PREFACE

Assalamualaikum Wr.Wb.
Praise be to Allah who gives strength and ability to the author for finishing this
Referat by the tittle Magnesium Sulfate as a Brain Protector.
This Referat is structured as a requirement in the joining and finishing of clinical
work of SMF Obstetrics and Gynecology at dr. Slamet Garut Hospital. In this occasion, the
author would like to thank gratefully to:
1. Dr. Dadan Supriyandi, Sp.OG as Preceptor
2. The Midwife and Employees in the section of SMF Obstetrics and Gynecology at dr.
Slamet Garut Hospital
3. Friends of Colleagues as young doctor at dr. Slamet Garut Hospital
Every effort has been optimized to make this Referat to be good and helpful entirely
on the ability of the author. The author realizes that this writing is far from perfect. All the
suggestions and criticisms from the readers are needed to produce better writing later.
In the end, the author expects this Referat can provide benefits for readers, especially
for young doctors who require guidance through the application of science.
Wassalamualaikum Wr.Wb.

Garut, Februari 2017

Author
 CHAPTER I
INTRODUCTION

Advances in perinatal and neonatal medicine have significantly improved survival

raters of preterm infants. This improvement has ben associated with substantial risk of
neurodevelopmental impairments and with increased number of infants with special health
care needs. As a result, strategies designed to reduce adverse neurological outcomes have
been a major perinatal research focus.
Antenatal magnesium sulfate (MgSO4) is one such strategy. MgSO4 is commonly used
worldwide as obstetric practice as an anticonvulsant for treatment of eclampsia and for
seizure prophylaxis, and is no longer recommends for tocolysis because it us ineffective.
Following the first report of an association between perinatal administration of MgSO 4 and
reduction in the risk of peri/intraventricular (P/IVH) hemorrhage, its use as neuro-protective
therapy when given to women at risk of preterm birth has become established practice. While
MgSO4 has been shown to decrease the risk of P/IVH, cerebral palsy and the rate of
substantial gross motor dysfunction, the mechanisms underlying these effects remain poorly
understood.
MgSO4 has been proposed to act as a neuroprotectant through one or many of the
following mechanisms such as reduction of inflammatory cytokines or free radicals produced
during hypoxic-ischemic reperfusion, prevention of excitotoxic calcium-induced injury,
membrane stabilization by preventing the membrane depolarization, inhibition of the
glutamate receptors involved in injury to preoligodendrocytes, stabilization of fluctuations in
blood pressure that occur in neonates, and an increase in cerebral blood flow. During the
asphyxia, there is excessive release and reduced uptake of glutamate in the brain. Fetal and
newborn brains seem to be more susceptible to damage from glutamate release. Magnesium
is a naturally occurring NMDA receptor antagonist that blocks neuronal influx of calcium
within the ion channels, preventing posthypoxic brain injury.
 CHAPTER II
LITERATURE REVIEW

PHYSIOLOGY
Magnesium is the fourth most common cation in the body, and the second most
common intracellular cation after potassium. It has fundamental role as a co-factor in more
than 300 enzymatic reactions involving energy metabolism and nucleic acid synthesis. It is
also involved in several processes including hormone receptor binding, gating of calcium
channels, transmembrane ion flux and regulation of adenylate cyclase, muscle contraction,
neuronal activity, control of vasomotor tone, cardiac excitability, and neuronal transmitter
release. In many of its actions it has been likened to a physiological calcium antagonist.
The significance of magnesium and its relationship to the origin of life has been
traced from the composition of the earths crust (rich in iron-magnesium silicate) and the
primeval ocean rich in magnesium to the formation of chlorophyll with magnesium at the
center of the molecule, and finally to its incorporation into the animal cell containing
adenosine triphosphate (ATP) with its dependence on magnesium. The central role of
magnesium within the chlorophyll molecule and as a co-factor for the enzymes in the 12
transphosphorylation reactions in photosynthesis makes it probably the most important
inorganic element in the production of food and fossil fuels.
In humans, less than 1 % of total body magnesium is found in serum and red blood
cells. It is distributed principally between bone (53%) and the intracellular compartments of
muscle (27%) and soft tissues (19%). Ninety percent of this intracellular magnesium is bound
to organic matrices. Serum magnesium comprises only approcimately 0.2 % of total body
magnesium, where it present in three states-ionized (62%), protein bound (33%), mainly to
albumin, and complexed to anions such as citrate and phosphate (5%). Equilibrium between
tissue pools is reached slowly with half life for majority of radiolabelled magnesium varying
between 41 and 181 days. Thus serum magnesium estimations may not provide representative
information on the status of other stores.
Magnesium units are commonly expressed in mg, mmol, or mEq. While there is an
absolute requirement for magnesium, the daily estimated average requirement (EAT) is 200
mg for females and 250 mg for males. Rich sourch=es of magnesium in the diet include
cereals and legumes, but the processing of the former may lead to marked depletion of
inherent magnesium, leaving only 3-28% of the original content. Magnesium absorption is
inversely proportional to intake and occurs principally from the ileum and colon. Excretion
and serum magnesium control occur via the kidney. In common with other cations,
magnesium is filtered at the glomerulus but differs in that reabsorption is predominantly in
the ascending limb f the loop of Henle and not in the proximal convoluted tubule.
It has been estimated that magnesium intake has declined by more than half during
this century. Although modern food processing has caused loss of magnesium found in food,
there are several other factors which have reduced magnesium within the ecosystem as a
whole. Acid rain causes exchange between magnesium and aluminium in the soil. This,
coupled with intensive faming of the soils, has lead to a reduction in magnesium within the
food chain. This has been implicated in a number of environmental issues including the death
of forests, and in lactating cows a condition variously known as grass staggers or spring
tetany whereby hypomagnesaemia causes twitching and later convulsions.

