Cochrane Database of Systematic Reviews

Interventions for preventing pre-eclampsia and its

consequences: generic protocol (Protocol)

Meher S, Duley L, Prevention of Pre-eclampsia Cochrane Review Authors

Meher S, Duley L, Prevention of Pre-eclampsia Cochrane Review Authors.

Interventions for preventing pre-eclampsia and its consequences: generic protocol.
Cochrane Database of Systematic Reviews 2005, Issue 2. Art. No.: CD005301.
DOI: 10.1002/14651858.CD005301.

www.cochranelibrary.com

Interventions for preventing pre-eclampsia and its consequences: generic protocol (Protocol)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
 TABLE OF CONTENTS
HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
WHAT’S NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16

Interventions for preventing pre-eclampsia and its consequences: generic protocol (Protocol) i
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
[Intervention Protocol]

Interventions for preventing pre-eclampsia and its

consequences: generic protocol

Shireen Meher1 , Lelia Duley2 , Prevention of Pre-eclampsia Cochrane Review Authors3

1 C/o Cochrane Pregnancy and Childbirth Group, School of Reproductive and Developmental Medicine, Division of Perinatal and

Reproductive Medicine, The University of Liverpool, Liverpool, UK. 2 Centre for Epidemiology and Biostatistics, University of Leeds,
Bradford, UK. 3 Liverpool, UK

Contact address: Shireen Meher, C/o Cochrane Pregnancy and Childbirth Group, School of Reproductive and Developmental Medicine,
Division of Perinatal and Reproductive Medicine, The University of Liverpool, First Floor, Liverpool Women’s NHS Foundation Trust,
Crown Street, Liverpool, L8 7SS, UK. s.meher@liv.ac.uk.

Editorial group: Cochrane Pregnancy and Childbirth Group.

Publication status and date: Edited (no change to conclusions), published in Issue 1, 2010.

Citation: Meher S, Duley L, Prevention of Pre-eclampsia Cochrane Review Authors. Interventions for preventing pre-eclamp-
sia and its consequences: generic protocol. Cochrane Database of Systematic Reviews 2005, Issue 2. Art. No.: CD005301. DOI:
10.1002/14651858.CD005301.

Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

ABSTRACT

This is the protocol for a review and there is no abstract. The objectives are as follows:

To determine the effectiveness and safety of interventions for prevention of pre-eclampsia and its complications.

BACKGROUND as a protocol. Reviews developed or updated using this protocol

will be available separately in The Cochrane Library.

