Womens Health

Preeclampsia in Low and Middle Income

CountriesHealth Services Lessons Learned
From the PRE-EMPT (PRE-EclampsiaEclampsia
Monitoring, Prevention & Treatment) Project
Peter von Dadelszen, MBChB, DPhil,1,2 Tabassum Firoz, MD,2,3
France Donnay, MD, MPH, FACOG, FRCOG,4 Rebecca Gordon, BSc,1,2
G. Justus Hofmeyr, FRCOG,5 Shifana Lalani, MSc,1 Beth A. Payne, BSc,1,2
James M. Roberts, MD,6 Katherine C. Teela, MHS,4 Marianne Vidler, MPH,1,2
Diane Sawchuck, RN, PhD,1,2 Laura A. Magee, MD, MSc1,2,3
1
Department of Obstetrics and Gynaecology, University of British Columbia, Vancouver BC
2
Child and Family Research Institute Reproduction and Healthy Pregnancy Cluster, Vancouver BC
3
Department of Medicine, University of British Columbia, Vancouver BC
4
Maternal Health, Family Health Department, Bill & Melinda Gates Foundation, Seattle WA
5
Department of Obstetrics and Gynaecology, Walter Sisulu University, East London, South Africa
6
Magee-Womens Research Institute, University of Pittsburgh, Pittsburgh PA

Abstract
The hypertensive disorders of pregnancy, in particular
preeclampsia, matter because adverse events occur in women
with preeclampsia and, to a lesser extent, in women with the
other hypertensive disorders. These adverse events are maternal,
perinatal, and neonatal and can alter the life trajectory of each
individual, should that life not be ended by complications. In this
review we discuss a number of priorities and dilemmas that we
perceive to be facing health services in low and middle income
countries as they try to prioritize interventions to reduce the health
burden related to preeclampsia. These priorities and dilemmas
relate to calcium for preeclampsia prevention, risk stratification,
antihypertensive and magnesium sulphate therapy, and mobile
health. Significant progress has been and is being made to reduce
the impact of preeclampsia in low and middle income countries,
but it remains a priority focus as we attempt to achieve Millennium
Development Goal 5.
Rsum
Les troubles hypertensifs de la grossesse, particulirement la
prclampsie, ont de limportance puisque des vnements
indsirables se manifestent chez des femmes prsentant une
prclampsie et, dans une moindre mesure, chez des femmes
prsentant dautres troubles hypertensifs. Ces vnements
indsirables sont de nature maternelle, prinatale et nonatale,
et peuvent modifier la vie des personnes qui les connaissent,
lorsque celles-ci survivent aux complications. Dans cette analyse,
nous discutons dun nombre de priorits et de dilemmes auxquels
doivent faire face les services de sant des pays revenu faible
ou moyen au moment de tenter de hirarchiser les interventions
en vue dattnuer le fardeau de sant li la prclampsie. Ces
priorits et ces dilemmes sont lis ladministration de calcium
aux fins de la prvention de la prclampsie, la stratification
du risque, aux traitements aux antihypertenseurs et au sulfate
de magnsium, et la sant mobile. Bien que des progrs
significatifs aient t raliss et continuent dtre raliss en vue
dattnuer les effets de la prclampsie au sein des pays revenu
faible ou moyen, cette problmatique demeure une priorit dans le
cadre de nos tentatives datteindre lobjectif 5 du Millnaire pour le
dveloppement.

Key Words: Preeclampsia, hypertensive disorders of pregnancy,

global health
Competing Interests: None declared.
Received on July 12, 2012
Accepted on July 18, 2012
J Obstet Gynaecol Can 2012;34(10):917926

OCTOBER JOGC OCTOBRE 2012 l 917

Womens Health
BACKGROUND
P reeclampsia, although commonly defined by the
presence of both significant hypertension and heavy
proteinuria, is a pregnancy- and placenta-specific form
of systemic inflammation with multiple target organs
(Figure).1 As far as we can determine, preeclampsia and
eclampsia claim the lives of approximately 72000 women
and 500000 fetuses and newborns each yeara loss of
almost 1600 lives per day.2 Over 99% of these losses occur
in low and middle income countries, particularly in sub-
Saharan Africa and on the Indian subcontinent.2 In the
Americas, preeclampsia and eclampsia are the leading
cause of direct maternal mortality.35
Currently, the singular way to initiate resolution of the
maternal syndrome of preeclampsia is to deliver the placenta.1
However, the maternal syndrome of preeclampsia may
present de novo postpartum and, especially with early-onset
preeclampsia, cause transient postpartum deterioration.1
Therefore, even timely delivery does not necessarily avoid
all end-organ complications of the disorder. In addition,
the life-altering and life-threatening complications (e.g.,
stroke, acute renal failure, eclampsia, pulmonary edema, and
placental abruption) probably increase the significant health
burden of preeclampsia by at least five-fold.6,7
As a group, we believe that the global community (clinicians,
researchers, policy makers, governments, health authorities,
and other stakeholders) should focus efforts on reducing
the excess number of adverse maternal and perinatal
events in women whose pregnancies are complicated by
preeclampsia, rather than focus solely on the surrogate of
these risks, the diagnosis of preeclampsia.
Given that preeclampsia-related maternal and perinatal
deaths and permanent sequelae result primarily from delays
in diagnosis, triage, transport, and treatment,2 an important
direction for new initiatives related to improving preeclampsia-
ABBREVIATIONS
AUC ROC area under the receiver-operator characteristic curve
BP blood pressure
EPIC European Prospective Investigation into Cancer and
Nutrition study
HR hazard ratio
LMIC low and middle income countries
MDG Millennium Development Goal
PIERS Pre-eclampsia Integrated Estimate of RiSk
PRE-EMPT Pre-eclampsiaEclampsia Monitoring, Prevention &
Treatment
RDA recommended daily allowance
RR relative risk
918 l OCTOBER JOGC OCTOBRE 2012
related outcomes may be to enhance the availability of life-
saving interventions in the communities in which vulnerable
women reside. Such interventions may vary from improving
the status of pregnant women and facilitating timely decision-
making when complications arise, to initiating life-saving
therapies (e.g., magnesium sulphate and antihypertensive
agents) prior to urgent transfer to an effective and adequately
resourced emergency obstetric care facility.
In 2011, the University of British Columbia was awarded
the four-year PRE-eclampsiaEclampsia Monitoring,
Prevention & Treatment project grant by the Bill & Melinda
Gates Foundation. The overarching theme of this proposal
is reducing the maternal and perinatal consequences of
preeclampsia. Through this grant we aim to determine the
impact of this program of research on those outcomes.
The primary objectives of PRE-EMPT are three community-
level and primary health centre-level intervention studies
tailored to LMIC settings and related to prevention,
monitoring, and treatment. The secondary objectives are
1. developing a multifaceted international research
collaboration, and
2. LMIC-oriented preeclampsia knowledge translation
activities.
We describe here examples of what we have learned to
date from these objectives, and the implications derived
from our current position for health service decision-
making, especially in resource-challenged settings.
PREVENTION
Calcium Supplementation to Reduce the
Incidence of Preeclampsia: Should We Provide
This to High-Risk Women? If Yes, at What Dose?
In general, preeclampsia is considerably more prevalent
in low and middle income communities than in affluent
communities.8 Two striking exceptions have been identified
in Ethiopia and in the Mayan Indians of Guatemala,
where diets contain high levels of calcium.9,10 Subsequent
epidemiological, clinical, and laboratory studies linking
preeclampsia to calcium deficiency have been outlined in
a recent systematic review of calcium supplementation
during pregnancy.11 The conclusion of this systematic
review, and that of a parallel meta-analysis,12 was that
supplemental calcium (at least 1g daily) from mid-
pregnancy is associated with a modest reduction in rates
of preeclampsia, and a more notable reduction in its severe
manifestations, particularly among women at increased
risk or with low dietary calcium intake. However, we have
found no report of randomized controlled trials of calcium
supplementation commenced before pregnancy.
 Preeclampsia in Low and Middle Income CountriesHealth Services Lessons Learned From the PRE-EMPT Project

