OBSTETRICS

Magnesium Sulphate for Eclampsia and

Fetal Neuroprotection: A Comparative
Analysis of Protocols Across Canadian
Tertiary Perinatal Centres
Dane A. De Silva, MPH,1,2 Diane Sawchuck, RN, PhD,1 Peter von Dadelszen, MBChB,1,2
Melanie Basso, RN, MSN,3 Anne R. Synnes, MDCM, FRCPC, DPhil,2,4
Robert M. Liston, MBChB, FRCSC,1 Laura A. Magee, MD, FRCPC2,5,6;
on behalf of the MAG-CP Collaborative Group (Appendix 1)
Department of Obstetrics and Gynaecology, University of British Columbia, Vancouver BC
1

Child and Family Research Institute, University of British Columbia, Vancouver BC

2

Children’s and Women’s Health Centre of British Columbia, Vancouver BC

3

Department of Pediatrics, University of British Columbia, Vancouver BC

4

Department of Medicine, University of British Columbia, Vancouver BC

5

Department of Medicine, British Columbia Women’s Hospital and Health Centre, Vancouver BC
6

Abstract Results: Twenty-two of the 25 centres submitted protocols for

Background: Magnesium sulphate (MgSO4) has been recommended
for fetal neuroprotection to prevent cerebral palsy, with national
societies adopting new guidelines for its use. A knowledge
translation project to implement Canadian guidelines is ongoing.
Discussion about MgSO4 for fetal neuroprotection could not occur
distinct from MgSO4 for eclampsia prophylaxis and treatment.
Thus, in order to explore standardization of MgSO4 use in Canada,
we sought to compare local protocols for eclampsia and fetal
neuroprotection across tertiary perinatal centres.
Methods: Twenty-five Canadian tertiary perinatal centres were
asked to submit their protocols for use of MgSO4 for eclampsia
prophylaxis/treatment and fetal neuroprotection. Information
abstracted included date of protocol, definitions of indications for
treatment, details of MgSO4 administration, maternal and fetal
monitoring, antidote for toxicity, and abnormal signs requiring
physician attention. Descriptive analyses were used to compare
site protocols with known definitions of preeclampsia. Data from
the Canadian Perinatal Network (CPN) were used to verify what
was done in clinical practice.
Key Words: Magnesium sulphate, fetal neuroprotection,
preeclampsia, eclampsia, protocol
Competing Interests: None declared.
Received on March 13, 2015
Accepted on April 16, 2015
eclampsia prevention/treatment. Eleven of these provided a
definition of preeclampsia that warranted treatment; five of the
22 advised treatment of severe preeclampsia only. Criteria for
treatment and monitoring procedures varied across centres.
Sixteen of the 22 sites with protocols had data from the CPN.
Of 635 women with pre-eclampsia, 422 (66.5%) received
MgSO4. Twenty of 25 centres provided protocols for fetal
neuroprotection. Definitions of indications were consistent
across sites, except for gestational age cut-off.
Conclusion: This study suggests that local protocols are often
inconsistent with published evidence. While this may be related
to local institutional practices, relevant processes must be put
in place to maximize uniformity of practice and improve patient
care.
Résumé
Contexte : L’utilisation de sulfate de magnésium (MgSO4) a été
recommandée à des fins de neuroprotection fœtale dans le but
de prévenir l’infirmité motrice cérébrale; des sociétés nationales
adoptent d’ailleurs de nouvelles lignes directrices quant à son
utilisation. Un projet de transfert des connaissances visant la
mise en œuvre des lignes directrices canadiennes est en cours.
Le rôle du MgSO4 en ce qui concerne la neuroprotection fœtale
ne peut être abordé sans que l’on mentionne son utilisation dans
le cadre de la prophylaxie et de la prise en charge de l’éclampsie.
Ainsi, pour explorer la standardisation de l’utilisation de MgSO4
au Canada, nous avons cherché à comparer les protocoles
locaux qui en régissent l’utilisation en matière d’éclampsie et de
neuroprotection fœtale dans les centres périnataux tertiaires.