Generic protocol
This is a generic protocol for the development and maintenance
Introduction
of reviews evaluating interventions for prevention of pre-eclamp- Hypertension (high blood pressure) is common during pregnancy.
sia. The protocol outlines a common methodology for selection Around 10% of women will have their blood pressure recorded as
and assessment of studies. It was developed in consultation with above normal at some point before delivery. Pre-eclampsia (tox-
existing review authors, who are listed under ’Contributions of aemia) is defined as hypertension accompanied by proteinuria
reviewers’. We hope that the use of this protocol will provide a (protein in the urine) (NHBPEP 2000). It usually occurs dur-
systematic and comprehensive approach to the topic and increase ing the second half of pregnancy and complicates 2% to 8% of
consistency across these reviews, making them easier to read and pregnancies (WHO 1988). For women who have hypertension
to use. If any review deviates substantially from this protocol, the alone, pregnancy outcome is similar to that for women with nor-
reasons will be stated. mal blood pressure. Outcome deteriorates once proteinuria de-
Unlike other protocols in The Cochrane Library, this generic pro- velops. Women with mild pre-eclampsia generally have no symp-
tocol will not become a full review, but will remain permanently toms. Women with severe pre-eclampsia, or very high blood pres-
Interventions for preventing pre-eclampsia and its consequences: generic protocol (Protocol) 1
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
sure may feel unwell with symptoms such as headache, upper ab-
dominal pain or visual disturbances. Pre-eclampsia can lead to
problems in the liver, kidneys, brain, and to abnormalities of the
clotting system. Rare but serious complications include eclampsia
(seizures in a woman with pre-eclampsia), stroke, HELLP syn-
drome (haemolysis, elevated liver enzymes and low platelets) and
disseminated intravascular coagulation. These complications are
associated with an increased risk of maternal death (DH 2001).
The placenta is also involved in pre-eclampsia, and so risks for the
baby are increased. The most common problems are those related
to poor growth and premature birth.
Although the outcome following pre-eclampsia or eclampsia is
good for most women, these conditions remain major causes of
maternal mortality. Over half a million women die each year from
pregnancy related causes, and 99% of these deaths occur in the
developing world (WHO 2000). An estimated 10% to 15% of
maternal deaths in developing countries are associated with pre-
eclampsia or eclampsia (Duley 1992), as are 13% to 15% of the
direct obstetric deaths in the UK (DH 2001) and USA (ACOG
1996). Perinatal mortality is also increased following pre-eclampsia
(Ananth 1995; DH 2001).
There is less information about morbidity for either mother or
baby, but it is likely that this too is high. For example, pre-eclamp-
sia accounts for an estimated one fifth of antenatal admissions
(Rosenberg 1990) and two thirds of referrals to day care assess-
ment units (Anthony 1992) in the UK, and a quarter of obstetric
admissions to intensive care units in France (Bouvier-Colle 1996).
For many women, developing pre-eclampsia can be a difficult and
unexpected experience, especially if they become ill, give birth
too early (Engelhard 2002), or iftheir baby dies. Psychological
morbidity following a difficult pregnancy or labour, or perinatal
death is well documented (Clement 1998), although there are few
data specific to pre-eclampsia. There is also growing evidence that
women who have had gestational hypertension or pre-eclampsia
may be at increased risk later in life of hypertension, stroke, and
ischaemic heart disease (Hannaford 1997; Wilson 2003). For the
babies, pre-eclampsia is an antecedent for up to 12% of those born
small for gestational age (Kramer 2000) and 19% of those born
preterm (Hewitt 1988). Such babies are at an increased risk of
developmental delay and chronic ill health in childhood.
Definitions and classification
Pre-eclampsia is part of a spectrum of conditions known as the
hypertensive disorders of pregnancy. These disorders have a con-
tinuum with normal pregnancy. During normal pregnancy there is
enormous maternal physiological adaptation to accommodate the
growing fetus and placenta. For example, cardiac output increases
by about 40% in the first trimester. In contrast, blood pressure re-
mains relatively unchanged in the first trimester, falling by about 5
to 10 mmHg in the second trimester, and rising back to pre-preg-
Interventions for preventing pre-eclampsia and its consequences: generic protocol (Protocol)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
nancy levels by term. Cardiac output is influenced by peripheral
resistance and blood pressure. As normal pregnancy is associated
with increased cardiac output and normal or slightly lowered blood
pressure, peripheral resistance falls (de Swiet 2002). Changes in
kidney function also occur in normal pregnancy, with increased
protein excretion especially in the third trimester. In pregnancy,
up to 300 mg protein in 24 hours urine is accepted as normal.
Classification and definitions of hypertensive disorders of preg-
nancy have, in the past, been controversial. More recently, there
has been a shift towards agreeing standard definitions, and en-
suring they are relevant for clinical practice (Brown 2001). What
follows is based on current consensus.
Definition of hypertension
Hypertension in pregnancy is usually defined as systolic blood
pressure of at least 140 mm Hg and/or diastolic blood pressure
of at least 90 mmHg. Any rise in blood pressure should be con-
firmed by a second measurement, ideally at least four hours later.
Blood pressure should be measured with an auscultatory device, as
oscillometric techniques systematically under record during preg-
nancy (Quinn 1994). The debate over which auscultatory sound
to use for assessment of diastolic blood pressure, muffling (Ko-
rotkoff phase IV) or disappearance (Korotkoff phase V), has been
resolved, and Korotkoff V is now recommended as more reliable
(Brown 2001; Rubin 1996).
The suggestion that a change in blood pressure is more important
than any absolute level (Redman 1988) is no longer included due
to lack of evidence that it is related to outcome (Brown 2000;
Brown 2001; NHBPEP 2000).
Definition of proteinuria
Proteinuria during pregnancy is defined as 300 mg protein, or
more, in 24 hours. In a single midstream urine sample, this usually
correlates with 30 mg/dL, 1+ or more on a dipstick, or a spot urine
protein/creatinine ratio of at least 30 mg/mmol (Brown 2000;
