British Journal of Obstetrics and Gynaecology

June 1997,Vol. 104, pp. 689-696

Antioxidants in the treatment of severe pre-eclampsia:

an explanatory randomised controlled trial
*A. Metin Giilmezoglu Principal Medical Oficer, *G.Justus Hofmeyr Professor (Obstetrics and Gynaecology),
tMathys M. J. Oosthuisen Head
*Departmentof Obstetricsand Gynaecology,Coronation/JGStrijdom Hospitals,Johannesburg;
fBiochernishyLaboratory, Department of Surgery, University of the Witwatersrand,Johannesburg, South Africa

Objective To determine whether antioxidant therapy alters the disease process in severe early onset pre-
eclampsia, in support of the hypothesis that increased lipid peroxides and reactive oxygen species
production play an important role in the pathogenesis of the disease.
Design Randomised, double-blind, placebo controlled trial.
Setting Two tertiary care, referral hospitals in Johannesburg, South Africa.
Participants Women with severe pre-eclampsia diagnosed between 24 and 32 weeks of gestation.
Intervention Combined antioxidant treatment with vitamin E (800 Wday), vitamin C (1000 mg/day),
and allopurinol(200 mg/day).
Main outcome measures Primary outcomes: 1. prolongation of pregnancy and 2. biochemical
assessment of lipid peroxides and antioxidants. Secondary outcomes: data on maternal
complications, side effects of treatment, infant outcomes and regular assessment of haematologic
and renal parameters.
Results The proportion of women delivered within 14 days in the antioxidant group was 52% (14/27)
compared with 76% (22/29) in the placebo group (relative risk 0.68, 95% confidence interval
0.45-1.04). One woman in each group had eclampsia. Eleven women (42%) in the antioxidant and
16 (59%) in the placebo group required two antihypertensives for blood pressure control. Trial
medications were well tolerated with few side effects. Lipid peroxide levels were not significantly
altered in the antioxidant and placebo groups. Serum uric acid levels decreased and vitamin E levels
increased significantly.
Conclusion The results of this explanatory randomised trial do not encourage the routine use of
antioxidants against pre-eclampsia. However, further research with modified strategies such as
earlier initiation of therapy or different combinations seem worthwhile.

INTRODUCTION modified by an immunologic factor'. Roberts et ~ 1 and . ~

Pre-eclampsia is a systemic disorder associated with
the presence of placental tissue. The pathogenetic
mechanisms involved in the initiation and progression
of the disease process are not clear. Pre-eclampsia is
associated with inadequate or shallow trophoblastic
invasion of the decidual vessels, resulting in a high
resistance-low flow uteroplacental circulation which
causes placental ischaemia and hypoxia. The events
behind this inadequate trophoblast invasion are
unknown, but the trophoblast behaviour is probably
Correspondence: Dr A. Metin Giilmezoglu, UK Cochrane Centre,
Summertown Pavilion, Middle Way, Oxford OX2 7LG, UK.
This study has been funded in part by South African Medical
Research Council and South African Druggists. The trial medications
(active and placebo) have been donated by South African Druggists
and Her-Sol Laboratories, Johannesburg, South Africa.
Hubel et UP hypothesised that placental ischaemia
could trigger lipid peroxidation causing endothelial
damage, which would then initiate the self propagating
course and the systemic manifestations of the disorder.
Lipid peroxides are formed in two ways. The first is
the free radical process in which free radicals form in
excess, overcome the antioxidant defences and attack
polyunsaturated fatty acids. These free radicals initiate
chain reactions within the hydrophobic core of the cell
membrane lipid bilayer, leading to membrane fiagmen-
tation. The second is an enzymatic process involving
lipooxygenase and cyclooxygena~e~. Free radicals and
lipid peroxides can initiate reactions that damage cells
and cell membranes; however, the latter mechanism is
often a late component which accompanies cellular
injury5.
The mechanism of uric acid elevation in pregnancy is
controversial. Most obstetricians would agree that it

