mag sulphate story

6Over half a million women die each year of pregnancy-related causes, 99% of thesedeaths occur in the developing world.5,6 Put another way, women in industrialised

Best Practice & Research Clinical Obstetrics and GynaecologyVol. 19, No. 1, pp. 5774, 2005doi:10.1016/j.bpobgyn.2004.10.010

available online at http://www.sciencedirect.comcountries have an average lifetime risk (calculated as the average number of pregnanciesmultiplied by the risk associated with each pregnancy) of dying from pregnancy-relatedcauses of between 1 in 4000 and 1 in 10 000, whereas women in low- to middle-incomecountries have a risk that is between 1 in 15 and 1 in 50. In poor countries, maternal

* Tel.: C44 1865 226 642; Fax: C44 1865 227173.E-mail address: [email protected] and practice: the magnesium

sulphate story

Lelia Duley* MD (Hons), MSc (Epid), FRCOGObstetric Epidemiologist

Resource Centre for Randomised Trials, Institute of Health Sciences, Old Road, Oxford OX3 7LF, UK

There is now strong evidence from systematic reviews of randomised trials to support the use ofmagnesium sulphate for the prevention and treatment of eclampsia. Magnesium sulphate more thanhalves the risk of eclampsia for women with pre-eclampsia (relative risk (RR) 0.41, 95% confidenceinterval (CI) 0.290.58; number needed to treat (NNT) 102 (95% CI 72173) compared toplacebo. For treatment of eclampsia, magnesium sulphate lowers the risk of maternal death(RR 0.59, 95% CI 0.370.94) and of recurrence of further fits (RR 0.44, 95% CI 0.340.57)compared to diazepam. Magnesium sulphate also reduces the risk of further fits comparedto phenytoin (RR 0.31, 95% CI 0.200.47) and to lytic cocktail (RR 0.09, 95% CI 0.030.24).

Key words: magnesium sulphate; eclampsia; pre-eclampsia; systematic reviews.

Eclampsia is defined as the occurrence of one or more convulsions superimposed onthe syndrome of pre-eclampsia. Pre-eclampsia is relatively common, complicating 28%of pregnancies.1 Although a major cause of maternal morbidity, perinatal death, andpremature delivery, it is only rarely associated with maternal death. Eclampsia occursfar less frequently, complicating between 1 in 100 and 1 in 1700 pregnancies in thedeveloping world13, and about 1 in 2000 pregnancies in Europe and other developedcountries.4 Compared to pre-eclampsia it carries a much higher risk of death for thewoman and her baby, however. In the UK, for example, 1 in 50 of the women who haveeclampsia will die.41521-6934/$ - see front matter Q 2004 Elsevier Ltd. All rights reserved.

mortality is 100200 times higher than in Europe and North America.7 There is noother public health statistic for which the disparity between developed and developing

was magnesium sulphate (Horn 1906, from Ref. 12). Reports of the successful controlof convulsions due to tetanus gave impetus to its introduction for eclampsia.14,15 By the

58 L. Duley1920s, magnesium sulphate was being used for eclampsia in Europe12 and in the UnitedStates.1517 Although not everyone reported favourable results18, magnesium sulphateadministration became established clinical practice in several parts of the world. Itbecame the drug of choice in North America19 although, until recently, supported onlyby data from uncontrolled case series.20,21 Despite the lack of adequate controls, thesereports had a huge influence on the clinical practice of several generations ofobstetricians.22 This use of magnesium sulphate was rapidly extended to women withpre-eclampsia17,23, in the hope it would prevent the onset of eclampsia and so improveoutcome.24,25

For decades there has been huge geographical variation in the use of magnesiumsulphate. Places that looked to the United States for guidance used magnesium sulphatecountries is so wide. Although rare, eclampsia probably accounts for 50 000 maternaldeaths a year worldwide. In areas where maternal mortality is high, infection andhaemorrhage are the main causes of death but, as deaths from these causes becomeless common, those associated with eclampsia and pre-eclampsia assume greater

importance. In the UK, eclampsia is a factor in 15% of direct maternal deaths.8

This chapter tells the story of magnesium sulphate for the prevention and treatmentof eclampsia. The story begins at the turn of the 19th century. It includes the evolutionof our understanding of the underlying disease, salutary lessons about the delays inproper evaluation of care9, and concludes with a summary of the evidence fromsystematic reviews. The incomplete postscript is about how to get this evidence intopractice.

EVOLUTION OF CARE FOR PREVENTION AND TREATMENTOF ECLAMPSIA

The occurrence of seizures during pregnancy has been noted since ancient Egyptiantimes, but was thought to be a form of epilepsy.10 In 1843, eclampsia was shown to beassociated with proteinuria and was assumed to be a disease of the kidneys duringpregnancy, a form of pregnancy nephritis.11 Measurement of blood pressure did notbegin until around 1910, so hypertension was not part of the diagnosis until much later.

Before the mid-19th century, management of eclampsia consisted largely of bleedingand purging. Sedatives such as morphine and chloral hydrate were introduced but didlittle to reduce the very high mortalitybetween 20 and 30%associated witheclampsia.11,12 It was recognised that convulsions often ceased after delivery, andinterventions to expedite delivery became popular.

In the early 20th century, two contrasting approaches to the care of women witheclampsia emerged. One was based on the belief that prompt termination of thepregnancy would prevent disease progression and obstetric intervention shouldtherefore be maximal and early, the other aimed to prevent further fits and avoidoperative delivery.13,14 The rationale behind early policies for expectant managementwas that heavy sedation would stabilise the woman and prevent further convulsions.Later, agents believed to have a more specific anticonvulsant action were introduced.

One of the first drugs suggested to have a specific anticonvulsant effect for eclampsia

for both eclampsia and pre-eclampsia. In other countries, it was used hardly at all, moreconventional anticonvulsants such as diazepam or phenytoin being preferred. Part of

for the prevention and treatment of eclampsia.33,34 Magnesium sulphate is now the drugof choice for both the prevention and treatment of eclampsia.35

Evidence and practice: magnesium sulphate 59PREVENTING THE ONSET OF ECLAMPSIA

The first question about magnesium sulphate as a prophylactic anticonvulsant forwomen with pre-eclampsia is whether it reduces the risk of eclampsia. Even if itdoes, additional information is required before magnesium sulphate can safely berecommended for clinical practice; in particular, information is needed about thesize of any risk reduction, effects on other important outcomes for the woman andchild, and the disease severity at which benefits outweigh the risks. The methodsfor the systematic review summarised below are described in detail elsewhere.36 Inbrief, the review included randomised trials (Table 1) of any anticonvulsant forwomen with pre-eclampsia, regardless of whether before or after delivery, whethera singleton or multiple pregnancy, or whether an anticonvulsant had been givenbefore trial entry.