MAGNESIUM DEFICIENCY
Magnesium deficiency is common and is frequently multifactorial. Epidemiological
studies trace the prevalence of cardiovascular disease and cardiac deaths to the degree of
magnesium depletion induced by a diet and drinking water low in magnesium. Magnesium
deficiency has been demonstrated in 7-11% of hospitalized patients and is found to co-exist
in up to 40% of patients with other electrolyte abnormalities, particularly hypokalaemia or
hypophosphat-aemia and, to a lesser extent, hyponatraemia and hypocalcaemia.
The co-existence of secondary electrolyte abnormalities plays a key role in the clinical
features of magnesium depletion. Of these the relationship between magnesium and calcium
has been the best documented. Absorption of both magnesium and calcium appears to be
inter-related, with concomitant deficiencies of both ions well described. A common link is
that of parthyroid hormone (PTH), secretion of which is enhanced by hypocalcaemic-induced
PTH release, which is corrected within minutes after infusion of magnesium. The rapidity of
correction of PTH concentrations suggest that the mechanism of action of magnesium is
enhanced release of PTH. Magnesium is also required for the sensitivity of the target tissues
to PTH and vitamin D metabolites. In contrast, calciotrophic hormones (PTH and calcitonin)
have a profound effect on magnesium homeostasis, with PTH release enhancing magnesium
reabsorption in the kidney, absorption in the gut and release from bone.
A more fundamental interaction between magnesium and other ions occurs at the
cellular level. Intracellular calcium concentrations are controlled within narrow limits, with
transient increases rapidly giving way to return to normal levels. The release of intracellular
calcium plays a key role in many cell functions, both basic (cell division and gene
expression) and specialized (excitation, contraction and secretion). A common pathway for
the release of intracellular calcium from many stimuli such as hormones, growth factors and
neurotransmitters is phospholipase C activation and hydrolysis of phosphatidylinositol 4,5-
biphosphate into inositol 1,4,5-triphosphate (IP3). IP3 acts by binding to the transmembrane
IP3 receptor causing opening of calcium channel, which is part of the same molecule.
Magnesium acts as a non-competitive inhibitor of the IP3-gated calcium channel and od IP3
binding, Therefore, it may be considered as an intracellular calcium antagonist acting at IP3
sensitive calcium release channels. It may also have a role as a calcium antagonist at other
cell sites such is the ryanodine subgroup of calcium release channel receptors in the
sarcoplasmic reticulum.
In addition to interactions with calcium, magnesium has a marked effect on the
regulation of transmembrane sodium and potassium movement.

MAGNESIUM THERAPHY

MAGNESIUM IN OBSTETRICS
The use of magnesium sulphate (MgSO,) in obstetrics has consistently aroused controversy
despite many years of experience with its use. MgSO, was first used to prevent eclamptic
seizures in 1906 by Horn in Ger- many, who injected it intrathecally' . An intramuscular
regimen was used in 1926 to prevent recurrent seizures in women with eclampsia2and the
drug was given intra- venously in 1933 to women with pre-eclampsia and eclampsia3.

Despite such early suggestions of its potential, the choice of MgSO, for seizure prophylaxis
has continued to vary enormously. In the United States, for example, MgSO, is the
anticonvulsant of choice for women with either eclampsia or pre-eclampsia4, while in the
United Kingdom in 1992 it was used by only 2% of obstetri- c i a n ~O~v.er the years the use
of MgSO, for pre-eclamp- sideclampsia was deemed more a 'religious conviction than a
scientifically established treatrnenP. The Collab- orative Eclampsia Trial7 has now provided
irrefutable evidence of the superiority of MgSO, when compared with diazepam and
phenytoin in the prevention of recur- rent seizures in women with eclampsia. Other recent
studies indicate that MgSO, has potential benefits for the fetus Rand can significantly reduce
the incidence of eclamptic convulsions in women with pre-eclampsiag. The purpose of this
review is to present the clinical pharmacology of MgSO, as it applies to obstetric prac- tice
that may serve a source of reference for clinicians.