0 RCOG 1997 British Journal of Obstetrics and Gynaecology 689

690 A. M. G l J L M E Z O d L U E T A L .

is an indicator of the severity of the disease, whether the the disease. This effect would be manifest in prolonga-
problem lies in the renal handling of uric acid or in tion of pregnancy.
the p l a ~ e n t a ~It, ~has
. been suggested that ischaemia An exploratory randomised trial was designed in
of the placental villi may damage the nuclear rich which allopurinol, vitamin E and vitamin C were
syncytiotrophoblasts resulting in a high rate of purine administered as antioxidants to a group of women with
catabolism, which would raise uric acid levels and severe early onset pre-eclampsia who were to be man-
possibly correlate with the severity of the diseasex.The aged conservatively. The main clinical outcome mea-
fetus can also generate uric acid at concentrations high sure was prolongation of pregnancy. Serial biochemical
enough to be detected in the maternal blood9. assessments were also undertaken to investigate the
An important consequence of ischaemia is inade- effect of this therapeutic regimen on lipid peroxides (as
quate cellular oxygenation. Oxygen is used in the cell to measured by the malondialdehyde-thiobarbituric acid
generate energy in the form of adenosine triphosphate reactive assay[MDA-TBAR]) as well as antioxidant
(ATP). When there is inadequate oxygen supply to the levels. The secondary outcomes were, maternal morbid-
cells a process called ATP degradation occurs. ATP ity, side effects, fetal and neonatal outcome and changes
degradation leads to the release of purine intermediate in haematological and renal function.
products and increased uric acid as the end product.
This process is important for two reasons. Firstly, when
purines are degraded to uric acid they cannot be re-used
METHODS
within the energy generating system of the cell. Eligibility
Secondly, under hypoxic conditions, the enzyme
The trial was conducted at two tertiary care academic
xanthine dehydrogenase is shifted to the oxidase form
hospitals which serve a low income urban population
generating free oxygen radicalst0.This mode of cellular
with a mixed racial composition. The study group com-
injury has been studied extensively in adult respiratory
prised women who were admitted to the antenatal wards
distress syndrome" and neonatal hypoxic-ischaemic-
with a diagnosis of severe pre-eclampsia as defined by
encephalopathyi2J3. A family with mitochondrial
Odendaal et all9. Briefly, these women had at least 2+
dysfunction characterised by a deficiency in energy
proteinuria on urine dipstix testing (in at least two con-
production within the cells and a high incidence of
secutive tests 4 to 6 hours apart), with a blood pressure
pre-eclampsideclampsia has been rep~rted'~. The find-
of 160/110 mmHg, or 3+ proteinuria with blood pres-
ing of morphologic evidence of mitochondrial injury in
sure L 150/100 mmHg. With these criteria proteinuric
pre-eclamptic women also supports this mechani~m'~.
hypertensive women were selected regardless of the
Oxidative stress can also cause rises in intracellular
presence or absence of underlying hypertensive or renal
free calcium ions by interfering with normal calcium
disease. Gestational age limits for inclusion were
sequestering mechanisms5. In the presence of intracel-
between 24 and 32 weeks. In these two hospitals
lular energy deficiency, calcium ions that enter the cell
women with severe pre-eclampsia before 24 weeks are
cannot be removed by the calcium-pump. Calcium
advised termination of pregnancy while after 32 weeks,
supplementation reduces parathyroid hormone release
delivery can usually be undertaken. Only women with a
and intracellular calcium, which decreases smooth mus-
live single fetus and who did not have any systemic
cle reactivity. Calcium supplementation is currently
disorder, such as diabetes or systemic lupus erythemato-
a promising intervention for the prevention of hyper-
sus or allergy to the study medications, were eligible.
tensive disorders of pregnancyI6. Calcium channel
Conservative management of early onset severe pre-
blockers may also have a beneficial effect by preventing
eclampsia is the standard treatment in these hospitals
calcium influx into the cell17.
once the woman's condition is stabilised in the ward
In a preliminary case-control study lipid peroxide
and biochemical indices are acceptable. The latter are
levels were significantly highest in women with absence of significant renal impairment, the syndrome
eclampsia followed by severe pre-eclampsia and
of haemolysis, elevated liver enzymes and low platelets
healthy pregnant controls, suggesting an increase in
(HELLP) syndrome, or thrombocytopenia alone. These
lipid peroxides which followed the disease severitylx. women are advised to stay in hospital until delivery
Our hypothesis for this study was that the pathology with weekly betamethazone injections up to 32 to 34
that follows placental ischaemia is a local cellular
weeks and frequent fetal and maternal monitoring. Uric
energy deficiency which initiates excessive free radical
acid levels are not used for decision making.
production and triggers the multiple chain reactions
which result in widespread endothelial damage.
Sample s u e
Another hypothesis was that by giving antioxidants
which act at different sites we could slow down the dis- The sample size calculation was based on reports indi-
ease process or interrupt the self-propagatory course of cating that 80% of such women needed delivery within