Magnesium sulphate versus placebo or no anticonvulsant

Six trials (11 444 women) compared magnesium sulphate with placebo or noanticonvulsant. Magnesium sulphate is associated with more than a halving in the riskof eclampsia (relative risk (RR) 0.41, 95% confidence intervals (CI) 0.290.58; riskdifference (RD) K0.01, 95% CI K0.02 to K0.01, number needed to treat (NNT) 102(95% CI 72173) compared with placebo or no anticonvulsant. This relative risk isthe scepticism about magnesium sulphate was the lack of any plausible hypothesis forhow it might work. The mode of action for magnesium sulphate is still not clearlyunderstood, but it might cause vasodilatation with subsequent reduction of cerebralischaemia26, and/or block some of the neuronal damage associated with ischaemia.27,28

A possible mechanism for vasodilatation is relaxation of smooth muscle. It has beensuggested that magnesium might have a generalised effect on all smooth muscle,including the peripheral vasculature and uterus, hence the hypotheses that it might alsohave antihypertensive and tocolytic effects. Alternatively, any effects of magnesiumsulphate in control of eclamptic convulsions might be, wholly or partially, through itsrole as a blocker of N-methyl-D-aspartate (NMDA) receptors in the brain.27 TheseNMDA receptors are activated in response to asphyxia, leading to calcium influx intothe neurons, which causes cell injury. Magnesium might block these receptors, so

reducing calcium influx and protecting the neurones.27,28

Case control studies have suggested that in utero exposure to magnesiumsulphate might reduce the risk of cerebral palsy for low birthweight (!1500 g)babies.29 Later, there was concern that magnesium sulphate exposure for thesevulnerable babies might be associated with an increased mortality.30 It has beenargued that a link between exposure to magnesium sulphate before preterm birthand an increase in mortality is unlikely31, and there are now data from arandomised trial suggesting that such exposure is associated with a moderateimprovement in paediatric outcome.32

Two large collaborative trials have evaluated policies for the use of anticonvulsants

Table 1. Characteristics of trials evaluating anticonvulsants for women with pre-eclampsia.

Trial Methods Participants Interventions

Anticonvulsant versus none

Magpie Trial

2002 (nZ10 141)33

Central telephone service (2037 women), or

consecutively numbered, sealed treatment

packs, stratified by centre (8104). Computer-

generated sequence. Five women excluded: 4

no data, 1 entered into wrong trial. 175

centres in 33 countries. 85% women from low-

to middle-income countries

Uncertainty about whether to use MgSO4,

before birth or 24-hour postpartumCDBP

R90 mmHg, SBP R140 mmHg !2 3060 minutes apart, R1Cproteinuria. Excluded:hypersensitivity to Mg, hepatic coma with risk

of renal failure, myasthenia gravis

MgSO4: 4 g i.v. bolus. Then either 1 g/hour

infusion or 10 g i.m. followed by 5 g every

4 hours. Continued for 24 hours. Two centres

used 5 g i.m. then 2.5 g every 4 hours. Placebo:

by identical regimen. Dose halved if oliguria

South Africa

1998 (nZ822)45

Sealed opaque envelopes containing cards

labelled A or B. Cards consecutively num-

bered. Batches of 20, with equal A and B.

Identity of A and B changed periodically. 137

women (17%) excluded after randomisation

Severe PE: R2 of DBP 110 mmHg, proteinuria,symptoms of imminent eclampsia. Also, O16years and no prior anticonvulsant

MgSO4: 4 g i.v. in 200 ml over 20 minutes, then

1 g/hour until 24 hours after delivery. Control:

placebo by same regimen. Both groups had

clonazepam at trial entry

South Africa

1994 (nZ228)46

Consecutively numbered sealed opaque

envelopes

DBP: 110 mmHg for 46 hoursCprotein and

delivery planned. Excluded if prior antic-

onvulsant (except phenobarbitone)

MgSO4: 4 g i.v. over 20 minutes, 10 g i.m., then

5 g i.m. every 4 hours for 24 hours. Control:

no anticonvulsant

Taiwan 1995

(nZ64)47Randomised, no other information

BP 150/100 mmHg and R1 of 11 features ofPE. Excluded if IUD, or chronic HT

MgSO4: 4 g i.v. over 10 minutes, then 1 g/hour

until 24 hours after delivery. Control: no

anticonvulsant

USA-Memphis

1997 (nZ135)48

Sealed, sequentially numbered opaque envel-

opes

R37 weeks gestation with recent onset PE (BP140/90 mmHg and proteinurea 300 mg in

24 hours). Excluded if severe PE, fetal mal-

presentation, congenital anomaly, non-reas-

suring fetal testing

MgSO4: 6 g i.v. bolus over 1520 minutes, then

infusion of 2 g/hour. Continued until 12 hours

postpartum. Placebo: saline solution by iden-

tical regimen

USA-Tennes-

see 2003 (nZ222)49

Randomised placebo-controlled trial. No

further information

222 women with mild PE during labour.

Excluded: chronic HT, severe PE

MgSO4: 6 g i.v., then infusion of 2 g/hour.