NOVEMBER JOGC NOVEMBRE 2015 l 975

Obstetrics
Méthodes : Nous avons demandé à 25 centres périnataux tertiaires
canadiens de nous soumettre leurs protocoles quant à l’utilisation
du MgSO4 aux fins de la neuroprotection fœtale et de la
prophylaxie / prise en charge de l’éclampsie. Les renseignements
que nous avons tirés de ces protocoles comprenaient la date du
protocole, les définitions des indications de traitement, les détails
de l’administration du MgSO4, le monitorage maternel et fœtal,
l’antidote pour contrer la toxicité et les symptômes anormaux
nécessitant l’offre de soins médicaux. Des analyses descriptives
ont été utilisées pour comparer les protocoles de ces centres aux
définitions connues de la prééclampsie. Des données issues du
Réseau périnatal canadien (RPC) ont été utilisées pour vérifier ce
qui se faisait dans le cadre de la pratique clinique.
Résultats : Vingt-deux des 25 centres nous ont soumis leurs
protocoles de prévention / prise en charge de l’éclampsie. Onze
de ces centres nous ont fourni une définition de ce qui était
considéré comme une prééclampsie justifiant une prise en charge;
cinq des 22 centres ne préconisaient que la prise en charge de la
prééclampsie grave. Les critères des interventions de traitement
et de monitorage variaient d’un centre à l’autre. Seize des 22 sites
comptant des protocoles présentaient des données issues du RPC.
Au sein d’un groupe de 635 femmes connaissant une prééclampsie,
422 (66,5 %) ont reçu du MgSO4. Vingt des 25 centres nous ont
fourni leurs protocoles de neuroprotection fœtale. Les définitions
des indications étaient uniformes d’un site à l’autre, sauf en ce qui
concerne le seuil en matière d’âge gestationnel.
Conclusion : Cette étude avance que les protocoles locaux
ne concordent souvent pas avec les données probantes
publiées. Bien que cela puisse être attribuable aux pratiques
institutionnelles locales, des processus pertinents doivent être mis
en place pour maximiser l’uniformité de la pratique et améliorer
les soins offerts aux patientes.
J Obstet Gynaecol Can 2015;37(11):975–987
INTRODUCTION
M agnesium sulphate has long been used in obstetrics
for prophylaxis and treatment of preeclampsia
and eclampsia, and historically as a tocolytic for preterm
labour.1–5 Recently, administration of MgSO4 has been
advocated for fetal neuroprotection in the preterm infant
to decrease the risk of cerebral palsy, based on evidence
from randomized controlled trials and meta-analyses.6–12
The Society of Obstetricians and Gynaecologists of
Canada and similar national societies have therefore
adopted guidelines for use of MgSO4 in women with
imminent preterm birth at < 32 weeks’ gestation.13,14
ABBREVIATIONS
CIHR Canadian Institutes of Health Research
CPN Canadian Perinatal Network
HDP hypertensive disorders of pregnancy
IM intramuscular
IV intravenous
MAG-CP MgSO4 for Fetal Neuroprotection of the Preterm Infant
MgSO4 magnesium sulphate
976 l NOVEMBER JOGC NOVEMBRE 2015
MAG-CP is a knowledge translation project funded by
the Canadian Institutes of Health Research and designed
to promote the implementation of the 2011 SOGC
clinical practice guideline “Magnesium sulphate for fetal
neuroprotection”13 in Canadian tertiary perinatal centres.
This project was stimulated by knowledge that practice
change does not usually follow simple dissemination
of information; rather, practice change requires active
knowledge translation, a recognized mandate of the CIHR.15
Active knowledge translation can take many forms. As one
of many approaches being undertaken by MAG-CP, site
visits were conducted to address the impact of each site’s
organizational culture on practice change within that site.
Early in the course of these site visits, it became clear that
discussion of MgSO4 for fetal neuroprotection could not
occur distinct from discussion about the administration
(and ideally, standardization) of MgSO4 for other
indications, namely eclampsia prevention and treatment.
In order to explore existing standardization of MgSO4
administration in Canadian tertiary perinatal centres, we
undertook a comparative analysis of MgSO4 protocols for
preeclampsia/eclampsia and fetal neuroprotection.
METHODS
From May 2012 to May 2013, the coordinator or site
investigator of each of Canada’s 25 tertiary perinatal
centres was asked to submit its English or French language
MgSO4 protocols for eclampsia prophylaxis and treatment
and for fetal neuroprotection. Protocols that were in draft
form were accepted. Between January and June 2014, the
centres were contacted to obtain any subsequent updated
protocols. These protocols were written by respective leads
in each of the sites, using appropriate documentation and
evidence from the literature.
The following information was abstracted from both the
local preeclampsia/eclampsia and fetal neuroprotection
protocols: date of protocol, definitions of preeclampsia/
eclampsia and fetal neuroprotection that provided the
indication for treatment, routes of MgSO4 administration,
availability of pre-mixed bags of MgSO4 and concentration
used, loading and maintenance dosage and duration of
treatment, the nature of maternal and fetal monitoring and
its frequency, abnormal signs requiring physician attention,
and any antidote for toxicity. The anonymity of the centres
was preserved and each was identified by a letter, rather
than by name.
Descriptive analyses were used to describe site protocol
recommendations; they were then compared with the
 Magnesium Sulphate for Eclampsia and Fetal Neuroprotection: A Comparative Analysis of Protocols
1997 and 2008 definitions of preeclampsia (of gestational
hypertension and either proteinuria or one/more adverse
condition),1–4 current recommendations to use MgSO4
for eclampsia prevention and treatment (grade I-A for
women with severe preeclampsia and I-C for women
with non-severe preeclampsia, using grading described
in the Canadian Task Force on Preventive Health Care16),
the MgSO4 dosing regimens of the 2002 Magpie Trial
for eclampsia prevention in women with preeclampsia,17
and the 1995 Collaborative Eclampsia Trial of MgSO4
for eclampsia treatment18 (i.e., 4 g MgSO4 intravenously,
followed by 1g/hour intravenously until 24 hours after
delivery).
In order to verify what was actually done in clinical practice
in the sites that provided protocols, we used data from
the Canadian Perinatal Network.19 In brief, from 2005
to March 31 2011, the CPN collected information on
pregnancies at high risk of very preterm delivery (between
22+0 and 28+6 weeks’ gestation) because of preterm
labour, preterm pre-labour rupture of membranes, short
cervix or prolapsed membranes, antepartum hemorrhage,
gestational hypertension, and/or intrauterine fetal growth
restriction. Information on interventions (such as MgSO4)
and maternal and perinatal outcomes were recorded. We
examined the data from preeclamptic women who received
MgSO4 for eclampsia prevention or treatment, including
their gestational age, characteristics of preeclampsia,
primary indication for admission, route of administration
of MgSO4, maternal outcomes, administration of
anticonvulsants, and whether calcium gluconate was
administered.
Descriptive analyses were undertaken to describe
who received MgSO4 in these centres, and how their
characteristics compared with both their local institutional
protocol and the 2008 recommendations by the SOGC.4
Ethics approval for this quality assurance project was
obtained centrally from the University of British Columbia
Research Ethics Board and at each study site.
RESULTS
Preeclampsia/Eclampsia Prophylaxis Protocols
Of 25 Canadian tertiary perinatal centres, 22 (88.0%)
submitted one or more protocols describing MgSO4 for
either eclampsia prevention, eclampsia treatment, and/
or fetal neuroprotection: British Columbia Women’s
Hospital and Health Centre (Vancouver); Victoria
General Hospital (Victoria); Royal Columbian Hospital
(New Westminster); Foothills Medical Centre (Calgary);
Royal Alexandra Hospital (Edmonton); Royal University
Hospital (Saskatoon); Regina General Hospital (Regina);
Health Sciences Centre Winnipeg (Winnipeg); Mount
Sinai Hospital (Toronto); Sunnybrook Health Sciences
Centre (Toronto); Kingston General Hospital (Kingston);
McMaster University Medical Centre (Hamilton); London
Health Sciences Centre (London); The Ottawa Hospital
(Ottawa); Centre Hospitalier Universitaire Sainte-Justine
(Montreal); Centre Hospitalier Universitaire de Québec
(Québec); Centre Hospitalier Universitaire de Sherbrooke
(Sherbrooke); Health Sciences Centre (St. John’s); IWK
Health Centre (Halifax); The Moncton Hospital (Moncton);
Dr Everett Chalmers Regional Hospital (Fredericton); and
Saint John Regional Hospital (Saint John). The remaining
three centres did not respond to our request for their local
protocol(s).
Eclampsia Prevention/Treatment
Of 25 Canadian tertiary perinatal centres, 22 sites
(88.0%) responded and provided protocols for eclampsia
prevention/treatment. The protocols were approved
locally between 2002 and 2012, all on or after publication
of the Collaborative Eclampsia Trial18 in 1995, the 1997
SOGC Guidelines on the hypertensive disorders of
pregnancy,1–3 and the Magpie Trial in 2002.17 Fifteen
protocols (68.2%) were approved after publication of
the 2008 SOGC HDP guideline4; this guideline endorsed
the 1997 definition of preeclampsia (i.e., gestational
hypertension with proteinuria or one or more “adverse
conditions”), recommended MgSO4 for women with
severe preeclampsia (recommendation grade I-A16), and
suggested that MgSO4 be considered for women with non-
severe preeclampsia (recommendation grade I-C16).
A definition of preeclampsia warranting treatment with
MgSO4 was provided by 11/22 eclampsia prevention/
treatment protocols (50.0%). Six protocols advised
treatment of any preeclampsia, with an equal number not
specifying a definition that would fit the definition used in
the Magpie Trial.17 Five protocols advised treatment only
in severe preeclampsia, often defined other than in the
Magpie Trial. Blood pressure and proteinuria were less often
specified within definitions, as were “adverse conditions”
(Table 1). When specified, blood pressure criteria ranged
from “any hypertension” to “severe hypertension”;
one protocol included a definition of hypertension that
is outdated and no longer in any international HDP
guideline (i.e., a relative rise in blood pressure). Proteinuria
was variably defined according to dipstick, 24-hour urine
collection, or not at all. The “adverse conditions” specified
were usually maternal symptoms (n = 8, 36.4%) or signs
(n = 8, 36.4%); headache and epigastric/abdominal pain
were the most frequent symptoms, and pulmonary edema
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Obstetrics