0 RCOG 1997 Br J Obstet Gynaecol 104, 689-696

 ANTIOXIDANTS I N THE TREATMENT OF PRE-ECLAMPSIA
14 days of admissionzo.We estimated that the number
of women delivering within 14 days would be halved
to 40%, which yielded a sample size of 54 women
( a = 0.05; 1 - = 80%).
Conduct of the trial
Once conservative management was initiated the
women were approached and asked to participate in
the trial. Of the 59 women approached, 56 gave written
informed consent and comprised the study population.
Logistical problems, such as distance, or difficulties
with communication, with the second hospital resulted
in a high proportion of missed data with regard to blood
and placental samples, especially for lipid peroxide
assays which constituted the laboratory part of the trial.
For this reason enrolment in this hospital was stopped
after eight women; the women in this hospital who gave
consent for participation in the trial were transferred to
the co-ordinating hospital.
Intervention
The study medications were vitamin E (400 IU twice
daily), vitamin C (500 mg tabs twice daily) and allo-
purinol (100 mg twice daily) or matching placebos,
administered twice daily. For allopurinol and vitamin C,
placebos were identical. Vitamin C placebos were used
as placebos for vitamin E as well because it was not
possible to obtain two separate sets of placebos from the
supplier. Vitamin E tablets were similar in appearance
but slightly thicker and cream coloured compared with
the lighter colour of their placebos. To preserve double
blinding all medications were placed in dark brown
coloured bottles and 20-day supply of all three medica-
tions (active or placebo) were placed in consecutively
numbered sealed opaque paper bags. None of the
authors was involved in the day to day management of
the women. One of the authors (GJH) had access to the
code. This was necessary for those who remained unde-
livered for more than 20 days (only a 20 day treatment
could fit into the bottles), where a separately coded,
‘second’ treatment pack could be used. The treatment
packs were randomised by computer generated random
numbers in blocks of ten. The randomisation was done
by an independent researcher who was not involved in
the study. As all of the women were kept in hospital,
these medications were left with them and the ward
sisters were asked to observe whether the women were
taking their medications or not. After delivery the
bottles were taken back and any remaining tablets
counted at the end of the trial to check for compliance.
Statistical methods
There were no exclusions after enrolment. All women
0 RCOG 1997 Br J Obstet Gynaecol 104, 689-696
691
remained in their allocated group for analysis (inten-
tion-to-treat) regardless of whether they continued their
allocated treatment or not. The duration of pregnancy
from the time of randomisation had a nonnormal distri-
bution and therefore was analysed by the nonparametric
Mann-Whitney test. Wilcoxon paired ranks test was
used in the analysis of umbilical artery Doppler flow
measurements. Categorical data were analysed by the X~
test with Fisher’s exact test where appropriate. Relative
risks (RR) and 95% confidence intervals (CI) were
calculated for dichotomous outcomes using Epi Info
version 6.02.
Biochemical assessment methods
For the purposes of this study the full blood counts,
liver function tests, urea and electrolytes, as well as
lipid peroxide and vitamin E assays, were performed on
day 0, 3, 7 and weekly afterwards until delivery. An
attempt was made to repeat the tests close to the time of
delivery if they had not been performed within the pre-
ceding 24 to 48 hours. All blood samples were cen-
trifuged and the supernatant snap frozen at -70°C
within 30 minutes of collection. For lipid peroxides,
malondialdehyde-thiobarbituric acid reactive (MDA-
TBAR) assay was performed with the standard curve
generated using tetramethoxypropane as working
stock2’.Sera for vitamin E measurements were handled
as above and protected from light until analysis.
Measurements were made by high performance liquid
chromatography2zand the assay validated by the United
States National Institute of Standards and Technology
Standard Reference Material 968 a.
Fetal monitoring consisted of daily nonstress tests,
weekly Doppler umbilical artery resistance index mea-
surements and ultrasound scanning every two weeks for
fetal growth. Renal function was monitored by urea,
creatinine and weekly creatinine clearance measure-
ments. More frequent testing or other relevant tests
(such as lupus anticoagulant or coagulation tests) were
decided on by the obstetric staff.
All laboratory tests were performed without any
knowledge of trial group allocations.
The trial was approved by the Committee for
Research on Human Subjects of the University of the
Witwatersrand.
RESULTS
Clinical results
Of the 56 women enrolled, 27 were in the antioxidant
and 29 were in the placebo group. The groups were
comparable with regard to entry characteristics
(Table 1). The number of women who were delivered
692 A . M. G U L M E Z O C L U ET A L .