Brown 2001).
Categories of hypertensive disorders of pregnancy
Four main categories are now widely agreed.
(1) Gestational hypertension or pregnancy-induced
hypertension
This is hypertension detected for the first time during the second
half of pregnancy (after 20 weeks gestation) in the absence of
proteinuria. It resolves within three months of birth.
2
(2) Pre-eclampsia/eclampsia
Pre-eclampsia is defined as hypertension and proteinuria detected
for the first time in the second half of pregnancy (after 20 weeks
gestation). Eclampsia is the occurrence of seizures in a woman with
pre-eclampsia.
There is no widely accepted definition of severe pre-eclampsia.
Nevertheless, the following are generally regarded as features of
severe disease: severe hypertension (blood pressure at least 160
mmHg systolic, or 110 mmHg diastolic), severe proteinuria (usu-
ally at least 3 g (range 2 g to 5 g) protein in 24 hours, or 3+ on
dipstick), reduced urinary volume (less than 400 ml to 500 ml
in 24 hours), neurological disturbances such as headache, visual
disturbances, and exaggerated tendon reflexes, upper abdominal
pain, pulmonary oedema (fluid in the lungs), impaired liver func-
tion tests, high serum creatinine, low platelets, intrauterine growth
restriction or reduced liquor volume (ACOG 1996; Brown 2000;
Brown 2001).
(3) Chronic hypertension
This is hypertension known to be present before pregnancy, or
detected before 20 weeks gestation. It is essential hypertension if
no underlying cause is found, and secondary hypertension if there
is an underlying cause such as renal, cardiac, or endocrine disease.
Chronic hypertension may present for the first time as gestational
hypertension. Hence, gestational hypertension that does not re-
solve after birth should be reclassified as chronic hypertension.
(4) Pre-eclampsia superimposed on chronic hypertension
Women with chronic hypertension may develop pre-eclampsia.
This is diagnosed where there is new onset of proteinuria, or sud-
den worsening of either hypertension or proteinuria, or develop-
ment of other signs and symptoms of pre-eclampsia after 20 weeks
gestation.
Aetiology
Despite a growing understanding of the pathophysiology of pre-
eclampsia, the underlying cause of the syndrome remains unclear.
Factors that appear to have a role include the placenta, maternal
immune response, genetic predisposition, maternal vascular dis-
ease, and diet. Whether an individual woman will develop this
syndrome probably depends on which of these factors she has, and
how they interact.
Placenta
The placenta plays a key role in pre-eclampsia. Pre-eclampsia oc-
curs only in the presence of a placenta, and its resolution begins
with the removal of the placenta at delivery. Pre-eclampsia can oc-
cur when there is no fetus, as in a molar pregnancy (Scott 1958),
Interventions for preventing pre-eclampsia and its consequences: generic protocol (Protocol)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
and when the pregnancy is not in the uterus, as in an abdominal
pregnancy (Piering 1993). Abnormal implantation of the placenta
(Khong 1986) and excessive placental tissue are both factors in the
underlying pathology of pre-eclampsia.
Maternal immune response
Normal pregnancy requires adaptation of the maternal immune
response, so that the fetus, who also carries the father’s genes, is
not rejected as foreign tissue. It has been suggested that for some
women pre-eclampsia may occur because this adaptation is inade-
quate, for example in a first pregnancy with a new partner (Roberts
1998). In subsequent pregnancies with the same partner the im-
mune tolerance is more complete, and the risk of pre-eclampsia is
therefore lower. Even a first trimester miscarriage or termination
provides some protection (Dekker 1998; Strickland 1986).
Genetic predisposition
Pre-eclampsia tends to run in families, suggesting that genetic
predisposition is a factor. The risk is higher for sisters and daughters
of women who had eclampsia and pre-eclampsia (Adams 1961;
Chesley 1968). A number of genes are currently under evaluation
for possible links with pre-eclampsia (Pridjian 2002).
Maternal disease
Medical conditions associated with vascular (blood vessel) disease
also increase the risk of a woman developing pre-eclampsia. For
example, the risk is doubled with diabetes (Garner 1990), and one
fifth of women with chronic hypertension develop pre-eclampsia
(Rey 1994). In addition, thrombophilia is associated with severe
early onset pre-eclampsia (Dekker 1995). This is a group of con-
ditions with a tendency for thrombosis, or blood clotting. They
include disorders such as protein S deficiency, activated protein
C resistance, Factor V Leiden mutation and autoimmune diseases
such as antiphospholipid syndrome and systemic lupus erythe-
matosus. A raised blood level of homocysteine, a metabolite of
the amino acid methionine, has also been linked to pre-eclampsia
(Powers 1998).
Nutrition and diet
Certain nutritional factors have been linked to the risk of pre-
eclampsia. For example, Mayan Indians in Guatemala, who tra-
ditionally soak their corn in lime before cooking, have a high cal-
cium intake and a low incidence of pre-eclampsia and eclamp-
sia. This led to the hypothesis that an increase in calcium intake
during pregnancy might reduce the risk of pre-eclampsia among
women with low calcium intake. Similarly, pre-eclampsia is rel-
atively infrequent in Greenland Inuits who eat a lot of oily fish
3
(Dyerberg 1985), suggesting consumption of fish oil might pre-
vent pre-eclampsia. Other nutritional factors that have been sug-
gested to have a role in preventing pre-eclampsia include magne-
sium, zinc, selenium, antioxidants such as vitamins C and E, folic
acid, garlic, and rhubarb.
Mode of development of pre-eclampsia
Pre-eclampsia is thought to occur as a result of inadequate blood
supply to the placenta. In normal pregnancy, as the placenta im-
plants in the uterus, important changes take place in the uterine
blood vessels to ensure that the growing placenta and fetus have
adequate blood supply from the mother. During implantation, the
placental cells invade blood vessels in the uterus known as spiral
arterioles, replace their endothelial lining and remodel them into
large diameter vessels with more capacity to handle blood flow
to the placenta (Brosens 1972). In pre-eclampsia, these vascular
adaptations may be patchy or fail to extend into the deeper layers
of the uterus (Khong 1986), resulting in small diameter, high resis-
tance blood vessels that are unable to meet the increasing demand
for blood supply to the placenta. Alternatively, placentation may
be normal but there may be a relative reduction in placental blood
