British Journal of Obstetrics and Gynaecology

January 1996, Vol. 103, pp. 39-47

ECPPA: randomised trial of low dose aspirin for the

prevention of maternal and fetal complications in high
risk pregnant women
ECP P A (Estudo Colaborativo para Preveno da Pr-eclampsia

com Aspirina)

Collaborative

Group*

* Collaborators and participating centres are Iisted on pages 45-46

Objective
To determine
outcomes associated

the effectiveness of low dose aspirin

with pre-eclampsia.

Design A collaborative randomised trial comparing

placebo on pre-eclampsia and other materno-fetal
Setting

Twelve teaching maternity

hospitais

in women

at high risk of adverse

the effects of low dose aspirin (60 mg) with

complications associated with hypertension.

and 182 obstetricians'

offices in Brazil.

Subjects
One thousand and nine women considered to be at high risk for the development of preeclampsia, or its complications, entered the study between 12 and 32 weeks of gestation. They
were randomly allocated to receive aspirin (498 women) or placebo (511 women) until delivery,
and follow up was obtained for 96 %.
Resu1ts There were no significant differences between the treatment groups in the incidence of
proteinuric
pre-eclarnpsia
(6'7 % aspirin-allocated
compared with 60 % placebo-allocated
women), of preterm delivery (22'3 % compared with 261 %), of intrauterine growth retardation
(8'5 % compared with 101 %), or of stillbirth and neonatal death (7'3 % compared with 60 %),
nor were there significant differences in the incidence of proteinuric
pre-eclampsia
in any
subgroup of women studied, including those who had systolic blood pressures of 120 mmHg
or above at entry (8'5 % compared with 73 %) or those who were chronically hypertensive
(10'0 % compared with 71 %). Aspirin was not associated with a significant excess of maternal
or fetal bleeding.
ConcIusion
The results of this study do not support the routine prophylactic administration
of low
dose aspirin in pregnancy to any category of high risk women (even those who have chronic
hypertension or who are considered to be especially liable to ear1y onset pre-eclarnpsia).

INTRODUCTION

Pre-eclampsia is a major cause of maternal and

fetal morbidity and mortality', and placental
ischaemia is considered to have a central role in
the pathogenesis of these complications". Preeclampsia is associated with deficient intravascular
production of prostacyclin and with excessive
production of thrornboxane". There is also evidence of activation of the clotting system and early
involvement of platelets". This has led to the use of
antiplatelet regimens (usually low dose aspirin) in
an attempt to prevent ar delay the development
and progression of the condition.
Some small trials of antiplatelet therapy in
pregnancy have reported large reductions in the
Correspondence: Dr A. N. Atallah, Department of Medicine, D
Clinica Medica, Escola Paulista de Medicina, Rua Botucatu 740,
CEP 04023-900 So Paulo, Brazil.

RCOG

1996 British Journal of Obstetrics and Gynaecology

incidence of pre-eclampsia with the use of \ow

dose aspirin (sometimes with the addition of
dipyridamole''").
But these findings have not
generally been confirmed by more recent large
randomised controlled trials'"!'. Despite this it has
been suggested, usually after retrospective datadependent subgroup analysis, that the benefits of
antiplatelet prophylaxis may still be of use in
certain restricted groups of women. For example,
the CLASP investigators concluded that low dose
aspirin might be beneficial for those at especially
high risk of early onset pre-eclampsiall. Similar
exploratory analyses in another study'" led to the
suggestion that low dose aspirin was efficacious in
primigravid women presenting with systolic blood
pressures of 120 mmHg ar more. Pre-eclampsia
and its sequelae are relatively common in Brazil,
and an observational study conducted there found
that about half of the chronically hypertensive
39

40

ECPPA

COLLABORATIVE

GROUP

pregnant women had severe materno-fetal

complications attributable to hypertension'". The
present report is of the Estudo Colaborativo para
Preveno da Pr-eclampsia com Aspirina
(ECPPA). This multicentre randomised controlled
double-blind trial was designed to determine
whether low dose aspirin is effective in women at
particularly high risk of adverse outcomes associated with pre-eclampsia.
METHODS
One thousand and nine women were recruited into
the trial from 12 university teaching hospitaIs and
182 obstetricians' offices throughout Brazil between December 1989 and March 1993. The study
was approved by the Ethics Committee Board of
Escola Paulista de Medicina, So Paulo.
Eligibility