Table 1. A comparative analysis of MgSO4 protocols for eclampsia prophylaxis and

treatment for 22/25 (88.0%) Canadian Perinatal Network sites
N = 22
protocols
Criteria for diagnosis of preeclampsia provided 11 (50.0%)
Only “severe” preeclampsia warrants treatment 5 (45.5%)
Magpie Trial definition of severe hypertension and ≥ 3+ proteinuria met* 2
Magpie Trial definition of moderate hypertension, ≥ 2+ proteinuria, and 0
≥ 2 signs/symptoms of “imminent eclampsia” met†
Other definitions 3
Adverse condition(s) only (including CNS symptoms/signs) 2/3
Severe hypertension or one/more adverse (maternal conditions) 1/3
“Any” preeclampsia warrants treatment 6 (27.3%)
Magpie Trial definition met‡ 3
Other definitions 3
Any hypertension, ≥ 2+ proteinuria, or adverse condition(s) 2/3
Resistant hypertension, proteinuria, or adverse condition(s) 1/3
Details of preeclampsia definitions provided
BP criteria specified 8 (36.4%)
≥ 140/90 mmHg or “hypertension” 3
> 160/110 mmHg (n = 3) 3
“Resistant hypertension” 1
“PIH that cannot be controlled by bedrest or elevation of sBP > 30 and dBP > 15” 1
Proteinuria criteria specified 9 (40.9%)
Any proteinuria 8
Dipstick ≥ 2+ 3/7
“Proteinuria/new proteinuria” 4/7
≥ 0.3 g/d 1/7
Heavy proteinuria 2
>3 g/d 1
Adverse conditions of preeclampsia 11 (50.0%)
Maternal symptoms† 8 (36.4%)
Headache 8
Epigastric or right upper quadrant abdominal pain 8
Visual symptoms 6
Chest pain/dypsnea 3
Nausea/vomiting 2
Maternal signs (other than hypertension)† 8 (36.4%)
Pulmonary edema 5
Papilledema 1
Hyperreflexia and/or clonus 4
Oliguria 3
Eclampsia 2
“Cerebral disturbances” (decreased level of consciousness or confusion) 2
Worsening edema 2
“Hepatic involvement” 1
Placental abruption 1
Continued

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 Magnesium Sulphate for Eclampsia and Fetal Neuroprotection: A Comparative Analysis of Protocols

Table 1. Continued
N = 22
protocols
Abnormal laboratory results† 5 (22.2%)
Hemolytic anemia 1
Low platelets 4
Elevated liver enzymes 4
“HELLP” not otherwise defined 1
Low serum albumin 1
Elevated uric acid 1
Fetal signs† 2 (9.1%)
Intrauterine fetal growth restriction 2
Oligohydramnios 1
Umbilical artery abnormalities 1
Details of MgSO4 administration 22 (100%)
Route of administration 22 (100%)
Intravenous option 22
Intramuscular option 3
Concentration used (all 50% [50 g/100 mL]) 10 (45.5%)
Pre-mixed bags available 17 (77.3%)
No pre-mixed bags available 3 (13.6%)
No information provided about pre-mixed bags 2 (9.1%)
Loading dose specified 22 (100%)
Intravenous dose, g 22 (100%)
4 21
6 1
Intramuscular dose, in each buttock, g 3 (13.6%)
5 1
10 2
Maintenance therapy dosing specified 22 (100%)
Intravenous dose (g/hr) 21 (95.5%)
0.5 to 3 1
1 6
1 to 2 8
1 to 4 1
2 4
2 to 3 1
Intramuscular dose, g 1 (4.5%)
5 in each alternate buttock every 4 hours 1
Duration of treatment 6 (27.3%)
24 hours postpartum 4
Intrapartum and 24 hours postpartum 1
24 hours total or 24 hours postpartum 1
Maternal and fetal monitoring parameters specified 22 (100%)
Serum Mg level guidance provided 11 (50.0%)
Routine levels recommended 5
Continued

