Does magnesium sulfate increase the incidence of postpartum hemorrhage? A systematic review

doi:10.4236/ojog.2011.14032

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Open Journal of Obstetrics and Gynecology, 2011, 1, 168-173 OJOG

doi:10.4236/ojog.2011.14032 Published Online December 2011 (http://www.SciRP.org/journal/ojog/).

Published Online December 2011 in SciRes. http://www.scirp.org/journal/OJOG

Does magnesium sulfate increase the incidence of postpartum

hemorrhage? A systematic review

Laura M. Héman, Pau l J. Q. Van Der Linden

Department of Gynaecology and Obstet rics, Deventer Ziekenhuis, Devent er, The Netherlands.

Email: [email protected]

Received 4 October 2011; revised 22 November 2011; accepted 3 December 2011.

ABSTRACT

The incidence of Postpartum Hemorrhage (PPH) is

increasing in the western world. We hypothesize that

magnesium sulfate (MgSO4) could be a contributing

factor. MgSO4 might increase the incidence of PPH

by induction of vasodilation, tocolytic effects, and

effects on the blood like red cell deformity, platelet

activity inhibition and a prolonged bleeding time.

Based on these effects of MgSO4 a correlation with

PPH is suspected. MgSO4 is widely used in the pre-

vention of eclampsia. However, the working mecha-

nism of this effective drug is largely unknown. We

performed a systematic search to find all Random-

ized Controlled trials (RCTs) containing MgSO4 in

preeclamsia as well as all MgSO4 studies with infor-

mation on PPH. Titles, abstracts and references of

publications were evaluated for appropriateness and

whether they met the inclusion criteria. RCTs about

MgSO4 with original data on PPH prevalence were

included in our systematic review. We calculated the

relative risk of PPH in every study as well as an

overall relative risk. Four relevant and valid RCTs

were found, totalling 11,621 relevant patients. The

relative risk of PPH in women treated with MgSO4 is

0.964 (95% CI 0.886 - 1.050). In this systematic re-

view we found no significant increase in PPH in

women treated with MgSO4. However, there is still

room for discussion due to the heterogeneity in

methods (dosage and duration of treatment), results,

and tertiary outcomes, as well as the small number of

studies found with respect to this important issue.

Keywords: Magnesium Sulfate (MgSO4); Postpartum

Hemorrhage (PPH)

1. INTRODUCTION

In high resource countries we see an increase in Post-

partum Hemorrhage (PPH) during the last decade [1,2].

We suspect a correlation with magnesium sulfate (MgSO4)

because of three following effects.

Firstly, magnesium sulfate is widely used in obstetri-

cal care for the prevention of eclampsia during preg-

nancy, although the exact pharmacological mechanism

of MgSO4 in pr even ting e cla mpsi a i s not kno wn [3 ]. Ce -

rebral vasoconstriction has been reported in women with

eclampsia [4]. Magnesium sulfate vasodilates intracra-

nial vessels distal to the middle cerebral artery and hence

may exert a main effect in the prophylaxis and treatment

of eclampsia by relieving cerebral ischemia. Further-

more, MgSO4 is effective as an antihypertensive drug.

This antihypertensive effect is also explained by vaso-

dilatation [5 ]. Vasodilatation could induce PPH .

Secondly, MgSO4 can be applied as a tocolytic drug.

Magnesium maintenance therapy is a type of tocolytic

therapy used after an episode of preterm labour in an at-

tempt to prevent the onset of further preterm contractions

[6]. Therefore, atonia or hypotonia of the uterus could be

possible when using magnesium sulfate. Uterus atonia is

the most c ommo n cause of postp artum hemorrha ge (PPH)

[7].

Thirdly, there are several effects of magnesium sulfate

reported on blood. Although results are conflicting, side

effects are described. Several authors find a significant

increased bleeding time in preeclamptic patients treated

with MgSO4, [8-10] while another author did not find a

difference in bleeding time in healthy volunteers given

MgSO4 [11]. Furthermore, significantly inhib ite d platelet

aggre gation [ 10] and an incre ased RBC -defor mability in

a 24 ho ur intr ave nou s ma gnes ium t hera py ar e me ntioned

[12].

In 1964 authors already had the impression that the

observed external blood loss, during and soon after, de-

livery was excessive when using MgSO4. However they

did not show proof [13]. In the latest Cochrane review

conflicting results are reported [14]. When comparing

MgSO4 with placebo, no significant difference in PPH is

found. However, when comparing MgSO4 with Nimo-

dipine (calcium channel blocker), a significant increase

in PPH is found. An expla nation for these differences is

L. M. Héman et al. / Open Journal of Obstetrics and Gynecology 1 (2011) 168-173

169

not given.