Women were eligible if they were between 12 and

32 weeks of gestation and, in the opinion of the
responsible clinician, were at sufficient risk of preeclampsia or its sequelae for the use of low dose
Table 1. Pre-randomisation

characteristics

aspmn to be contemplated, but without clear

indications for or against its use. Women might be
considered at sufficient risk for a number of
reasons, including chronic hypertension detected
before or during pregnancy, primigravidity
(especially with other risk factors, such as young or
old age), diabetes, renal disease, a history of preeclampsia or intrauterine growth retardation
(IUGR) in a previous pregnancy or evidence of
their presence in the current pregnancy. Contraindications included an increased risk of bleeding,
asthma, allergy to aspirin, gastric ulcer, and
placenta praevia. Consent to participate was sought
from eligible women.
Randomisation

Entry to the study was attained by telephoning a

central 24 h service at Escola Paulista de Medicina
in So Paulo. Baseline details of the women (Table
1) were recorded directly on computer-generated
randomisation lists prepared by the Clinical Trial
Service Unit, Oxford University. Only after complete baseline information had been provided was

of women studied. Figures in parentheses

are percentages

unless otherwise stated.

No. (%) in allocated treatment

Aspirin
(n = 498)

group
Placebo
(n=511)

Woman's age (years)

< 20
20-29
30-39
~ 40

27-5 (SD 7-4)

79 (16)
218 (44)
172 (35)
29
(6)

27-5 (SD 7-4)

84 (16)
228 (45)
174 (34)
25
(5)

Estimated duration of gestation (weeks)

< 12*
12 ~ 20
> 20 ~ 28
> 28

22-1 (SD 6-2)

18
(4)
186 (37)
194 (39)
100 (20)

22-4 (SD 6-0)

20
(4)
161 (32)
233 (46)
97 ( 19)

Systolic blood pressure (mmHg)

< 120
120-139
~ 140

127-3 (SD 20-5)

153 (31)
171 (34)
174 (35)

126-8 (SD 20-5)

159 (31)
183 (36)
169 (33)

Diastolic blood pressure (mmHg)

< 90
90-109
~ 110

81-3 (SD 15-0)

314 (63)
155 (31)
29
(6)

80-3
333
159
19

Other features of current pregnancy

Proteinuria andjor facial oedema
Evidence of IUGR
Obstetric and medical history
Primigravid
Multiparous, no fetal loss
Multiparous, with fetal loss
Chronic hypertension
Diabetes or hyperglycaemia

(SD 14-8)
(65)
(31)
(4)

21
34

(4)
(7)

27
28

(5)
(5)

221
188
89
242
25

(44)
(38)
(18)
(49)
(5)

250
175
86
231
37

(49)
(34)
(17)
(45)
(7)

* Women randomised before 12 weeks of gestation were to start treatment at 12 weeks,

RCOG

1996 Br J Obstet Gynaecol103, 39-47

ECPPA:

a specific numbered trial treatment pack allocated.

Women could be randomised before an estimated
gestational age of 12 weeks, but in such cases were
instructed not to start taking the tablets before the
12th week. After randomisation, no woman was
excluded from the trial, irrespective of whether
treatment was dispensed ar taken. For the purposes of analysis, women remained in the treatment
group to which they had been originally allocated
(i.e., intention to treat analyses are reported).
Treatment

Women were assigned calendar-packed treatment

with either one 60 mg film coated aspirin tablet
daily ar a placebo tablet, identical in appearance,
containing microcrystalline cellulose and com
starch. The dose of aspirin was chosen to be
sufficient to inhibit platelet aggregatiori'", and was
one that had been reported to prevent preeclampsia" while keeping side effects to a minimum.
Women were asked to take the study treatment
every day until delivery, unless advised otherwise.
Other aspirin-containing preparations were to be
avoided, with paracetamol recommended when
analgesia was necessary. The actual contents of
the allocated study treatment were not revealed,
even after delivery, unless there was a c1ear medical
reason for the treatment to be made known. Drug
stability was confirmed at intervals throughout the
study by testing a sample of the study treatment
packs.
Follow up