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Obstetrics

Table 1. Continued
N = 22
protocols
Levels advised only under certain circumstances 6
Signs with magnesium toxicity 3/6
Renal insufficiency present 1/6
Maintenance dose > 1 g/hr 1/6
At discretion of physician 1/6
Maternal monitoring – parameters specified† 22 (100%)
BP 20
Heart rate 20
Respiratory rate 22
Oxygen saturation 9
Reflexes 21
Fluid balance 18
Fetal monitoring and frequency specified† 21 (95.5%)
Fetal heart rate monitoring 21
Continuous 19/21
Uterine activity 7
When to notify physician for ANY of (and value given to prompt call to physician)† 21 (95.5%)
BP 11
Heart rate 2
Respiratory rate (e.g., < 12) 19
Oxygen saturation (e.g., < 94%) 9
Reflexes (decreased or absent) 20
Fluid balance 21
“Signs of magnesium toxicity” 17
Other medications mentioned 1 (4.5%)
Diazepam (to have on hand) 1
Antidote listed for MgSO4 toxicity 21 (95.5%)
Calcium gluconate 20
Calcium chloride 1
Eclampsia TREATMENT specified 19 (86.4%)
Guidance for eclampsia prior to receipt of MgSO4 0
Guidance for eclampsia while receiving MgSO4 11 (57.9%)
Loading dose of MgSO4 recommended, g 11
2 5/11
4 3/11
“Bolus” or “bolus as ordered” 2/11
Infusion up to 4 to 5 g/hour 1/11
Diazepam “if seizures occur” 2
BP: blood pressure; CNS: central nervous system; PIH: pregnancy-induced hypertension
*In the Magpie Trial17 severe preeclampsia was defined as: (1) severe hypertension (sBP ≥ 170 or dBP ≥ 110 mmHg twice
unless women were not on antihypertensive therapy) and 3+ proteinuria; or (2) moderate hypertension (sBP ≥ 150 or
dBP ≥ 100 mmHg), 2+ proteinuria and ≥ 2 symptoms/signs of “imminent eclampsia” (not defined).
†Not mutually exclusive
‡In the Magpie Trial17 preeclampsia was defined as hypertension (≥140/90 mmHg) and ≥ 1+ proteinuria.
BP criteria should be met twice, if women were not on antihypertensive therapy within the last 48 hr

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 Magnesium Sulphate for Eclampsia and Fetal Neuroprotection: A Comparative Analysis of Protocols
and hyperreflexia/clonus the most common signs. Fewer
protocols specified abnormal laboratory tests (n = 5,
22.2%) or fetal signs (n = 2, 9.1%) as indications for
MgSO4.
Although all sites outlined an intravenous option for
loading and maintenance doses for eclampsia prophylaxis,
only three sites included an intramuscular option. The
concentration of MgSO4 used was provided by 10
protocols (45.5%), and detailed as 50% (50 g/100 mL)
in all, although we are aware that one site used a 20%
solution during a shortage of MgSO4 during 2013. Most
sites (n = 17, 77.3%) specified having access to pre-mixed
bags of MgSO4 designed to minimize drug administration
errors; three sites had no such bags available. With one
exception (at a site that administered a 6 g dose), all
protocols specified a loading dose of 4 g, given over 15
to 30 minutes. Maintenance dosing was usually 1 g/hour,
but it ranged from 0.5 to 3 g/hour and one site did not
specify dosing. The duration of maintenance therapy was
usually not specified; it was for 24 hours postpartum when
it was specified. Routine testing of serum magnesium
was specified by five protocols. Six other protocols
recommended measuring serum magnesium levels under
certain circumstances.
Maternal and fetal monitoring procedures also varied
across sites, as did the thresholds of signs and symptoms
for notifying the physician. Maternal vital signs to be
monitored almost always included respiratory rate, heart
rate, blood pressure, deep tendon reflexes, and fluid
balance, although parameters for notification of the
physician were given consistently only for respiratory rate,
deep tendon reflexes, and urine output (oliguria). Fetal
heart rate monitoring was almost uniform. An antidote for
magnesium toxicity (usually 1 g of IV calcium gluconate)
was listed by all but one protocol for all women
No site had a separate document for eclampsia treatment,
but the site contacts confirmed that eclampsia prevention
protocols were followed. Three protocols did not mention
eclampsia treatment, and only 11 protocols specified
MgSO4 dosing (usually 2 g IV) to administer if eclampsia
developed. Three sites with protocols pre-dating the 2008
SOGC guidelines4 also listed the use of diazepam to
control seizures if necessary.
Fetal Neuroprotection Protocols
We received a total of 20/25 (80.0%) written fetal
neuroprotection protocols, most of which were finalized.
A comparative analysis is shown in Table 2. Three protocols
were part of the eclampsia prevention/treatment protocol.
One site representative disclosed that their site did not use
MgSO4 for fetal neuroprotection. Almost all protocols
were dated between 2011 and 2013 (n = 18), all after the
publication of the 2011 SOGC guidelines on MgSO4 for
fetal neuroprotection.13
Definitions of indications for treatment were quite
consistent across sites with protocols in place, except for the
gestational age cut-off. Protocols indicated treatment for
preterm birth with a gestational age specified from viability
at 23 to 24 weeks through to 33+6 weeks. Definitions
for imminent preterm birth included active labour with
≥ 4 cm cervical dilatation with or without preterm pre-
labour rupture of membranes or planned preterm delivery
for maternal or fetal indications. All protocols outlined
IV administration of MgSO4 without specifying an IM
option, and a loading dose of 4 g over 10 to 30 minutes.
Maintenance dosing was usually 1 g/hour until delivery.
Only half of the protocols mentioned retreatment, usually
citing this as an option. Measuring serum magnesium levels
was not recommended routinely. Monitoring procedures
and signs to notify the physician usually followed each
site’s preeclampsia/eclampsia protocol with the same
frequency; three sites (15.0%) omitted the need to monitor
fluid balance. All but one protocol listed calcium gluconate
as an antidote for magnesium toxicity.
Canadian Perinatal Network Data
Sixteen of 22 sites that submitted MgSO4 protocols
had participated in the initial CPN project and had
data for analysis (2005 to March 31, 2011). From those
16 sites, 635 women were admitted with preeclampsia
and their characteristics are presented in Table 3. Most
women had at least one episode of severe hypertension
and were proteinuric. Approximately one half were
delivered for an adverse condition according to the 2008
SOGC guideline.4 One hundred seventy-four (27.4%)
were considered “severe” using 2008 SOGC guideline
definitions (Appendix 2). There were no maternal
deaths. One quarter of women suffered one or more
severe adverse maternal outcomes based on the level
of care required or end-organ complications. The most
common of these were high dependency unit/intensive
care unit admission, pulmonary edema, or the need for
supplemental oxygen (> 50% for more than one hour).20
Ten women suffered eclampsia.
MgSO4 treatment was administered to 422 of these women
with preeclampsia (66.5%), at a median gestational age of
27.4 weeks (interquartile range 25.9, 28.4). At the six sites
that specified treatment of all women with preeclampsia,
215/325 women overall (66.2%) were treated: 150/243 with
non-severe preeclampsia (61.7%) and 65/82 with severe
preeclampsia (79.3%) were treated. At the four sites that
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Obstetrics