The origins and consequences of preeclampsia

immunological factors decidual immune cell - normal placentation

antigen exposure EVT interactions (late-onset preeclampsia)
primigravidity ( ) / primipaternity ( ) macrosomia
donor gamete(s) ( ) (invasion & uteroplacental multiple pregnancy
duration of cohabitation ( ) artery remodelling) lowered threshold
barrier contraception ( ) / fellatio ( )
prior miscarriage ( )
smoking ( )
inadequate placentation
(early-onset preeclampsia)
genetic factors
familial risks
SNPs uteroplacental mismatch
epigenetics
placental IUGR
intervillous soup ( maternal syndrome)
lowered threshold pre-eclampsia-specific shared with IUGR
metabolic syndrome placental debris angiogenic imbalance
chronic infection / inflammation innate immune activation
pre-existing hypertension oxidative stress
chronic renal disease / DbM eicosanoids
high altitude cytokines

endothelial cell activation

cardiorespiratory CNS renal hepatic hematological

hypertension eclampsia glomerular endotheliosis periportal inflammation microangiopathic hemolysis
ARDS TIA / RIND / CVA proteinuria hepatic dysfunction / failure thrombocytopenia
pulmonary edema PRES ATN hepatic hematoma / rupture DIC
cardiomyopathy / LV dysfunction ARF
intravascular volume constriction
generalised edema

maternal syndrome
In this model of the origins of preeclampsia, we describe preeclampsia that arises primarily because of imperfect placentation (early-onset or placental
preeclampsia) and that arises because of either a lowered maternal threshold or excessive physiological placentation (late-onset or maternal preeclampsia).
Some aspects of the preeclampsia process are specific to it, while others are shared with normotensive intrauterine growth restriction. A lowered maternal threshold
may influence the development of early-onset preeclampsia as well through direct endothelial cell activation. The consequences of the endothelial cell activation
that appears consistent between all women who develop preeclampsia include a variable impact on multiple vulnerable organ systems. Disease severity generally
correlates with the degree and number of organ dysfunctions.
: increased risk of preeclampsia; : decreased risk of preeclampsia; EVT: extravillous trophoblasts; SNP: single nucleotide polymorphism; IUGR: intrauterine
growth restriction; DbM: diabetes mellitus; ARDS: acute respiratory distress syndrome; LV: left ventricular; TIA: transient ischemic attack; RIND: reversible ischemic
neurological deficit; CVA: cerebrovascular accident; PRES: posterior reversible encephalopathy syndrome; ATN: acute tubular necrosis; ARF: acute renal failure;
DIC: disseminated intravascular coagulation

Hofmeyr and colleagues conducted an RCT nested within
the large World Health Organization trial of calcium
supplementation (1.5g daily from at least 20 weeks gestation)
in pregnant women with low dietary calcium intake13; this
failed to demonstrate an effect of calcium supplementation
on biochemical measures commonly elevated in preeclampsia
(serum urate, platelet count, and urine protein/creatinine
ratio). The lack of effect on proteinuria is consistent with
the findings of the main WHO trial, in which there was
a trend towards a reduced risk of preeclampsia (RR 0.92;
95% CI 0.75 to 1.13) and severe preeclampsia (RR 0.74;
95% CI 0.48 to 1.15), but no reduction in proteinuria
(RR 1.01; 95% CI 0.88 to 1.15).14 Tentative evidence for an
effect on the offspring is the finding of reduced rates of
childhood hypertension in the children of participants in
RCTs of calcium supplementation.11
The fact that calcium supplementation reduces the
incidence of preeclampsia without evidence of an effect on
proteinuria (but possibly an effect on heavy proteinuria by
reducing glomerular tuft arterial pressure, once glomerular
endothelial integrity has been lost) and other markers for
preeclampsia seems contradictory. To reconcile this, we
agree with the hypothesis that calcium supplementation in
the second half of pregnancy reduces blood pressure, and
therefore reduces the diagnosis of both preeclampsia
and severe preeclampsia without having a significant
effect on the underlying pathology.15

