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.
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

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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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Copyright © 2011 Sci Re s. OJOG
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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Table 2. PPH in MgSO4 treatmen t .
Table 1. Primary results.

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Copyright © 2011 Sci Re s. OJOG
172
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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