Table 2. A comparative analysis of MgSO4 protocols for fetal neuroprotection at 20/25

(80.0%) Canadian Perinatal Network sites
N = 20
protocols
Fetal neuroprotection for preterm infant
Status of the protocol
Final 16 (80.0%)
Part of the eclampsia prophylaxis/treatment protocol 3 (15.0%)
Draft form* 4 (20.0%)
Indications for treatment (list full definitions)
Gestational age, weeks 17 (85.0%)
Viability to 31+6 4
23 or 24 to 31+6 5
> 24 2
< 32 5
24 to 33+6 1
“Imminent preterm birth” 14 (70.0%)
Definition consistent with 2011 SOGC CPG† 14
Administration
Route 20 (100%)
Intravenous option 20
Intramuscular option 0
Loading dose 20 (100%)
4 g intravenously 20
Maintenance therapy 20 (100%)
Dose 20
1 g/hour intravenously 18/20
1 to 2 g/hour intravenously 2/20
Duration of treatment 19 (95.0%)
Until delivery or for a maximum of 24 hours of treatment 16
Minimum of 4 hours also specified 1
For 4 hours before delivery if scheduled, or 24 hours if imminent 1
“Maximum of 12 hours, at which point physician reassesses” 1
Retreatment discussed 11 (55.0%)
Can be considered 8
NOT recommended 3
Maternal and fetal monitoring outlined 20 (100%)
Serum levels discussed 8 (40.0%)
Routine 0
Only under certain circumstances 8
Signs with magnesium toxicity 6/8
Renal insufficiency present 1/8
At discretion of physician 1/8
Maternal monitoring – parameters specified‡ 20 (100%)
BP 19
Heart rate 19
Respiratory rate 20
Oxygen saturation 9
Reflexes 16
Fluid balance 15
Continued

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 Magnesium Sulphate for Eclampsia and Fetal Neuroprotection: A Comparative Analysis of Protocols
Table 2. Continued
Fetal monitoring and frequency‡
Fetal heart rate monitoring
Continuous
Uterine activity
Notify physician for ANY of (and value given to prompt call to physician)‡
BP
Heart rate
Respiratory rate (e.g., < 12/minute)
Oxygen saturation (e.g., < 94%)
Reflexes (decreased or absent)
Fluid balance
“Signs of magnesium toxicity”
Antidote listed for MgSO4 toxicity
Calcium gluconate
CPG: clinical practice guideline; BP: blood pressure
*As of December 2014
†Imminent preterm birth is defined as active labour with ≥ 4 cm cervical dilatation with/without preterm pre-labour
rupture of membranes, or planned preterm delivery due to maternal or fetal indications
‡Not mutually exclusive
specified treatment of only severe preeclampsia, 73 of 106
women with non-severe preeclampsia (68.9%) were treated
and 38 of 45 women with severe preeclampsia (84.4%)
were treated. At the remaining six sites that did not specify
whether the severity of preeclampsia should influence
treatment decisions, 110/180 women with preeclampsia
(61.1%) overall were treated with MgSO4; 80 of 39 women
with non-severe preeclampsia (57.6%) and 30 of 41 with
severe disease (73.2%) were treated. The proportion of
women with severe and non-severe preeclampsia who
were treated with MgSO4 was similar across the three
groups of centres (P = 0.437 and P = 0.192, respectively).
Of the 10 women who suffered eclampsia, all were treated
with MgSO4 and three had received MgSO4 for eclampsia
prevention. One woman also received phenytoin with
MgSO4 to treat seizures; this centre had not outlined an
alternative to MgSO4 for seizure treatment. The route of
MgSO4 administration was IV except in one woman who
received an IM injection for eclampsia treatment (at a site
that included an IM option for MgSO4 administration in
its protocol). No woman received calcium gluconate for
toxicity. The CPN database does not collect information
on duration of MgSO4 treatment or dose.
Seventy-two women who delivered at < 32 weeks (1.5%)
received MgSO4 for fetal neuroprotection between 2010
and 2011, before the release of both the national guidelines
and local protocols. In these cases guideline adherence
cannot be assessed.
N = 20
protocols
19 (95.0%)
19 (95.0%)
17
6 (30.0%)
19 (95.0%)
8
2
19
11
18
15
16
17 (85.0%)
17
DISCUSSION
Of 25 Canadian tertiary perinatal centres, we received
preeclampsia/eclampsia protocols from 22; 15 of these
were updated following the publication of the 2008
SOGC HDP guidelines.4 Consistency between protocols
was seen with regard to loading and maintenance dosing
of MgSO4, use of calcium gluconate as the treatment for
magnesium toxicity, and standard monitoring procedures
(i.e., vital signs). In contrast, differences were seen between
protocols regarding whether specific components of
the definition of pre-eclampsia were specified; whether
all women with preeclampsia or only those with severe
preeclampsia should receive MgSO4; availability of pre-
mixed bags of MgSO4 to avoid dosing errors21,22; and
monitoring parameters for notification of the most
responsible physician. Importantly, many guidelines lacked
sufficient detail to guide maternity care providers in the
use of MgSO4, and several contained misinformation: this
included routine monitoring of serum magnesium levels
(5 protocols) and use of diazepam to treat seizures (2
protocols). No guideline dealt specifically with eclampsia
as the initial presentation of preeclampsia.
There was more consistency among fetal neuroprotection
protocols, which generally followed the recommendations
of the 2011 SOGC guidelines,13 with minor variations
in the upper gestational age cut-off. This age cut-off
is an area of continuing controversy. Most sites tried
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Obstetrics

