Magnesium is a critical physiological ion, and magnesium deficiency might contribute to the development of pre-eclampsia, to impaired neonatal development and to metabolic problems extending into adult life. Pharmacologically, magnesium is a calcium antagonist with substantial vasodilator properties but without myocardial depression. Cardiac output usually increases following magnesium administration, compensating for the vasodilatation and minimising hypotension. Neurologically, the inhibition of calcium channels and antagonism of the N -methyl- d -aspartic acid (NMDA) receptor raises the possibility of neuronal protection, and magnesium administration to women with premature labour may decrease the incidence of cerebral palsy. It is the first-line anticonvulsant for the management of pre-eclampsia and eclampsia, and it should be administered to all patients with severe pre-eclampsia or eclampsia. Magnesium is a moderate tocolytic but the evidence for its effectiveness remains disputed. The side effects of magnesium therapy are generally mild but the major hazard of magnesium therapy is neuromuscular weakness.
Magnesium is the fourth most-prevalent cation in the body and is found predominantly in bone but also substantially in muscle and neuronal tissue; less than 1% of the total body magnesium is found in the plasma and red blood cells. Plasma magnesium (Mg 2+ ) is 62% ionised while the remainder is either bound to albumin or complexed with ions such as citrate and phosphate. A variety of units are used in the international literature to describe magnesium concentrations and these are summarised in Table 1 . The recommended dietary allowance (RDA) for magnesium is 350 mg per day for a male adult and 280 mg per day for a female. The magnesium requirement is increased during pregnancy and lactation (360–400 mg daily). Human milk containing about 30–40 mg l −1 is believed to provide adequate magnesium for the growing infant. The main dietary sources of magnesium are green vegetables, cereals, meat and drinking water.
| mg dL −1 | mEq L −1 | mmol L −1 | |
|---|---|---|---|
| Normal range | 1.8–2.4 | 1.5–2.0 | 0.75–1.0 |
| Therapeutic range | 4.8–8.4 | 4–7 | 2–3.5 |
| Neuromuscular toxic level | >12 | >10 | >5 |
Biochemistry and metabolism
Magnesium is vital for many biochemical processes, activating over 300 enzyme systems including those involved in carbohydrate metabolism, protein synthesis, oxidative phosphorylation and the synthesis of ATP, DNA and RNA. Magnesium is the physiologic calcium antagonist.
Magnesium regulation depends on renal excretion. The excretion capacity of the kidney ranges widely depending on the plasma Mg 2+ concentration. Excess plasma calcium (Ca 2+ ) or Mg 2+ activates a calcium receptor in the kidney that induces a diuresis increasing elimination of both ions. Hence, infused magnesium tends to induce its own clearance, an important safety factor provided that renal function is normal.
Magnesium deficiency
Magnesium deficiency has many consequences, including chronic fatigue states and delirium, muscle weakness and tetany, disordered glucose metabolism, numerous myocardial arrhythmias, vascular disorders and electrolyte disturbances, particularly of potassium. The generally accepted normal range for total serum Mg 2+ is 0.75–1.0 mmol l–1. However, since magnesium is primarily an intracellular ion, whole body magnesium depletion may exist in the presence of normal or even elevated plasma Mg 2+ concentrations. Most Western diets are magnesium deficient.
Magnesium levels have been shown to decline during pregnancy, reaching their lowest point at the end of the first trimester, due partly to dilution and expansion of the extracellular space and partly to absolute magnesium deficiency. Magnesium deficiency may contribute towards placental insufficiency, and thus to the development of pre-eclampsia, as it contributes towards uterine artery spasm and foetal growth retardation and has an essential regulatory role in prostaglandin synthesis. It has also been suggested that magnesium supplementation during pregnancy can reduce maternal morbidity and improve foetal outcome, but this study was too small and non-specific to indicate any effect on the development of pre-eclampsia. Magnesium deficiency has also been associated with pre-term labour and an increased incidence of leg cramps during pregnancy.
Magnesium deficiency during pregnancy may result in permanent harm to the unborn child, with animal evidence of growth retardation, an increased incidence of abnormal fat metabolism, insulin resistance and diabetes. It has also been reported that magnesium deficiency during pregnancy may be associated with the sudden infant death syndrome.