OCTOBER JOGC OCTOBRE 2012 l 919

Womens Health
This may also explain an anomaly identified in the
systematic review.11 The incidence of preeclampsia
(defined as proteinuric gestational hypertension [blood
pressure 140/90mmHg]) was reduced overall by
55% (RR 0.45, 95% CI 0.31 to 0.65) and the composite
outcome maternal death or severe morbidity was
reduced by 20% (RR 0.80; 95% CI 0.65 to 0.97).
The observed reduction in maternal death or severe
morbidity includes severe hypertension, the outcome
that is likely to be modified by the antihypertensive effect
of calcium. However, the risk of HELLP syndrome
was increased 2.7-fold with calcium supplementation
(RR 2.67; 95% CI 1.05 to 6.82).
We believe that these considerations should lead to
reflection prior to the programmatic introduction of
calcium supplementation to pregnant women in low intake
areas. There are four main reasons to pause and reflect.
The first is the possible risk associated with calcium
supplementation, which should be balanced against the
probable benefit; the second is the issue of calcium dose;
the third is the timing of the intervention; and the fourth
is the issue of mineral balance.
Calcium: Balancing Potential Risks
Against Probable Benefit
While reducing the incidence of the diagnosis of
preeclampsia through its antihypertensive effect, calcium
supplementation may mask, without altering, the underlying
pathology of preeclampsia.15 Consequently, we suggest
that any program of calcium supplementation introduced
with the intent of reducing the burden of preeclampsia in
a given jurisdiction should be monitored until it is clear that
the rate of adverse outcomes (maternal and perinatal severe
morbidity and mortality) actually falls, rather than increases.
This is particularly relevant in view of the recent findings of
the EPIC-Heidelberg observational cohort study that, after
an average follow-up time of 11 years, having a moderate
total dietary and dairy calcium intake significantly reduced
the risk of developing a myocardial infarction (HR 0.69;
95% CI 0.50 to 0.94 and HR 0.68; 95% CI 0.50 to 0.93,
respectively).16 Overall, associations between calcium intake
and stroke risk or cardiovascular disease mortality were not
found. Users of supplements that included calcium had a
significantly higher risk of myocardial infarction (HR 1.86;
95% CI 1.17 to 2.96) than non-users of any supplements,
and the risk was more pronounced for users of calcium
supplements only (HR 2.39; 95% CI 1.12 to 5.12). This
parallels the evidence for a benefit from antioxidants in
the prevention of preeclampsia; a diet rich in antioxidants
appears to protect against preeclampsia,17,18 whereas the
ingestion of isolated vitamins C and E does not.19
920 l OCTOBER JOGC OCTOBRE 2012
Calcium: Dietary Replacement Versus
Dietary Supplementation
It appears that dosing studies on calcium replacement
or supplementation are required. The current WHO
recommendation, derived from meta-analyses, suggests
a dose of 1.5g to 2g calcium/day,20 which is 30% to
80% greater than the recommended daily allowance of
1200mg,21 in addition to current dietary intake. The study
of dietary calcium intake in primiparous women cited
above showed a median daily dietary calcium intake of
approximately 600mg.22 The recommended calcium dose
for supplementation during pregnancy has significant cost
implications. Ministries of health must consider cost
benefit ratios in their decisions to scale up interventions
that may affect health outcomes, and often need to
justify their decisions to ministries of finance within their
respective regional and federal governments. Without
substantive evaluation of the costbenefit equation for the
higher doses, especially in the absence of calcium dosing
studies, many countries will be hesitant to scale up this
recommendation.
Furthermore, in a placebo-controlled calcium supple
mentation in pregnant women in The Gambia, women
receiving calcium (1500g/day) had significantly lower hip,
lumbar spine and distal radial lower bone mineral content,
bone area and bone mineral density throughout lactation
than women who received placebo.23 The authors surmise
that such levels of calcium supplementation in pregnant
women may disrupt metabolic adaptation to pregnancy
and alter bone health.
For women in LMICs, dietary replacement with 500mg
calcium/day would achieve a median daily intake of
approximately 1100mg22; this could be achieved with
food fortification, and represents the difference in daily
calcium intake between high income and low income
countries. Higher levels of true supplementation to
1.5g/day to 2.0g/day are unacceptable to the palate,
are greater than RDA amounts, and are of significant
programmatic cost.
Calcium: Timing the Intervention
Another issue requiring explanation is the modest effect
of calcium supplementation on preeclampsia in contrast to
the striking epidemiological differences in populations with
good and poor dietary calcium. It is possible that calcium
supplementation in the second half of pregnancy is too late
to influence the underlying processes of preeclampsia.15 For
example, inadequate placentation occurs in early pregnancy1
and would not be influenced by an intervention in the
second half of pregnancy. While deficient dietary calcium
before and during early pregnancy may increase the risk for
 Preeclampsia in Low and Middle Income CountriesHealth Services Lessons Learned From the PRE-EMPT Project
preeclampsia, there may be limited potential to reverse this
effect by calcium supplementation later in the pregnancy.
Therefore, in response to both the dose and timing
issues, the Calcium And Pregnancy RCT is testing the
hypothesis that 500mg of calcium replacement daily (to
the RDA), begun before pregnancy in women at high risk
of preeclampsia or eclampsia, will reduce the incidence
of hypertension and other pregnancy outcomes more
effectively than supplementation of 1.5g/day to 2.0g/day
once pregnancy is diagnosed as currently recommended by
the WHO.20 This RCT is currently recruiting women with
low calcium intake in South Africa and Zimbabwe, and,
with supplemental funding from the WHO, will recruit
in Argentina. In this trial women will be randomized to
calcium or placebo from pre-pregnancy until 20 weeks
gestation, after which time all women will receive open
label calcium (1500mg/d) to supplement calcium intake
to WHO-recommended amounts.24
Calcium: Mineral Balance
Another explanation for the apparent paradox of the
modest effect of calcium supplementation on preeclampsia,
in contrast to the striking epidemiological differences
in populations with good and poor dietary calcium, is
the difference in mineral balance between dietary and
supplemental calcium intake. As noted in the EPIC-
Heidelberg study, dietary calcium intake appears beneficial
in terms of cardiovascular health, whereas supplements do
not.16 It is possible that the balance of minerals (calcium,
potassium, and magnesium, in particular) obtained
through diet provides health benefits not matched by
