Commentary and Review by:

Malcolm Griffiths, MD, MRCOG, MFFP, Cert.Mgmnt
OBGYN.net Advisory Board Member

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Title: Is tocolytic magnesium sulphate associated with increased total paediatric mortality?
Reference: Lancet 1997; 350:1517-1518
Authors: Robert Mittendorf, Robert Covert, Julie Boman, Babak Khoshnood, Kwang-Sun Lee, Mark Siegler
Institutions: Department of Obstetrics and Gynaecology (R Mittendorf), Section of Neonatology, Department of Paediatrics, and MacLean Center for Clinical Medical Ethics, Pritzker School of Medicine, University of Chicago, Chicago, IL 60637, USA

Division of Paediatrics, Obstetrics & Gynaecology, Imperial College School of Medicine, Hammersmith Hospital Campus, London, W12 0HS, UK.
(Bennett & Edwards)
Study Design: Randomised controlled trial
Rating:

This was accompanied by a commentary:

Use of magnesium sulphate in obstetrics
Phillip Bennett, David Edwards
Lancet 1997; 350:1491
(Not available via online version)

Abstract:

None available from authors, but full text available via www.thelancet.com - after FREE registration - go to Nov 22 issue.

Reviewer's Abstract:

The Magnesium and Neurologic Endpoints Trial (MAGnet) was and RCT with four arms. In the tocolytic arms, women in preterm labour at less than 34 weeks' gestation and 4 cm dilated or less were randomised to either MgSO4 (4 g bolus, then 2-3 g/hour infusion) or other tocolytic (unblinded obstetrician's choice of ritodrine, terbutaline, indomethacin, or nifedipine). In the doubly-blinded preventive arms, women in preterm labour, but with advanced cervical dilatation, who were not eligible for tocolysis, were randomised to either a 4 g bolus of MgSO4, or saline control. Pre-eclamptic women were excluded because all receive prophylactic MgSO4 in the USA.

In the tocolytic arms, switchovers between MgSO4 and other tocolytic were permitted if the obstetrician believed initial tocolysis had failed. Primary study outcomes were total paediatric mortality (sum of fetal, neonatal, and post-neonatal mortality) and cerebral palsy.

Interim safety monitoring showed nine paediatric deaths (one fetal, four neonatal, and four post-neonatal) of those randomised and exposed to MgSO4 (seven tocolytic, two preventive), one death in those randomised but not exposed to tocolytic MgSO4, and one death in the preventive arms in those randomised but not exposed to saline (precipitate labour). In the tocolytic arms, all deaths occurred in those initially randomised to MgSO4.

Overall, there were ten paediatric deaths (five singletons, three twin pairs in which one sibling died, one twin pair in which both siblings died [thus, nine unique pregnancies]) in 75 maternal randomisations (65 singletons, ten twin pairs) to MgSO4 and one paediatric death (singleton) among 75 maternal randomisations (69 singletons, six twin pairs) to other or saline control. With intent to treat analysis, the difference was statistically significant (risk difference 107%, 95% CI 29%-185%; two-sided Fisher's exact test, p=002). In the tocolytic arms, eight paediatric deaths (three singletons, three twin pairs in which one sibling died, one twin pair in which both siblings died [thus, seven unique pregnancies]) occurred in 46 maternal randomisations (37 singletons, nine twin pairs) to MgSO4 and no paediatric deaths in 47 maternal randomisations (42 singletons, five twin pairs) to other tocolytic (risk difference 152%, 95% CI 44-260%; p=001). In the preventive arms, two paediatric deaths (both singletons) occurred in 29 maternal randomisations (28 singletons, one twin pair) to MgSO4 and one paediatric death in 28 maternal randomisations (27 singletons, one twin pair) to saline (not significant).

Analysis of the four groups showed no confounding variables. Five infant deaths were unexpected and sudden and we do not yet have a physiological explanation (table).

Commentary:

MgSO4 was introduced as a tocolytic in the USA in 1969 on the basis of laboratory work only. There have been a small number of RCTs of magnesium sulphate for tocolysis - largely against other tocolytics, rather than placebo. Clear evidence of benefit of MgSO4 is lacking.

Recently interest in the possible neuro-protective effects of MgSO4 (authors first reference) prompted this study. Indeed this effect is also to be studied as a secondary outcome measure in the MAGPIE study (an RCT of prophylactic MgSO4 vs. placebo in severe pre-eclampsia - details on request to reviewer).

