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of pregnancy
Lelia Duley
Resource Centre for Randomised Trials, Institute of Health Sciences, Headington, Oxford, UK
Introduction
Correspondence to: Lelia
Duley, Resource Centre
Pre-eclampsia is a multisystem disorder of unknown aetiology, unique to
for Randomised Trials, pregnancy. Women with pre-eclampsia usually develop raised blood pres-
Institute of Health sure and proteinuria, but the condition is also associated with abnormali-
Sciences, Old Road,
ties of the coagulation system, disturbed liver function, renal failure and
Headington,
Oxford OX3 7LF, UK. cerebral ischaemia1. It complicates an estimated 28% of pregnancies and
E-mail: rcrt@ndm.ox.ac.uk is a major cause of maternal morbidity, perinatal death and premature
British Medical Bulletin 2003; 67: 161176 British Medical Bulletin, Vol. 67 The British Council 2003; all rights reserved
DOI: 10.1093/bmb/ldg005
Pregnancy: reducing maternal death and disability
delivery, although outcome for most women is good. Eclampsia, the occur-
rence of one or more convulsions superimposed on the syndrome of pre-
eclampsia, occurs less frequently, complicating between 1 in 1001700
pregnancies in the developing world2 and about 1 in 2000 pregnancies in
Europe and other developed countries. Eclampsia is often a serious and
life-threatening condition. Compared to pre-eclampsia it carries a much
higher risk of death and serious morbidity for the woman and her baby. In
the UK, for example, 1 in 50 of the women who have eclampsia die3.
Worldwide, over half a million women die each year of pregnancy-
related causes, and 99% of these deaths occur in the developing world4.
Put another way, women in industrialized countries have an average life-
time risk (calculated as the average number of pregnancies multiplied by
Pathophysiology of pre-eclampsia
Although the exact mechanisms which lead to pre-eclampsia are not
clear, several factors are known to play a part in determining who will
develop this disease. Some women have predisposing factors. These
include family history, age and parity. Current thinking is that the
primary pathophysiology in pre-eclampsia is placental13,14. Pre-eclampsia
occurs in women who have an abdominal pregnancy and in those with a
hydatidiform mole, indicating that uterine and fetal factors are not
essential. In addition, it is more common amongst women who have
conditions associated with a large placenta (such as multiple pregnancies
and hydrops fetalis), and in women who have microvascular disease
(such as diabetes, hypertension and collagen vascular disease). In pre-
eclampsia, trophoblastic implantation is abnormal, with reduced placen-
tal perfusion. As normal implantation is complete by around 20 weeks,
this deficient implantation occurs weeks or months before the disease
becomes clinically apparent.
The secondary pathology in pre-eclampsia appears to be endothelial cell
injury. The proposed model is that reduced blood supply to the placenta
Prevention of pre-eclampsia
Diet and exercise
For decades, women have been advised to make a range of changes to
their diet and lifestyle, in the expectation that it might reduce their risk
of developing pre-eclampsia. Many of these are now obsolete. There is
no reliable evidence that any are effective. Interventions that have been
evaluated in randomized trials include aerobic exercise17,18, protein
restriction19, protein supplementation20,21, increasing or decreasing salt
intake22, magnesium supplementation23 and zinc supplementation24. All
the studies in these reviews were small and, even taken together, provide
insufficient evidence to provide a reliable basis for clinical decisions.
Therefore, in the absence of good evidence of either benefit or harm,
womens diet and lifestyle during pregnancy should be determined by
their own personal preferences.