A very simple single page follow up form was

completed after hospital discharge of both mother
and baby (ar at six weeks postpartum, ifeither had
not been discharged). Brief details were to be
recorded of proteinuria developing during the
pregnancy, the highest recorded blood pressure
(other than during labour), 1UGR, fetal loss or
any maternal or neonatal bleeding. The mode of
delivery, birthweight, whether live birth, stillbirth
ar neonatal death and any neonatal complications
were also to be recorded. The duration of tablet
taking was assessed crudely by recording the
approximate date when study treatment was
stopped and, in addition, a small random sample
ofwomen in the study were interviewed about their
compliance. Efforts were made to check and
correct any incomplete and inconsistent data
wherever possible.
Outcome measures

The main prespecified outcome measures were:

estimated duration of pregnancy; maximum
RCOG

1996 Br J Obstet Gynaecol103,

39-47

A RANDOMISED

TRIAL

OF LOW

DOSE

ASPIRIN

41

maternal blood pressure recorded after entry;

crude birthweight; stillbirth and neonatal death;
maternal and fetal complications related to
bleeding; blood transfusion. The study outcome of
proteinuricpre-eclampsia req uired thedevelopmen t
of hypertension plus the detection of protein in the
urine after randomisation. Hypertension was
defined for those with baseline diastolic pressure
below 90 mmHg as a rise of at least 25 mmHg to
90 mmHg ar higher; for those with initial diastolic
pressure of 90 mmHg ar above, an increment of
15 mmHg was required 11. Preterm delivery was
defined as delivery before 37 weeks of estimated
gestation and 1UGR as birthweight below the
third centile for sex and estimated gestational
maturity'". Stillbirths included ali deaths at ar
after 24 weeks of gestation and neonatal deaths
included all deaths after birth, up to 28 days.
Comparisons and statistical methods

The main comparison was to be of all women

allocated aspirin against ali those allocated
placebo. In addition, subsidiary comparisons were
made of the results subdivided according to
gestational age, parity and the existence of chronic
hypertension at randomisation. Further exploratory analyses were conducted in response to some
of the findings of CLASPl1 and other studies'".
Statistical analyses involve simple comparisons of
total numbers affected. Standard methods were
used to calculate the apparent ratio of the odds of
an outcome occurring in the aspirin group compared with the odds in the control group, along with
its confidence interval: 95 % for principal analyses,
and, to take account of the number of comparisons, 99 % for subgroup analyses14.15. Alternatively, the reduction (or increase) in the odds of
the event in the aspirin group and its standard
deviation (SD) are cited; an odds ratio of 0,8, for
example, corresponds to an odds reduction of
20 % (such odds reductions are slightly larger than
the corresponding risk reductions).
In the high risk women to be studied in ECPPA,
it should have been possible to detect reliably a
reduction in the incidence of pre-eclarnpsia of
about three quarters (as suggested by the results
available when this study was designed) in a study
of about 600 women. Such an effect seemed,
however, to be too much to hope for and so the
study was designed to detect somewhat smaller
benefits. Resources were available to continue
recruitment until March 1993 (when the study was
stopped in ignorance of the results), by which time
1009 women had been randomised. No interim
analyses of ECPPA were conducted during re-

42

ECPPA

COLLABORATIVE

GROUP

only after 75 % ofthe time between randomisation

and delivery had been completed,
and 69 %
stopped after 95 % of this time. Interviews with a
random
sample of 88 women in the study
supported the overall estimate of compliance, with
88 % of the sample confirming that they had taken
more than 75 % of the scheduled study tablets.

cruitment and the results remained concealed until

after data collection had been completed. The
reassuring data monitoring committee reports to
the steering committee of the larger CLASP study
were, however, provided to the principal investigator of ECPPA during the study.