Placebo: matching regimen

Magnesium sulphate versus phenytoin

60

L.D

uley

USA-Texas

1995 (nZ2138)50

Numbered opaque envelopesBP 140/90 mmHg. Excluded if postpartum,

delivery imminent or epilepsy

MgSO4: 10 g i.m., then 5 g every 4 hours. If

severe PE, 4 g before first i.m. dose. Phenytoin:

1000 mg i.v. over 1 hour. 10 hours later,

500 mg orally

USA-Alabama

1995 (nZ54)51Blinded computer-generated random number

tables

Singleton pregnancy, medical induction for PIH,

unfavourable cervix

MgSO4: 4 g i.v., then infusion 2 g/hour. Pheny-

toin: 15 mg/kg over 2 hours then 200 mg i.v.

every 8 hours

USA-Maryland

1993a (nZ115)52

Sealed opaque envelopes. 12 exclusions after

trial entry

BP 140/90 mmHg, or rise SBP 30 mmHg or

DBP 15 mmHg. Excluded if prior MgSO4 or

seizure disorder

MgSO4: 6 g i.v., then infusion 2 g/hour for

24 hours. Phenytoin: 10001500 mg, depend-

ing on weight. Serum levels to determine next

dose, for 24 hours

Magnesium sulphate versus diazepam

Mexico 1992

(nZ38)53Numbered opaque envelopes

28 weeks, SBP R150 mmHg, DBPR110 mmHg, proteinuria, at least one symp-tom. No epilepsy

MgSO4: 4 g i.v. over 15 minutes, then 1 g/hour

infusion. Diazepam: 30 mg in 500 ml 5%

glucose at 60 mg/hour

Malaysia 1994a

(nZ28)54Consecutive sealed envelopes DBP R110 mmHg plus proteinuria

MgSO4: Pritchards regimen. Diazepam: not

stated

Magnesium sulphate versus nimodipine

Nimodipine

Study Group

2003 (nZ1750)55

Sealed opaque envelopes. Blocks of 6

Antepartum women with severe PE and no

previous therapy. BP R140/90, R1Cprotei-nurea, R1 sign or symptom of imminenteclampsia

MgSO4: either 6 g i.v. and 2 g/hour or 4 g i.v.

and 1 g/hour. Nimodipine: 60 mg 4 hourly,

orally. Continued for up to 24 hours post-

partum

Magnesium sulphate versus methyl dopa

Denmark 2000

(nZ33)56

Numbered sealed opaque envelopes. Two

exclusions from MgSO4 group (1 withdrawal, 1

given methyl dopa)

Nulliparous, singleton pregnancy and BP O140/90 mmHg !2 over 3 hours. Excluded:pre-existing HT, cardiac or renal disease, BP O180/120 mmHg after hydralazine

MgCl2: 80 mmol i.v. in 24 hours, 40 mmol in

next 24 hours. Then 15 mmol/day MgOH2orally until 3 days after delivery. Methyl dopa:

250 mg !4/day. After delivery reduced by

250 mg/day

BP, blood pressure; DBP, diastolic blood pressure; HT, hypertension; i.m., intramuscular; IUD, intrauterine death; i.v., intravenous; MgOH2, magnesium hydroxide;

MgSO4, magnesium sulphate; PE, pre-eclampsia; PIH, pregnancy-induced hypertension; PPH, postpartum haemorrhage; SBP, systolic blood pressure.a Women with eclampsia in these trials not included in this review.

Evid

ence

and

practice:

magn

esium

sulp

hate

61

Studyor sub-category

Magnesiumn/N

Controln/N

RR (fixed)95% cl

RR (fixed)95% cl

South Trial 2002South Africa 1994

South Africa 199801 severe pre-eclampsia

Subtotal (95% Cl)

Subtotal (95% Cl)

Total (95% Cl)

Total events: 17 (Magnesium), 48 (Control)



Test for heterogeneity: Chi2=3.73, df=2(P=0.15),I2=46.4%

Test for heterogeneity: Chi2=5.22, df=4(P=0.27),I2=23.4%

Test for overall effect: Z=3.58 (P=0.0003)

Test for overall effect: Z=5.02 (P

consistent regardless of severity of pre-eclampsia (Figure 1) or of whether the womenwere antepartum at trial entry, or of gestation at trial entry (data not shown).

magnesium sulphate rather than placebo or no anticonvulsant (RR 0.97, 95% CI 0.95

Evidence and practice: magnesium sulphate 630.99).For women randomised before delivery, the relative risk of placental abruption

was reduced if they were allocated magnesium sulphate rather than placebo (RR0.64, 95% CI 0.500.83; RD K0.01, 95% CI K0.02 to 0.00; NNT 100, 95% CI 501000). Women allocated magnesium sulphate had a small (5%) increase in the riskof caesarean section compared to those allocated placebo or no anticonvulsant (RR1.05, 95% CI 1.011.10; RD 0.03, 95% CI 0.010.04; NNT 34, 95% CI 10025).There was no evidence of a clinically important effect on the risk of induction oflabour (RR 0.99, 95% CI 0.941.04), postpartum haemorrhage (RR 0.96, 95% CI0.881.05) or manual removal of placenta (RR 0.90, 95% CI 0.721.12).

For the babies, there was no overall difference in the risk of stillbirth or neonataldeath (three trials, 9961 women), although a small increase or decrease in mortalityassociated with the use of magnesium sulphate remains possible (RR 1.04, 95% CI 0.931.15) (Figure 2). The result is consistent regardless of gestation at trial entry (data notshown). For the composite outcome of death or in special care baby unit for O7 days,there is also no clear evidence of a clinically important difference (RR 1.01, 95% CI0.951.08). There was no clear evidence of any difference in neonatal morbiditybetween the two groups.

Toxicity was uncommon, occurring in around 1% of women given magnesiumsulphate and 0.5% of those allocated placebo. There was no clear evidence of anoverall difference in the risk of absent or reduced tendon reflexes (RR 1.00, 95%CI 0.701.42). Although respiratory depression and other respiratory problemswere rare (52/5344 versus 26/5333), the relative risk of these was increased forwomen allocated magnesium sulphate (RR 1.98, 95% CI 1.243.15; NNT 206, 95%CI 1000100). A quarter of women allocated magnesium sulphate had side effects(24 versus 5%; RR 5.26, 95% CI 4.596.03; NNT 6, 95% CI 65). By far the mostcommon side effect was flushing. Problems at the injection site were morecommon for women allocated magnesium sulphate than those allocated placebo,and for those who had intramuscular (i.m.) as opposed to intravenous (i.v.)treatment (i.m. 12 versus 8%; i.v. 5 versus 2%).