calcium supplements alone.2527 Other micronutrients (and
their balance) present in dairy foods may be important in
modulating the consistently observed benefit of adequate
calcium intake.27
MONITORING
Once a woman has developed preeclampsia or another
hypertensive disorder of pregnancy, can her risks be
further stratified? We believe that they can.
An initial step towards improved, streamlined, and
evidence-based monitoring of women with preeclampsia is
to standardize care, including initial clinical and laboratory
assessment and ongoing surveillance. At the BC Womens
Hospital and Health Centre we achieved a greater than
80% reduction in the incidence of a combined adverse
maternal outcome simply by standardizing assessment and
surveillance of women admitted with either gestational
hypertension or gestational proteinuria.28 To test this
experience beyond a single tertiary centre in a high
resource setting, we repeated this exercise across British
Columbia, with the addition of specific advice about items
of drug and fluid management, and observed a more
than 30% reduction in the incidence of adverse maternal
outcomes across the province after a process of active
guideline implementation.29 This latter effect was seen
most in smaller units where day-to-day exposure to women
with preeclampsia, especially complicated preeclampsia, is
infrequent. We presumed that the effect in smaller units
was achieved by increasing in-house competence and care
provider confidence in those units.
In LMICs, pregnant women often rely on community
health professionals, many of whom have under 12 months
training, to facilitate antenatal and maternity care. These
pregnant women are often concentrated in rural areas with
inadequate access to comprehensive emergency obstetric
care. Therefore, to achieve reductions in adverse outcomes
similar to those observed in British Columbia, one must
consider cost-effective health care delivery options that
will increase the skill level and confidence of community
health professionals. Following extensive inquiry, we
believe that mobile health (mHealth) technologies have
the capacity to strengthen the ability of community-
level health professionals to provide evidence-based care
(decision-making and initiation of therapies) in a timely
fashion and within the household or primary health clinic
prior to transport.
The WHO defines mHealth as mobile technologies
as well as advancements in their innovative application
to address health priorities.30 The mobile phone has
become a novel tool to address public health challenges
and shift the paradigm of health care access and delivery
from traditional facility-based care to community care.
The United Nations Millennium Development Goal 8,
specifically 8F, calls for the benefits of new technology,
particularly information technology, to be made available
by increasing the number of mobile phone subscribers.31
In 2010, a consortium of international groups called for
the use of mobile phones to reduce maternal mortality and
achieve MDG 5 by 2015.32 Mobile phones have been used
effectively in a number of capacities for advancing maternal
health, including data collection and management, point
of care diagnostics and support, capacity strengthening,
health promotion, text messaging of prenatal education,
automated prenatal care appointment reminders, and
access to emergency obstetric care.33
To provide such an mHealth platform, it is important to
develop decision-making tools that can be integrated into
a mobile platform, such as a mobile phone, so that clinical
OCTOBER JOGC OCTOBRE 2012 l 921
Womens Health
variables (e.g., symptoms and easily observed signs) can
be entered and evidence-based, standardized therapeutic
advice generated automatically using the software capacity
of the mobile device. An example is the phone oximeter,
described below.
Over the past decade, we have been developing and
validating two risk stratification models to be used in
women with clinical preeclampsia (i.e., time of disease,
rather than prediction of disease)the Pre-eclampsia
Integrated Estimate of RiSk models.28,3445 The two models
are fullPIERS (based on symptoms, signs, and laboratory
tests)34 and miniPIERS (based on symptoms and signs).46
Development and internal validation of fullPIERS has been
funded by the Canadian Institutes for Health Research,
and miniPIERS development and full validation by the
PRE-EMPT grant, the WHO, and Canadian Institutes of
Health Research.
In the fullPIERS data set (using data from tertiary centres in
Canada, New Zealand, Australia, and the United Kingdom),
we were able to identify women with preeclampsia who
are at increased risk of maternal complications, and we
have been able to grade this risk.34 With 2023 women in
the fullPIERS database, the AUC ROC is 0.88 (95% CI
0.84 to 0.92), and stratification capacity is robust. The
independent predictors of adverse maternal outcome are
gestational age at eligibility, chest pain/dyspnea, SpO2,
serum creatinine, serum AST, and platelet count. The
fullPIERS model assesses risk up to seven days after
eligibility (AUC ROC 0.76; 95% CI 0.72 to 0.80). The
fullPIERS model requires external validation before it can
be advocated for use outside research settings, and will be
applicable only to facilities with full laboratory support.
A powerful component of the fullPIERS model is pulse
oximetry, which has independent power to identify women
at risk of adverse outcomes of preeclampsia, including
non-cardiorespiratory outcomes.39
The final analytical stages of developing and validating
the miniPIERS model are currently being completed.
The model will use data derived from women with any
hypertensive disorder of pregnancy within 24 hours of
admission to academic centres in Brazil, Fiji, Pakistan,
South Africa, and Uganda, and will be based on gestational
age, parity, symptoms, and signs.47
Once the miniPIERS model has been validated we will
transfer the model to an mHealth platform as a mobile
phone application, using funding from Saving Lives at
Birth and the PRE-EMPT award. This application, PIERS
on the Move, will be developed initially for two purposes.
The first will be to host miniPIERS on a mobile phone
922 l OCTOBER JOGC OCTOBRE 2012
application, with the results of the miniPIERS model
guiding care within the context of a planned cluster
randomized control trial of community level, community
health worker-administered, interventions for preeclampsia
that will recruit women in South Asia and sub-Saharan
Africa. Funding for the Community-Level Interventions
for Pre-eclampsia trial will be obtained from PRE-EMPT.
The second purpose will be to incorporate the phone
oximeter, a mobile phone-supported pulse oximeter,
into a user-friendly application to guide care, as well as to
recalibrate the miniPIERS model to include SpO2.48 Again,
we envisage an mHealth application that will both stratify
risk and support clinical decision-making, building care
provider confidence through integral decision trees that