The possible role of magnesium deficiency in the genesis of pre-eclampsia has been the subject of considerable debate. Studies in ewes with pregnancy-induced hypertension demonstrated higher arterial pressure and lower foetal weights in sheep fed on a magnesium-deficient diet. In a human study of 568 women given magnesium aspartate or placebo from 16 weeks’ gestation or earlier, the magnesium group had fewer hospital admissions, less frequent pre-term labour and fewer neonatal intensive care unit (ICU) admissions. Kisters et al. studied the plasma and intracellular magnesium concentrations in pre-eclamptic and normal pregnant women. Plasma Mg 2+ concentrations were not significantly different, but showed a greater scatter in the pre-eclamptic women. Both groups showed lower red cell magnesium concentrations than normal non-pregnant values, and the pre-eclamptic group had a significantly lower red cell concentration than the normal pregnant women. They suggested that this decrease in intracellular magnesium might contribute to the vascular lesions of pre-eclampsia. Standley and colleagues studied Mg 2+ and Ca 2+ concentrations in 31 normal pregnant patients of whom nine eventually developed pre-eclampsia. All subjects showed a decrease in ionised Mg 2+ concentration with increasing gestational age. However, total Mg 2+ concentrations were lower and ionised Ca 2+ /Mg 2+ ratio increased in the second and third trimesters in those women who became pre-eclamptic. A nuclear magnetic resonance spectroscopic study showed a lower brain and muscle intracellular magnesium content in seven patients with pre-eclampsia.
Conversely, Seydoux and colleagues were unable to demonstrate any effect of pre-eclampsia on either plasma or intracellular magnesium concentrations and concluded that magnesium deficiency had no causative role to play in the genesis of pre-eclampsia. Fong et al. studied serum and cerebrospinal fluid (CSF) magnesium concentrations in normal pregnant patients and pre-eclamptic patients presenting for caesarean section under spinal anaesthesia. There were no between-group differences.
There is, therefore, conflicting data regarding the possible contribution of magnesium deficiency to the genesis of pre-eclampsia from which no firm conclusions can be drawn at present. However, it would seem wise to offer magnesium supplementation to any pregnant woman who becomes magnesium deficient. This may be particularly important in diabetic mothers as magnesium deficiency is common in diabetics and may also worsen the pathology of the disease.
Magnesium deficiency
Magnesium deficiency has many consequences, including chronic fatigue states and delirium, muscle weakness and tetany, disordered glucose metabolism, numerous myocardial arrhythmias, vascular disorders and electrolyte disturbances, particularly of potassium. The generally accepted normal range for total serum Mg 2+ is 0.75–1.0 mmol l–1. However, since magnesium is primarily an intracellular ion, whole body magnesium depletion may exist in the presence of normal or even elevated plasma Mg 2+ concentrations. Most Western diets are magnesium deficient.
Magnesium levels have been shown to decline during pregnancy, reaching their lowest point at the end of the first trimester, due partly to dilution and expansion of the extracellular space and partly to absolute magnesium deficiency. Magnesium deficiency may contribute towards placental insufficiency, and thus to the development of pre-eclampsia, as it contributes towards uterine artery spasm and foetal growth retardation and has an essential regulatory role in prostaglandin synthesis. It has also been suggested that magnesium supplementation during pregnancy can reduce maternal morbidity and improve foetal outcome, but this study was too small and non-specific to indicate any effect on the development of pre-eclampsia. Magnesium deficiency has also been associated with pre-term labour and an increased incidence of leg cramps during pregnancy.
Magnesium deficiency during pregnancy may result in permanent harm to the unborn child, with animal evidence of growth retardation, an increased incidence of abnormal fat metabolism, insulin resistance and diabetes. It has also been reported that magnesium deficiency during pregnancy may be associated with the sudden infant death syndrome.
The possible role of magnesium deficiency in the genesis of pre-eclampsia has been the subject of considerable debate. Studies in ewes with pregnancy-induced hypertension demonstrated higher arterial pressure and lower foetal weights in sheep fed on a magnesium-deficient diet. In a human study of 568 women given magnesium aspartate or placebo from 16 weeks’ gestation or earlier, the magnesium group had fewer hospital admissions, less frequent pre-term labour and fewer neonatal intensive care unit (ICU) admissions. Kisters et al. studied the plasma and intracellular magnesium concentrations in pre-eclamptic and normal pregnant women. Plasma Mg 2+ concentrations were not significantly different, but showed a greater scatter in the pre-eclamptic women. Both groups showed lower red cell magnesium concentrations than normal non-pregnant values, and the pre-eclamptic group had a significantly lower red cell concentration than the normal pregnant women. They suggested that this decrease in intracellular magnesium might contribute to the vascular lesions of pre-eclampsia. Standley and colleagues studied Mg 2+ and Ca 2+ concentrations in 31 normal pregnant patients of whom nine eventually developed pre-eclampsia. All subjects showed a decrease in ionised Mg 2+ concentration with increasing gestational age. However, total Mg 2+ concentrations were lower and ionised Ca 2+ /Mg 2+ ratio increased in the second and third trimesters in those women who became pre-eclamptic. A nuclear magnetic resonance spectroscopic study showed a lower brain and muscle intracellular magnesium content in seven patients with pre-eclampsia.