Two trials (2241 women) compared magnesium sulphate with phenytoin.Magnesium sulphate appears to be better than phenytoin at reducing the risk ofeclampsia (RR 0.05, 95% CI 0.000.84; RD 0.01, 95% CI K0.02 to 0.00; NNT 111,95% CI 67333), although the number of events was small (0 versus 10).Magnesium sulphate was associated with a greater risk of caesarean section thanTwo trials (10 795 women) reported maternal deaths. Risk of dying was reduced by46% for women allocated magnesium sulphate rather than placebo or no antic-onvulsant, although this did not achieve statistical significance (RR 0.54, 95% CI 0.261.10). For the two trials (10 332 women) reporting serious maternal morbidity, therelative risk was 1.08 (95% CI 0.891.32). For the individual measures of seriousmorbidity, such as pneumonia, renal failure and liver failure, there was also no clearevidence of an overall difference in effect between the two groups. There was a small(3%) reduction in the need for antihypertensive therapy associated with the use of

Magpie Trial 2002South Africa 1998

South Africa 199401 severe pre-eclampsia01 severe pre-eclampsia

Subtotal (95% Cl) 1650 1691

3353 3367

49585003

Total events: 292 (Magnesium), 293 (Control)Test for heterogeneity: Chi2=2.42, df=2(P=0.30),I2=17.5%Test for overall effect: Z=0.30 (P=0.77)

Subtotal (95% Cl)Total events: 342 (Magnesium), 318 (Control)Test for heterogeneity: not applicableTest for overall effect: Z=0.63 (P=0.53)

02 not severe pre-eclampsiaMagpie Trial 2002

Total (95% Cl)Total events: 634 (Magnesium), 611 (Control)Test for heterogeneity: Chi2=2.50, df=3(P=0.48),I2=0%Test for overall effect: Z=.067 (P=0.50)

20/117234/118538/348

25/118230/1219

342/3353 318/3267

28/354

0.81 [0.48, 1.37]

1.05 [0.91, 1.21]1.05 [0.91, 1.21]

1.04 [0.93, 1.15]

1.00 [0.85, 1.18]1.38 [0.87, 2.20]1.02 [0.88, 1.18]

0.1 0.2 0.5 1 2 5 10Favours magnesium Favours control


Magnesiumn/N

Controln/N

RR (fixed)95% cl

RR (fixed)95% cl

Figure 2. Magnesium sulphate versus placebo or no anticonvulsant: effect on stillbirths and neonatal deaths (subgrouped by severity of pre-eclampsia).

64

L.D

uley

phenytoin (RR 1.21, 95% CI 1.051.41; RD 0.05, 95% CI 0.010.08; NNT 21 95%CI 8312). There is no information on other important measures of maternal

those with moderate or mild pre-eclampsia. Therefore, fewer women need to be

to be considerably higher for mild pre-eclampsia. Although unpleasant side effects

In the comparisons of magnesium sulphate with alternative agents, magnesium is

Evidence and practice: magnesium sulphate 65clearly better than either phenytoin or nimodipine. The remaining trials are too smallfor any firm conclusions.are common with magnesium sulphate, toxicity is rare. Almost all these data arebased on a 24-hour treatment regimen, clinical monitoring (of tendon reflexes,respiratory rate and urine output), and either intramuscular maintenance therapy,or an intravenous infusion of 1 g/hour. The reassurance about safety and lack ofserious side effects cannot, therefore, be extrapolated to higher doses, longerduration or serum monitoring.treated to prevent one case of eclampsia for severe pre-eclampsia, than for non-severe pre-eclampsia. Few women in this review had mild pre-eclampsia, as thenon-severe category primarily includes women with moderate disease. The numberof women who would need to be treated to prevent one case of eclampsia is likelymorbidity. Confidence intervals for estimates of the differential effects on measuresof morbidity and mortality for the baby are wide, and cross the no effect line.

Magnesium sulphate versus nimodipine

One trial compared magnesium sulphate with nimodipine (1750 women). Fewerwomen allocated magnesium sulphate, rather than nimodipine, had eclampsia (RR 0.33,95% CI 0.140.77). Mortality for the baby is not reported.

Comparisons of other agents

Two trials (66 women) have compared magnesium sulphate with diazepam and anotherhas compared magnesium chloride with methyl dopa (31 women).

Discussion

There is strong evidence from placebo-controlled trials that, for women with pre-eclampsia, magnesium sulphate more than halves the relative risk of eclampsia. Itseems likely that it also leads to a clinically important reduction in the risk ofmaternal death. The only other effects associated with magnesium sulphate are areduction in the risk of placental abruption and a small (5%) increase in the risk ofcaesarean section. Side effects from magnesium sulphate are common, butunpleasant rather than serious. There is no substantive effect on stillbirth orneonatal mortality. Longer-term follow-up of the children is required to providereassurance that this apparent short-term safety continues into childhood, and totest the hypothesis that exposure to magnesium sulphate might reduce the risk ofcerebral palsy for low birthweight infants. Such data from the Magpie Trial37 shouldbe available by the end of 2004.

The relative effect on eclampsia is consistent regardless of the severity of pre-eclampsia. Eclampsia is more common in women with severe pre-eclampsia than in

Table 2. Characteristics of trials evaluating anticonvulsants for women with eclampsia.


Magnesium sulphate versus diazepam

Collabora-

tive Trial

1995 (nZ910)34

Consecutively num-

bered sealed identical

treatment packs. Five

women excluded

Eclampsia: 54% allo-

cated MgSO4 had antic-

onvulsant before entry,

as had 50% allocated

diazepam. 30% ran-

domised after delivery

MgSO4: 4/5 g i.v. over 5 minutes.

Then either 10 g i.m. and 5 g every

4 hours for 24 hours or 1 g/hour

for 24 hours. For recurrent fits, 2 g

i.v. Diazepam: 10 mg i.v. bolus, then

40 mg in 500 ml for 24 hours. 20 mg

in 500 ml for a further 24 hours. For

recurrent fits, 10 mg i.v.

Egypt 1993

(nZ105)67Randomly allocated,

no further details

105 women with

eclampsia and 13 with

imminent eclampsia.

For eclampsia, 44 allo-

cated MgSO4 were

recruited before deliv-

ery, and 29 allocated

diazepam

MgSO4: 4-6 g i.v. Then 12 g/hour i.

v. 1 g if !55 kg, 2 g if O55 kg.Diazepam: 1020 mg i.v. over 2

5 minutes. Then 2030 mg in

500 ml i.v. to keep woman drowsy

until delivery

India 2001

(nZ100)57Randomly distributed,

no further details

Eclampsia: 70 women in

first pregnancy and 79

recruited before deliv-

ery

MgSO4: 4 g in 25% MgSO4 over

10 minutes. 5 g i.m. 4 hourly until

24 hours after delivery or, if post-

partum at randomisation, for

24 hours. Diazepam: 10 mg i.v.

bolus, 40 mg/500 ml i.v. for

24 hours. 20 mg/500 ml for a

further 24 hours. Then 10 mg i.m.,

changed when possible to oral. For


Malaysia

1994 (nZ11)54

Consecutive sealed

envelopesEclampsia

MgSO4: Pritchards regimen. Dia-

zepam: not stated

Zimbabwe

1990 (nZ51)58

Consecutively num-

bered sealed envelopes.