reflect best evidence-based practice and the current WHO
recommendations.20
Monitoring: Removing the Primacy of Proteinuria
in Risk Stratification in High Resource Settings
It is a historical accident that proteinuria has achieved a
preeminent role in the diagnosis and ongoing surveillance
of women with preeclampsia. While significant proteinuria
(i.e., 300mg/24h, 30mg protein/mmol creatinine on
a random urine collection, or ++ protein by urinary
dipstick) is central to all diagnostic criteria, the presence
of hyperuricemia, for example, is as effective for perinatal
risk stratification as proteinuria.49 However, there is no
clear gold standard for the assessment of proteinuria in
pregnancy. Through the PIERS project, we have determined
that 24-hour urine collections are vulnerable to both over-
and under-collection approximately one half of the time,
with under- and over-collection being equally common.50
Similarly, we have identified that the method of protein
measurement may alter the quantification performance of
proteinuria and albuminuria estimations in dilute urine,51,52
which may explain some of the uncertainties that derive
from the literature, especially for albumin/creatinine ratios.53
Once significant proteinuria (however defined) has been
observed, is there any further benefit to be derived from
ongoing risk stratification including proteinuria? In high
resource settings, we have determined that all three methods
of proteinuria estimation perform as well (or as poorly) as
each other, and none of them have adequate stratification
capacity to be used to guide clinical decision-making.54 In
the fullPIERS model, measures of proteinuria estimation
were displaced from the model by serum creatininean
observation made previously by Lindheimer and Kanter,
as rising serum creatinine is more proximate to the
occurrence of an adverse outcome than is the degree of
proteinuria.55 The level of dipstick proteinuria will not be a
necessary component of the miniPIERS model.
 Preeclampsia in Low and Middle Income CountriesHealth Services Lessons Learned From the PRE-EMPT Project
TREATMENT
Overcoming the Reductionist View of the
Management of Severe Pregnancy Hypertension
While eclampsia is the most commonly recognized and
visible cause of death associated with preeclampsia, the
specific causes of death for women with preeclampsia
or eclampsia in LMIC have not been well studied.
Although the prevalence and burden of illness of severe
hypertension of preeclampsia or eclampsia is not accurately
documented in LMIC, data from well-resourced settings
indicate that failure to treat sustained severe hypertension
adequately is an important contributor to maternal
mortality in preeclampsia or eclampsia.5658 These findings
are supplemented by the institutional data that contribute
to the Fourth Report on Confidential Enquiries into Maternal
Deaths in South Africa, in which 45% of maternal deaths
attributed to preeclampsia were secondary to cerebral
complications other than eclampsia.59
Severe hypertension is defined as a systolic blood pressure
160mmHg and/or a diastolic BP 110mmHg.60 The sustained reductions in BP cannot be expected.75
Confidential Enquiries into Maternal Deaths in the United
Kingdom have shown that failure to initiate effective
antihypertensive therapy for sustained severe hypertension
was the most common source of substandard care in the
management of women with preeclampsia or eclampsia.56,57
In the recent reports, the majority of women who died
from preeclampsia had either intracerebral hemorrhage or
cerebral infarction secondary to inadequately-controlled
severe hypertension.56,57 Therefore, sustained severe
maternal hypertension is considered an obstetric near
miss, a potentially lethal complication that women survive,
due either to excellent medical care or to chance alone.61 It is
widely accepted in all international pregnancy hypertension
guidelines that women with severe hypertension are at
increased risk of stroke and other central nervous system
complications, and would therefore benefit from blood
pressure reduction.20,60,6265 The relevant WHO guidelines
rate as strong the recommendation to treat severe
hypertension with antihypertensive therapy.20
The Priority Medicines for Mothers and Children was published
in March 2011 by the WHO, United Nations Population
Fund, and the United Nations Childrens Fund.66 The
New York Times has described Priority Medicines for Mothers
and Children as the top 30 medicines to save mothers
and children.67 These medicines have been taken from
among the 350 medicines contained within the WHO
Essential Medicines List.68 Priority Medicines specifically
lists eight drugs for management of the three leading
causes of maternal morbidity and mortality (postpartum
hemorrhage, maternal sepsis, and preeclampsia/
eclampsia), as well as for sexually transmitted infections and
HIV.66 In theory, medicines on this list should be available
within functioning health systems at all times, in adequate
amounts, in the appropriate dosage forms, with assured
quality and adequate information, and at a price that the
individual and the community can afford. Although the
reality in each LMIC may be different, the Priority Medicines
for Mothers and Children is designed to be an advocacy tool.
The current Priority Medicines for Mothers and Children lists only
magnesium sulphate (and calcium gluconate for treatment of
magnesium toxicity) as a priority medicine for management
of severe preeclampsia or eclampsia.66 The presence of
magnesium sulphate on the list is entirely appropriate,
because it reduces, by at least 50%, both the incidence and
recurrence of eclampsia; in addition, it probably reduces
maternal mortality.6973 However, magnesium sulphate is
not an effective antihypertensive agent.74 There is limited
observational evidence describing no or transient decreases
in BP; a transient decrease in BP may occur 30 minutes after
the administration of 2g to 5g of magnesium sulphate, but
However, as there have been no RCTs of antihypertensive
therapy for severe pregnancy hypertension, some have
viewed this absence of RCT evidence as a lack of
evidence. This apparently reductionist view (that no RCT
evidence equates to no evidence) may be the reason that
antihypertensive agents have neither been prioritized in
LMIC efforts in preeclampsia or eclampsia management
nor included in the Priority Medicines for Mothers and Children,
and may have led to the avoidable burden of maternal
mortality related to uncontrolled severe pregnancy
hypertension observed in the United Kingdom and
elsewhere.5658
Therefore, what medication should be selected as the
drug of choice for the treatment of severe pregnancy
hypertension? Medications in the Priority Medicines for
Mothers and Children are chosen on the principles of efficacy,
safety, and familiarity at both the national and individual
prescriber level.66 There are a number of options for the
choice of antihypertensive agent. In RCTs, parenteral