RESULTS
One thousand and nine women were randomised,
with good balance between the treatment groups
for the main pre-randomisation
characteristics
(Table I). Of the women enrolled, 16 % were
under 20 years of age, 38 % were at 20 weeks of
gestation or earlier, 47 % were primigravidae,
47 % had chronic hypertension
and 6 % had a
history of diabetes mellitus or hyperglycaemia.
Post-delivery follow up forms were obtained for
96 % of the randomised women (476 allocated
aspirin and 494 allocated placebo), and these
women had 985 infants or fetallosses (482 aspirin
compared with 503 placebo). Reported compliance
with study treatment was good, with no difference
between the groups allocated aspirin or placebo.
Of the 967 randomised women for whom the date
of stopping trial tablets was known, 90 % stopped

Incidence of proteinuric pre-eclampsia

Proteinuric pre-eclarnpsia in ECPPA was recorded
in 67 % of women allocated aspirin versus 61 %
of those allocated placebo (Fig. Ia). Although this
represents an 11 % (SD 28) increase in the odds of
developing proteinuric
pre-eclampsia,
this difference is not conventionally significant and is still
consistent with a reduction of as much as onequarter (as well as with more than a doubling in
risk). There was an absence of good evidence that
the effect on proteinuric
pre-eclampsia
differed
among the different subgroups of women studied,
inc1uding women with evidence of chronic hypertension (10'0% compared with 7'1%; Fig. Ia).
or those who had systolic blood pressures of
120 mmHg or over at entry: 28 (8' 5 %) of 331 such
(b)PRETERM DELIVERY

(a)PROTEINURIC PRE-ECLAMPSIA
Entry
characteristic

Events/Women
Aspirin
Placebo

Odds ratio & CI

(Aspirin: Placebo)

EventslWomen
Aspirin
Placebo

Odds ratio & CI

(Aspirin: Placebo)

Gestation
,; 20 weeks

16/192

8/172

53/192

49/172

> 20weeks

16/284

22/322

53/284

80/322

nulliparae

8/210

10/241

41/210

50/241

multlparae

24/266

20/253

65/266

79/253

yes

23/231

16/224

56/231

70/224

no

9/245

14/270

501245

59/270

32/ 476
(6.7%)

30/494
(6.1%)

106/476
(22.3%)

129/494
(26.1%)

Parity

Chronic hypertension

Ali women entered:

11% SO 28
increase
(2p=0.7)
0.5
1.0
1.5
Aspirin
Asplrin
better
worse

~ 19%5014
reduction
(2p=0.2)

0.5
1.0
1.5
Aspirin
Aspirin
better
worse

Fig. 1. Effects of aspirin on (a) proteinuric pre-eclampsia developing after randomisation and (b) preterm delivery. The outcome of
proteinuric pre-eclampsia required the development of hypertension and proteinuria after randomisation, and preterm delivery was
defined as delivery before 37 weeks of estimated gestation (as in Cl.Af'!'). Odds ratios (. = area proportional
to amount of
information contributed "') and 99 % confidence intervals (Cl : horizontalline) are plotted for certain subgroups ofthe study population.
A black square to the left of the solid verticalline suggests a benefit (but this is significant at 2P < 001 only if the whole Cl is to the
left of the solid verticalline). The overall results for ali women (and 95 % Cl) are represented by diamonds, with the observed reductions
or increases in the odds of the outcome developing given to the right of the solid verticalline. X2 tests for differences between the effects
observed in the different subgroups were ali nonsignificant.

ReOG 1996 Br J Obstet Gynaeco/103,

39-47

ECPPA:

A RANDOMISED

(a)INTRAUTERINE GROWTH RETAROATION

Entry
characteristic

Events/Babies
Aspirin
Placebo

TRIAL

OF LOW

DOSE

ASPIRIN

43

(b)STILLBIRTHS ANO NEONATAL OEATHS

Odds ratio & CI

(Aspirin: Placebo)

Events/Babies
Aspirin
Placebo

Odds ratlo & CI

(Aspirin: Placebo)

Gestation
520 weeks

13/196

9/174

121196

9/174

20 weeks

28/286

421329

231286

21/329

nulllparae

14/214

19/249

10/214

11/249

mulliparae

27/268

321254

25/268

19/254

yes

26/233

26/226

221233

17/226

no

15/249

25/2n

13/249

13/2n

>

Parity

Chronic hypertension

Ali babies:

41/482
(8.5%)

51/503
(10.1%)

18% 50 20
reduction
(2p=0.4)

35/482
(7.3%)

0.5
1.0
1.5
Aspirin
Aspirin
better
worse

30/503
(6.0%)