Blocks of 6, no stratifi-

cation

Antepartum eclampsia:

R28 weeks, live fetus.67% had diazepam

before entry; 71% of

those allocated MgSO4,

and 63% diazepam

MgSO4: 4 g i.v. over 35 minutes

and 10 g i.m. Then 5 g every 4 hours


i.v. Diazepam: 10 mg i.v. bolus, then

80 mg in 1 l for 24 hours. 40 mg in

1 l for a further 24 hours. For


Zimbabwe

1998 (nZ69)59

Consecutively num-

bered sealed treatment

packs

Eclampsia: 40% of

women had already had

an anticonvulsant and

43% had delivered

MgSO4: Either (a) 4/5 g i.v. over

5 minutes and 10 g i.m. Then 5 g i.m.

every 4 hours for 24 hours. Or (b)

4/5 g i.v. over 5 minutes, then 1 g/

hour for 24 hours. If recurrent fits

2 g i.v. Diazepam: 10 mg i.v. bolus.

Then infusion of 40 mg/500 ml for

24 hours. 20 mg/500 ml for next

24 hours. If recurrent fits, 10 mg i.v.

(continued on next page)

66 L. Duley

Table 2 (continued)



Collabora-

tive Trial

1995 (nZ777)34

Consecutively num-

bered sealed identical

treatment packs. Two

women lost to follow

up

Eclampsia: 76% allo-

cated MgSO4 had antic-

onvulsant before trial

entry, and 80% allo-

cated phenytoin. 19%

postpartum centres in

South Africa and India

MgSO4: 4/5 g i.v. over 5 minutes.

Then, either 10 g i.m. and 5 g every

4 hours for 24 hours or 1 g/hour


i.v. Phenytoin: 1 g i.v. over 20 min-

utes, then 100 mg every 6 hours for

24 hours. For fits, diazepam 10 mg

India 1999

(nZ50)60

Sealed envelopes.

Sequence generated by

computer

Eclampsia: 29 women

had an anticonvulsant

before entry

MgSO4: 4 g i.v.C8 g i.m. Then 4 g i.

v. 4 hourly, until 24 hours after

delivery. Phenytoin: 15 mg/kg at

50 mg/min10 mg/kg initially then

5 mg/kg 2 hours later. 500 mg i.v.

12 hours later. Then 250 mg either

i.v. or oral, 12 hourly for 4 doses. All

women: 10 mg diazepam i.v. for fits,

5 mg nifedipine sl at entry

South

Africa 1990

(nZ22)61Random number tables

Antepartum eclampsia.

No prior anticonvulsant

MgSO4: 4 g i.v. over 2030 minutes,

then 12 g/hour for 24 hours. Phe-

nytoin: 500 or 1000 mg i.v. at max

50 mg/minute. Then 500 mg over

4 hours, 12 hours later, 500 mg

over 4 hours. All had clonazepam at

trial entry

South

Africa 1996

(nZ24)62

Computer-generated

random numbers in

sealed envelopes

Eclampsia

MgSO4: 4 g i.v. and 10 g i.m.

Phenytoin: 1 g in 200 ml over 15

20 minutes. Both described as

loading dose only

USA-Mary-

land 1993

(nZ2)63

Sealed opaque envel-

opes

Antepartum eclampsia

(103 with PE included in

PE review)

MgSO4: 6 g i.v. bolus then infusion of

2 g/hour. Phenytoin: infusion of

1000, 1250, or 1500 mg

USA-Mem-

phis 1995

(nZ24)64Randomly allocated

Eclampsia: 9 women

allocated MgSO4 and 5

phenytoin had MgSO4before trial entry. 79%

not delivered

MgSO4: 6 g i.v. over 15 minutes,

then 2 g/hour to keep serum levels

4.89.6 mg/dl. Phenytoin: 1-1.5 g i.v.

Additional doses to keep serum

levels 1020 m/ml

Magnesium sulphate versus lytic cocktail

India 1994

(nZ91)65

Sealed, numbered, opa-

que envelopes in blocks

of 8. One woman

excluded

Eclampsia

MgSO4: 4 g i.v.C8 g i.m., then 4 g 4

hourly until 24 hours after delivery.

If recurrent fits, 1.5 g i.v. Lytic

cocktail: pethidine, promethazine

and chlorpromazine as described

by Menon

(continued on next page)

Evidence and practice: magnesium sulphate 67

Table 2 (continued)

68 L. DuleyCONTROLLING THE ACUTE CONVULSION AND PREVENTINGRECURRENCE OF ECLAMPSIA

When a woman has eclampsia, the immediate question is how best to control the acutefit. Once the first fit has subsided, the next question is how best to reduce the risk ofher having further fits.

Currently, immediate care for women with eclampsia is to give a loading dose ofanticonvulsant. If the woman is still fitting this will, usually, control the acute fit. It alsoensures therapeutic levels are achieved rapidly. Maintenance therapy is then started,with the aim of reducing the risk of further fits. This is usually continued for 24 hours,although some advocate continuing until 24 hours after delivery. The choice ofanticonvulsant has been controversial but magnesium sulphate is now the drug ofchoice.34,38

Systematic reviews have compared magnesium sulphate with diazepam39, pheny-toin40 and lytic cocktail.41 Methods for these reviews are described in detailelsewhere.3941 In brief, they include trials (Table 2) comparing alternative antic-onvulsant regimens for eclampsia regardless of whether the first fit was before or afterdelivery, whether the pregnancy was singleton or multiple, and irrespective of whetheran anticonvulsant had been given before trial entry.Trial Methods Participants Interventions

India 1995

(nZ108)66Randomly allocated.