labetalol, parenteral hydralazine, and oral nifedipine
(intermediate-acting tablets or short-acting capsules)
have been evaluated most often. All are reasonable
choices for lowering severely elevated BP. Hydralazine
may be associated with more maternal hypotension than
the other agents.76 Labetalol is not listed in the WHO
Essential Medicines List 68and may therefore not be widely
available, and prescribers may not be familiar with its use.
Concurrent use of magnesium sulphate and nifedipine
may be associated with neuromuscular blockade; however,
OCTOBER JOGC OCTOBRE 2012 l 923
Womens Health
a retrospective cohort study and data synthesis found the
incidence to be <1%, and inadvertent magnesium toxicity
can be treated effectively by calcium gluconate.77 Based on
this, several national guidelines have accepted that there
is no significant interaction.20,60,6375 Furthermore, the
American Society of Hypertension and WHO guidelines
specifically state that there is no interaction between
nifedipine and magnesium sulphate.20,63
Although nifedipine is not listed as an antihypertensive
agent in the Priority Medicines for Mothers and Children, it is
listed for the prevention of preterm birth.66 As nifedipine
is administered orally and there may be limited resources
in LMIC for intravenous access, nifedipine may be an
ideal medication for treatment of severe hypertension
in pregnancy. Also, the oral administration of this
medication opens up the possibility of administration in
the community setting. However, ultimately, the choice of
an antihypertensive agent will depend upon the clinician,
regional differences in practice, and availability.
As we believe that the omission of antihypertensive therapy
for severe hypertension represented a missed opportunity
to advocate for an affordable and effective intervention
that may decrease maternal mortality and move us closer to
achieving MDG 5, we contacted the WHO Department of
Essential Medicines and Health Products. In response to
our contact, we have received confirmation from Dr Clive
Ondari, Team Coordinator, Medicine Access and Rational
Use, Essential Medicines and Health Products, WHO that
an antihypertensive for severe pregnancy hypertension
(most logically nifedipine) will be added to the updated
Priority Medicines for Mothers and Children in 2012.
Once the issue of antihypertensive management for severe
pregnancy hypertension has been accepted as a health
services priority, in addition to magnesium sulphate, the
question then is: at what level of the health system could
and should life-saving therapy be initiated?
CONCLUSION
The hypertensive disorders of pregnancy, in particular
preeclampsia, matter. They matter because adverse events
occur in women with preeclampsia and, to a lesser extent,
the other hypertensive disorders. These adverse events
are maternal, perinatal, and neonatal, and can alter the life
trajectory of each individual, if that life is not cut short
by complications. The majority of these complications
occur in LMICs. The PRE-EMPT project will attempt to
address prevention, monitoring, and treatment through
three community-level and primary health centre-level
intervention studies tailored to LMIC settings.
924 l OCTOBER JOGC OCTOBRE 2012
We should not assume that preventing the diagnosis of
preeclampsia will equate to reduced rates of adverse
events. This underlies our hesitancy to recommend
programmatic implementation of non-dietary calcium
supplementation with the current level of knowledge.
Resolving the unsettled questions related to the relationship
between calcium and preeclampsia is an urgent research
priority. In the interim, it is incumbent on those initiating
programs of calcium supplementation to ensure that
outcomes improve beyond reduction in the incidence of
the diagnosis of preeclampsia.
Risk stratification of women with preeclampsia is now
possible, so that maternal risks can be balanced against the
perinatal risks of prematurity, which are better known to
caregivers. Importantly, we suggest that heavy proteinuria
no longer be an indication to deliver a woman in the
absence of either a term pregnancy or other precipitants
included in the PIERS models. Mobile health platforms
can deliver the PIERS models and PIERS-directed clinical
care algorithms into the hands of community health care
providers, to whom initiation of lifesaving therapies can be
shifted. Such mHealth platforms can be augmented through
technology transfer into robust mobile applications, such
as the mobile phone oximeter.
We advocate that the management of severe pregnancy
hypertension is as important an intervention in women
with preeclampsia as the RCT-supported use of magnesium
sulphate prevention and treatment of eclampsia. There
will never be a randomized placebo-controlled trial of
antihypertensives for this indication, nor should there be.
Preeclampsia is a multisystem disorder with a number
of biological pathways leading to the clinical syndrome
that we recognize. It will be through multisystem
interventions (basic and clinical research methodologies,
clinical trials, implementation research, health services
planning, and programmatic scale-up) and multilevel
collaboration (women, their families and communities,
clinicians, researchers, policy makers, governments, health
authorities, and other stakeholders) that we will reduce
the unacceptable personal, family, community and societal
burden associated with preeclampsia.
REFERENCES
1. Steegers EA, von Dadelszen P, Duvekot JJ, Pijnenborg R. Pre-eclampsia.
Lancet 2010;376:63144.
2. Firoz T, Sanghvi H, Merialdi M, von Dadelszen P. Pre-eclampsia in low
and middle income countries. Best Pract Res Clin Obstet Gynaecol
2011;25:53748.
3. Health Canada. Special report on maternal mortality and severe morbidity
in Canadaenhanced surveillance: the path to prevention. Ottawa:
Minister of Public Works and Government Services Canada; 2004.
 Preeclampsia in Low and Middle Income CountriesHealth Services Lessons Learned From the PRE-EMPT Project
4. Khan KS, Wojdyla D, Say L, Gulmezoglu AM, Van Look PF.
WHO analysis of causes of maternal death: a systematic review.
Lancet 2006;367:106674.
5. US Department of Health and Human Services, Health Resources and
Services Administration. Womens Health USA 2011. Rockville, MD:
US Department of Health and Human Services; 2011.
6. Kaye DK, Kakaire O, Osinde MO. Systematic review of the magnitude
and case fatality ratio for severe maternal morbidity in sub-Saharan Africa
between 1995 and 2010. BMC Pregnancy Childbirth 2011;11:65.
7. Tuncalp O, Hindin MJ, Souza JP, Chou D, Say L. The prevalence of
maternal near miss: a systematic review. BJOG 2012;119:65361.
8. Langer A, Villar J, Tell K, Kim T, Kennedy S. Reducing eclampsia-related
deathsa call to action. Lancet 2008;371:7056.
9. Belizn JM, Villar J. The relationship between calcium intake and edema-,
proteinuria, and hypertension-getosis: an hypothesis. Am J Clin Nutr
1980;33:220210.
10. Hamlin RH. The prevention of eclampsia and pre-eclampsia.
