water yielded a salty residue he named ‘Epsom salt’, for which he obtained a Royal patent. In 1755, Sir Humphrey Davey isolated and identified Epsom salt as magnesium sulphate, naming the element magnesium after the region of Magnesia in Thessaly, Greece.

We now know magnesium is one of the most abundant substances in the body, participating in literally hundreds of metabolic processes, from glucose metabolism to DNA synthesis. Our intake is from green leafy vegetables, wholegrains and nuts, and magnesium is excreted renally. Magnesium homeostasis is closely linked to that of potassium and calcium. During pregnancy, measureable levels of magnesium may vary markedly. The physiological haemodilution of pregnancy and changes in the volume of the extracellular space can reduce magnesium concentrations in serum and this can be further altered with nausea and vomiting in pregnancy, resulting in gastrointestinal losses.

Use of magnesium sulphate in obstetrics

A century ago, eclamptic seizures were relatively common in countries such as the USA. Few therapeutic options were then available for treatment of convulsions and the use of intraspinal magnesium sulphate had already been popularised in the treatment of status epilepticus. Taking a lead from this, obstetricians in the USA adopted the use of intravenous magnesium sulphate to treat eclamptic seizures and noted its effectiveness and dramatic falls in the mortality of the condition. During that era, magnesium sulphate was often used as part of a cocktail of medications deployed to manage eclampsia and it was not until after the Second World War that research was done to establish the fact that it was good for managing eclampsia, but not so good for management of hypertension.

The oral absorption of magnesium sulphate is notoriously unpredictable, so parenteral routes – either intravenous or intramuscular – are the only reliable methods of administration. Standard solutions contain 50 per cent magnesium sulphate as a heptahydrate in sterile water, with five grams of magnesium in 10ml of the solution. The absorption is rapid, with peak serum levels achieved within one hour of intramuscular injection, and almost immediately following intravenous use. Owing to its pharmacology, it must be used with extreme caution in patients with heart block and myasthenia gravis.

Incredibly, after a century of use in obstetrics, the exact mechanism of action of magnesium sulphate remains unclear. Magnesium is a calcium antagonist at the motor endplate of nerves in many types of muscle, including cardiac muscle. Calcium is thus integral to smooth muscle contraction and calcium inhibition results in muscle relaxation, including that of the myometrium. Increased magnesium levels appear to disrupt the balance between calcium and magnesium ions, altering muscle action. As well as its peripheral effects, magnesium sulphate blocks N-methyl-D-aspartic acid (NDMA) receptors in the central nervous system and this appears not only to reduce involuntary muscle action, but also to reduce nerve excitability and possibly seizure activity. It also has an effect on catecholamines, causing arterial vasodilation and thus reducing blood pressure.

Safety of magnesium sulphate

Magnesium sulphate is, in general, a safe medication to use, and it is rare to induce any serious adverse consequences administering a bolus dose to control an acute eclamptic seizure. Pre-eclampsia is a state of vasoconstriction and the powerful vasodilatory effect of magnesium sulphate is likely to be one of the main mechanisms of its effect in eclampsia. However, with continued use, magnesium sulphate has the potential to cause a neuromuscular blockade and resulting respiratory depression. Fortunately, simple assessments of respiratory rate and the patellar reflexes provide a sensitive guide to the degree of neuromuscular blockade and predict impending overdose and toxicity.

Noting the well-recognised effects of magnesium sulphate on smooth muscle activity, early researchers conducted experiments using strips of myometrial muscle excised at caesarean sections, immersing them in solutions with varying concentrations of magnesium sulphate. As might be predicted, the higher the concentration of magnesium in the solution the greater the effect to inhibit myometrial muscle contraction. These results, coupled with clinical observations, led many clinicians in the USA to use prolonged courses of high-dose magnesium sulphate as a tocolytic in women with threatened preterm labour. What was not readily appreciated was that the cumulative doses required to provide tocolysis, doses that were much higher than required for seizure management, were associated with a greater incidence of adverse side effects and subsequent trials demonstrated that other methods of tocolysis were safer.

Magnesium sulphate for neuroprotection

The widespread use of magnesium sulphate and the number of large studies in which it was used, meant that a great deal of data were available about neonatal outcome after its antenatal use. A number of researchers noted that, although it was not usually a primary outcome in studies, there seemed to be fewer children delivered preterm who were subsequently diagnosed with cerebral palsy when magnesium sulphate had been administered in the peripartum period.

There was a reasonable body of evidence to underpin this, providing a possible mechanism of action. The competition between magnesium and calcium inhibits NMDA receptors, and it was known that activation of NDMA receptors with resulting calcium influx into neurons seemed to cause irreversible neuronal injury. Treatment of adult patients with magnesium sulphate was already known to reduce cerebral excitability and increase cerebral blood flow. Magnesium sulphate also seemed to have an anti-inflammatory action, presumably owing to blockage of reactive oxygen species and other pro-inflammatory cytokines.