i Day14

(D
In
II

I ......- ...
I I I I I I -_ I I I
0 5 10 15 20 25 30 35 40 45 50 55 60 65 70
Days

Fig. 1. Enrolment-delivery interval (days) in the two groups. -= antioxidant; - - - =placebo.

Table 1. Baseline data in the antioxidant and placebo groups Table 2. Reasons for delivery in the two groups. Values are given as
expressedas median [range] or proportions (%). n (%)

Antioxidant group Placebo group Antioxidant group Placebo

(n = 27) (n = 29) (n = 27) (n = 28*)

Age (years) 29 [ l W ] 28 [1742] Fetal? 12 (44) 15 (54)

Gestational age (weeks) 30 [25-321 29 [25-331 Maternal 3 (11) 6 (21)
Mean arterial pressure 130 [116.7-156.7] 130 [116.7-153.3] Both 5 (18.5) 3 (11)
Race (African) 18 (67) 23 (79) Spontaneouslabour and delivery 5 (19) 3 (11)
Smoker 2 (7) 5 (17) Obstetric (rupture of membranes) 2 (7) 1 (4)
Primigravid 7 (26) 8 (28)
Previous miscarriage 9 (33) 8 (28) *Missing data for 1 woman. ?Seven women in each group delivered
Impaired fetal growth because of intrauterine fetal death.
at enrolment 10 (37) 10 (34)
Proteinuria (g/24 h) 2.57 [0.08-15.01] 2.02 [0.09-12.24]
Serum uric acid (mmoUL) 0.37 [0.24-054] 0.36 [0.19-059]

pulmonary oedema occurred within 24 hours after

within 14 days (the main outcome measure) was 14
(52%) in the antioxidant group and 22 (76%) in the
placebo group (RR 0-68,95%CI 0.45-1.04). Figure 1 is
a Kaplan-Meier survival curve, 'survival' being the time
from enrollment to delivery. Although the logrank test
for survival (number still pregnant) was not statistically
significant (P = 0-24), there was a trend towards women
in the antioxidant group delivering later. There were no
maternal deaths but serious complications occurred in
both groups. In the antioxidant group, one woman had
mild postpartum pulmonary oedema and one woman
had eclampsia with the HELLP syndrome. In the
placebo group, two women had mild postpartum
pulmonary oedema, one had eclampsia and one had
disseminated intravascular coagulation with shock and
renal failure which required dialysis. All three cases of
delivery. Three women in the antioxidant and six in the
placebo group received magnesium sulphate. One
woman in each group received this treatment because of
eclampsia. Placental abruption was diagnosed clinically
in two of the antioxidant women (7%) and six controls
(21%). Sixteen women (59%) in the antioxidant group
and 11 (38%) in the placebo group were delivered by
pre-labour caesarean section. The reasons for delivery
are listed in Table 2.
All but one woman in each group were put on anti-
hypertensive treatment. Alpha methyldopa was the first
choice and nifedipine second in the majority of the
patients. Eleven women (4 1%) in the antioxidant and 16
(57%) in the placebo group required two antihyperten-
sives for blood pressure control (RR 0-74, 95% CI
0.43- 1'2 8).

0 RCOG 1997 Br J Obstet Gynaecol 104, 689-696

 ANTIOXIDANTS IN THE TREATMENT OF PRE-ECLAMPSIA 693

Table 3. Perinatal outcomes. Values are given as n (%) or median [range].