Table 3. Characteristics of women with preeclampsia in the Canadian Perinatal

Network, presented as n (%) or median [IQR] as appropriate
Women with preeclampsia
(N = 635)
Characteristics of preeclampsia
Blood pressure, mmHg
Peak systolic BP 177 [162 to 190]
Peak diastolic BP 110 [100 to 115]
Systolic BP ≥ 160 or diastolic BP ≥ 110 mmHg 546 (86.0)
Proteinuria 602 (94.8)
3+ on dipstick or ≥ 3 g/day 367 (57.8)
Delivery for adverse conditions* 311 (49.0)
Preeclampsia considered to be non-severe 461 (72.6)
Preeclampsia considered severe† 174 (27.4)
MgSO4 administered 422 (66.5)
Death or severe maternal morbidity (No. of women with one or more) 164 (25.8)
Maternal death 0
Receipt of blood products 42 (6.6)
ICU or HDU admission 57 (9.0)
Chorioamnionitis 18 (2.8)
Placental abruption 22 (3.5)
Third injectable antihypertensive 9 (1.4)
Eclampsia 10 (1.6)
Disseminated intravascular coagulation 7 (1.1)
Sepsis 0
Endometriosis 1 (0.2)
Intubation 6 (0.9)
Ventilation 3 (0.5)
Pulmonary edema 37 (5.8)
Requirement of > 50% O2 26 (4.1)
Renal failure 7 (1.1)
Hepatic failure 13 (2.0)
Hepatic hematoma 1 (0.2)
*Delivery for “adverse conditions” included oligohydramnios, intrauterine growth restriction, and/or an abnormal
umbilical artery Doppler velocimetry result
†Severity was defined by using the 2008 SOGC guidelines on the hypertensive disorders of pregnancy4
BP: blood pressure; ICU: intensive care unit; HDU: high dependency unit

to align dosing and monitoring of MgSO4 for fetal
neuroprotection with their preeclampsia protocol for
simplicity.
In the CPN data, there were documented cases of use
of MgSO4 for fetal neuroprotection, even though the
SOGC guidelines13 were published in May 2011, and
CPN data collection ceased on March 31, 2011. It is likely
that use reflected emerging awareness on the topic and
receptiveness to use of the intervention, possibly because
of familiarity with use of MgSO4 for eclampsia prevention
and treatment, and ease of administration.
Focusing on eclampsia treatment, all 10 women
with eclampsia had treatment with MgSO4 for their
seizures. However, for preeclampsia there were some
inconsistencies apparent between local protocols and local
CPN data. First, the number of women with preeclampsia
or severe preeclampsia who were treated with MgSO4
was similar regardless of the relevant recommendation
in the local protocols. Although prioritizing treatment of
severe preeclampsia is consistent with the 2008 SOGC
recommendations (based on cost considerations4,23),
clinicians appear to be uncomfortable if they do not treat
most women with non-severe disease, and are barely able