Since magnesium sulphate is a small and simple molecule, it crosses the placenta essentially unhindered, meaning the fetal serum concentration of magnesium will closely approximate the maternal concentration. This led researches to question whether fetal exposure to magnesium sulphate might induce similar protective effects on the vulnerable developing brain.

Nelson and Grether published the results of a case-control study, comparing children of low birthweight who developed cerebral palsy, compared to similarly small babies who did not. They found that the mothers of the children without cerebral palsy were much more likely to have been treated with magnesium sulphate during pregnancy, a finding that supported the hypothesis that transplacental magnesium sulphate did indeed have a neuroprotective effect.

Despite some worrying results from the relatively small Magnesium and Neurological Endpoints Trial (MagNET) study, the much larger Australian-coordinated Australasian Collaborative Trial of Magnesium Sulphate (ACTOMgSO4) randomised over 1000 women who were likely to deliver within the next day, where the pregnancy was not beyond 30 completed weeks. All of the adverse neonatal and childhood outcomes occurred less frequently in the magnesium sulphate treatment arm, though they did not reach statistical significance. Importantly, the distribution of other adverse outcomes was similar in the two groups. When the results of the Australian and other similar prospective trials were assessed in systematic reviews, it became clear that antenatal use of magnesium sulphate shortly before birth in very preterm babies reduces the risk of cerebral palsy.

Summary

What an amazing story this is, from a farmer who couldn’t get his cattle to drink bitter water contaminated with Epsom salts, to the realisation that those same salts – magnesium sulphate – can cross the placenta and protect the developing brain. To make things even more interesting, despite the use of this remarkable little molecule in obstetrics for many decades, the exact mechanisms by which it exerts its amazing effects remains still remain to be learned. Who says the days of wonder have gone?

Further reading

Hunter L, Gibbins K. Magnesium sulfate: past, present, and future. J Midwifery Women Health 2011; 56: 566-74.
Fawcett W, Haxby E, Male D. Magnesium: physiology and pharmacology. Br J Anaesth 1999; 83: 302-20.
James M. Magnesium in obstetrics. Best Prac Res Clin Obstet Gynaecol 2010; 24: 327-37.
Makrides M, Crowther C. Magnesium supplementation in pregnancy.
Cochrane Database Syst Rev 2010; 4: CD000937.
Idama T, Lindow S. Magnesium sulphate: a review of clinical pharmacology applied to obstetrics. BJOG 1998; 105: 260-68. Simhan H, Caritis S. Prevention of preterm delivery. N Engl J Med 2007; 357: 477-87.
The Magpie Trial Collaboration Group. Do women with preeclampsia and their babies benefit from magnesium sulfate? The Magpie trial: a randomized placebo control trial. Lancet 2002; 359: 1877-1890. Sibai B. Diagnosis, prevention, and management of eclampsia. Obstet Gynecol 2005; 105: 402-10.
Grimes D, Nanda K. Magnesium sulfate tocolysis: time to quit. Obstet Gynecol 2006; 108: 986-9.
Conde-Agudelo A, Romero R. Antenatal magnesium sulfate for the prevention of cerebral palsy in preterm infants less than 34 weeks’ gestation: a systematic review and meta-analysis. Am J Obstet Gynecol 2009; 200: 595-609.
Stanley F, Crowther C. Antenatal magnesium sulfate for neuroprotection before preterm birth? N Engl J Med 2008; 359: 962-3.
Nelson K, Grether J. Can magnesium sulfate reduce the risk of cerebral palsy in very low birth weight infants? Pediatrics 1995; 95: 263-9.
Crowther C, Hiller J, Doyle L, Haslam R. Australasian Collaborative Trial of Magnesium Sulphate (ACTOMgSO4). Effect of magnesium sulfate given for neuroprotection before preterm birth: a randomized controlled trial. JAMA 2003; 290: 2669-76.
Marret S, Marceau L, Zupan-Simunek V, et al. Magnesium sulphate given before very-preterm birth to protect infant brain: the randomized controlled PREMAG trial. BJOG 2007; 114: 310-18.
Rouse D, Hirtz D, Thom E, et al. A randomized controlled trial of magnesium sulfate for the prevention of cerebral palsy. N Engl J Med 2008; 359: 895- 905.
Doyle L, Crowther A, Middleton P, Marret S, Rouse D. Magnesium sulphate for women at risk of preterm birth for neuroprotection of the fetus. Cochrane Database Syst Rev 2009; (1): CD004661.