No other informationEclampsia

MgSO4: 4 g i.v.C10 g i.m. loading

dose, then 5 g 4 hourly up to

24 hours after delivery. Lytic cock-

tail: 100 mg pethidineC25 mgchlorpromazine i.v. and 50 mg

chlorpromazineC25 mg prometha-

zine i.m. 100 mg pethidine i.v. over

24 hours, 25 mg promethazine 4

hourlyC50 mg chlorpromazine 8

hourly for 48 hours i.m.

i.m., intramuscular; i.v., intravenous; MgSO4, magnesium sulphate; PE, pre-eclampsia; sl, sublingual.Magnesium sulphate versus diazepam

Seven trials (1441 women) compared magnesium sulphate with diazepam. Magnesiumsulphate is associated with a reduction in the risk of maternal death compared todiazepam, although the confidence intervals are wide (RR 0.59, 95% CI 0.370.94). Forrecurrence of convulsions, there is a substantial reduction in risk associated withmagnesium sulphate (RR 0.44, 95% CI 0.340.57) (Figure 3). So, on an average, for everyseven women treated with magnesium sulphate rather than diazepam, one recurrenceof convulsions will be prevented (95% CI 610 women). There is no clear difference inany other measure of maternal morbidity.

For the baby, the only statistically significant differences associated with the use ofmagnesium sulphate, rather than diazepam, are a reduction in the risk of an Apgar score


Magnesiumn/N

othern/N

RR (fixed)95% cl

RR (fixed)95% cl

Subtotal (95% Cl)

Subtotal (95% Cl)

Subtotal (95% Cl)


Total events: 4 (Magnesium), 49 (Other)

Test for heterogeneity: Chi2=1.56, df=4(P=0.82),I2=0%

Test for heterogeneity: Chi2=0.00, df=1(P=0.98),I2=0%

Test for overall effect: Z=5.48 (P

!7 at 5 minutes (RR 0.72, 95% CI 0.550.94), and in length of stay in special care babynursery O7 days (RR 0.66, 95% CI 0.460.95.

and a greater risk of toxicity.

70 L. DuleyDiscussion

Magnesium sulphate is the drug of choice for women with eclampsia. There isstrong evidence that it is better than either diazepam or phenytoin, and reasonableevidence that it is preferable to lytic cocktail. Women allocated magnesiumsulphate had magnesium sulphate for treatment of the acute fit, for maintenancetherapy and for control of any recurrence. It has been argued that diazepamshould be used for control of the acute fit42, but this view is not supported byevidence.43

In these trials, women allocated magnesium sulphate for treatment of eclampsialargely had the same regimens as those discussed above for pre-eclampsia; loading doseof 4 g i.v., and then either intramuscular injections or an infusion of 1 g/hour, continuedfor 24 hours, with clinical monitoring. Higher dose or longer duration are unlikely toconfer greater benefit but would almost certainly be associated with more side effectsMagnesium sulphate versus lytic cocktail

Two trials (199 women) compared magnesium sulphate with lytic cocktail, usually amixture of chlorpromazine, promethazine and pethidine. Magnesium sulphate issubstantially better for preventing further fits than lytic cocktail (RR 0.09, 95% CI0.030.24; RD 0.43, 95% CI K0.53 to K0.34; NNT 3, 95% CI 23) (Figure 3).Although magnesium sulphate is associated with fewer maternal deaths than lyticcocktail, the numbers are small and the difference is not statistically significant (RR0.25, 95% CI 0.041.43). Both trials report data on respiratory depression, the riskof which was reduced with magnesium sulphate (RR 0.12, 95% CI 0.020.91).There were no cases of respiratory depression in the magnesium sulphate group(0/96 versus 8/102). Other measures of maternal morbidity were reported by onlyone trial.Magnesium sulphate versus phenytoin

Six trials (897 women) compared magnesium sulphate with phenytoin. Magnesiumsulphate is associated with a 69% reduction in the relative risk of recurrent convulsions,compared to phenytoin (RR 0.31, 95% CI 0.200.47) (Figure 3). On an average, forevery eight women treated with magnesium sulphate rather than phenytoin, onerecurrence of convulsions will be prevented (95% CI 613 women). The trend inmaternal mortality favours magnesium sulphate (RR 0.50, 95% CI 0.241.05).Magnesium sulphate is also associated with a lower risk of pneumonia (RR 0.44, 95%CI 0.240.79), ventilation (RR 0.66, 95% CI 0.490.90) and admission to an intensivecare unit (RR 0.67, 95% CI 0.500.89) than phenytoin.

Babies whose mothers were allocated magnesium sulphate, rather than phenytoin,had fewer admissions to a special care baby unit (RR 0.73, 95% CI 0.580.91) and fewerdied or were in special care for O7 days (RR 0.77, 95% CI 0.630.95).

CONCLUSIONS

After decades of dispute about whether to use an anticonvulsant for prophylaxis ofeclampsia, and which one to use for treatment of eclamptic fits, both these issues havebeen resolved.44 This achievement is due largely to the collaboration of women,clinicians and researchers in the conduct of two large randomised trials: one involved1687 women and their carers in 27 hospitals in nine developing countries34, the other10 141 women (85% from developing countries) and their carers in 175 hospitals in 33countries.33 Thanks to their collective efforts, we now have reliable evidence thatmagnesium sulphate can both prevent and control eclamptic convulsions. Medical,midwifery or nursing staff, provided they are appropriately trained, can perform theadministration and clinical monitoring of magnesium sulphate. As this is an inexpensivedrug, it is especially suitable for use in low-income countries: it is time for concertedaction to ensure that women all over the world benefit from the results of theimportant research on magnesium sulphate.44

Practice points

magnesium sulphate is the anticonvulsant of choice for women with eclampsia magnesium sulphate should be considered for women with pre-eclampsia for

whom there is concern about the risk of eclampsia intravenous administration is preferable, as side effects and injection site

problems seem lower duration of treatment should not normally exceed 24 hours and if maintenance

therapy is by intravenous infusion this should not exceed 1 g/hour women should have clinical monitoring before and during treatment whether a loading dose of magnesium sulphate should be used at primary care

level before transfer to hospital is unclear. Other factors in this decision arelikely to include how long it will take to get the woman to hospital, how ill she isand what support is available during transfer

Evidence and practice: magnesium sulphate 71Research agenda

what is the minimum effective dose of magnesium sulphate? when is the optimal time to start prophylaxis? what is the role of magnesium sulphate at the primary care level? is magnesium sulphate for prevention of pre-eclampsia cost effective? what are the long-term consequences of exposure for the mother and her

child? any new agents for the prophylaxis or treatment of eclampsia should be

compared with magnesium sulphate in large randomised trials before beingintroduced into clinical practice

theories about the pathogenesis of eclampsia need to take account of thesedata

REFERENCES

72 L. Duley1. World Health Organization International Collaborative Study of Hypertensive Disorders of Pregnancy.

Geographic variation in the incidence of hypertension in pregnancy. Am J Obstet Gynecol 1988; 158: 8083.