Identification of literature

A systematic review of all papers pertaining to MgSO, was carried out using the CD-ROM
MEDLINE system (1966-1 996 initially and subsequently extended to March 1997) using the
textwords magnesium sulfate and magnesium sulphate respectively. Secondly, the Cochrane
database of systematic reviews was searched for reviews of MgSO, therapy. Finally, the
reference lists of identified articles were examined to find addi- tional relevant studies.
English language publications only were used for this review. Studies were included if they
addressed issues relating to the clinical pharmacol- ogy of MgSO,. In order to facilitate
selection, a list of subheadings as they appear in the review was drawn up. Studies addressing
issues related to one or more of these subheadings were identified. In all, 421 papers printed
in the English language were identified; 198 contained relevant information of which 122
provided useful information for the purpose of this review. The selection of articles was
performed independently by both authors and disagreement was resolved by consensus
without the need to rely on arbitration. Where there were similar studies with similar findings
in human and animal species, the studies in humans were chosen.

Administration

The two most widely used regimens of MgSO, adminis- tration are the intramuscular regimen
popularised by and the continuous intravenous regimen rec- ommended by Zuspan" . In the
intramuscular regimen, a continuous intravenous loading dose of 4 g (usually in 20%
solution) is given over five minutes (preferably 10-15 min) followed immediately by 5 g
(usually in 50% solution) as a deep intramuscular injection into the upper outer quadrant of
each buttock. Maintenance therapy is in the form of a further 5 g intramuscularly every four
hours, to be continued for 24 hours after the last fit. Alternatively the intravenous regimen
involves a loading dose of 4 g intravenously ( 5 g is used in some centres) which is followed
by an intravenous infusion of

1 g/h continued for 24 hours after the last fit. If convul- sions recur, both regimens advocate a
further 2-4 g (depending on the woman's weight, 2 g if < 70 kg) to be given intravenously
over five minutes.
Controversy exists regarding the optimum mainte- nance dose. An infusion of 1 g/hwas used
in the collab- orative trial, but some authors have advocated 2 g/hI29l3 and even suggested
that 3 g/hI2 might be needed for the first three hours of treatment in some cases. Sibai14has
evaluated several modifications of the continuous intra- venous regimen in order to achieve
acceptable serum magnesium levels throughout the infusion and feels the best regimen is a 6
g loading dose followed by a mainte- nance dose of 2 g/h. Higher doses than are normally
used in protocols for eclamptic seizure prophylaxis are often required to arrest preterm
labourI5. Magnesium may be administered orally as a gluconate preparation (2 g every four
hours) and is also available in slow- release formulations. Oral magnesium is as effective and
associated with fewer side effects compared with p- adrenergic agentsIb and can be used to
convert from intravenous to oral tocolytic therapy.

Distribution and plasma levels

Maternal plasma levels of magnesium after parenteral administration depend on the volume
of distribution and renal excretion of the magnesium ion. In the presence of severe oliguria or
advanced renal failure, the volume of distribution alone determines the serum concentration.
Infused magnesium is distributed rapidly throughout the entire extracellular fluid space1' and
some is takenupbybone17-1bRutnonebyredbloodcellslJOA.n intravenous loading dose of 4 g
to 6 g results in an immediate but transient increase in plasma levels to 2.1-3.8 mmoVL
which will fall to 1.3-1.7 mmoVL within 60 minutes; within 90 minutes, about 50% of the
infised magnesium moves into bone and other cells',. A delay in the peak level was noted by
Chesley17 who found the time of the average peak level to be at 60 min- utes. At a constant
rate serum levels plateau when the rate of urinary excretion of magnesium equals the rate of
infusionlg.With an infusion of 1 g/h, MgSO, levels

0 RCOG 1998 Br J Obstet Gynaecol 105, 260-268

plateau after 24 hours at a level of 1.7 mmol/L; with an infusion rate of 2 gh; this will occur
at six to eight hours at a level of 2.2 mmoVL".

Various authors20.2'observed that the concentration of magnesium in plasma rises gradually

after intramus- cular injections, with 90-1 20 minutes being the usual time required to reach
maximal levels in plasma, and indeed, that was the basis for initiating therapy with the
intravenous dose. The rapid distribution of magnesium in a large pool is a buffering action
that prevents accum- mulation and attainment of toxic concentrations in plasmaI7.Data from
Sibai et a l l 2 suggest that levels are consistently < 1.7 mmovL using a regimen of 1 g/h
(used in the collaborative trial). In contrast, mean serum levels range from 1.7 to 3.3 mmol/L
with a 2 g/h main- tenance infusionI4.

Although there is no single accepted therapeutic level of magnesium, Pritchard22 suggests a

level of 2.0-33 mmoYL and 1.8-3.0 mmovL as satisfactory for women with severe and mild
pre-eclampsia, respec- tively. Other authorsigsuggest that the levels may be lower than those
recommended by Pritchard. In general the therapeutic level is considered to be between 2 and
4 mmoVL. However, this is based on clinical experience and not directly related to the
suppression of eclamptic convulsions. Elliot15 suggested that a maternal serum magnesium
level of 2.3-3.1 mmol/L is necessary to inhibit uterine contractions. Although pre-eclampsia/
eclampsia and preterm labour utilises different clinical endpoints of therapy, quite similar
serum values result23.