Antioxidant Placebo RR 95%CI

Stillbirth 7/27 (26) 9/29 (31) 0.84 0.361.93

Apgar 1 min -= 7 8/20 (40) 11/18* (61) 0.65 0.34-1.26
Apgar 5 min < 7 4/20 (20) 6/19* (32) 0.63 0.21-1 '90
Umbilical artery pH < 7.2 3/15 (20) 3/14' (21) 0.93 0'22-3'88
Admission to intensive care unit 5/20 (25) 6/20 (30) 071 0.30-2'29
Mechanical ventilation 2/20 (10) 6/20 (30) 0.33 0'08-1.46
Neonatal death 5/20 (25) 1/20 (5) 5.00 0.639.06
Perinatal death 12/27 (44) 10/29 (34) 1.29 0'67-2.48
Birthweight (g) 1210 [620-30901 1240 [620-26101

*Missing data.

woman in each group received low dose aspirin as part

Table 4. Reasons for poor perinatal outcome. Values are given as
n ("h).
of their management.
~

Antioxidant Placebo
group
(n = 12)
Abruption (diagnosed clinically) 2 (17)
Death before delivery with severely
impaired fetal growth 2 (17)
Severe hyaline membrane disease 3 (25)
Grade I11 intraventricular haemorrhage + sepsis - 1 (10)
Eclampsia 1 (8)
No specific cause found 4 (33)
Dopplerjndings
The umbilical artery resistance index measurements
were similar in the two groups at enrolment and one
week after enrolment. The paired measurements within
groups also did not reveal any significant changes.
Compliance and adverse events
A compliance index was calculated for each trial
medication. This was the ratio of the number of tablets
thought to have been taken (according to the count) to
the expected number if compliance was perfect. The
median compliance indexes were 89% (antioxidant)
compared with 100% (placebo) for vitamin C, 93%
compared with 86%for allopurinol, and 84%compared
with 75% for vitamin E. In the antioxidant group one
woman complained of an increase in acne, two of
transient weakness at the beginning of treatment, and
one woman had a skin rash after delivery on the day the
medications were stopped. One woman who com-
plained of weakness stopped the trial medications after
taking four doses altogether. In the second case it was
found that she had been given a higher than prescribed
dose of antihypertensives at night. No side effects were
reported in the placebo group.
Three women in each group received vitamin C
(1 00 mg/day), together with iron supplementation; one
0 RCOG 1997 Br J Obstet Gynaecol 104, 689-696
Perinatal outcome
group
(n = 10) The perinatal outcome is shown in Table 3. Poor peri-
2 (20) natal outcome was defmed as having either stillbirth or
neonatal death. The reasons that were thought to cause
3 (30) the poor outcome are shown in Table 4.
-
- Lipidperoxide and vitamin E levels
4 (40)
Baseline MDA-TBAR concentrations were higher in
the control group compared with the antioxidant group
(P = 0.02). As the women were enroled according to
clinical criteria and all other enrolment characteristics
were comparable (Table l), we believe this difference
must be a chance effect. MDA levels did not show any
consistent changes in the active or placebo groups over
the course of the study. There were also no significant
differences between groups with respect to changes in
MDA-TBAR measurements between baseline and
day 3. After day 14, the number of patients in each
group (six in active and four in placebo) became too
small for meaningful comparison.
Serum vitamin E levels greatly increased in the
antioxidant group, whose treatment included vitamin E.
Of interest was a statistically significant increase in
vitamin E levels in the placebo group (P= 0.02). The
change in vitamin E concentrations was evident both in
measurements before delivery and paired analyses
of the difference between baseline and day 7 measure-
ments. The change in vitamin E in the antioxidant group
was greater than that in the placebo group (P= 0.003).
Haematological and renalfunctionparameters
The greatest change was in serum uric acid levels which
decreased significantly within the first few days in the
antioxidant group and increased slightly in the placebo
group. In the antioxidant group the platelet count
694 A. M. GULMEZOCLU E T AL.
(median difference between day 7 and baseline,
12 x 109/L [range -59 to 215 x lo9]) and white cell
counts (median difference 0.6 x 109/L [range -8 to
4.8 x lo’]) tended to remain static compared with a trend
toward a decrease in platelet counts (median difference
0 [range -190 to 93 x lo’]), and a more prominent
increase in white cell counts (median difference
1.65 x 109/L[range -2.6 to 11.7 x lo9]) in the placebo
group, but these changes were not statistically sig-
nificant. There were no discernible changes in renal
function between the two groups.
There were no statistically significant differences
between placental MDA-TBAR and glutathione levels
in the antioxidant and placebo groups. Placental lipid
peroxide and glutathione results have been discussed in
more detail ~eparately~~.