flow, where the normal uterine blood supply becomes inadequate
because the placenta is large, for example in a multiple pregnancy.
Implantation and vascular changes are complete by 20 to 22 weeks
gestation. So, although pre-eclampsia is usually diagnosed in the
second half of pregnancy, the antecedents are present much earlier.
Current thinking is that inadequate blood supply to the placenta
leads to the release of unknown factors or materials into the ma-
ternal circulation which activate or injure the endothelial cells, re-
sulting in endothelial dysfunction (abnormal functioning of cells
lining blood vessels) (Roberts 2002). Several pathways for this
link between reduced perfusion of the placenta and endothelial
dysfunction have been proposed. One hypothesis is that reduced
placental perfusion may give rise to oxidative stress. In an envi-
ronment where oxidants exceed neutralizing antioxidant (Hubel
1997), excessive formation of free radicals leads to lipid peroxi-
dation and cell membrane damage (Hubel 1997). Alternatively,
lack of oxygen in the placenta may trigger the release of small pro-
teins, known as cytokines, that start an inflammatory response in
the endothelium (Conrad 1997). Another proposed mediator for
the endothelial cell injury is micro fragments of placental tissue.
These are transferred into the maternal circulation in increased
amounts in women with pre-eclampsia (Knight 1998), and have
been shown to alter endothelial function in laboratory studies
(Cockell 1997).
Endothelial dysfunction results in a series of changes including
reduced production of vasodilators and anticoagulants (such as
prostacyclin and nitric oxide), increased production of vasocon-
strictors and platelet aggregators (such as thromboxane A2 and
endothelin), increased responsiveness of endothelium to the vaso-
pressor Angiotensin II, and an elevation in the proteins of the co-
Interventions for preventing pre-eclampsia and its consequences: generic protocol (Protocol)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
agulation cascade (such as von Willebrand factor). These changes
result in widespread vasoconstriction and activation of platelets
and the coagulation system. Injured endothelial cells allow leak-
age of fluid out of the blood vessels and into surrounding tissues,
causing oedema and a reduction in the circulating blood volume.
There is then inadequate blood flow to many of the woman’s or-
gans, especially the kidneys, liver, and brain. It is the vasoconstric-
tion, micro clots, and reduced circulating blood volume that result
in the clinical manifestations of pre-eclampsia.
Reduced perfusion of the placenta is not sufficient to explain
pre-eclampsia. The abnormal implantation needs to interact with
maternal constitutional factors (genetic, environmental and be-
havioural) to produce the syndrome of pre-eclampsia. The contri-
butions of reduced perfusion and maternal factors may be balanced
differently in different pregnancies. For example, profoundly re-
duced perfusion could lead to pre-eclampsia in women with min-
imal predisposing risk, while for others the maternal constitution
might present such a high risk that even minimal reduction of
placental perfusion would be sufficient to result in pre-eclampsia.
Identifying women at risk of pre-eclampsia
Screening for women at risk of pre-eclampsia is an important part
of antenatal care. Once women are identified as high risk, they
can be targeted for more intensive antenatal surveillance and pro-
phylactic interventions. Most current strategies for risk assessment
are based on the obstetric and medical history, and clinical exam-
ination. However, there is surprisingly little reliable evidence on
the actual risk associated with individual factors, and how they
might interact. Systematic reviews of strategies for predicting pre-
eclampsia are under way (Gupta 2004). When available, results
from these reviews will be incorporated into this protocol.
Risk factors with a particularly high association with pre-eclamp-
sia (more than one in 10 risk) include maternal diabetes (Caritis
1998; Conde-Agudelo 2000; Ness 1999), chronic hypertension
(Caritis 1998; Conde-Agudelo 2000; Rey 1994), and renal dis-
ease (Cunningham 1990). Thrombophilia and autoimmune dis-
ease have a strong association with severe early onset pre-eclamp-
sia (Dekker 1995). Obstetric factors associated with high risk
are multiple pregnancy (Conde-Agudelo 2000; Long 1987), his-
tory of pre-eclampsia in a previous pregnancy especially if se-
vere or early onset (Caritis 1998; Hnat 2002; Sibai 1991) and
a current hydropic (Scott 1958) or molar pregnancy (Taylor
1988). Other factors linked with pre-eclampsia, but associated
with a somewhat lower risk include first pregnancies (Brown 2000;
Conde-Agudelo 2000; Taylor 1988), age less than 20 or more than
35 years (Conde-Agudelo 2000; Ness 1999), a family history of
pre-eclampsia (Adams 1961; Chesley 1968), and obesity (Baeten
2001; Conde-Agudelo 2000; Sebire 2001).
Routine screening for pre-eclampsia is based on measurement of
blood pressure and urinalysis for proteinuria. Overall, 15% to 25%
of women with gestational hypertension progress to pre-eclampsia
4
(Saudan 1988). Although various physiologic and biochemical
screening tests have also been developed (Friedman 1999), so far
none have proved to be of good predictive value and few are used
in clinical practice. Doppler ultrasound of the uterine arteries is
a non-invasive imaging test to assess blood flow to the placenta,
and at present holds more promise (Papegeorghiou 2004).
Strategies for prevention
Primary prevention is preventing the onset of a disease, for exam-
ple prevention of any signs or symptoms of pre-eclampsia. Sec-
ondary prevention is the reversing, stopping or slowing down of its
progress, for example prevention of proteinuria in a woman with
gestational hypertension. Tertiary prevention is the prevention of
complications in established disease, for example, prevention of
eclampsia in a woman with pre-eclampsia. This protocol covers
primary and secondary prevention. Tertiary prevention is dealt
with in other Cochrane reviews such as those on anticonvulsants
for pre-eclampsia (Duley 2003c), and eclampsia (Duley 2000;
Duley 2003b; Duley 2003d), plasma volume expansion (Duley
1999b), corticosteroids for HELLP syndrome (Matchaba 2002),
timing of delivery for severe pre-eclampsia (Churchill 2002), and
alternative antihypertensive agents for very high blood pressure
(Duley 2002).
As the cause of pre-eclampsia is not completely understood, and
screening tests remain unreliable, it is difficult to develop ratio-
nal strategies for prevention of pre-eclampsia. Current strategies