Excretion

Magnesium is excreted almost solely by the kidney and after four hours about 50% of the
infused dose is excreted in the urineI4. The renal clearance of magne- sium increases linearly
and steeply with an increase in the plasma level2,. In the presence of oliguria or signifi- cant
renal failure, the maintenance dose should be either reduced or discontinued and maternal
plasma levels should be monitored frequentlyI4.

Rapid urinary excretion of magnesium has been

reportedbyvariousauthors.Cruikshanketal.25demon- strated that urinary magnesium excretion
increased twentyfold during MgSO, infusion; 75% of the infused dose was excreted during
the infusion; by 24 hours after the infusion, 90% had been eliminated. Pritchard'O
demonstrated that 99% of the magnesium in an intra- venous bolus of 4 g of MgSO, was
excreted within 24 hours. Chesley and Tepper2, noted excretion of 44% of a 10 g
intramuscular dose within four hours and Ches- leyI7 found that 38% to 53% of a 13 g dose
(10 g intra- muscularly and 3 g intravenously) was excreted within four hours.

Toxicity and side effects

The first sign of magnesium toxicity is usually the loss of tendon (patella) reflexes. This
occurs with plasma lev- els > 5 mmoVL, with respiratory depression occurring at levels > 6
mmol/L26.Other early signs and symptoms of toxicity include nausea, feeling of warmth,
flushing, somnolence, double vision, slurred speech and weak- ness (usually at 3.8 to 5
mm01L)14.Muscular paralysis and respiratory arrest will develop at plasma levels of 6.3 to
7.1 mmol/Ll4. Cardiac arrest will develop at plasmalevelsof 12.5to 14.6mm~l/L?~.

Magnesium toxicity is extremely rare with correct preparation of the infused magnesium
solution and dili- gent clinical monitoring. MgSO, was responsible for the only death in the
series reported by Pritchard28 and nearly led to one maternal death in Sibai's series2'. In both
cases the women accidentally received 20 g of magnesium during a few minutes instead of
the load- ing dose of 4 g. In addition, Pritchard28reported three instances of respiratory arrest
requiring intubation, and Sibail, has encountered one such instance in a woman with
eclampsia who had received large doses of diazepam and phenobarbital in association with
MgSO,. With magnesium use laryngeal reflexes are usually intact, which protects against
aspiration pneu- monia29.Injection abscess can occur with the intramus- cular route7.

It is important to keep an ampoule containing 1 g (10 mL of a 10% solution) calcium

gluconate at the bed- sideto be used for intravenousadministrationas an anti- dote in cases of
magnesium toxicity. This medication should be administered slowly to avoid hypotension or
bradycardia. In addition, in case of cardiorespiratory arrest, the patient should be intubated
immediately and managed with assisted ventilation until resumption of spontaneous
respiration2'.

There are no absolute contraindications to magne- sium therapy other than perhaps
myasthenia gravis and heart muscle damage, particularly if associated with conduction
defects.

Effect on the nervous system and cerebrovascular system

The mechanism and site of action of MgSO, remain unknown and subject to debate. Some
authors3"3' believe its action to be mainly peripheral at the neuro- muscular junction with
minimal or no central effects, whereas others22believe that the main action is central with
minimal neuromuscular blocking effect. It has been suggested3(' that in eclampsia any
apparent central effects of MgSO, must be the result of disruption of the blood-brain barrier
and leakage of Mg" into the brain.

Katz et al.32reported that MgSO, suppressed elec- troencephalographic seizures induced by

hyperbaric

oxygen in rats and as this occurred with an intact blood-brain bamer, they suggested that
MgSO, might work through calcium-regulated intraneural enzymatic processes that alter
neuronal excitability and produce seizures. Calcium entry into neurons is regulated by, among
other things, specific excitatory amino acid receptor-linked channels". Excitatory amino
acids, such as L-glutamate and L-aspartate, are major neuro- transmitters in the mammalian
central nervous system3,. These neurotransmitters produce their effects by inter- acting with
certain receptors on the cell surface, the excitatoryaminoacid receptor^^^.

The N-methyl-D-asparate (NMDA) receptor is the best characterised excitatory amino acid
receptor sub- type. The NMDA receptor has its channel blocked by
magnesiumion34.Ithasbeenshownthattheanticonvul- sant activity of MgSO, may be partially
mediated by blockade or suppression of the NMDA receptor activa- ti~n~~,~'.

Although the cause of seizures in eclampsia has not

been definitely established, pre-eclampsia and eclampsia
are characterised by intense vasospasm and increased sensitivityto pressor substances.This
has led to the pro-
posal that seizures are a consequence of reduced cere-
bral blood flow. Vasospasm in pre-eclampsia is thought
to be the consequence of endothelial dysfunction, which
in turn is believed to be due to injury mediated by free radicals. MgSO, is a potent
vasodilator, especially in
the cerebral vasculature, and the administration of MgSO, to women with pre-eclampsia
reduces intracere-
bra1 arterial spasm when measured by Doppler exami- nation of the middle cerebral
artery38.Evidence of reduced cerebrovascular resistance following MgSO, administration is
provided by Doppler studies of the internal carotid and the middle cerebral arteries in women
with severe pre-e~lampsiaa~n~d eclampsia4", respectively. MgSO,, both in vivo4' and in ~ i
t r o ~ ~ , increases the production of the endothelial vasodilator, prostacyclin. Magnesium
also protects against injury by freeradicalsto endothelialcellsin~iti-0,~.