2. Crowther CA. Eclampsia at Harare Maternity Hospital. An epidemiological study. S Afr Med J 1985; 68:

927929.

3. Bergstrom S, Povey G, Songane F & Ching C. Seasonal incidence of eclampsia and its relationship to

meteorological data in Mozambique. J Perinat Med 1992; 20: 153158.

4. Douglas KA & Redman CW. Eclampsia in the United Kingdom. BMJ 1994; 309: 13951400.

*5. Mahler H. The safe motherhood initiative: a call to action. Lancet 1987; 1: 668670.

6. Rosenfield A & Maine D. Maternal mortalitya neglected tragedy. Where is the M in MCH? Lancet 1985;

2: 8385.

7. World Health Organization and UNICEF. Revised 1990 Estimates of Maternal Mortality. Geneva: WHO;

1990.

*8. The National Institute for Clinical Excellence, The Scottish Executive Health Department, The

Department of Health Social Services and Public Safety Northern Ireland. Why Mothers Die 19971999:

The Fifth Report of the Confidential Enquiries into Maternal Deaths in the United Kingdom. London: RCOG

Press; 2001.

9. Chalmers I & Grant A. Salutary lessons from the Collaborative Eclampsia Trial. Evidence-Based Med 1996;

1: 3940.

10. Chesley LC. A short history of eclampsia. Obstet Gynecol 1974; 43: 559602.

11. Loudon I. Death in Childbed: An International Study of Maternal Care And Maternal Mortality 18001950.

Oxford: Clarendon Press; 1992.

12. Chesley L. Survey of management and case fatality. In Chesley L (ed.) Hypertensive disorders of pregnancy.

New York: Appelton Century Crofts, 1978, pp. 309340.

13. Eden TW. Eclampsia: a commentary on the reports presented to the British Congress of Obstetrics and

Gynaecology, June 29th 1922. J Obstet Gynaecol Br Emp 1922; 29: 386401.

14. Stroganoff W & Davidovitch O. Two hundred cases of eclampsia treated with magnesium sulphate. A

preliminary report. J Obstet Gynaecol 1937; 44: 289299.

15. Lazard EM. A preliminary report on the intravenous use of magnesium sulphate in puerperal eclampsia.

Am J Obstet Gynecol 1925; 9: 178188.

16. Dorsett L. The intramuscular injection of magnesium sulfate for the control of convulsions in eclampsia.


17. Lazard EM. An analysis of 575 cases of eclamptic and pre-eclamptic toxemias treated by intravenous

injections of magnesium sulphate. Am J Obstet Gynecol 1933; 26: 647656.

18. Irving FC. The treatment of eclampsia by plasmaphaeresis. N Engl J Med 1930; 203: 10701072.

19. Gifford R, August P, Chesley L et al. National high blood pressure education program working group

report on high blood pressure in pregnancy. Am J Obstet Gynecol 1990; 163: 16911712.

20. Pritchard JA & Pritchard SA. Standardized treatment of 154 consecutive cases of eclampsia. Am J Obstet

Gynecol 1975; 123: 543552.

21. Pritchard JA, Cunningham FG & Pritchard SA. The Parkland Memorial Hospital protocol for treatment of

eclampsia: evaluation of 245 cases. Am J Obstet Gynecol 1984; 148: 951963.

22. Sibai BM. Magnesium sulfate is the ideal anticonvulsant in preeclampsiaeclampsia. Am J Obstet Gynecol

1990; 162: 11411145.

23. Eastman NJ & Steptoe PP. The management of preeclampsia. Can Med Assoc J 1945; 52: 562568.

24. Zuspan FP. Problems encountered in the treatment of pregnancy-induced hypertension. A point of view.


25. Pritchard JA. The use of the magnesium ion in the management of eclamptogenic toxemias. Surg Gynecol

Obstet 1955; 100: 131140.

26. Belfort MA & Moise Jr. KJ. Effect of magnesium sulfate on maternal brain blood flow in preeclampsia: a

randomized, placebo-controlled study. Am J Obstet Gynecol 1992; 167: 661666.

27. Sadeh M. Action of magnesium sulfate in the treatment of preeclampsiaeclampsia. Stroke 1989; 20: 1273

1275.

28. Goldman RS & Finkbeiner SM. Therapeutic use of magnesium sulfate in selected cases of cerebral

ischemia and seizure. N Engl J Med 1988; 319: 12241225.

29. Nelson KB & Grether JK. Can magnesium sulfate reduce the risk of cerebral palsy in very low birthweight

*

*

*

*

*

*

*

*

Evidence and practice: magnesium sulphate 73infants? Pediatrics 1995; 95: 263269.

30. Scudiero R, Khoshnood B, Pryde PG et al. Perinatal death and tocolytic magnesium sulfate. Obstet Gynecol

2000; 96: 178182.

31. Grether J, Hoogstrate J, Selvin S & Nelson KB. Magnesium sulphate tocolysis and risk of neonatal death.


32. Crowther C, Hiller J, Doyle L, Haslam R & for the Australasian Collaborative Trial of Magnesium Sulphate

(ACTOMgSO4) Collaborative Group. Effect of magnesium sulfate given for neuroprotection before

preterm birth. JAMA 2003; 290: 26692676.

33. Magpie Trial Collaborative Group. Do women with pre-eclampsia, and their babies, benefit from magnesium

sulphate? The Magpie Trial: a randomised placebo-controlled trial. Lancet 2002; 359: 18771890.

34. Eclampsia Trial Collaborative Group. Which anticonvulsant for women with eclampsia? Evidence from the

Collaborative Ecampsia Trial. Lancet 1995; 345: 14551463.

35. Roberts JM, Villar J & Arulkumaran S. Preventing and treating eclamptic seizures. Magnesium sulphate is

effective and recommended for use. BMJ 2002; 325: 609610.

36. Duley L, Gulmezoglu AM & Henderson-Smart DJ. Magnesium sulphate and other anticonvulsants for

women with pre-eclampsia. The Cochrane Library12003;: CD000025.

37. Magpie Trial Follow Up Study Management Group. The Magpie Trial Follow Up Study: outcome after

discharge from hospital for women and children recruited to a trial comparing magnesium sulphate with

placebo for pre-eclampsia [ISRCTN86938761]. BMC Pregnancy and Childbirth 2004; 4(5).