for prevention focus on antenatal surveillance, modification of
lifestyle, nutritional supplementation, and pharmacological ther-
apy.
Antenatal care
Antenatal care is a complex package of interventions. The com-
ponents may vary, dependent on factors such as country, setting,
and the characteristics of the individual woman.Evaluation of an-
tenatal care for women at risk of pre-eclampsia should include
an evaluation of individual components, such as how to measure
blood pressure or proteinuria. It should also include comparisons
of packages with different settings, providers of care, and frequency
of visits.
Lifestyle choices
Certain lifestyle choices have been suggested to influence risk of
hypertension, such as whether to exercise, how much to rest in
bed, and whether to modify salt content in the diet. As these would
normally be matters of personal preference, it is important that
any recommendation that women modify their life style should
be based on adequate evidence.
Interventions for preventing pre-eclampsia and its consequences: generic protocol (Protocol)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Nutrition and diet
Various hypotheses have been proposed to link pre-eclampsia with
specific dietary deficiencies, either before or during pregnancy. For
example, calcium (Atallah 2002) and fish oil supplementation were
suggested based on observations of an association between dietary
intake and the incidence of pre-eclampsia in various communities.
Zinc (Mahomed 1997a) and magnesium supplements (Makrides
2001b) were suggested to optimise normal physiological function
during pregnancy. Antioxidants such as vitamin C and E, selenium
and garlic have been suggested to counteract oxidative stress. Folic
acid may correct raised blood levels of homocysteine.
Pharmacological interventions
A wide range of drugs have been advocated for primary and sec-
ondary prevention of pre-eclampsia. For example, diuretics were
popular when oedema was considered to be an important symp-
tom of pre-eclampsia. Antiplatelet agents were suggested based
on the hypothesis that they would increase production of the va-
sodilator prostacyclin, and reduce the vasoconstrictor thrombox-
ane, hence reducing the risk of pre-eclampsia (Duley 2003a). An-
ticoagulants have also been suggested for women at particularly
high risk, such as those with thrombophilia (Walker 2003). An-
tihypertensive drugs are widely used for women with gestational
or chronic hypertension in the hope that early control of blood
pressure may prevent progression to pre-eclampsia (Abalos 2001).
Recently, there has been interest in nitric oxide, a vasodilator and
inhibitor of platelet aggregation. Alternative therapies such as Chi-
nese herbal medicine have also been used for pre-eclampsia.
The generic protocol and Cochrane reviews
A number of reviews and protocols evaluating interventions for
prevention of pre-eclampsia are already available on The Cochrane
Library. Some of these reviews have prevention of pre-eclampsia
and its complications as their main focus. We refer to these as ’core
reviews’. For other reviews, the aim is to assess the impact of a
specific intervention on a range of outcomes, one of which is pre-
eclampsia. We refer to these as ’non-core reviews’. This generic
protocol will serve as a template for core reviews for prevention of
pre-eclampsia, either in the development of new reviews or in the
updating of existing reviews. Review authors of non-core reviews
are welcome to use or adapt this protocol for their review.
Currently, core reviews evaluate the following interventions:
• Antenatal care (ambulatory versus conventional methods
for blood pressure monitoring (Bergel 2001))
• Lifestyle choices (bed rest with or without hospitalisation
(Abalos 2002))
• Nutrition and diet (salt intake (Duley 1999a); calcium
(Atallah 2002); fish oil and other prostaglandin precursors
(Makrides 2001a); antioxidants (Rumbold 2003c))
5
 • Pharmacological interventions (antiplatelet agents (Duley
2003a); diuretics (Churchill 2003); antihypertensive drugs
(Abalos 2001); oral beta blockers (Magee 2003))
Currently, non-core reviews evaluate the following interventions:
• Antenatal care (patterns of antenatal care for low risk
pregnancies (Villar 2001); antenatal day care units versus
hospital admission for women with complicated pregnancies
(Kroner 2001))
• Lifestyle choices (aerobic exercise (Kramer 2002))
• Nutrition and diet (Zinc (Mahomed 1997a); magnesium
(Makrides 2001b); folate (Mahomed 1997b); protein and energy
intake (Kramer 2003); vitamin C (Rumbold 2003a); vitamin E
(Rumbold 2003b))
• Pharmacological interventions (heparin in women with
thrombophilia (Walker 2003)
To help make information from these primary reviews more ac-
cessible and clinically relevant, we plan to prepare four summary
reviews. These summary reviews will group interventions based
on (1) antenatal care, (2) lifestyle choices, (3) nutrition and diet,
and (4) pharmacological interventions.
OBJECTIVES
To determine the effectiveness and safety of interventions for pre-
vention of pre-eclampsia and its complications.
METHODS
Criteria for considering studies for this review
Types of studies
Adequately randomised trials evaluating any interventions for pre-
vention of pre-eclampsia and its complications.
Studies with a quasi-random design, such as allocation by alterna-
tion, day of week, or hospital numbers will be excluded whenever
possible as they have a greater potential for bias (Schulz 1995). If a
review does include such studies, there will be a sensitivity analysis
based on excluding studies with a quasi-random design.
Types of participants
Pregnant women will be included, regardless of gestation at trial
entry.
Whenever possible and relevant, women will be grouped on the
basis of their risk at trial entry as follows.
Interventions for preventing pre-eclampsia and its consequences: generic protocol (Protocol)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
(1) Normotensive women
(a) High risk: defined as having one or more of the following: dia-
betes, renal disease, thrombophilia, autoimmune disease, previous
severe or early onset pre-eclampsia, or multiple pregnancy.
(b) Moderate risk: defined as none of the above, but having either
previous pre-eclampsia that was not severe or early onset (or sever-
ity unspecified), or a first pregnancy and at least one of the follow-
ing: teenager or over 35 years age, family history of pre-eclamp-
sia, obesity (body mass index of 30 or more), increased sensitivity
to Angiotensin II, positive roll over test, abnormal uterine artery
doppler scan.
(c) Low risk: defined as pregnancy that does not qualify as either
high or moderate risk.