In su mmary, magne sium sul fate may i nduce va sodil a-

tion, tocolytic effects, and effects on blood (i.e. red cell

defor mity, inhibited platelet activity and pro longed blee-

ding time). If the risk of PPH is increased in women

treated with MgSO4 one should be more aware and pre-

pared for obstetric blood loss. Therefore, we performed a

systematic review of the literature to analyze whether

MgSO4 treat me nt increases the risk of PPH.

2. MA TERIALS AND METHODS

We created two queries for the database “Pubmed.” The

elements of our question are “Magnesium sulphate” and

“PPH.” We compiled a query with synonyms. Synonyms

were connected with “OR” in the search string while the

intervention (MgSO4) and outcome (PPH) were con-

nected with “AND.” Using this procedure we found 234

hits. We screened the titles and abstracts and excluded

non relevant articles, case reports and articles in other

langua ges t han En glish, Ger man and Dutc h. We o nly i n-

cluded Randomized Controlled Trials (RCTs) involving

MgSO4 treatment which gave original data about PPH.

Of the three remaining articles [13,15,16] one met our

inclusion criteria and was the refore included in this sys-

tematic review [15].

We assumed that in some randomised controlled trials

concerning MgSO4 in preeclampsia the incidence of

PPH has been examined, but not mentioned in the ab-

stract. Therefore, we searched with a nother searc h stri ng

for RCTs with MgSO4 in preeclampsia treatment. With

this procedure we found 28 hits wherein 7 possible rele-

vant trials [15-21]. After reading these articles full text, 2

studies remained [15,17]. On screening references, 3

additional articles were found [22-24] of which one was

relevant [22].

Furthermore, we searched in the Cochrane Library for

PPH studies as well as solitary MgSO4 studies. We found

the three articles we already included [15,17,22] but also

two additional relevant articles in which MgSO4 was

given for neonatal neuroprotection before preterm birth.

[25,26]. However, one [26] gave no clear definition of

PPH and was therefore not included after reading full

text. So, eventually a total of 4 RCTs were included in

our review (see Figure 1 Fl ow char t).

Within the patient populations described in these arti-

cles [15,17,22,25] we selected the women of whom there

was information about PPH, mostly women who were

followed and treated during labour.

Some authors calculated the relative risk of PPH in

women treated with MgSO4 [15,17,25]. For the remain-

ing article we calcula ted (usin g the information pr ovided)

the relative risk of the incidence of PPH and the 95%

confidence interval.

Finally, we calculated a relative risk and the 95% con-

fidence interval of the combined studies.

3. RESULTS

In Table 1 the primary results of the trials are shown.

The Magpie trial [22] included by far the most patients

(10.141). Heterogeneity between the included studies

has been found when comparing the primary outcome

measurements i. e . eclampsia, duration of labour, disease

progression and neuroprotection of the infant as well as

the comparison i.e. placebo or Nimodipine.

Information on PPH was given on a total of 11,621

wome n. T he re sults with r espect to the incidence of PPH

differ in the various articles (Ta ble 2 ). The researchers

of the Magpie trial [22] and Crowther et al. [25] did not

found a significant change in the incidence of PPH in

women when treated with MgSO4.

Belfort et al. [17] however, do find a significant dif-

ference. PPH occurs in 2.4% of the women treated with

MgSO4 versus 1 .0% of wome n in the contr ol group (RR

2.4695%C I 1.09 - 5.56; p = 0.03.)

Witlin et al. [15] report a fourfold greater incidence of

PPH in the MgSO4 group, although this finding is not

significant. There was a significant difference in the ma-

ximum dose of oxytocin used with Magnesium sulphate

versus placebo (p = 0.036).

The calculated overall relative risk does not show an

increase of the risk of PPH when using MgSO4 (RR

0.964 (95%CI 0.886 - 1.050)).

4. DISCUSS I O N

In this systematic review we do not find a significant

increase in PPH in women treated with MgSO4.

Still, there are some interesting remarks to make. Two

of four articles in this systematic review report a trend

[15] or a significant difference in PPH [17]. However,

the data given by the Magpie trial (with no significant

difference) overrule all other results because of the large

patient population. PPH was one of the many secondary

outcome measures of this study. We wonder if we can

draw any conclusions yet. Moreover, because the lo-

west dose of MgSO4 was used in the two studies which

showed no significant increased risk of PPH, including

the Magpie stud y. T hey treated with 4 gram loading d ose

continued with 1 gram per hour for 24 hours at most.