Two further forms of supplementation have been evaluated in trials:
sources of prostaglandin precursors such as fish oil, and calcium. Fish
oil contains long chain fatty acids, which have antiplatelet and anti-
thrombotic effects thought to be beneficial in prevention of pre-
eclampsia. Observational studies suggested the possibility of a prophylactic
effect of fish oil and prompted more rigorous randomized trials. Other
sources of fatty acids, such as oil of evening primrose, have also been
evaluated in randomized trials. Over 2000 women have now been ran-
domized into these studies25. Taken together, the confidence intervals
suggest that the true effect could be anything between a 40% reduction
Treatment Control RR RR
Study n/N n/N (95%CI Fixed) (95%CI Fixed)
01 Low-risk women
L-Jaramillo 1989 2 / 55 12 / 51 0.15[0.04,0.66]
Purwar 1996 2 / 97 11 / 93 0.17[0.04,0.77]
Villar 1987 1 / 25 3 / 27 0.36[0.04,3.24]
Crowther 1999 10 / 227 23 / 229 0.44[0.21,0.90]
Belizan 1991 15 / 579 23 / 588 0.66[0.35,1.26]
CPEP 1997 158 / 2163 168 / 2173 0.94[0.77,1.16]
Subtotal(95%CI) 188 / 3146 240 / 3161 0.79[0.65,0.94]
Test for heterogeneity chi-square=15.10 df=5 p=0.0099
Test for overall effect z=2.57 p=0.010
.1 .2 5 10
Antioxidant vitamins
One small trial has evaluated high doses of vitamins C and E as anti-
oxidant agents for prevention of pre-eclampsia28. The results are
promising, but require confirmation in larger studies before being rec-
ommended for clinical practice. Several such studies are currently
planned or recruiting.
Bed rest
Women with high blood pressure during pregnancy have often been
advised to rest in bed, either at home or in hospital. Confinement to bed
either at home or in hospital may result in financial or social costs for
the woman and her family. Admission to hospital may be stressful and
has, in addition, major cost implications for the health services. These
interventions would only be justified if there were clear health benefits.
Three small trials (408 women) have compared hospital admission with
care at home for hypertension alone29. Two trials (145 women) have
compared bed rest in hospital with normal ambulation for women with
pre-eclampsia. Even taken together, these trials are too small for any
reliable conclusions30.
Antihypertensive agents
Antihypertensive agents are used to lower blood pressure during preg-
nancy, in the belief that these delay progression to more severe disease,
and so improve outcome. Twenty-four trials (2815 women) have com-
pared an antihypertensive drug with placebo/no antihypertensive drug
for women with mildmoderate hypertension during pregnancy31.
Unsurprisingly, antihypertensive drugs reduce by half the risk of devel-
oping severe hypertension (17 trials, 2155 women; RR 0.52, 95% CI
0.41, 0.64), but with little evidence of a difference in the risk of pre-
Treatment Control RR RR
Study n/N n/N (95%CI Fixed) (95%CI Fixed)
.1 .2 1 5 10
Favours Treatment Favours Control
Timing of delivery
For women who have severe pre-eclampsia before 34 weeks, the deci-
sion about the best time to deliver the baby is often difficult. The haz-
ards to the baby of being born too early need to be balanced against the
risks to both the woman and the baby if the pregnancy is continued for
too long. Two trials (133 women) have compared a policy of early elec-
tive delivery by induction of labour or by caesarean section, with a pol-
icy of delayed delivery. There are insufficient data for any reliable
recommendation about which policy of care should be used for women
with severe early onset pre-eclampsia.
Magnesium Control RR RR
Study n/N n/N (95%CI Fixed) (95%CI Fixed)
01 Severe pre-eclampsia
South Africa 1998 1 / 345 11 / 340 0.09[0.01,0.69]
Magpie Trial 2002 15 / 1297 37 / 1345 0.42[0.23,0.76]
South Africa 1994 1 / 112 0 / 116 3.11[0.13,75.46]
Subtotal(95%CI) 17 / 1754 48 / 1801 0.37[0.22,0.64]
Test for heterogeneity chi-square=3.73 df=2 p=0.15
Test for overall effect z=3.58 p=0.0003
.1 .2 5 10
Favours magnesium Favours control
magnesium other RR RR
Study n/N n/N (95%Cl Fixed) (95%Cl Fixed)
.1 .2 1 5 10
favours magnesium favours other
Conclusions
A wide range of interventions has been suggested for the prevention and
treatment of pre-eclampsia. Many thousands of women have now been
entered into randomized trials evaluating some of these interventions,
and this evidence provides the basis for a more rational approach to
some aspects of care. Many important unanswered questions remain,
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