Cardiovascularand respiratory effects

Although it is recognised as an anticonvulsant, signifi- cant falls in blood pressure have been
observed during use of the recommended therapeutic doses of MgSO,. Pritchard'" found
variable effects of MgSO, on blood pressure and believed the hypotensive action was tran-
sient. This transient hypotensive effect has been consis- tently noted with a bolus
infu~ion'".a~n,d~h~igh dose continuous infusion by some authors46.

James et ~ 1dem. on~stra~ted a dose related reduction in systemic vascular resistance which
confirmed the vasodilator properties of Mg" previously demonstrated

animals4Rand humans4y.The vasodilator properties may be causally related to the effect of

magnesium on the movement or translocation of Caw across the vascu- lar membranes and
intracellularly. Thus magnesium may exert a regulatory role in vascular tone, vascular
reactivity or peripheral vascular resistance50. An absence of effects on venous pressure
suggests that the major role of MgSO, in intact animals is on resistance rather than
capacitance vessels4I although this hypothe- sis has been questioned5(.

The importance of endothelial cell damage in the pathophysiologic characteristics of pre-

eclampsia have been r e c o g n i ~ e dT~h~e. endothelium regulates the reac- tivity of
vascular smooth muscle through production of both vasodilators and
vasoconstri~tors~B~ar.ton et aL60 have shown that cyclic guanosine monophosphate
excretion increases in women with pre-eclampsia dur- ing MgSO, infusion. Cyclic guanosine
monophosphate is a second messenger in the cascade of effects of endothelium derived
relaxing factor; a known mediator of vascular smooth muscle relaxation. Endothelium
derived relaxing factor is believed to be nitric oxide.

An increase in renal prostacyclin production was reported in patients in preterm labour after
MgSO, infu- sion61.An in vitro study has suggested that MgSO, might increase the
prostacyclin production from endothelial
cells42.Mastrogiannisetal.62haveobservedasigmficant reduction of endothelin- 1 levels after
MgSO, therapy; this effect was limited to women with pre-eclampsia. Endothelin-1 is the
most potent naturally occurring

Hypotension has not been consistently produced by

MgSO, in the management of pregnancy induced
hypertension2',28.Part of the explanation for this incon-
sistency may lie in the rapid clearance of MgSO, from
the plasma. High Mg" levels are difficult to maintain in
the presence of normal renal function47.In addition to
poorly maintained MgSO, levels, the other factor
thought to contribute to the lack of sustained hypoten-
sion is the effect of MgSO, on cardiac output. MgSO,
administration has been shown to either increase47or
maintaincardiacoutputandincreasestrokevol~me~~v,a~so~co.nstrictoryetidentified.Otherauth
ors63-"have

James et al.47 suggested that the maintenance of blood pressure can be explained by a
concomitant increase in cardiac output which largely compensated for the fall in systemic
vascular resistance although selective micro- circulatory actions may also be involved5!.

Magnesium is generally regarded as having a nega- tive inotropic action. Magnesium inhibits
the contractile force of isolated heart muscle53,although the effect is small as long as the
calcium level remains within nor- mal limits5,. A reduction in myocardial performance in
humans has been claimed55but increased cardiac output demonstrated by others52 argues
against significant myocardial depression.

Magnesium, when used in experimental dogs, has been found to produce

electrocardiographic (ECG) changes, namely prolongation of the P-R interval and QRS
c~mplex'~J.ames et al.47state that the levels of magnesium used in clinical practice seem
unllkely to produce serious ECG abnormalities other than a possi- ble prolongation of atrial
conduction time.

MgSO, tends to decrease maternal respiratory rate in human subjects3g.There have been case
reports suggest- ing that the use of MgSO, as a tocolytic agent might be associated with an
increased risk of pulmonary
edema^^. Yeast et al.23have demonstrated that par- enteral MgSO, therapy does not cause
significant changes in colloid osmotic pressure values until nearly 48 hours of continuous
therapy; they found consistently lower values in women with pre-eclampsia than those with
preterm labour and the use of corticosteroids with MgSO, resulted in higher values than in
patients not given steroids. Other risk factors for pulmonary oedema, such as anaemia and
multiple pregnancy, may have been contributory in the cases reported57.

0 RCOG 1998 Br J Obstet Gynnecol 105, 260-268

shown MgSO, to reduce or attenuate the activity of other vasocontrictor or pressor

substances. Mg" pos- sesses platelet antiaggregant propertie@ and appears to prolong the
bleeding time in pregnancy66.