(d) Undefined risk: when the risk is unclear or not specified.
(2) Hypertensive women, without proteinuria
These women are all at high risk of developing pre-eclampsia.
They fall into two groups.
(a) Gestational hypertension: hypertension detected for the first
time after 20 weeks gestation, in the absence of proteinuria.
(b) Chronic hypertension: essential or secondary hypertension de-
tected prior to pregnancy or before 20 weeks gestation. Some
women with chronic hypertension may have longstanding pro-
teinuria due to their underlying disease. These women will be in-
cluded, as their proteinuria is not due to pre-eclampsia.
If a trial includes women with pre-eclampsia as well as those with
non-proteinuric hypertension (gestational or chronic), where pos-
sible only the women with non-proteinuric hypertension alone
will be included in the review. Trials that do not report results
separately for the two categories may be included in the review
and if so, will be presented as a separate subgroup.
(3) Undefined
When it is unclear, or not specified, whether or not the women
have hypertension.
Individual reviews may address one particular group of women
only, such as high risk normotensive women. Alternatively they
may combine different groups, such as normotensive moderate
risk and low risk, or include all women regardless of risk of pre-
eclampsia, and then explore risk as a subgroup analysis.
Women will be excluded if they have given birth prior to trial entry
or if they have established pre-eclampsia.
Types of interventions
Comparison of an intervention, or combination of interventions,
with placebo or no intervention. Comparisons of one or more
interventions with another intervention may also be included.
Studies that compare an intervention with no intervention rather
than placebo have more potential for bias. If a review includes
6
such studies, there will be a sensitivity analysis based on excluding
studies with no placebo.
If appropriate for specific reviews, maximum and/or minimum
dosage regimens and duration of therapy may be justified and
specified.
Types of outcome measures
The following outcomes will be included. If an important outcome
is not reported, whenever possible authors will be contacted. To
avoid losing valuable data, trials that use acceptable variations of
the definitions specified below will also be included, as will those
that do not state their definitions.
Summary reviews will include only those outcomes listed below
that are marked with *.
For the woman
Main outcome
(1) Pre-eclampsia*: defined where possible as hypertension (blood
pressure ≥ 140 mmHg systolic or ≥ 90 mmHg diastolic) with
proteinuria (≥ 300 mg protein in a 24 hour urine collection or
≥ 30 mg/dL in a single sample or ≥ 1+ on dipstick or ≥ 30 mg/
mmol urine protein/creatinine ratio). For a woman with chronic
hypertension and proteinuria at trial entry, pre-eclampsia is de-
fined as sudden worsening of proteinuria and/or hypertension, or
other signs and symptoms of pre-eclampsia after 20 weeks gesta-
tion.
(2) Severe hypertension* may be used as a main outcome for re-
views which include women with hypertension during pregnancy
(for definition of severe hypertension, see below).
Other outcomes
(3) Death*: during pregnancy or up to 42 days after end of preg-
nancy.
(4) Severe morbidity*: including eclampsia, liver or renal fail-
ure, haemolysis, elevated liver enzymes and low platelets syn-
drome, disseminated intravascular coagulation, stroke and pul-
monary oedema. These outcomes will be reported individually,
and as a composite measure where the information is available.
(5) Severe pre-eclampsia: as defined above (see background).
(6) Early onset of pre-eclampsia: defined where possible as pre-
eclampsia before 33 completed weeks.
(7) Severe hypertension*: defined where possible as blood pressure
≥ 160 mmHg systolic or ≥ 110 mmHg diastolic.
(8) Gestational hypertension*: defined where possible as hyper-
tension (blood pressure ≥ 140 mmHg systolic or ≥ 90 mmHg
diastolic) after 20 weeks gestation.
(9) Use of antihypertensive drugs or need for additional antihy-
pertensive drugs.
Interventions for preventing pre-eclampsia and its consequences: generic protocol (Protocol)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
(10) Abruption of the placenta or antepartum haemorrhage.
(11) Elective delivery*: induction of labour or caesarean section.
(12) Caesarean section*: emergency and elective.
(13) Postpartum haemorrhage: defined as blood loss of 500 ml or
more.
(14) Side-effects*: any side-effects or adverse events related to the
intervention, intervention stopped due to side-effects.
(15) Use of hospital resources: visit to day care unit, antenatal
hospital admission, intensive care (admission to intensive care unit,
length of stay, ventilation, dialysis).
(16) Women’s experiences and views of the interventions: preg-
nancy and childbirth experience, physical and psychological
trauma, mother-infant interaction and attachment.
For the Child
Main outcomes
(1) Death*: including all deaths before birth and up to discharge
from hospital.
(2) Preterm birth*: defined as birth before 37 completed weeks
gestation.
(3) Small for gestational age*: defined as growth below the 3rd
centile, or lowest centile reported.
Other outcomes
(4) Death, classified by timing of death: miscarriage (fetal loss up
to 19 completed weeks gestation or however defined in the study),
stillbirth (death in utero at or after 20 weeks gestation), perinatal
death (stillbirth or death in the first seven days of life), neonatal
death (death in the first 28 days after birth), infant death (death
in the first year of life).
(5) Severity of preterm birth: very preterm birth (before 33 com-
pleted weeks) and extremely preterm birth (before 27 completed
weeks).
(6) Apgar score at five minutes: low (< 7) and very low (< 4) or
lowest reported.
(7) Endotracheal intubation or use of mechanical ventilation.
(8) Neonatal morbidity*: respiratory distress syndrome, chronic
lung disease, sepsis, necrotizing enterocolitis, retinopathy of pre-
maturity, and intraventricular haemorrhage.
(9) Long-term growth and development*: blindness, deafness,
seizures, poor growth, neurodevelopmental delay and cerebral
palsy.
(10) Side-effects associated with the intervention*.
(11) Use of hospital resources*: admission to neonatal intensive
care unit, duration of hospital stay after delivery.
7
Economic outcomes
1. Costs to health service resources: short term and long term
for both mother and baby.
2. Costs to the woman, her family, and society associated with
the intervention.
Search methods for identification of studies
Electronic searches
We will search the Cochrane Pregnancy and Childbirth Group’s