Conversely, Seydoux and colleagues were unable to demonstrate any effect of pre-eclampsia on either plasma or intracellular magnesium concentrations and concluded that magnesium deficiency had no causative role to play in the genesis of pre-eclampsia. Fong et al. studied serum and cerebrospinal fluid (CSF) magnesium concentrations in normal pregnant patients and pre-eclamptic patients presenting for caesarean section under spinal anaesthesia. There were no between-group differences.
There is, therefore, conflicting data regarding the possible contribution of magnesium deficiency to the genesis of pre-eclampsia from which no firm conclusions can be drawn at present. However, it would seem wise to offer magnesium supplementation to any pregnant woman who becomes magnesium deficient. This may be particularly important in diabetic mothers as magnesium deficiency is common in diabetics and may also worsen the pathology of the disease.
Pharmacology of hypermagnesaemia
Hypermagnesaemia to control eclamptic convulsions was first reported by Lazard and popularised by Pritchard in 1955. Subsequently, it was used with some success as a tocolytic.
Pharmacologically, magnesium is a calcium competitor that is effective, not only at the dihydropyridine receptors, but also at other calcium channels unaffected by traditional calcium channel antagonists. Magnesium is also an effective antagonist of the N -methyl- d -aspartic acid (NMDA) receptor in the central nervous system. In order to achieve pharmacological plasma Mg 2+ concentrations, parenteral administration is necessary as oral salts are poorly absorbed and renal excretion is rapid. Magnesium toxicity is primarily a consequence of neuromuscular blockade with consequent respiratory embarrassment. This occurs most readily in the presence of renal dysfunction, since renal clearance is the only route of elimination of magnesium.
Magnesium and neuromuscular function
Hypermagnesaemia inhibits the release of acetylcholine at the motor end plate. Consequently, magnesium therapy increases the sensitivity of the motor end plate to non-depolarising relaxants and produces neuromuscular blockade in its own right at plasma Mg 2+ concentrations above 5 mmol l −1 . Clinically important neuromuscular block is unlikely to be seen at Mg 2+ concentrations below 5 mmol l −1 ; the use of the patellar tendon reflex as a monitor of the degree of neuromuscular transmission block has stood the test of time and is a useful measure of the danger of impending neuromuscular weakness, but this may be misleading if epidural analgesia has been initiated. Patients with neuromuscular disorders, including myasthenia gravis, Eaton–Lambert syndrome and myotonic dystrophy are at increased risk of neuromuscular paralysis if exposed to magnesium.
Magnesium and respiratory function
Several reports have characterised a decrease in respiratory volumes with magnesium infusions, notably forced expiratory volume in 1 s (FEV 1 ) and forced vital capacity (FVC) all of which suggest a reduction in mechanical ventilatory power, rather than respiratory depression. Magnesium has been shown to limit respiratory muscle reserve in pre-eclamptic women at rather low plasma concentrations. This should not be taken to imply that increases in PaCO 2 are likely to occur in pregnant women treated with magnesium sulphate (MgSO 4 ), but may mean that women treated with magnesium may be sensitive to increased respiratory work, although the ion has been used to assist in the management of severe, non-responsive asthma, especially in children. There is no evidence that magnesium affects the CO 2 response curve.
Magnesium and cardiovascular function
Magnesium is generally regarded as having little haemodynamic effect, since the changes seen in blood pressure and heart rate in clinical settings are often minimal. However, magnesium has extensive cardiovascular actions of clinical relevance.