Lancet 1952;1:648.
11. Hofmeyr GJ, Atallah AN, Duley L. Calcium supplementation during
pregnancy for preventing hypertensive disorders and related problems.
Cochrane Database Syst Rev 2006;3:CD001059.
12. Meads CA, Cnossen JS, Meher S, Juarez-Garcia A, ter Riet G, Duley L,
et al. Methods of prediction and prevention of pre-eclampsia: systematic
reviews of accuracy and effectiveness literature with economic modelling.
Health Technol Assess 2008;12(6):iiiiv, 1270.
13. Hofmeyr GJ, Mlokoti Z, Nikodem VC, Mangesi L, Ferreira S, Singata M,
et al. Calcium supplementation during pregnancy for preventing
hypertensive disorders is not associated with changes in platelet count,
urate, and urinary protein: a randomized control trial. Hypertens
Pregnancy 2008;27:299304.
14. Villar J, Abdel-Aleem H, Merialdi M, Mathai M, Ali M, Zavaleta
N, et al.World Health Organization randomized trial of calcium
supplementation among low calcium intake pregnant women.
Am J Obstet Gynecol 2006;194:63949.
15. Hofmeyr GJ, Duley L, Atallah A. Dietary calcium supplementation for
prevention of pre-eclampsia and related problems: a systematic review
and commentary. BJOG 2007;114:93343.
16. Li K, Kaaks R, Linseisen J, Rohrmann S. Associations of dietary calcium
intake and calcium supplementation with myocardial infarction and stroke
risk and overall cardiovascular mortality in the Heidelberg cohort of the
European Prospective Investigation into Cancer and Nutrition study
(EPIC-Heidelberg). Heart 2012;98(12):9205.
17. Raijmakers MT, Dechend R, Poston L. Oxidative stress and preeclampsia:
rationale for antioxidant clinical trials. Hypertension 2004;44:37480.
18. Poston L, Igosheva N, Mistry HD, Seed PT, Shennan AH, Rana S, et al.
Role of oxidative stress and antioxidant supplementation in pregnancy
disorders. Am J Clin Nutr 2011;94(6 Suppl):1980S1985S.
19. Conde-Agudelo A, Romero R, Kusanovic JP, Hassan SS.
Supplementation with vitamins C and E during pregnancy for the
prevention of preeclampsia and other adverse maternal and perinatal
outcomes: a systematic review and metaanalysis. Am J Obstet Gynecol
2011;204:50312.
20. World Health Organization. World Health Organization recommendations
for prevention and treatment of pre-eclampsia and eclampsia. Geneva:
World Health Organization; 2011.
21. Institute of Medicine. Dietary reference intakes for calcium and vitamin
D. Washington, DC: National Academy Press; 2010.
22. Hofmeyr GJ, Mlokoti Z, Nikodem VC, Mangesi L, Ferreira S, Singata M,
et al.; WHO Calcium Supplementation for the Prevention of Pre-
eclampsia Trial Group. Calcium supplementation during pregnancy
for preventing hypertensive disorders is not associated with changes in
platelet count, urate, and urinary protein: a randomized control trial.
Hypertens Pregnancy 2008;27:299304.
23. Jarjou LM, Laskey MA, Sawo Y, Goldberg GR, Cole TJ, Prentice A. Effect
of calcium supplementation in pregnancy on maternal bone outcomes in
women with a low calcium intake. Am J Clin Nutr. 2010 Aug;92(2):4507.
24. HofmeyrGJ, NovikovaN, SingataM, FawcusS, OyebajoA, MunjanjaS,
et al. Protocol 11PRT/4028: Long term calcium supplementation in
women at high risk of pre-eclampsia: a randomised, placebo-controlled
trial (PACTR201105000267371). Available at: http://www.thelancet.com/
protocol-reviews/11PRT4028. Accessed August 15, 2012.
25. Abbott RD, Curb JD, Rodriguez BL, Sharp DS, Burchfiel CM,
Yano K. Effect of dietary calcium and milk consumption on risk of
thromboembolic stroke in older middle-aged men. The Honolulu Heart
Program. Stroke 1996;27:8138.
26. Iso H, Stampfer MJ, Manson JE, Rexrode K, Hennekens CH, Colditz GA,
et al. Prospective study of calcium, potassium, and magnesium intake and
risk of stroke in women. Stroke 1999;30:17729.
27. Massey LK. Dairy food consumption, blood pressure and stroke.
J Nutr 2001;131:18758.
28. Menzies J, Magee LA, Li J, MacNab YC, Yin R, Stuart H, et al.;
Preeclampsia Integrated Estimate of RiSk (PIERS) Study Group.
Instituting surveillance guidelines and adverse outcomes in preeclampsia.
Obstet Gynecol 2007;110:1217.
29. von Dadelszen P, Sawchuck D, McMaster R, Douglas MJ, Lee SK,
Saunders S, et al. The active implementation of pregnancy hypertension
guidelines in British Columbia. Obstet Gynecol 2010;116:65966.
30. World Health Organization. mHealth: new horizons for health through
mobile technologies: based on the findings of the second global survey
on eHealth. Global observatory for eHealth series, vol 3. Geneva: WHO;
2011.
31. United Nations Statistics Division. Millennium Development
Goals indicators. New York: United Nations. Available at:
http://mdgs.un.org/unsd/mdg/default.aspx. Accessed April 4, 2012.
32. The Partnership for Maternal, Newborn and Child Health. International
groups call for collaboration in use of mobile technology to reduce
maternal and newborn mortality. Geneva: WHO; 2010. Available at:
http://www.who.int/pmnch/media/press_materials/pr/2010/20100624_
ict_use/en/index.html. Accessed April 10, 2012.
33. Tamrat T, Kachnowski S. Special delivery: an analysis of mHealth in
maternal and newborn health programs and their outcomes around the
world. Matern Child Health J 2012;16:1092101.
34. von Dadelszen P, Payne B, Li J, Ansermino JM, Broughton PF,
Cote AM, et al. Prediction of adverse maternal outcomes in
pre-eclampsia: development and validation of the fullPIERS model.
Lancet 2011;377:21927.
35. Firoz T, Magee LA, Payne BA, Menzies JM, von Dadelszen P. The PIERS
experience: research or quality improvement? J Obstet Gynaecol Can
2012;34:37981.
36. Kozic JR, Benton SJ, Hutcheon JA, Payne BA, Magee LA,
von Dadelszen P. Abnormal liver function tests as predictors of adverse
maternal outcomes in women with preeclampsia. J Obstet Gynaecol Can
2011;33:9951004.
37. Laskin S, Payne B, Hutcheon JA, Qu Z, Douglas MJ, Ford J, et al.
The role of platelet counts in the assessment of inpatient women with
preeclampsia. J Obstet Gynaecol Can 2011;33:9008.
38. Menzies J, Magee LA, MacNab YC, Ansermino JM, Li J, Douglas MJ,
et al. Current CHS and NHBPEP criteria for severe preeclampsia do not
uniformly predict adverse maternal or perinatal outcomes. Hypertens
Pregnancy 2007;26:44762.
39. Millman AL, Payne B, Qu Z, Douglas MJ, Hutcheon JA, Lee T, et al.
Oxygen saturation as a predictor of adverse maternal outcomes in women
with preeclampsia. J Obstet Gynaecol Can 2011;33:70514.
40. Payne B, Magee LA, von Dadelszen P. Assessment, surveillance and
prognosis in pre-eclampsia. Best Pract Res Clin Obstet Gynaecol
2011;25:44962.
41. von Dadelszen P, Magee LA, Roberts JM. Subclassification of
preeclampsia. Hypertens Pregnancy 2003;22:1438.
OCTOBER JOGC OCTOBRE 2012 l 925
Womens Health
42. von Dadelszen P, Magee LA, Devarakonda RM, Hamilton T,
Ainsworth LM, Yin R, et al. The prediction of adverse maternal
outcomes in preeclampsia. J Obstet Gynaecol Can 2004;26:8719.
43. von Dadelszen P, Menzies J, Magee LA. The complications of
hypertension in pregnancy. Minerva Med 2005;96:287302.