Placental transfer

Magnesium readily crosses the placenta1J5 and fetal blood magnesium levels correlate well
with maternal leveP7.It is believed that equilibration between mother and fetus usually occurs
within two hourslO.Hallak et al.68have demonstrated that magnesium levels increase in fetal
serum within one hour and amniotic fluid within three hours after maternal intravenous
administration. They postulate that this is consistent with fetal urinary excretion of MgSO, as
the primary source of magne- sium in the amniotic fluid. Prolonged maternal MgSO,
administration leads to accumulation of magnesium in the amniotic

Uterine activity

The tocolytic effects of MgSO, were initially reported by Hall et al." in 1959. Stallworth et
aL7I found a tran- sient mild decrease in frequency of uterine contractions during the MgSO,
loading dose but no significant change in the intensity of uterine contractions. They
concluded that there is probably no clinically significant tocolytic effect of MgSO, when used
for treatment of pre-eclampsia in women at term in active labour. Atkin- son et al.72showed
that, compared with phenytoin, MgSO, seizure prophylaxis in women with pregnancy-
associated hypertension does not prolong the induction of labour nor does it result in
an.increase in caesarean

deliveries. Witlin et al.73 have also recently showed that the use of MgSO, during labour in
women with mild pre-eclampsia at term did not affect any component of labour but
necessitated use of a higher dose of oxytocin. Meta-analysis of clinical studies on MgSO, as a
tocolytic agent do not provide evidence that it is more effective in the treatment of preterm
labour than either placebo or beta mimetic^^^,'^.

Placental blood flow

Studies on the fetal and maternal components of placen- tal blood flow indicated that MgSO,
has a vasodilator effect, but the clinical significance is uncertain. Harbert et
al.76demonstrated that uterine blood flow in monkeys increased in response to an infusion of
MgSO,. Studies on isolated human maternal uteroplacental arteries77 and results obtained in
experimental animal^^^?^^ have demonstrated that infusion of Mg++increases uterine and
placental blood flow.

Effect on fetal heart rate

The effect of MgSO, on fetal heart rate variability has been a controversial issue, as there are
conflicting data in the literature. Babaknia and NiebylgOnoted a decrease in long term
variability without an associated change in short term variability. Petrie et al.g' reported an
increase in both short and long term variability in 10 women receivinga 2 g bolus of MgSO,.
Stallworthet al.71stud- ied 19 women and observed no significant difference in either short or
long term variability due to magnesium administered by either the intramuscular or
intravenous route. Canez et a1.82noted no signficant effect on fetal heart rate variability in 57
patients treated with intra- venous MgSO,.

Atkinson et al.83,using computerised fetal heart rate analysis, concluded that although
MgSO, was associated with an objectively measured statistically significant decrease in short
term variability, the decrease was not clinically signficiant, furthermore, it was not associated
with a decrease in long term variability or in the number of accelerationsmeasured.

Effect on fetus and newborn

Some authors have indicated that intravenous MgSO, decreases fetal breathingR4vSt5hereby
contributing to a decrease in the total biophysical profile score84~8isn term fetuses. Gray et
a1.86found that administration of intravenous MgSO, for tocolysis did not significantly affect
the individual components of the fetal biophysi- cal profile or the total score in healthy
preterm fetuses.
An apparent depression in serum calcium has been reported in fetuses of mothers treated with
MgS0487.

OthersR8have reported that maternal MgSO, therapy does not cause neonatal hypocalcaemia
and that the induced neonatal hypermagnesaemia is resolved within the first 48 hours of life.
The fetus is partially protected from hypermagnesaemiaand hypocalcaemiaby the pla-
centaI9. Although clinical neurological depression has been reported in the newborn babies of
women treated for pre-eclampsia with MgS0:9, occurrence of adverse effects on the offspring
is quite rareg0,with failure to identify any adverse effect on Apgar scoresp1,neonatal
mortalityg0or neonatal neurologic assessment examina- tion~~~.

Kuban et al.93noted MgSO, administered solely to prevent preterm delivery also appeared to
protect against cerebral haemorrhage. The magnitude of the apparent effect was substantial,
and the authors argued that it might be causal. In an experimental model of birth asphyxia,
magnesium aloneg4or in combinationgs was associated with less evidence of brain injury and
magnesium administration may decrease secondary neuronal damage following traumatic
brain injuryg6sg7. MgSO, has been associated with improved neonatal survival in extremely
low birthweight infantsg8,and with a lower risk of cerebral palsy in very low' and extremely
lowy9birthweight survivors.

Anaesthesia

Periodically the anaesthetist may be faced with a patient treated with MgSO, undergoing
general anaesthesia. At the neuromuscular junction magnesium decreases the presynaptic
release of acetylcholineIo0.Reduced sensi- tivity of the postjunctional membrane (motor end
plate) and decreased excitability of the muscle fibres have also been reportedlOOJO1S.uch
neuromuscular blocking effects of magnesium would be expected to potentiate the
nondepolarising blocking agents and to antagonise the depolarising block of
succinylcholinelo2.Magne- sium, however, has been shown to potentiate the activity of both
depolarising and nondepolarising neuromuscu- lar blocking agent~"~J"''.