Magnesium produces vasodilatation by both a direct action on the arterial blood vessels and an interference with the action of a wide range of vasoconstrictor substances, notably alpha-adrenergic inhibition. In animals, magnesium infusions induce a dose-related reduction in systemic vascular resistance accompanied by sustained cardiac filling leading to increased cardiac output and stroke volume. Consequently, at plasma magnesium concentrations below 5 mmol l −1 only mild reductions in arterial pressure occur despite substantial arterial dilatation. Whether or not this haemodynamic effect contributes usefully to control of arterial pressure in pre-eclampsia has not been sufficiently carefully studied to draw firm conclusions, although the improvements in tissue blood flow should be beneficial. In an animal model of pre-eclampsia (using L-Nitro-Arginine Methyl Ester (L-NAME) to induce hypertension in pregnant rats) magnesium infusions not only improved blood pressure control but also enhanced foetal growth.
Provided that respiratory failure and hypoxia are avoided, magnesium is remarkably safe from a cardiac perspective with plasma Mg 2+ concentrations as high as 12.5 mol l −1 being required before cardiac arrest occurs. Studies in animal models and pregnant women have failed to demonstrate any myocardial depression and have reported an increase in cardiac output associated with raised plasma Mg 2+ concentrations. In dogs, magnesium enhanced inotropy and lusitropy with increased cardiac output up to plasma concentrations of 6 mmol l −1 , and this level was described as ‘haemodynamically safe’. Accidental overdose resulting in levels above 7 mmol l −1 have been reported without adverse cardiac events; in one case report, the patient suffered respiratory arrest, but made a rapid and full recovery without cardiovascular difficulties following immediate institution of respiratory support. Increased cardiac output and decreased systemic vascular resistance have been reported in human subjects with pre-eclampsia whilst only mild effects were seen in patients receiving magnesium infusions for pre-term labour. The evidence suggests that, at clinically used concentrations, magnesium infusions have no significant negative inotropic effects and may improve myocardial performance through significant vasodilator actions in pre-eclamptic patients. However, the sympatholytic action of magnesium may impair the haemodynamic response to haemorrhage. Consequently, it is important that adequate fluid therapy is maintained in patients receiving magnesium treatment.
Calcium channel blockers
Some authors regard the interaction of magnesium with the calcium channel blockers as potentially hazardous whilst others use the combination frequently for blood pressure control in severe pre-eclampsia. In the isolated heart, magnesium potentiated the cardiac depressant effects of both verapamil and nifedipine, and it has been recommended that the combination be used with caution. However, a study of the haemodynamic effects of nifedipine in pre-eclamptic hypertensives who were receiving magnesium failed to demonstrate any dangerous myocardial depression. On the contrary, at mean plasma Mg 2+ concentration of 2.5 mmol l −1 , cardiac index increased and peripheral resistance decreased. No increase in adverse effects was seen in subjects given magnesium and nifedipine for the management of severe pre-eclampsia compared with patients given magnesium alone. These reports do not conclusively answer the question regarding the safety of the combination of calcium channel blockers and magnesium in the obstetric patient but suggest that there might be less of a risk than the in vitro experiments suggest, and the few reported adverse events might be an idiosyncratic response rather than a predictable drug interaction. It has been suggested that the combination might increase the risk of neuromuscular weakness than magnesium alone, but no such impairment was reported in the Magpie trial, in which 1469 women assigned to receive MgSO 4 also received nifedipine.
Magnesium is a highly effective vasodilator and an alpha-adrenergic antagonist, reducing excessively elevated blood pressure, particularly when that increase is due to catecholamine release. It maintains cardiac filling and thus increases cardiac output. Consequently, only moderate reductions in blood pressure occur in patients with pre-eclampsia, although tissue blood flow and cardiac output probably improve significantly.
Magnesium and cerebral function
The control of convulsions by magnesium has been highly contentious since magnesium penetrates the blood–brain barrier poorly and has no anaesthetic or major sedative actions when given parenterally, and is not an effective anticonvulsant against standard forms of epilepsy. The debate was resolved by the Collaborative Eclampsia Study and subsequent meta-analyses, which concluded that magnesium was significantly better than either phenytoin or diazepam for the treatment of eclampsia. It has also been shown to be more effective in preventing the progress of pre-eclampsia to eclampsia than other agents. Several possibilities for the mechanism of magnesium’s anticonvulsant action in eclampsia have been suggested, including NMDA antagonism, calcium antagonism and cerebral vasodilatation. Magnesium causes relaxation of arterial musculature from most organs, including the brain, and increases cerebral blood flow in sheep. Reversal of vasospasm may, therefore, be an important component of the anticonvulsant effect of magnesium in eclampsia. Other possibilities include a reduction in pinocytosis and a down-regulation of aquaporin 4 in the cerebral tissue, limited the opening of tight junctions through calcium antagonism (decreasing cerebral oedema) and prevention of hypertensive encephalopathy through a reduction in cerebral perfusion pressure.