DISCUSSION
Control of severe early onset pre-eclampsia remains a
problem for those in charge of the care of affected
women. The reason for this is that there is no way to
treat effectively the underlying disease. Decisions are
dictated by gestational age, assessments of fetal well-
being and neonatal facilities. Currently, conservative
management is widely practised, although it increases
the risk of maternal m ~ r b i d i t y ~The
~ , ~high
~ . maternal
morbidity rate in both groups reflects the risks of expec-
tant management in severe pre-eclampsia. The perinatal
mortality rate in this trial, although higher than devel-
oped countries, is comparable to previous reports from
South A f r i ~ a ~Neonatal
~ 9 ~ ~ . outcome is influenced most
by the capacity of neonatal intensive care units, which
admit only newborn infants whose birthweight is
> 1000 g or who are 28 weeks of gestational age in the
two hospitals in which this trial was undertaken. It is not
uncommon for a baby to have no intensive unit care or
mechanical ventilation, despite being above these limits
in these hospitals.
The results did not show any effect of the antioxidant
treatments on MDA-TBAR levels. This could be due to
several factors. One possibility is that, although all
samples were handled similarly and snap frozen within
a reasonable time (< 30 min), it may be that the amount
of artefactual h4DA produced between thawing and
measuring, concealed any real differences that might
have existed. Secondly, the enrolment to delivery times
in this study were relatively short (median 11 and 9 days
in active and placebo groups, respectively) and the bio-
chemical effects may take longer to appear. Duthie et
a1.28used 1000 mg a-tocopherollday for 14 days in
smokers and did not detect any significant changes in
MDA-TBAR despite significant changes in the levels of
conjugated dienes. In a more recent study29the same
researchers used 280 mg dl-a tocopherol acetate for 10
weeks and could show a statistically significant sup-
pression of both conjugated dienes and MDA-TBAR.
As expected, vitamin E supplementation increased
serum concentrations significantly in the antioxidant
group (Table 5). This increase is probably indicative of
good compliance. There could be several reasons for the
increase in the placebo group. Vitamin E is known to be
mobilised from the tissues to sites of oxidative stress29.
This could indicate increasing oxidative stress with
continuation of pregnancy in severe pre-eclampsia. The
other possibility is the effect of increasing gestational
age. Wang et al.30 determined vitamin E levels longitu-
dinally throughout normal pregnancy and observed a
progressive increase in vitamin E concentrations which
was most prominent between 24 and 32 weeks. A sub-
group analysis of baseline vitamin E levels in early
(< 28 weeks) and late (2 28 weeks) groups showed a
trend towards higher levels in the latter group (P =
0-06).
Serum uric acid concentrations were suppressed
within the first few days of treatment. However, this
was not associated with any change in the condition of
the mother or the fetus. Although creatinine clearance
before delivery was higher in the antioxidant group, a
suggestion of improvement in renal function would be
highly speculative as neither the change within one
week (baseline to day 7; data not shown) nor other renal
function tests supported this finding. The trends in
platelet and white cell count may be important.
Leucocyte activation is a well documented feature of
pre-eclampsia3’ and vitamin E’s modulatory effect on
adhesion molecule expression32could play a role in
restricting leucocyte activation as well as its antioxidant
effects.
Although the results are negative with regard to the
primary study objective, there was a tendency towards
prolongation of pregnancy in the antioxidant group
(Fig. 1). The trial was not designed, in terms of sample
size, to detect differences in perinatal outcome. There
may be several reasons for the lack of significant
results:
1. The trial was too small. If the true effect of antioxi-
dants was to decrease the number of women who
delivered after 14 days by 25% the number of
women necessary to show this difference would be
182 ( a = 0.05; 1 - f3 = 0.80).
2. The treatment was initiated when these women were
diagnosed as having severe pre-eclampsia. As the
pre-eclamptic process begins around the time of tro-
phoblast invasion of decidual vessels it may be
argued that the treatment was initiated too late to
have a significant effect.
3. There is no known ideal antioxidant dose or combi-
nation, although the doses used in this trial were
0 RCOG 1997 Br J Obstet Gynaecol 104, 689-696
 ANTIOXIDANTS IN THE TREATMENT OF PRE-ECLAMPSIA 695

