Magnesium in obstetrics

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.56,57 Several publication
shaveargued against the use of magnesium for this purpose, citing absence of efficacy and
apossible in crease inside effects, particularly foeta ldeath.58,59 A meta- analysis of the data
concluded that the only available randomised controlled trials were in adequate to allow firm
conclusions.60 Perhaps surprisingly,there is no evidence that MgSO4 therapy prolongs the
duration of normal labour.61–63 The effect on caesarean section rate is less clear, with some
studies showing no increasein the frequency of caesare an deliveries 64,62 while alargemeta-
analysis found a significant increase int he risk of caesarean section (relativeratio (RR)
1.21,95% confidence interval (CI)1.05–1.41) in magnesium- treated women.43

Spora dicreports of neonatalhy potonia,65 respiratory depression and altered parathyroid

hormone function66 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.65 Foetal heart rate (FHR) variability is decreased by
magnesium,67,68,18 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.61 Current evidence in preeclampsia would
suggest that there is no real concern forn eonatal well-being. However, the situation regarding
premature infants born to mothers treated for early labourisless clear with arguments that
magnesium may be beneficial or harmful. The oretically, the calciumand NMDA antagonism
of magnesium could protect the developing brain from hypoxia. 69 Fine Smith et al. found
that magnesium protected exposed neonates against developing cysticperiventricular
leukomalacia, 70 but Canterino et al. found no benefit.71 Nelson and Grether noted an
increased survival and decreased incidence of cerebralpalsy in very low-birth-weight infants
whose mothers had received MgSO4 either as atocolytic or for pre-eclampsia,72 but sub
sequently, the same group failed to confirm this effect in premature infants, although they
concluded that magnesium did not increase the risk of neonatal death.73 Other studies have
tended to confirm the possible protection but have been inconclusive. Are trospective study
failed to demonstrate any association between magnesium therapy and alterations in
favourable or unfavourable outcomes in magnesium-exposedinfants.75 Other authors have
suggested that magnesium inpreterm labour increased the risk of harminvery-low- birth
weight infants.76–78 Recently, however, two meta-analyses suggested that magnesium
administration to women atrisk of delivery before 34 weeks of gestation reduced the risk of
cerebral palsy,79 and onec oncluded ‘‘the neuro protective role for antenatal MgSO4 therapy
given to women at riskof preterm birth for the preterm foetus is no we stablished.’’80 Whilst
the selater studies are strongly suggestive of abeneficial effect, neurologic protection of the
preterm foetus cannot beregarded as firmly established at the present time, although the trend
of currentevidence seems to suggest a possible benefit.
Clinical use of magnesium in obstetrics Pre-eclampsia While magnesium is now the agent of
choice for the prevention of eclamptic convulsions, the argument as to whetherall pre-
eclamptic patients should begiven magnesium is not resolved. Although magnesium is very
safe, it is not entirely without risk, particularly in areas where monitoring may be limited, and
consideration has to begiven to the benefit / risk ratio of using the agent against the exposure
of al argenum berof patients to a therapy which most of them do not need. There are also
risks attached tousing an unfamiliar for mof treatment in areas where severe preeclampsia is
in frequent.81 Most adverse effects are mild, but overdose may lead to respiratory
embarrassment and even death if not carefully managed. It can there for ebeargued that
magnesium should be administered selectively to patients at greates trisk of eclamptic
convulsions.The greatest risk/ benefit ratio has been shown in countries with high perinatal
mortality where severe pre-eclampsia is common.38 Such patients are more likely to
experience convulsions, and the numbers needed to treat (NNTs) to prevent one eclamptic
convulsion in this group of patients is71. In more developed countries, where mild
preeclampsia predominates, the NNT is around 385, thus requiring large numbers of patients
to be exposed to magnesium to benefitonly a small number. Unfortunately, approximately
20% of eclamptic women do not have any premonitory signs or symptoms before the onset of
convulsions. In attempting to resolve this conundrum,one study investigated the
consequences of changing from aregimen of MgSO4 administration in all preeclamptic
women to one in which magnesium was only administeredif mild pre-eclampsia pro- gressed
to severe disease. 82 This change resulted in a50% overall increase in the prevalence of
eclampsia and an increase in maternal and neonatal morbidity.83 There is no clarity as to the
best way to resolve the balance of risks and a randomised controlled trial to investigate this
problem would require vast numbers. Every woman with severe disease or who has had an
eclamptic convulsion should receive magnesium. Where to draw the line in patients with mild
disease is currently impossible to state. Related to this issue is the problem of when to stop
therapy following delivery. Again, there is no clarity, although current opinion generally
recommends continuing the magnesium infusion for 24 hafter delivery although one, fairly
small, study in which the infusion was stopped at 12 hafter delivery failed to demonstrate any
increase in convulsions or progression of disease.84