23%5029
Increase
(2p=0.4)
0.5
1.0
1.5
Asplrln
Asplrln
better
worse

Fig. 2. Effects of aspirin on (a) intrauterine growth retardation and (b) stillbirth and neonatal death. Intrauterine growth retardation
was defined as birthweight below the third centile for sex and estimated maturity, and stillbirths and neonatal deaths as deaths at or
after 24 weeks gestation and up to 28 days after birth. Symbols and conventions as in Fig. 1. X2 tests for differences between the effects
observed in the different subgroups were all nonsignificant.

women allocated aspirin compared with 25 (7'3 %)

of 343 allocated placebo.
There was also a lack of support for the
hypotheses generated by CLASP of a reduction in
early onset pre-eclampsia:
among women who
were delivered before 32 weeks, pre-eclampsia
occurred in 3/28 patients in the aspirin group and
in 3/27 patients in the placebo group; among
women who were delivered between 32 and 37
weeks, pre-eclampsia occurred in 10/78 patients in
the aspirin group, compared with 13/102 patients
in the placebo group. Among women who were
delivered after 37 weeks, pre-eclampsia occurred
in 19/370 patients in the aspirin group and in
14/365 in the placebo group (X2 test for trend =
0,64, 2P = 0-4). Sixty women with a history of
diabetes or hyperglycaemia
were followed up;
proteinuric pre-eclampsia developed in none of the
24 women allocated aspirin and in only 3 out of 36
of those allocated placebo (NS).
There was no difference between the treatment
groups in the medians ofthe highest blood pressures
recorded after randomisation
and before labour
(140/90 mmHg among both those allocated aspirin and those allocated placebo). Proteinuria
without hypertension severe enough to be defined
as pre-eclampsia was slightly less common among
aspirin-allocated
women (41 (8'6 %) compared
with 52 (10'5 %); 2P = 0'3), while hypertension
RCOG 1996 Br J Obstet Gynaecol103,

39-47

without associated proteinuria was slightly more

common (68 (14'3 %) compared with 56 (l1'3 %);
2P = 0'2).
Duration of pregnancy
The mean duration of pregnancy was about two
days longer among aspirin-allocated
women than
among placebo-allocated
women (38'08 weeks
(SD 3-48) compared with 3778 weeks (SD 3'71)),
but this difference was not statistically significant.
The likelihood of preterm delivery, that is before
37 weeks of estimated gestation, was lower among
women allocated aspirin (22'3 % compared with
261 %: Fig. 1b). However, although the odds of
delivering preterm was 19% (SD 14) lower among
aspirin-allocated
women, this difference was not
significant (95 % CI: 40 % reduction
to 9 %
increase). As was the case for proteinuric preeclampsia, the effects on preterm delivery did not
appear to differ significantly
in the different
subgroups studied.
Birthweight
The mean birthweight of all babies bom to women
allocated aspirin was 30218 g (SD 763'3) compared with 29650 g (SD 756'0) in the placebo
group, but this slight increase of 568 g (SD 48'7)
was not statistically significant. Aspirin was asso-

44

ECPPAcaLLABaRATIVEGRaUp

Table 2. Effects of aspirin on delivery type, bleeding and fetal

loss after randomisation. Values are shown as n (%).

Pregnancies with data

Fetal outcomes
Labour and delivery
Caesarean section
Forceps delivery

Aspirin

Placebo

n = 476
n = 482

n = 494
n = 503

291 (61'1)
36 (7-6)

301 (60'9)
36 (7'3)

Maternal bleeding
Placenta I abruption
Other antepartum bleed
Postpartum bleed
Transfusion

5
6
3
7

Fetal bleeding
Intraventricular haemorrhage
Other neonatal bleeds

6 (1'2)
3 (0'6)

3 (0'6)
2 (O A)

Fetal losses
Losses < 24 weeks
Stillbirths (~ 24 weeks)
eonatal deaths 28 days)

4 (0'8)
28 (5'8)
7 (1'5)

6 (1'2)
23 (4'6)
7 (I A)

(1'1 )
(1'3)
(0,6)
( 1'5)

7
8
6
7

(l A)
( 1,6)
( 1'2)
(l A)

ciated with a slightly smaller prapartian of babies

with lUGR (8'5% compared with 101%: Fig.
2a), but, again, this difference was not significant,
either overall or in any of the subgroups studied.
Stillbirths and neonatal deaths