Ghoneim and Longlo3reported that succinylcholine (depolarising)and d-

tubocurarine(nondepolarising)are potentiatedbyMgSO,, butothernondepolarisingmus- cle
relaxants, whether long acting such as pancuro- niumIo5or intermediate acting such as
vecuroniumloh are also potentiated. More recent workers have shown that the neuromuscular
blockade of succinycholine is notpotentiatedinpatientsreceivingmagnesiumtherapy for
eclampsia'07or those undergoing elective surgerylo8. Succinylcholine is rapidly hydrolysed
by plasma cholinesterase in humanslogand magnesium does not impair and may even
increase the plasma cholinesterase activity1I0.Therefore a single dose of succinylcholine can
be safely used to facilitate tracheal intubation with-

deliveries. Witlin et al.73 have also recently showed that the use of MgSO, during labour in
women with mild pre-eclampsia at term did not affect any component of labour but
necessitated use of a higher dose of oxytocin. Meta-analysis of clinical studies on MgSO, as a
tocolytic agent do not provide evidence that it is more effective in the treatment of preterm
labour than either placebo or beta mimetic^^^,'^.

Placental blood flow

Studies on the fetal and maternal components of placen- tal blood flow indicated that MgSO,
has a vasodilator effect, but the clinical significance is uncertain. Harbert et
al.76demonstrated that uterine blood flow in monkeys increased in response to an infusion of
MgSO,. Studies on isolated human maternal uteroplacental arteries77 and results obtained in
experimental animal^^^?^^ have demonstrated that infusion of Mg++increases uterine and
placental blood flow.

Effect on fetal heart rate

The effect of MgSO, on fetal heart rate variability has been a controversial issue, as there are
conflicting data in the literature. Babaknia and NiebylgOnoted a decrease in long term
variability without an associated change in short term variability. Petrie et al.g' reported an
increase in both short and long term variability in 10 women receivinga 2 g bolus of MgSO,.
Stallworthet al.71stud- ied 19 women and observed no significant difference in either short or
long term variability due to magnesium administered by either the intramuscular or
intravenous route. Canez et a1.82noted no signficant effect on fetal heart rate variability in 57
patients treated with intra- venous MgSO,.

Atkinson et al.83,using computerised fetal heart rate analysis, concluded that although
MgSO, was associated with an objectively measured statistically significant decrease in short
term variability, the decrease was not clinically signficiant, furthermore, it was not associated
with a decrease in long term variability or in the number of accelerationsmeasured.

Effect on fetus and newborn

Some authors have indicated that intravenous MgSO, decreases fetal breathingR4vSt5hereby
contributing to a decrease in the total biophysical profile score84~8isn term fetuses. Gray et
a1.86found that administration of intravenous MgSO, for tocolysis did not significantly affect
the individual components of the fetal biophysi- cal profile or the total score in healthy
preterm fetuses.

An apparent depression in serum calcium has been reported in fetuses of mothers treated with
MgS0487.

OthersR8have reported that maternal MgSO, therapy does not cause neonatal hypocalcaemia
and that the induced neonatal hypermagnesaemia is resolved within the first 48 hours of life.
The fetus is partially protected from hypermagnesaemiaand hypocalcaemiaby the pla-
centaI9. Although clinical neurological depression has been reported in the newborn babies of
women treated for pre-eclampsia with MgS0:9, occurrence of adverse effects on the offspring
is quite rareg0,with failure to identify any adverse effect on Apgar scoresp1,neonatal
mortalityg0or neonatal neurologic assessment examina- tion~~~.

Kuban et al.93noted MgSO, administered solely to prevent preterm delivery also appeared to
protect against cerebral haemorrhage. The magnitude of the apparent effect was substantial,
and the authors argued that it might be causal. In an experimental model of birth asphyxia,
magnesium aloneg4or in combinationgs was associated with less evidence of brain injury and
magnesium administration may decrease secondary neuronal damage following traumatic
brain injuryg6sg7. MgSO, has been associated with improved neonatal survival in extremely
low birthweight infantsg8,and with a lower risk of cerebral palsy in very low' and extremely
lowy9birthweight survivors.

Anaesthesia

Periodically the anaesthetist may be faced with a patient treated with MgSO, undergoing
general anaesthesia. At the neuromuscular junction magnesium decreases the presynaptic
release of acetylcholineIo0.Reduced sensi- tivity of the postjunctional membrane (motor end
plate) and decreased excitability of the muscle fibres have also been reportedlOOJO1S.uch
neuromuscular blocking effects of magnesium would be expected to potentiate the
nondepolarising blocking agents and to antagonise the depolarising block of
succinylcholinelo2.Magne- sium, however, has been shown to potentiate the activity of both
depolarising and nondepolarising neuromuscu- lar blocking agent~"~J"''.