This report shows very significantly poorer outcomes in babes exposed to MgSO4 compared to those not. Unfortunately (and this is admitted by the authors) we currently lack a biologically plausible mechanism for these excess deaths, most of which occurred very remote in time from the exposure to MgSO4. These findings warrant caution in continued use of MgSO4 for more than short-term tocolysis. They should also prompt other institution that may have data available which could be analysed regarding MgSO4 exposure and perinatal outcome to look at their data. Organisers of future trials (such as MAGPIE) will need to consider the implications of this study. All future trials involving obstetric use of MgSO4 should collect data on neonatal outcome.

In the commentary Bennett & Edwards conclude:

"This trial tilts the balance of evidence firmly away from magnesium use as a tocolytic or cerebroprotectant in preterm labour. Magnesium should probably also be restricted to only the most severe forms of pre-eclampsia or to eclampsia, where its value may outweigh the neonatal risks."

The commentary also gives a more detailed set of references:

1. Cotton DB, StrassnerT, Hill LM, Schifrin BS, Paul RH. A comparison of magnesium sulfate, terbutaline and a placebo for the inhibition of preterm labour. J.Reprod Med 1984; 29..92-97
2. Witlin AG, Friedman SA, Sibai BM. The effect of magnesium sulfate therapy on the duration of labor in women with mild pre-eclampsia at a randomised, double blind, placebo controlled trial. Am J. Obstet Gynecol 1997; 176: 623-27
3. Atkinson MW, Guinn D,Owen 1, Hauth JC. Does magnesium sulfate affect the length of labor induction in women with pregnancyassociated hypertension? Am J. Obstet Gynecol 1995; 173: 1219-22
4. Higby K, Xenakis EMJ, Pauerstein Cj. Do tocolytic agents stop preterm labor) A critical and comprehensive review of efficacy and safety. Am J. Obstet Gynecol 1993; 168:1247-59
5. The Eclarnpsia Trial Collaborative Group. Which anticonvulsant for women with eclampsia? Evidence from the collaborative eclampsia trial. Lancet 1995; 345: 1455-63
6. Lucas M, Leveno K, Cunningham FG. A comparison of magnesium sulfate with phenytoin for the prevention of eclampsia. N.Engl.J. Med 1995;333:201-05.
7. Nelson KB, Grether JK. Can magnesium sulfate reduce the risk of cerebral palsy in very low birthweight infants? Pediatrics 1995; 95: 263-69
8. Schendel DE, Berg CJ,Yeargin-Allsopp M, Boyla C A, Decoufle P. Prenatal magnesium sulfate exposure and the risk for cerebral palsy or mental retardation among very low-birth-weight children aged 3 to 5 years. JAMA 1996; 276: 1805-1 1.
9. Panedi N, jetton J, Pintomartin J, et al. Magnesium sulfate in labor and risk of neonatal brain lesions and cerebral palsy in low birthweight infants. Pediatrics 1997; 99: El1-E16.
10. Penrice J, Arness PN, Punwani S, et al. Magnesium sulfate after transient hypoxia-ischemia fails to prevent delayed cerebral energy failure in the newborn piglet. Ped Res 1997; 41: 1-5.
11. Dehaan HH, Gunn AJ,Williams CE, Heyman MA, Gluckinan PD. Magnesium sulfate therapy during asphyxia in near term fetal lambs does not compromise the fetus but does not reduce cerebral injury. J.Obstet Gynecol 1997; 176:18-27.

References

1. Nelson KB, Grether JK. Can magnesium sulfate reduce the risk of cerebral palsy in very low birthweight infants? Pediatrics 1995; 95: 263-69.
2. Cox SM, Sherman ML, Leveno KJ. Randomized investigation of magnesium sulfate for prevention of preterm birth. Am J Obstet Gynecol 1990; 163: 767-72.
3. Lucas MJ, Leveno KJ, Cunningham FG. A comparison of magnesium sulfate with phenytoin for the prevention of eclampsia. N Engl J Med 1995; 333: 201-05.
4. The Eclampsia Trial Collaborative Group. Which anticonvulsant for women with eclampsia? Evidence from the Collaborative Eclampsia Trial. Lancet 1995; 345: 1455-63.