Faur (0'8 %) fetallosses occurred before 24 weeks

of gestation in the aspirin group and 6 (12 %)
accurred in the placebo graup (Table 2). There
were 28 stillbirths plus 7 neonatal deaths (35 total:
7'3%) in the aspirin group and 23 plus 7 (30:
60 %) in the placebo group (Fig. 2b). This 23 %
(SD 29) increase with aspirin is nat statistically
significant and the 95 % confidence interval is
wide. There was no apparent difference in the
effect in the variaus subgroups of women studied,
nor were there any significant differences in the
number of stillbirths and neonatal deaths associated with pre-ec1ampsia, maternal hypertension
ar lUGR (21 (4-4%) compared with 26 (5'2 % or
in thase associated with maternal or neonatal
bleeding (50'04%) compared with 80'59%.
Other outcomes

There were no significant differences between the

treatment graups in delivery by caesarean section
ar forceps, nor were there any significant differences in placental abruptions or other ante
partum bleeds (Table 2). All bleeds after delivery
were not explicitly recorded and were incompletely
reported (overall rate of 09 % compared with
26 % in CLASP), but maternal transfusions were
systematically sought, and there was no difference
between the treatment groups in the numbers

transfused. Two maternal deaths were reported in

this study: one in the aspirin-allocated group was
attributed to the HELLP syndrome and the other
in the placebo group was due to a car crash at 24
weeks of pregnancy. No significant differences in
the incidence of intraventricular haemorrhages or
other bleeds in the babies were observed.
DISCUSSION

The incidence of proteinuric pre-ec1ampsia in

ECPPA was similar to that reported in previous
studies, but stillbirths and neonatal deaths were
more common (6'6 % compared with 28 % in
CLASpll, 16% in the American study'" and
23 % in the Italian study"). Chronic hypertension
was present at entry in 47% of the ECPPA
patients (compared with 20 % in CLASP), and
47 % were primigravidae (compared with 28 % in
CLASP). The perinatal mortality rate among the
large chronically hypertensive group in ECPPA
was 85 %, which may reflect uterine vascular
lesions caused by chronic hypertension.
Despite the high risk population studied in
ECPPA, the effects of aspirin on adverse outcomes
appear to be much less promising than those
suggested by the results of the first small trials, and
similar to those of the more recent larger trials
(Fig. 3: updated from CLASPll). Possible explanations for the discrepancy between the results of
the small trials and the larger trials ha ve been
discussed in detail in the report of the CLASP
study. In particular, it seems likely that this may
be due, at least in part, to publication bias, with
small trials with unpromising results being less
likely to be published than those with particularly
promising results, and with some methodological
problems!" in at least one small tria\.
It was recently suggested " that the results of the
larger trials may have been diluted by their broad
entry criteria and by the wide variations in care
between the different participating countries.
However, it has not been possible, either in CLASP
or in ECPPA, to identify any particular category
of women-inc1uding
those in a substudy of
CLASP who were angiotensin II sensitive (as in
one particularly promising small study"), or those
with e\evated blood pressure at entry (as in a post
hoc subgroup analysis of one of the recent larger
trials10)-in whom the reduction in proteinuric
pre-ec1ampsia was as great as that reported in the
previous small trials (Fig. 3a). Moreover, although
it had been suggested from exploratory analyses of
CLASPll that aspirin may be justified for those at
especially high risk of early onset pre-ec1ampsia,
this is not supported by the results from ECPPA.
RCOG

1996 Br J Obstei Gynaecol103,

39-47

ECPPA:
(a)PROTEINURIC
No 01 Antlplatelet

Control

ortrial

trlals

therapy

TRIAL

(b)STILLBIRTHS

PRE-ECLAMPSIA

Trial categories

therapy

A RANDOMISED

Odds ratlo & 95,4 CI

(Antlplatelet:

Placebo)

OF LOW

ANO NEONATAL

No 01 Antlplatelet

Control

trlals

therapy

therapy

DOSE

45

ASPIRIN

OEATHS
Odds n.tlo
(Antlplatelet

& 95% CI
: Placebo)

Small trlals
10/ 319
(3.1%)

11

Wlth data

Wlthout data

-/

308

12

50/ 284
(17.6%)
-/

51 306
(2.0%)