Belfort et al., who do find a significant difference, used

the longest durati on of MgS O4 treatment. They treat with

a maximum of 24 hours (mean 8.8 hour) during labour

and always 24 hours post partum. This could expla in the

differences in outcomes, and thus the effects of MgSO4.

The dosage of MgSO4 might be crucial in the risk of

PPH. It could be possible that the dosage given in the

Magpie trial is safe but that there is a threshold to pro-

voke PPH.

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170

Fi gure 1 . Flow chart of the Literature search, *search string: (((“Post partum” OR “Po st labour” OR “Po st delivery” OR “Pu eperal”

OR “Uterine”) AND (“Hypotonia” OR “Hemorrhagic” OR “Hemorrhage” OR “Heamorrhage” OR “Bleeding” OR “Bleed” OR

“Blood loss”)) OR “Hypotonia” OR “Hemorrhage” OR “Heamorrhage” OR “Bleeding” OR “Blood loss”) AND (“Magnesium sul-

phat e” OR “Magnesi um sulfate” OR “MgSO4” OR “M agnesiu msulphat e” OR “Magnesi umsulfat e”)) (August 2010). **Search strin g:

((“PE” OR “preeclampsia”) AND (“Magnesium sulphate” OR “Magnesium sulfate” OR “MgSO4” OR “Magnesiumsulphate” OR

“Magnesiumsulfate”)) AND limit [RCT] (August 2010).

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171

Table 2. PPH in MgSO4 treatmen t .

Table 1. Primary results.

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Partic u lar l y, Witlin e t a l. report a significantly higher do-

sage of ox ytoci n needed in the MgSO4 gro up (p = 0.036).

Thi s may s ugge st t hat a po ssib le e ffect of M gS O4 can be

a hypotonic uterus.

Altho ugh we had to exclude the study of Friedman et

al. [21] because the authors did not give numbers about

PPH and therefore did not meet our inclusion criteria,

there are some remarkable results. The authors examined

side effects of MgSO4 compared to phenytoin. They

found a significant greater haematocrit fall after delivery

when using MgSO4 (7.6% vs. 4.7% (p = 0.0034)), as

well as a significant greater blood loss (606 ml vs. 418

ml (p = 0.04)).

We do not question the proven and great value of

MgSO4 in preventing eclampsia or the indication when

to start this treatment. But one can doubt the evidence

about side effects. One may suggest that since 2002 MgSO4

treatment possibly becomes more and more common. A

false sense of security in preventing eclampsia could

enha nce t he u se o f M gS O4 and the duration of treatment.

Remarkably, in this systematic review we found only

very few articles (4) that studied PPH in combination

with MgSO4 treatment, while knowing that MgSO4 is

extensively used all over the world and PPH is a dan-

gerous and frequent complication of labour [2].

It would be interesti ng to kno w the exact p harmacolo-

gical effect of MgSO4. This would help us to understand

the function of MgSO4 in preventing eclampsia as well

as other possible side effects such as PPH. Theoretically,

MgSO4 still could influence the uterus tonus, the bleed-

ing time and provoke vasodilatation.

To give a definitive answer on our question, ideally a

trial with PPH as a primary outcome should be perfo r-

med. Secondary, dosage and duration of MgSO4 therapy

should be considered, together with interventions to

pre vent P PH , i.e. the dosage of oxytocin. With respect to

PPH, the decrease in haemoglobin or haematocrit could

provide objective results. In women with HELLP syn-

drome the risk of PPH in combination with a possible

trombopenia should be considered.

A limitation of our study is that we mainly systemati-

cally searched the Pubmed database. However, a scree-

ning in Embase did not show any relevant articles. An-

other limitation of our overview could be the heteroge-

neity of the articles included. We d ecided to only use an

assessment for statistical heterogeneity with population

size. One could question if you can compare women

with preeclampsia with women with threatened preterm

birth who are given MgSO4 as neuroprotection for the

foetus. However, we decided that when researching the

unknown effect of MgSO4 on PPH the indication for

treatment are less relevant. Moreover, this heterogeneity

is an argument for more and specific research.

In this systematic review, we do not find a significant

risk of PPH when treating with MgSO4. MgSO4 has a

great, important and proven role in the prevention of

ecla mpsia . Ho wever, in our opinion, conse nsus o n the que -

stion whether MgSO4 does or does not influence blood

loss during delivery is not possible, due to few and non

specific studies and the heterogeneity of the relevant

studies.

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