38. Robson SC. Magnesium sulphate: the time of reckoning. Br J Obstet Gynaecol 1996; 103: 99102.

39. Duley L & Henderson-Smart D. Magnesium sulphate versus diazepam for eclampsia. The Cochrane Library

2004; 1: CD000127.

40. Duley L & Henderson-Smart D. Magnesium sulphate versus phenytoin for eclampsia. The Cochrane Library

2004; 1: CD000128.

41. Duley L & Gulmezoglu AM. Magnesium sulphate versus lytic cocktail for eclampsia. The Cochrane Library

2004; 1: CD002960.

42. Fox R & Draycott T. Prefer diazepam for initial control of pre-eclamptic fits. BMJ 1995; 311: 1433.

43. Duley L. Magnesium sulphate should be used for eclamptic fits. BMJ 1996; 312: 639.

44. Sheth SS & Chalmers I. Magnesium for preventing and treating eclampsia: time for international action.

Lancet 2002; 359: 18721873.

45. Coetzee EJ, Dommisse J & Anthony J. A randomised controlled trial of intravenous magnesium sulphate versus

placebo in the management of women with severe pre-eclampsia. Br J Obstet Gynaecol 1998; 105: 300303.

46. Moodley J & Moodley J. Prophylactic anticonvulsant therapy in hypertensive crises of pregnancythe

need for a large randomized trial. Hypertens Pregnancy 1994; 13: 245252.

47. Chen F, Chang S & Chu KK. Expectant management in severe preeclampsia: does magnesium sulfate

prevent the development of eclampsia. Acta Obstet Gynecol Scand 1995; 74: 181185.

48. Witlin A, Friedman S & Sibai B. The effect of magnesium sulfate therapy on the duration of labor in women

with mild preeclampsia at term: a randomized double-blind, placebo-controlled trial. Am J Obstet Gynecol

1997; 176: S15.

49. Livingston J, Livingston L, Ramsey R et al. Magnesium sulfate in women with mild preeclampsia: a

randomised controlled trial. Obstet Gynecol 2003; 217220.

50. Lucas M, Leveno K & Cunningham M. A comparison of magnesium sulfate with phenytoin for the

prevention of eclampsia. New Engl J Med 1995; 333: 201205.

51. Atkinson M, Guinn D, Owen J & Hauth J. Does magnesium sulfate affect the length of labor induction in

women with pregnancy-associated hypertension? Am J Obstet Gynecol 1995; 173: 12191222.

52. Friedman S, Kee-Hak L, Baker C & Repke J. Phenytoin versus magnesium sulphate in pre-eclampsia: a pilot

study. Am J Perinatol 1993; 10: 233238.

53. Walss RR & Levario A. Anticonvulsant treatment of severe pre-eclampsia: comparison of diazepam and

magnesium sulfate. Gynecol Obstet Mexico 1992; 60: 331335.

54. Adeeb N, Hatta A & Shariff J. Comparing magnesium sulphate to diazepam in managing severe pre-

eclampsia and eclampsia. Proceedings of 10th World Congress International Society for the Study of

Hypertension in Pregnancy 1996; 246.

55. Belfort M, Anthony J, Saade G, Allen J & for tNSG. A comparison of magnesium sulfate and nimodipine for

the prevention of eclampsia. N Engl J Med 2003; 348: 304311.

56. Rudnicki M, Frolich A, Pilsgaard K et al. Sanchez Mea. Comparison of magnesium and methyl dopa for the

control of blood pressure in pregnancies complicated with hypertension. Gynecol Obstet Invest 2000; 49:

231235.

57. Rani M, Sharma D, Prakash A. Maternal and perinatal outcome in eclampsia: diazepam vs magnesium

sulphate regimen (a prospective trial). Personnal Communication.

58. Crowther C. Magnesium sulphate versus diazepam in the management of eclampsia: a randomized

controlled trial. Br J Obstet Gynaecol 1990; 97: 110117.

59. Duley L & Mahomed K. Magnesium sulphate in eclampsia. Lancet 1998; 351: 10611062.

60. Sawhney H, Sawhney I, Mandal R et al. Efficacy of magnesium sulphate and phenytoin in the management

of eclampsia. J Obstet Gynaecol Res 1999; 25: 333338.

61. Dommisse J. Phenytoin sodium and magnesium sulphate in the management of eclampsia. Br J Obstet

Gynaecol 1990; 97: 104109.

62. Naidu S, Payne A, Moodley J et al. Randomised study assessing the effect of phenytoin and magnesium

sulphate on maternal cerebral circulation in eclampsia using transcranial Doppler ultrasound. Br J Obstet

Gynaecol 1996; 103: 111116.

63. Friedman S, Lim K, Baker C & Repke J. Phenytoin vs magnesium sulfate in preeclampsia: a pilot study. Am

J Perinatol 1993; 10: 233238.

64. Friedman S, Schiff E, Kao L & Sibai B. Phenytoin versus magnesium sulfate in patients with eclampsia:

preliminary results from a randomized trial. Am J Obstet Gynecol 1995; 172: 384.

65. Bhalla A, Dhall G & Dhall K. A safer and more effective treatment regimen for Eclampsia. Aust N Z J Obstet

Gynaecol 1994; 34: 144148.

66. Jacob S, Gopalakrishnan K & Lalitha K, Standardised clinical trial of magnesium sulphate regime in comparison

with M.K.K. Menons lytic cocktail regime in the management of eclampsia Proceedings of the 27th British

Congress of Obstetrics and Gynaecology, 47 July 1995, Dublin 1995 p. 303.

67. Sayed EH, Sayed GH, Abdel Aal DM et al, A comparative trial of magnesium sulphate and diazepam in the

management of eclampsia Proceedings of 10th Annual Scientific Conference of Assiut Faculty of Medicine April

1993.

74 L. Duley

Evidence and practice: the magnesium sulphate storyEvolution of care for prevention and treatment of eclampsiaPreventing the onset of eclampsiaMagnesium sulphate versus placebo or no anticonvulsantMagnesium sulphate versus phenytoinMagnesium sulphate versus nimodipineComparisons of other agentsDiscussion

Controlling the acute convulsion and preventing recurrence of eclampsiaMagnesium sulphate versus diazepamMagnesium sulphate versus phenytoinMagnesium sulphate versus lytic cocktailDiscussion

ConclusionsReferences

mag sulphate story

Documents