44. von Dadelszen P, Menzies JM, Payne B, Magee LA. Predicting adverse
outcomes in women with severe pre-eclampsia. Semin Perinatol
2009;33:1527.
45. Yen TW, Payne B, Qu Z, Hutcheon JA, Lee T, Magee LA, et al. Using
clinical symptoms to predict adverse maternal and perinatal outcomes in
women with preeclampsia: data from the PIERS (Pre-eclampsia Integrated
Estimate of RiSk) study. J Obstet Gynaecol Can 2011;33:8039.
46. PRE-eclampsia Eclampsia Monitoring, Prevention & Treatment. The
miniPIERS (Pre-eclampsia Integrated Estimate of RiSk) model. Available
at: http://pre-empt.cfri.ca/HOME.aspx. Accessed April 10, 2012.
47. Payne B, Hutcheon JA, Qu Z, Haniff F, Bhutta Z, Biryabarema C, et al.
MiniPIERS (Pre-eclampsia Integrated Estimate of RiSk): development
of a clinical prediction model for use in low and middle income countries
(LMICs) [abstract]. 18th World Congress of the International Society for
the Study of Hypertension in Pregnancy, Geneva, Switzerland, July 2012.
Pregn Hypertens 2012;2(3):1956.
48. Saving Lives at Birth. PIERS on the move: Pre-eclampsia Integrated
Estimate of Risk assessment on a mobile phone. Available at:
http://savinglivesatbirth.net/summaries/37. Accessed April 10, 2012.
49. Roberts JM, Bodnar LM, Lain KY, Hubel CA, Markovic N, Ness RB, et al.
Uric acid is as important as proteinuria in identifying fetal risk in women
with gestational hypertension. Hypertension 2005;46:12639.
50. Cote AM, Firoz T, Mattman A, Lam EM, von Dadelszen P, Magee LA.
The 24-hour urine collection: gold standard or historical practice?
Am J Obstet Gynecol 2008;199:6256.
51. De Silva DA, Halstead C, Cote AM, Sabr Y, von Dadelszen P, Magee
LA. Unexpected random urinary protein:creatinine ratio results
insights from clinician-laboratory medicine collaboration [abstract].
18th World Congress of the International Society for the Study of
Hypertension in Pregnancy, Geneva, Switzerland, July 2012. Pregn
Hypertens 2012;2:253.
52. De Silva DA, Halstead C, Cote AM, Sabr Y, von Dadelszen P,
Magee LA. Random urine albumin:creatinine ratio in high-risk
pregnancyis it clinically useful? [abstract]. 18th World Congress of
the International Society for the Study of Hypertension in Pregnancy,
Geneva, Switzerland, July 2012. Pregn Hypertens 2012;2:25355.
53. Cote AM, Brown MA, Lam E, von Dadelszen P, Firoz T, Liston RM,
et al. Diagnostic accuracy of urinary spot protein:creatinine ratio for
proteinuria in hypertensive pregnant women: systematic review. BMJ
2008;336:10036.
54. Payne B, Magee LA, Cote AM, Hutcheon JA, Li J, Kyle PM, et al. PIERS
proteinuria: relationship with adverse maternal and perinatal outcome.
J Obstet Gynaecol Can 2011; 33:58897.
55. Lindheimer MD, Kanter D. Interpreting abnormal proteinuria in
pregnancy: the need for a more pathophysiological approach. Obstet
Gynecol 2010;115(2 Pt 1):36575.
56. Centre for Maternal and Child Enquiries. Saving mothers lives: reviewing
maternal deaths to make motherhood safer: 20062008. The eighth report
on confidential enquiries into maternal deaths in the United Kingdom.
BJOG 2011;118(Suppl 1).
57. Lewis G, ed. The Confidential Enquiry into Maternal and Child Health
(CEMACH). Saving mothers lives: reviewing maternal deaths to make
motherhood safer20032005. The seventh report on confidential
enquiries into maternal deaths in the United Kingdom. London:
Confidential Enquiries into Maternal and Child Health; 2007.
58. Martin JN Jr, Thigpen BD, Moore RC, Rose CH, Cushman J, May W.
Stroke and severe preeclampsia and eclampsia: a paradigm shift focusing
on systolic blood pressure. Obstet Gynecol 2005;105:24654.
926 l OCTOBER JOGC OCTOBRE 2012
59. National Committee for the Confidential Enquiries into Maternal Deaths.
Saving mothers 20052007: fourth report on confidential enquiries
into maternal deaths in South Africa. Pretoria: National Department of
Health; 2011.
60. 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):S1S48.
61. Reichenheim ME, Zylbersztajn F, Moraes CL, Lobato G. Severe acute
obstetric morbidity (near-miss): a review of the relative use of its
diagnostic indicators. Arch Gynecol Obstet 2009;280:33743.
62. Brown MA, Lindheimer MD, de Swiet M, Van Assche A, Moutquin
JM. The classification and diagnosis of the hypertensive disorders
of pregnancy: statement from the International Society for the
Study of Hypertension in Pregnancy (ISSHP). Hypertens Pregnancy
2001;20(1):IXXIV.
63. Lindheimer MD, Taler SJ, Cunningham FG. ASH position paper:
hypertension in pregnancy. J Clin Hypertens (Greenwich) 2009;11:21425.
64. Lowe SA, Brown MA, Dekker G, Gatt S, McLintock C, McMahon L,
et al. Guidelines for the management of the hypertensive disorders of
pregnancy 2008. Society of Obstetric Medicine of Australia and New
Zealand: 2008.
65. Visintin C, Mugglestone MA, Almerie MQ, Nherera LM, James D,
Walkinshaw S; Guideline Development Group. Management of
hypertensive disorders during pregnancy: summary of NICE guidance.
BMJ 2010;341:c2207.
66. World Health Organization. Priority medicines for mothers and
children 2011. Geneva: WHO; March 2011. Available at:
http://www.who.int/medicines/publications/A4prioritymedicines.pdf.
Accessed April 10, 2012.
67. McNeil DG Jr. Treatments: WHO lists priority medicines for children and
pregnant women. New York Times; March 28, 2011. Available at: http://
www.nytimes.com/2011/03/29/health/29global.html.
Accessed April 10, 2012.
68. World Health Organization. WHO Model Lists of Essential Medicines.
Geneva: WHO; March 2011. Available at: http://www.who.int/
medicines/publications/essentialmedicines/en. Accessed April 10, 2012.
69. Duley L, Gulmezoglu AM, Henderson-Smart DJ, Chou D. Magnesium
sulphate and other anticonvulsants for women with pre-eclampsia.
Cochrane Database Syst Rev 2010;(11):CD000025.
70. Duley L, Henderson-Smart DJ, Walker GJ, Chou D. Magnesium
sulphate versus diazepam for eclampsia. Cochrane Database Syst Rev
2010;(12):CD000127.
71. Duley L, Henderson-Smart DJ, Chou D. Magnesium sulphate
versus phenytoin for eclampsia. Cochrane Database Syst Rev
2010;(10):CD000128.
72. Duley L, Gulmezoglu AM, Chou D. Magnesium sulphate versus lytic
cocktail for eclampsia. Cochrane Database Syst Rev 2010;(9):CD002960.
73. Duley L, Matar HE, Almerie MQ, Hall DR. Alternative magnesium
sulphate regimens for women with pre-eclampsia and eclampsia.
Cochrane Database Syst Rev 2010;(8):CD007388.
74. Magee LA, Abalos E, von Dadelszen P, Sibai B, Walkinshaw SA. Control
of hypertension in pregnancy. Curr Hypertens Rep 2009;11:42936.
75. Mroczek WJ, Lee WR, Davidov ME. Effect of magnesium sulfate on
cardiovascular hemodynamics. Angiology 1977;28:7204.
76. Magee LA, Cham C, Waterman EJ, Ohlsson A, von Dadelszen P.
Hydralazine for treatment of severe hypertension in pregnancy: meta-
analysis. BMJ 2003;327:95560.
77. Magee LA, Miremadi S, Li J, Cheng C, Ensom MH, Carleton B, et al.
Therapy with both magnesium sulfate and nifedipine does not increase
the risk of serious magnesium-related maternal side effects in women with
preeclampsia. Am J Obstet Gynecol 2005;193:15363.