It is also note stablished whether or not magnesium is a good agent for controlling a patient
who is actually convulsing. Many authorities would recommend theuse of diazepam as the
first-line agent to halt the convulsion and use magnesium there after to prevent furt her fits.
However, personal experience and that of others suggests that a bolus of 30–60mg kg_1
MgSO4 can be rapidly effective in halting convulsions.39 The best choice remains open to
question, and perhaps the pragmatic approach of using the mostreadily available agent is the
best route to follow at present.

Dosage and administration There are several dosage regimes for the use of magnesium in
preeclampsia, largely dependent on the availability of sophisticated delivery and monitoring
systems. The main risk of magnesium infusion is accidental massive overdose with
neuromuscular blockade and respiratory failure. 31 Intravenous magnesium should be
delivered using a syringe driver, rather than the farmorerisky approach of an infusion throug
had ripset. Where such facilities are not available, the intramuscularroute is reasonably well
tolerated and farless likely to produce dangerously high concentrations of plasma magnesium.

Commonly used intravenous approaches for pre-eclampsia recommend a loading dose of 4–

6g MgSO4 infuse dover15–20 min.Giving this size of dose more rapidly(over1–2min) is
unpleasant in the a wake patient, causing aburning sensation and nausea; in the unconscious,
ventilated patient, arapid injection of 60 mgkg–1 may be safely given and repeated after 5
min for the control of convulsions or to decrease excessively elevated arterial pressure. This
is then followed by a continuous infusion of 1–4gh_1. The target plasma concentration
should be between 2 and 3.5 mmoll–1 and deep tendon reflexes should be monitored
regularly. Monitoring of plasma concentrations becomes important where tendon reflexes are
absent orin the presence of renal dysfunction. In the intra muscular regimen, bilateral 5 g
intramuscular buttock injection sarefol- lowed by 5 g intramuscularly every 4 h there after.
Some suggested approaches to magnesium dosing are given in Table2.

Tocolysis A meta-analysis of tocolytics showed that allagent swere more effective than
placeboat delaying labourat 48 h and at 7 days, but there were no other significant
differences.85 This analysis suggested that prostaglandin inhibitors provided the best
combination of tolerance and delayed delivery. Magnesium achieved asuccessrate of 82% at
delaying labour by 48 h, superior to allother agents other than the prostaglandin inhibitors 85
but was less effective at 7 days. Part of the difficulty incomparing the controversial evidence
may lie in the variety of dosage regimes employed. Lew is point edout that dosage was
crucial with low-dose regimens (4g loading dose and 2 gh_1 infusion) achieving less than
75% efficacy, while a higher dose (6g loading dose and >2 gh_1) achieved over 85%
efficacy. 86 Elliott et al. Suggested a dosage regimen for MgSO4 of a 6-g loading dose
followed by an infusion of 3–5g h_1. 87 There seem, there fore, arguments both for and
against the use of magnesium for tocolysis, and the clinical choice should probably be
influenced by drug availability and familiarity until such time as convincing evidence of
efficacy and safety for the various agents is available. Where high-dose magnesium is to be
used, it appears important that adequate plasma levels are obtained, and this should be one
area where therapy is guided by measurements of plasma Mg2þ concentration with alower
limit of 2.5 mmoll_1 and an upper limit of 4 mmoll_1 probably being advisable, but there are
no studies to confirm the seranges. Magnesium sulphate and nifedipine remain the most
widely used first-line agents for tocolysis in the United Statesat present.