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 Magnesium Sulphate for Eclampsia and Fetal Neuroprotection: A Comparative Analysis of Protocols
to reach the goal of treating at least 80% of women with
severe disease. Perhaps this is not surprising; although the
2002 Magpie Trial provided definitive data that MgSO4 is
effective for all women with preeclampsia, the data also
demonstrated that MgSO4 was associated with adverse
maternal effects and high cost, particularly for treatment
of non-severe preeclampsia.17 These controversies
remained unresolved.24 Second, in the single centre
that used phenytoin to treat eclamptic seizures, there
was no recommendation to do so in the relevant local
protocol; phenytoin was not prescribed in either the 1995
Collaborative Eclampsia Trial18 or the 2002 Magpie Trial17
for women in their MgSO4 treatment arms, and phenytoin
was not listed as an option for eclampsia treatment or
prophylaxis in the 1997 SOGC HDP guidelines,3 which
predated protocols in the centre discussed. Both the 2008
and 2014 SOGC HDP guidelines recommend against use
of both benzodiazepines and phenytoin for treatment of
eclampsia.4,5
National guidelines (for diagnosis of preeclampsia, and
MgSO4 for eclampsia prevention and treatment and fetal
neuroprotection4,13) and high-quality evidence17,18 have been
presented as the standard against which CPN site protocols
were compared. In comparison to other guidelines, there
may be deviations from evidence-based practice and further
variation between protocols because of routine local
practices, fear of potential side effects, or the availability
of treatments or resources (e.g., MgSO4); these are all
factors found to be important in explaining differences
in clinical guidelines for managing lower back pain.25 A
recent comparison of international practice guidelines
on hypertensive disorders of pregnancy also identified
variation and inconsistencies in recommendations, and
suggested further research to develop standards.24
The major strength of our study is that it provided a
comprehensive review of MgSO4 protocols for eclampsia
prevention and treatment and fetal neuroprotection derived
from academic perinatal centres, which have processes
in place for standardization and quality improvement.
Additionally, we audited use of MgSO4 in the same centres to
determine how local practice compared with local guidance.
A limitation of the study is that all protocols were included.
We therefore included protocols dating back to 2002, well
before publication of the national guideline on MgSO4 use
for preeclampsia/eclampsia in 20084 (updated in 20145)
or for fetal neuroprotection in 2011.13 Nevertheless, these
were the protocols available for reference by treating
clinicians. A second limitation is that we included protocols
in draft form (confirmed as not having been finalized at
the time of writing), although this only affected the fetal
neuroprotection protocols and reflected local practice.
Third, before April 1, 2011, the CPN database did not
record MgSO4 dose and duration of therapy, rendering
assessments of adherence to dosing protocols or use of
repeat dosing impossible. Finally, our results apply only to
tertiary perinatal centres where the CPN is operative.
CONCLUSION
Administration of MgSO4 for eclampsia prevention and
treatment and for fetal neuroprotection is one of the few
interventions in obstetrics for which there are highest-
level recommendations based on high quality randomized
controlled trials. Our findings suggest that local protocols
pertaining to use of MgSO4 for eclampsia prevention and
treatment are often at variance with the published evidence
and specific guidance from the SOGC. Although this
variance may relate in part to local institutional culture and
practice patterns, patient care must not be compromised,
and maximizing uniformity of practice will facilitate audit
and feedback to improve care overall. Institutions need to
put relevant processes for use of MgSO4 in place.
REFERENCES
1. Helewa ME, Burrows RF, Smith J, Williams K, Brain P, Rabkin SW.
Report of the Canadian Hypertension Society Consensus Conference:
1. Definitions, evaluation and classification of hypertensive disorders in
pregnancy. CMAJ 1997;157:715–25.
2. Moutquin JM, Garner PR, Burrows RF, Rey E, Helewa ME, Lange IR,
et al. Report of the Canadian Hypertension Society Consensus
Conference: 2. Nonpharmacologic management and prevention of
hypertensive disorders in pregnancy. CMAJ 1997;157:907–19.
3. Rey E, LeLorier J, Burgess E, Lange IR, Leduc L. Report of the Canadian
Hypertension Society Consensus Conference: 3. Pharmacologic treatment
of hypertensive disorders in pregnancy. CMAJ 1997;157:1245–54.
4. Magee LA, Helewa M, Moutquin JM, von Dadelszen P. Diagnosis,
evaluation, and management of the hypertensive disorders of pregnancy.
J Obstet Gynaecol Can 2008;30(3 Suppl):S1–S48.
5. Magee LA, Pels A, Helewa M, Rey E, von Dadelszen P. Diagnosis,
evaluation, and management of the hypertensive disorders of pregnancy.
Pregnancy Hypertens 2014;4(2):105–45.
6. Crowther CA, Hiler JE, Doyle LW, Haslam RR. Effect of magnesium
sulfate given for neuroprotection before preterm birth: a randomized
controlled trial. JAMA 2003;290(20):2669–76.
7. Marret S, Marpeau L, Zupan-Simunek V, Eurin D, Lévêque C, Hellot MF,
et al. Magnesium sulphate given before very-preterm birth to protect
infant brain: the randomized controlled PREMAG trial*. BJOG
2007;114(3):310–8.
8. Mittendorf R, Dambrosia J, Pryde PG, Lee KS, Gianopoulos JG,
Besinger RE, et al. Association between the use of antenatal magnesium
sulfate in preterm labor and adverse health outcomes in infants. Am J
Obstet Gynecol 2002;186(6):1111–8.
9. Rouse DJ, Hirtz DG, Thom E, Varner MW, Spong CY, Mercer BM, et al.
A randomized, controlled trial of magnesium sulfate for the prevention
of cerebral palsy. N Engl J Med 2008;359(9):895–905.
NOVEMBER JOGC NOVEMBRE 2015 l 985
Obstetrics

10. Conde-Agudelo A, Romero R. Antenatal magnesium sulphate for the
prevention of cerebral palsy in preterm infants less than 34 weeks’
gestation: a systematic review and metaanalysis. Am J Obstet Gynecol
2009;200(6):595–609.
11. Costantine M, Weiner SJ. Effects of antenatal exposure to magnesium
sulphate on neuroprotection and mortality in preterm infants: a meta-
analysis. Obstet Gynecol 2009;114(2 Pt 1):354–64.
12. Doyle LW, Crowther CA, Middleton P, Marret S, Rouse D. Magnesium
sulphate for women at risk of preterm birth for neuroprotection of the
fetus. Cochrane Database Syst Rev 2009;(1):CD004661.
13. Magee LA, Sawchuck D, Synnes A, von Dadelszen P; Magnesium
Sulphate for Fetal Neuroprotection Consensus Committee; SOGC
Maternal Fetal Medicine Committee. SOGC Clinical Practice Guideline.
Magnesium sulphate for fetal neuroprotection. SOGC clinical guideline
no. 258, May 2011. J Obstet Gynaecol Can 2011;33(5):516–29.
14. The Antenatal Magnesium Sulphate for Neuroprotection Guideline
Development Panel. Antenatal magnesium sulphate prior to preterm birth
for neuroprotection of the fetus, infant and child: national clinical practice
guidelines. Adelaide (AV): The Australian Research Centre for Health of
Women and Babies, The University of Adelaide; 2010.
15. Canadian Institutes of Health Research. More about knowledge
translation at CIHR. Ottawa (ON): CIHR; 2014. Available at:
http://www.cihr-irsc.gc.ca/e/39033.html. Accessed February 12, 2015.
16. Woolf SH, Battista RN, Angerson GM, Logan AG, Eel W. Canadian
Task Force on Preventive Health Care. New grades for recommendations
from the Canadian Task Force on Preventive Health Care. CMAJ
2003;169(3):207–8.
17. Altman D, Carroli G, Duley L, Farrell B, Moodley J, Neilson J, et al.
Do women with pre-eclampsia, and their babies, benefit from magnesium
sulphate? The Magpie Trial: a randomized placebo-controlled trial. Lancet
2002;359(9321):1877–90.
18. The Eclampsia Trial Collaborative Group. Which anticonvulsant for
women with eclampsia? Evidence from the Collaborative Eclampsia Trial.
Lancet 1995;345(8963):1455–63.
19. Magee LA, von Dadelszen P, Allen VM, Ansermino JM, Audibert F,
Barrett J, et al. The Canadian Perinatal Network: a national network
focused on threatened preterm birth at 22 to 28 weeks’ gestation.
J Obstet Gynaecol Can 2011;33(2):111–20.
20. von Dadelszen P, Payne B, Li J, Ansermino JM, Broughton Pipkin F,
Côté AM, et al. Prediction of adverse maternal outcomes in
pre-eclampsia: development and validation of the fullPIERS model.
Lancet 2011;377(9761):219–27.
21. Simpson KR, Knox GE. Obstetrical accidents involving IV magnesium
sulfate. Am J Maternal Child Nurs 2004;29:161–71.
22. Grissinger M. Preventing magnesium toxicity in obstetrics. PT
2009;34(8):403.
23. Simon J, Gray A, Duley L. Cost-effectiveness of prophylactic
magnesium sulphate for 9996 women with pre-eclampsia from
33 countries: economic evaluation of the Magpie Trial. BJOG
2006;113(2):144–51.
24. Gillon TER, Pels A, von Dadelszen P, MacDonell K, Magee LA.
Hypertensive disorders of pregnancy: a systematic review of international
clinical practice guidelines. PLOS One 2014;9(12):e113715.
25. Koes BW, van Tulder M, Chung-Wei CL, Macedo LG, McAuley J,
Maher C. An updated overview of clinical guidelines for the
management of non-specific low back pain in primary care. Eur Spine J
2010;19(12):2075–94.