228

-I

320

10/ 289
(3.5%)
-/

223

Larger trials
Before

CLASP

CLASP
ECPPA

tOO/2697

139/2524

313/4659

3521 4650

32/

Ali larger trlals

Ali trlals wlth data

476

30/

494

445/7832
( 5.7%)

521/7668
( 6.8%)

18

455/8151
( 5.6%)

571/7952
( 7.2%)

t
o

Test lor heterogenelty

0.5
Antlplatelet
therapy
batter

- alllarger

1.0

35/

17%506
reductlon
(2p=0.006)
23%506
reductlon
(2p=0.00006)
1.5
Antlpletelet
therapy
worse

482

38/2524

1361 4821
30/

503

212/ 7989
( 2.7%)

20417848
( 2.6%)

1%5010
Inc .
(2p:O.9)

19

218/ 8295
( 2.6%)

214/ 8137
( 2.6%)

1%5010
reduct10n
(2p:O.9)

0.5
Antlplatelet
therapy
batter

1.0

1.5
Antlplatelet
therapy
worse

batween:

- ali trlals wlth data:

- smaller trials versus

48/ 2697
129/4810

largar trials:

trials:

X'"

= 40.2 (p = 0.0004)

X~, = 10.3 (p = 0.6)

X',

= 25.7 (p < 0.000001)

X~ = 1.3 (p = 0.3)

X'.

= 11.8 (p = 0.07)

X~

6.3

(p

= 0.4)

Fig. 3. Overview of effects reported from ali randomised trials of antiplatelet therapy in pregnancy on (a) proteinuric pre-eclampsia and
(b) stillbirths and neonatal deaths. Symbols and conventions as in Fig. 1. Available results from smaller trials (i.e. those that included
fewer than 200 women) and from larger trials were combined using standard overview methods'" and stratified odds ratios plotted.
Details of the trials included are given in CLASpll

Similarly, there were no subgroups

m these
generally higher risk Brazilian women, in whom
clear effects on lUGR, stillbirths or neonatal
deaths could be demonstrated.
Consequently, the
ECPPA results support the conclusion!'
that if
some special category of women exists that may
benefit substantially from aspirin, it must compose
a much smaller and more select group than had
previously been thought to be the case.
As in the previous trials, the results of ECPPA
are generally reassuring as regards maternal and
neonatal
complications,
with no significant
excesses of placental abruption, other antepartum
haemorrhage,
transfusion,
or mortality due to
bleeding. Prior to ECPPA, a systematic overview
of the available results from alI randomised trials
of antiplatelet therapy indicated a 25 % reduction
in the incidence of pre-eclampsia'",
in contrast
with the reduction of about three-quarters
suggested by the first small trials. The addition of
ECPPA reduces still further the apparent size of
this benefit (Fig. 3a), and if the small 'hypothesis
generating'
trials are excluded, the apparent
reduction in the larger trials combined is only
17 % (SD 6). ln absolute terms, these more modest
proportional
reductions imply that antiplatelet
therapy would typically prevent proteinuric preec1ampsia in about 1 woman per 100 treated (with
confidence interval ranging from about zero to
RCOG

1996 Br J Obstet Gynaecol103, 39-47

about 2 per 100). ECPPA and some previous large

scale trials!' do suggest that aspirin may prevent a
few preterm deliveries per 100 women treated. But,
overall, there is no evidence of an effect of aspirin
on the incidence of stillbirths and neonatal deaths
(218 (2'6 %) aspirin-allocated
compared with 214
(2'6 %) placebo-allocated
deaths: Fig. 3b).
ln conc1usion, as was suggested by the other
large trials, the present randomised
placebocontrolled study in 1009 women, with very good
follow up and compliance, does not support the
widespread routine use of aspirin for the prevention of pre-eclampsia
or other hypertensive
complications, even in the very high risk pregnant
women of a developing country.
Acknowledgements
The most important acknowledgement
is to the
hundreds of women who took part in ECPPA and
to the doctors who collaborated throughout Brazil.
The following investigators
participated
in the
study.
Data management, analysis and writing committee:
A N Atallah, R Collins, B Farrell, H Handoll.
Principal Investigator: A N Atallah, Americana: A
Freitas Jr, L Kinsu, O Fukushima, Andradina: M
Amorim, Araatuba: R Eduardo, Araraquara:
A
Durante, C Vieira, J Filho, Arararas: L Davolos,