Ghoneim and Longlo3reported that succinylcholine (depolarising)and d-

tubocurarine(nondepolarising)are potentiatedbyMgSO,, butothernondepolarisingmus- cle
relaxants, whether long acting such as pancuro- niumIo5or intermediate acting such as
vecuroniumloh are also potentiated. More recent workers have shown that the neuromuscular
blockade of succinycholine is notpotentiatedinpatientsreceivingmagnesiumtherapy for
eclampsia'07or those undergoing elective surgerylo8. Succinylcholine is rapidly hydrolysed
by plasma cholinesterase in humanslogand magnesium does not impair and may even
increase the plasma cholinesterase activity1I0.Therefore a single dose of succinylcholine can
be safely used to facilitate tracheal intubation with-

ut fear of delayed onset of relaxation or unduly pro- longed paralysisloRT. hese findings may
not apply when repeated doses of succinylcholine are used'04. Under these conditions, phase
I1block can develop and similar to nondepolarisingblock, it may be potentiated by mag-
nesium therapylo7.Magnesium has also been shown to reduce fasciculations" ' and potassium
releaseIo8after succinylcholine.

Magnesium does not appear to prolong the duration of action of succinylcholinebut the
interaction between magnesium and the nondepolarising relaxants must be borne in mind and
if this combination is to be used then thedosageofrelaxantshouldbereducedIo7M. agnesium
has been shown to provide adequate control of the car- diovascularresponseto
intubationinhypertensivepreg- nant patients' I2JI3.

The vasodilator properties of MgSO, could theoreti- cally increase the risk of maternal
hypotension with epidural anaesthesia, but anecdotal evidence suggests that anaesthetists
have successfully given epidural anaesthesia (for decades) to pre-eclamptic women who are
receiving MgSO, for seizure prophylaxis without problems. Vincent et al.78 working with
gravid ewes showed that the infusion of MgSO, slightly decreases maternal blood pressure
during epidural lidocaine anaesthesia, however, there was no decrease in uterine artery blood
flow or fetal oxygenation.
Interaction with nifedipine

Occasionally a patient is simultaneously exposed to MgSO, and nifedipine and because both
agents are calcium channel blockers, some interaction might be expected. A depressive effect
on blood pressure (increased hypotensive effect) has been observed when
theseagentsare~ombined"~C.asereportssuggest nifedipine may potentiate the neuromuscular
blockade effectandthereforetoxicityofMgS04115J1S6o.mehave advised caution to be
exercised when the combination is used116while others have advocated avoiding the
combination altogether116.Fenakel et al. l 7 studied nifedipine in women who were receiving
MgSO, and found effective blood pressure control in 96%of women without undesirable side
effects and no case of hypoten- sion in the 24 cases studied. It would therefore appear that
while a theoretical risk of interaction does exist, in practice this may be relatively uncommon.

Excretion in breast milk

Although many pre-eclamptic or eclamptic patients who are treated with MgSO, are too ill, or
their babies too premature, for consideration of breastfeeding in the early puerperium, a few
do seek advice. Cruikshank et al. l R

0 RCOG 1998 Br J Obstet Gynaecol 105, 260-268

REVIEWS 265

have demonstrated that intrapartum MgSO, treatment increases breast milk-colostrum

magnesium levels sig- nificantly for only 24 hours after discontinuation of the
infusion.After24hoursmilk-magnesium levelsarethe same as those of women acting as
controls. The breast- fed infant of a treated mother would receive only 1.5 mg of magnesium
more than the infant of a nontreated mother. McGuinness et a1." have shown that the serum
magnesium levels of the bottle-fed infants whose moth- ers received MgSO, return to control
values by 48 hours after birth.

Effect on maternal calcium homeostasis

Magnesium is intimately involved with calcium home- ostasis. Maternal

hypocalcaemiafollowing therapy with MgSO, has been described1'g-'20H.ypermagnesaemia
has been shown to decrease serum calcium levels and this has been postulated to result from
interference with synthesis or release of parathyroid hormone12'. However, women treated
for pre-eclampsia with MgSO, demonstrated elevated levels of parathyroid hormone which
tends to preserve maternal calcium lev- e l ~C~rui~ks.hank et al.25showed that MgSO,
therapy depresses maternal calcium levels by increasing urinary calcium loss and a resultant
increase in parathyroid hor- mone output prevents more marked hypocalcaemia.

Carney et al. 122 using micropuncture techniques have demonstrated that elevated
extracellular fluid magnesium levels lead to specific inhibition of calcium reabsorption in the
loop of Henle. It has therefore been postulated by Cruikshank et al.25that the most likely
explanation for the increased urinary calcium excretion during MgSO, infusion is that
magnesium and calcium compete for common reabsorptive sites or mechanisms in the
nephron. Thus the increased filtered load of mag- nesium leads to increased tubular
reabsorption of magnesium and the competition for reabsorptive sites leads to increased
urinary calcium loss, despite increased serum parathyroid hormone levels.

Conclusion

MgSO, therapy will doubtless remain a commonly used management for eclampsia and pre-
eclampsia and, to a lesser extent, preterm labour. This review aimed to demonstrate that
MgSO, is an extensively studied preparation with a long history of safe use. The mecha- nism
of action remains elusive, but it is likely there is more than one complementarymechanism
involved; the latest theory being its effect on the NMDA receptor. With diligent clinical
monitoring MgSO, is not only safe for both mother and infant, but it might actually be
beneficial to the fetus.