APPENDIX 1.
MAG-CP COLLABORATIVE GROUP

This includes the MAG-CP Steering Committee Members, MAG-CP Site Investigators, current MAG-CP Coordinator Dane De Silva,
MAG-CP Statistician Tang Lee, and MAG-CP Database Manager Larry Li.
The MAG-CP Steering Committee members are:
Laura Magee (University of British Columbia, Vancouver BC), Anne Synnes (University of British Columbia, Vancouver BC), Victoria
Allen (Dalhousie University, Halifax NS), Mark Ansermino (University of British Columbia, Vancouver BC), François Audibert (Université
de Montréal, Montreal QC), Rollin Brant (University of British Columbia, Vancouver BC), Emmanuel Bujold (Université Laval, Québec
QC), Joan Crane (Memorial University of Newfoundland, St. John’s NF), KS Joseph (University of British Columbia, Vancouver BC),
Robert Liston (University of British Columbia, Vancouver BC), Bruno Piedboeuf (Université Laval, Québec QC), Peter von Dadelszen
(University of British Columbia, Vancouver BC), Mark Walker (University of Ottawa, Ottawa ON), Wendy Whittle (University of Toronto,
Toronto ON), Carmen Young (University of Alberta, Edmonton AB).

The MAG-CP Site Investigators are:

Laura Magee (BC Women’s Hospital & Health Centre, Vancouver BC), Stephanie Cooper (Foothills Medical Centre, Calgary AB),
Carmen Young (Royal Alexandra Hospital, Edmonton AB), Femi Olatunbosun (Royal University Hospital, Saskatoon SK), George
Carson (Regina General Hospital, Regina SK), Graeme Smith (Kingston General Hospital, Kingston ON), Sarah McDonald (Hamilton
Health Sciences Centre, Hamilton ON), Renato Natale (London Health Sciences Centre, London ON), Wendy Whittle (Mount Sinai
Hospital, Toronto ON), Noor Ladhani (Sunnybrook Health Sciences Centre, Toronto ON), Mark Walker (The Ottawa Hospital, Ottawa
ON), Francois Audibert (Hôpital Sainte-Justine, Montréal QC), Emmanuel Bujold (Centre Hôspitalier de L’ Université Laval, Québec
City QC), Victoria Allen (IWK Health Centre, Halifax NS), Joan Crane (Women’s Health Program, Eastern Health, St. John’s NF),
Kimberly Butt (Dr Everett Chalmers Regional Hospital, Fredericton NB), James Andrews (Saint John Regional Hospital, Saint John
NB), and Laura Gaudet (The Moncton Hospital, Moncton NB).

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 Magnesium Sulphate for Eclampsia and Fetal Neuroprotection: A Comparative Analysis of Protocols

APPENDIX 2.
DEFINITIONS OF PREECLAMPSIA AND SEVERE PREECLAMPSIA
THAT INDICATE TREATMENT WITH MGSO4

1997 Hypertension 2008 Hypertension

Guidelines (1-3) Guidelines (4) Magpie Trial (16)
Preeclampsia
BP dBP ≥ 90 dBP ≥ 90 after 20 weeks’ GA dBP ≥ 90 or sBP ≥ 140 on two
occasions AND
Secondary signs Proteinuria ≥ 0.3 g/D • Proteinuria Proteinuria ≥ 1+
or symptoms ≥ 300 mg/day in a 24 hour urine
collection OR ≥ 30 mg/mmol
protein:creatinine ratio in a random
urine sample
OR
• One or more adverse conditions:
–– Oligohydramnios (if with
PPROM or indication for
delivery)
–– IUGR (if developed in
admission or indication for
delivery)
–– Umbilical artery Doppler result
(as indication for delivery)
Severe preeclampsia
BP and proteinuria • dBP > 110 mmHg • sBP ≥ 160 and/or dBP ≥ 110 • dBP ≥110 or sBP ≥ 170 on two
criteria • Proteinuria > 3 g/D (onset < 34 weeks GA) occasions AND
• Proteinuria > 3–5 g/day • Proteinuria ≥ 3+
OR
• dBP ≥ 100 or sBP ≥150 on
two occasions AND proteinuria
≥ 2+ AND at least two “signs
or symptoms of imminent
eclampsia” (CNS manifestations)
Adverse conditions • Pulmonary edema • Pulmonary edema • Hyperreflexia
• Chest pain or shortness of • Chest pain • Frontal headache
breath • Dyspnea • Blurred vision
• Frontal headache • Persistent/new unusual headache • Epigastric tenderness
• Visual disturbances • Visual disturbance
• Platelets < 100 × 106/L • Elevated serum creatinine
• Persistent RUQ pain • Platelets < 100 × 106/L
• Severe nausea and vomiting • Persistent epigastric or RUQ pain
• Elevated AST, ALT, LDH • Severe nausea or vomiting
• Serum albumin < 18 g/L • Elevated AST, ALT, LDH
• HELLP syndrome • Serum albumin < 20 g/L
• IUGR • IUGR
• Oligohydramnios • Oligohydramnios
• Absent or reversed end diastolic • Absent or reversed end diastolic
flow in the UA flow in the UA
• Suspected placental abruption • Suspected placental abruption
• Intrauterine fetal demise
AST: aspartate aminotransferase; ALT: alanine aminotransferase; IUGR: intrauterine growth restriction; LDH: lactate dehydrogenase; RUQ: right upper quadrant

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