Whatever the mechanism, MgSO 4 is the established drug of choice for the prevention of convulsions in pre-eclampsia and eclampsia.
Magnesium and coagulation
Although reduction of the Ca 2+ /Mg 2+ ratio alters laboratory estimations of coagulation including reduced platelet adhesiveness, no clinically significant abnormalities of coagulation have been attributed to magnesium. Magnesium has only a small effect on thrombelastography in vitro . Increased bleeding time in pre-eclamptic patients from a mean of 6 min 31 s to 11 min 56 s after magnesium infusion has been reported, but serum Mg 2+ concentrations were not measured. A more modest effect of magnesium infusion was reported at serum Mg 2+ concentrations of 1.5 mmol l −1 with an increase of bleeding time from 8 to 11.8 min, although no other aspect of platelet function or coagulation was altered. It is not clear if this simply represents a correction of abnormal coagulation to more normal values or indicates a real risk of increased bleeding. No increase in blood loss was reported nor was there an increased requirement for blood transfusion in the magnesium-treated groups in the Collaborative Eclampsia Trial. Magnesium might increase the risk of epidural haematoma consequent to neuraxial block in pre-eclamptic patients, but there is no evidence that this has ever happened in practice; the risk would appear to be, at worst, no greater than that related to aspirin therapy.
Magnesium and the uterus
Magnesium has been used since 1977 to treat premature labour, especially in the United States. Magnesium inhibits myometrial contraction as effectively as beta-agonists, but with a lower incidence of side effects. Several publications have argued against the use of magnesium for this purpose, citing absence of efficacy and a possible increase in side effects, particularly foetal death. A meta-analysis of the data concluded that the only available randomised controlled trials were inadequate to allow firm conclusions.
Perhaps surprisingly, there is no evidence that MgSO 4 therapy prolongs the duration of normal labour. The effect on caesarean section rate is less clear, with some studies showing no increase in the frequency of caesarean deliveries while a large meta-analysis found a significant increase in the risk of caesarean section (relative ratio (RR) 1.21, 95% confidence interval (CI) 1.05–1.41) in magnesium-treated women.
Magnesium and the foetus
Sporadic reports of neonatal hypotonia, respiratory depression and altered parathyroid hormone function have led to concerns that magnesium might adversely affect the foetus, especially if premature. Although the ion readily crosses the placental barrier, there is little hard evidence of harmful effects. Foetal heart rate (FHR) variability is decreased by magnesium, but without discernible harm to the neonate. However, this may make interpretation of FHR data difficult, and necessitates some other means of assessing foetal health. Fewer babies born to magnesium-treated pre-eclamptic mothers required intensive therapy than those whose mothers received either phenytoin or diazepam, and Apgar scores of the infants were better in the magnesium group. Current evidence in pre-eclampsia would suggest that there is no real concern for neonatal well-being. However, the situation regarding premature infants born to mothers treated for early labour is less clear with arguments that magnesium may be beneficial or harmful. Theoretically, the calcium and NMDA antagonism of magnesium could protect the developing brain from hypoxia. FineSmith et al. found that magnesium protected exposed neonates against developing cystic periventricular leukomalacia, but Canterino et al. found no benefit. Nelson and Grether noted an increased survival and decreased incidence of cerebral palsy in very low-birth-weight infants whose mothers had received MgSO 4 either as a tocolytic or for pre-eclampsia, but subsequently, the same group failed to confirm this effect in premature infants, although they concluded that magnesium did not increase the risk of neonatal death. Other studies have tended to confirm the possible protection but have been inconclusive. A retrospective study failed to demonstrate any association between magnesium therapy and alterations in favourable or unfavourable outcomes in magnesium-exposed infants. Other authors have suggested that magnesium in pre-term labour increased the risk of harm in very-low-birthweight infants. Recently, however, two meta-analyses suggested that magnesium administration to women at risk of delivery before 34 weeks of gestation reduced the risk of cerebral palsy, and one concluded “the neuroprotective role for antenatal MgSO 4 therapy given to women at risk of preterm birth for the preterm foetus is now established.” Whilst these later studies are strongly suggestive of a beneficial effect, neurologic protection of the pre-term foetus cannot be regarded as firmly established at the present time, although the trend of current evidence seems to suggest a possible benefit.
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