trials register.
This register is maintained by the Trials Search Co-ordinator and
contains trials identified from:
1. quarterly searches of the Cochrane Central Register of
Controlled Trials (CENTRAL);
2. monthly searches of MEDLINE;
3. handsearches of 30 journals and the proceedings of major
conferences;
4. weekly current awareness search of a further 37 journals.
Details of the search strategies for CENTRAL and MEDLINE,
the list of handsearched journals and conference proceedings, and
the list of journals reviewed via the current awareness service can be
found in the ’Search strategies for identification of studies’ section
within the editorial information about the Cochrane Pregnancy
and Childbirth Group.
Trials identified through the searching activities described above
are given a code (or codes) depending on the topic. The codes are
linked to review topics. The Trials Search Co-ordinator searches
the register for each review using these codes rather than keywords.
In addition, we will search CENTRAL (The Cochrane Library)
using the search strategy in Appendix 1.
We will also search EMBASE (from 2002 onwards) using the
search strategy in Appendix 2.
This is a generic search strategy to identify trials related to pre-
eclampsia. Individual reviews focusing on a particular interven-
tion may choose to expand this search strategy by including terms
relevant to the intervention being assessed.
We will not apply any language restrictions.
Data collection and analysis
Selection of studies
Assessment of each citation for inclusion in a review will be done
by at least two authors, independently. Any differences in opinion
will be resolved by discussion. If agreement cannot be reached, a
third party will be consulted.
Interventions for preventing pre-eclampsia and its consequences: generic protocol (Protocol)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Assessment of study quality
The quality of each included trial will be assessed independently
by at least two authors using the criteria outlined in the Cochrane
Reviewers’ Handbook (Clarke 2003). Methods used for generation
of the randomisation sequence will be described for each trial. Each
study will be assessed for quality of the concealment of allocation,
completeness of follow up and blinding.
(1) Allocation concealment
A quality score for concealment of allocation will be assigned to
each trial, using the following criteria:
(A) adequate concealment of allocation, such as telephone ran-
domisation, consecutively numbered sealed opaque envelopes;
(B) unclear whether concealment of allocation was adequate;
(C) inadequate concealment of allocation such as open random
number tables, sealed envelopes that are not numbered or opaque.
Where the method of allocation concealment is unclear, whenever
possible attempts will be made to contact authors to provide fur-
ther details.
(2) Completeness of follow up
Completeness of follow up will be assessed using the following
criteria:
(A) less than 5% of participants excluded from analysis;
(B) 5% to 10% of participants excluded from analysis;
(C) more than 10% and up to and including 20% of participants
excluded from analysis.
Studies will be excluded if:
1. more than 20% of participants are excluded from analysis.
2. more than 10% of participants are not analysed in their
randomised groups and it is not possible to restore participants
to the correct group.
3. there is more than 10% difference in loss of participants
between groups.
Data will be analysed based on the group to which the participants
were randomised, regardless of whether they received the allocated
intervention or not. Where data are missing, clarification will be
sought from the authors.
(3) Blinding
Blinding will be described using the following criteria:
1. blinding of participants (yes/no/unclear or unspecified);
2. blinding of caregiver (yes/no/unclear or unspecified);
3. blinding of outcome assessment (yes/no/unclear or
unspecified).
Data extraction and data entry
Data will be extracted by at least two review authors, and discrep-
ancies will be resolved through discussion. If agreement cannot
8
be reached, that item will be excluded until further clarification is
available from the authors. Data will be entered onto the Review
Manager software (RevMan 2003), and checked for accuracy.
Statistical analyses
Statistical analyses will be carried out using RevMan (RevMan
2003). For dichotomous data, results will be presented as summary
relative risk with 95% confidence intervals, and, where relevant,
as risk difference (RD) and number needed to treat (1/RD). The I
2
statistic will be used to assess heterogeneity between trials. In the
absence of significant heterogeneity, results will be pooled using
a fixed-effect model. If substantial heterogeneity is detected (I2
more than 50%), possible causes will be explored and subgroup
analyses for the main outcomes will be performed. Heterogeneity
that is not explained by subgroup analyses may be modelled using
random-effects analysis, where appropriate.
Sensitivity analyses
Sensitivity analysis will be carried out, where necessary, to explore
the effects of trial quality assessed by concealment of allocation.
Studies with clearly inadequate allocation of concealment (rated
C) will be excluded. A second sensitivity analysis will be based on
excluding trials with no placebo, where relevant. Reviews that in-
clude quasi-randomised studies will do a sensitivity analysis based
on excluding studies with quasi-random design.
Subgroup analyses
The prespecified subgroups are listed below. Not all of these will
be relevant to each review. As multiple analyses increase the risk
of being misled by the play of chance, the number of subgroups
in any review should be minimised. For each review, the authors
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5. type of intervention: type of drug or supplement;
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and prespecified.
ACKNOWLEDGEMENTS
As part of the pre-publication editorial process, this protocol has
been commented on by three peers (an editor and two referees
who are external to the editorial team), one or more member of
the Pregnancy and Childbirth Group’s international panel of con-
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http://www.who.int/reproductive-health/publications/
maternal_mortality_2000/maternal_mortality_2000.pdf
accessed 12 July 2004.
Wilson 2003
Wilson BJ, Watson S, Prescott GJ, Sunderland S, Campbell
DM, Hannaford P, et al. Hypertensive diseases of pregnancy
and risk of hypertension and stroke in later life: results from
a cohort study. BMJ 2003;326(7394):845.
∗
Indicates the major publication for the study