Table 5 Biochemical data, lipid peroxides (MDA-TBAR) and vitamin E levels at enrolment, before delivery and postpartum day 3 (the differ-
ences in sample sizes are due to missing data. Urine protein and creatinine clearance measured in 24 hour collection and were not repeated after
delivery)
~~ ~

Antioxidant group Placebo group

Variables n Median Range n Median Range P

Baseline
MDA-TBAR (nmol/mL) 27 1.86 (0.7-5.94) 29 2.45 (0.7-8.27) 0.02
Vitamin E (pmoVL) 27 23.6 (942.4) 29 22.8 (11.8-36.5) 0.29
Haematocrit (%) 22 35-8 (18.9-43.1) 20 34.2 (25.744) 0.78
White cell count ( 109/L) 27 8.9 (4.4-20.2) 21 8.8 (5.4-15.9) 0.37
Platelet count (1 09/L) 27 203 (103-529) 27 218 (91-365) 0.48
Serum uric acid (mmol/L) 26 0.37 (0.24-0.54) 26 0.36 (0.19459) 0.74
Creatinine clearance (mL/min) 23 70.5 (29.2-159'8) 24 68.6 (21.1-196.9) 0.79
Urine protein (g/day) 23 2.57 (0.08-15.01) 24 2.02 (0.09-12.24) 0.42
Delivery
MDA-TBAR (nmol/mL) 24 2.51 (0.82-10.83) 25 2.33 (0.93-9.43) 0.90
Vitamin E (pmol/L) 24 45 (23.3-126.2) 25 28.5 (1 1'9-775) 0,003
Haematocrit (%) 23 37.8 (24.747.8) 22 36,2 (21.6-41.3) 0.03
White cell count (109/L) 24 10.3 (5.1-22.5) 25 10.5 (4.9-22.00) 0.35
Platelet count ( 109/L) 24 250 (126-385) 25 218 (52-426) 0.29
Serum uric acid (mmol/L) 24 0.32 (0.194.81) 21 0.43 (0.28455) 0.004
Creatinine clearance (mumin) 18 87 (32.8-122.1) 13 63.6 (31.7-136.3) 0.04
Urine protein (&day) 18 4.14 (0.32-19.04) 13 2.21 (0.42-15.95) 0.96
Postpartum day 3
MDA-TBAR (nmol/mL) 26 2.33 (0.70-14.91) 25 1.86 (0.35487) 0.48
Vitamin E (pmoVL) 25 38.8 (5.80-83.5) 25 27 (14-50.5) 0.003
Haematocrit (%) 24 34.8 (19.142.3) 21 33.3 (22.8-42) 0.54
White cell count (1 09/L) 25 10.9 (6.7-22.9) 24 11.9 (10.5-35.4) 0.19
Platelet count (1 09/L) 25 217 (44477) 24 221 (69-386) 0.8 1
Serum uric acid (mmol/L) 22 0.35 (0.214*45) 23 043 (0.18455) 0.006

similar to those used in other reports of antioxidant
interventions and probably adequate for an anti-
oxidant effect.
4. It may be argued that women with severe early onset
pre-eclampsia are heterogeneous and are not truly
representative of 'pure' pre-eclampsia. However, we
believe that once the pathophysiological process of
pre-eclampsia is initiated the factors causing the
disorder and its self-propagatorycourse are likely to
be similar whether or not pre-eclampsia is super-
imposed on renal or chronic hypertension or there is
any other underlying factor.
randomised trials with modified strategies such as ear-
lier initiation of therapy or with different combinations
and more sensitive laboratory assays are worthwhile.
Acknowledgements
The authors would like to thank Her-Sol Laboratories
and South African Druggists for supplying the trial
medications, Professor C. J. Van Gelderen, Drs J. Paiker,
R. Kulier and A. da Ponte, Srs T. Nkonyane, C. Nikodem
and M. de Jager and to JG Strijdom Hospital Antenatal
Ward staff for assistance.

CONCLUSION
To our knowledge, this is the first randomised
controlled trial of antioxidants in pre-eclampsia. There
is considerable circumstantial epidemiological, labora-
tory and clinical evidence to suggest a significant role
for free radical activation, and deficient or over-
utilised antioxidant defences in the pathogenesis of pre-
eclampsia. The results of this explanatory randomised
trial do not encourage the routine use of antioxidants
against pre-eclampsia. However, further explanatory
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Received 7 May I996
Accepted 2 Januaiy 1997
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