APPENDICES

Appendix 1. Search strategy

1. pregnan*
2. pregnancy*ME
3. pregnancy-complications*ME
4. hypertension*ME
5. hypertens*
6. blood press*
7. ((#1 or #2 or #3) and (#4 or #5 or #6))
8. PIH
9. toxaemi* near pregnan*
10. toxemi* near pregnan*
11. pre-eclampsia*ME
12. pre-eclamp*
13. preeclamp*
14. pre next eclamp*
15. #7 or #8 or #9 or #10
16. #15 or #11 or #12 or #13 or #14

Interventions for preventing pre-eclampsia and its consequences: generic protocol (Protocol) 14
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Appendix 2. Search strategy
1. randomization/
2. double blind procedure/
3. crossover procedure/
4. intermethod comparison/
5. single blind procedure/
6. clinical study/
7. controlled study/
8. randomized controlled trial/
9. (clin$ adj2 trial$).tw.
10. ((singl$ or doubl$ or trebl$ or tripl$) adj2 (blind$ or mask$)).tw.
11. exp clinical trial/
12. placebo/
13. placebo$.tw.
14. random$.tw.
15. comparison/
16. drug comparison/
17. follow up/
18. evaluation.mp. and follow up/
19. “evaluation and follow up”/
20. exp “drug control”/
21. drug screening/
22. prospective study/
23. major clinical study/
24. (control$ or prospectiv$ or volunteer$).tw.
25. or/1-17
26. 26. or/19-24
27. 27. 25 or 26
28. 28. exp Eclampsia and Preeclampsia/
29. 29. (pre-eclamp$ or preeclamp$ or pre adj eclamp$).tw.
30. 30. (toxemi$ or toxaemi$) adj3 pregnan$).tw.
31. 31. (hypertens$ adj3 pregnan$).tw.
32. 32. pih.ti,ab
33. 33. 28 or 29 or 30 or 31 or 32
34. 34. 33 and 27
35. 35. limit 34 to human

WHAT’S NEW

Date Event Description

20 September 2008 Amended Converted to new review format.

Interventions for preventing pre-eclampsia and its consequences: generic protocol (Protocol) 15
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
CONTRIBUTIONS OF AUTHORS
This protocol was drafted by Shireen Meher and Lelia Duley in consultation with the Prevention of Pre-eclampsia Review authors
(PPRA). The PPRA authors include contact authors who have published Cochrane protocols and reviews in July 2004, and have
contributed to this document. These authors are: Edgardo Abalos, Eduardo Bergel, Guillermo Carroli, David Churchill, Caroline
Crowther, David Henderson-Smart, Justus Hofmeyr, James King, Michael Kramer, Laura Magee, Kassam Mahomed, Maria Makrides,
Alice Rumbold, Deborah Turnbull, Michael Walker, and Jose Villar.
Other review authors who become involved in new or existing reviews relevant to prevention of pre-eclampsia are invited to join the
list of PPRA review authors and use the generic protocol as appropriate.

DECLARATIONS OF INTEREST
None known.

SOURCES OF SUPPORT

Internal sources
• The University of Liverpool, UK.
• Medical Research Council, UK.
• University of Oxford, UK.

External sources
• Health Technology Assessment, UK.

Interventions for preventing pre-eclampsia and its consequences: generic protocol (Protocol) 16
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.