46

ECPPA

COLLABORA

TIVE

GROUP

Asis: R Zambotti, Bariri: C Negro, Batatais: O

Alves, Bauru: P'Tobias, Belo Horizonte: C Freire,
C Almeida, Birigui: J Neto, L Bertechini, Botucatu: I Maest, J Peraoli, Marilza V Rudge, I
Silva, S Filho, I Calderon, O Abujamra Jr, Bragana: A Neto, W Muniz, Jos Carlos Pinton, M
de Mello, Cachoeira Paulista: A Ferreira Jr,
Campinas: C Nogueira, A Sanches, A Mariano, C
Ferraz Costa, R de Lacerda, A Elias, R Y oshiassu,
S Lustre, S Ximenes, P de Godoy, Campinas: A de
Meio, Canguu: D de Campos, Carapicuiba: D
Bezerra, Cataguases: F Cesrio, Caxias do Sul: D
Tessari, Cruzeiro: M Kisse, W Sria, Erechim
-RS: A Teixeira, Fernandoplis: A Flumignan,
Franca: M Marcolini, Guaruj: E Rimi, Guarulhos: C Simes, V de Arujo, Itatiba: C
Pavanelri, Jaboticabal: L Martins, Jacare: J
Neto, C Bianco, C Antonlia, Jundia: E Gennari,
Limeira: Z Vinhal, Lins: J Leo, Londrina: F
Sobrinho, Marlia: J Prado, Mirandoplis: Z
Souza, Mogi: J Magalhes, R Esteves, Natal-RN:
H de Oliveira, Novo Hamburgo--RS: L Jaeger,
Novo Horizonte: R Melchiori, Olimpia: J Minari,
Osasco: E Santana, I Machida, Ourinhos: F
Cesme, H de Carvalho, Pejuara-RS:
L da
Silva, Pindamonhangaba: A Wolff, Piracicaba: C
Negretti, Porto Alegre: I Belli, L Napp, A Meneghetti, E Chaves, S Costa, C de Quadros Kroeff, S
Espinosa, Presidente Prudente: D Campos, J
Tsello, Ribeiro Preto: A Matthes, C dos Santos
Jr, G Duarte, Rio Claro: G Neto, W de Matos
Rezende, Rio Grande--RS:
P Gonalves, H
Rivoire, S. Bernardo: LC Joo, A Gradella, S.
Jos do R. Preto: R Bertazzo, I Moraes, J Dria,
M Trevisan, N Gabriel, Santa Maria-RS:
J da
Silva Ethur, F Jobim, Santo Andr: R Serre, S
Sanforlin, J da Silva, J Neves, O Ferraro, Santos:
Ma dos Santos, A Ribeiro, R de Freitas, So
Caetano: A Adans, So Leopoldo--RS: I Plentz,
So Paulo: J de Andrade, H Nightingale, J
Rebello, J Bencic, C da Costa Alves, C Campmany, A Pereira, A Kataguiri, L de Campos, J
Masonetto, D Bentivegna, M de Oliveira, M
Russo, A Celestini, A Azevedo, H Lippi, F
Zanotto, F Simon, G Frehse, H Halbe, L Primon,
P David, P Franco, P Pirozzi, D Klotzel, L
Awoke, L de Figueiredo, R Theodozio, I Conceio, I Daniel, J Kublikowski, J Adalaft Neto,
G Kenji, S Guimares, S Leung, T Gollop, V
Freitas, B Carvalho, G Porto, J dos Santos, A
Andrade, E Cavalcante, A Henrich, W Arl, H
Ari, T de Oliveira, D Silvestrini, E de Souza, A de
Arajo, A Allegrini, L Sakamoto, L Takano, R
Mattar, W Taborda, H Paraventi, M Miyazawa,
N Sass, R de Souza Mesquita, M Lemos, M

Bevilqua, I Wulkan, G Paramo, J Mottola Jr, M

Scott, Sertozinho: A Sde, R Clemente, Sorocaba: L Neto, Sorocaba: C Barros, Sorocaba: N
Bressan, Taubat: M de Assis, X Mazzini.
ECPPA Co-ordinating Centre: A N Atallah, E
Clarizia, M L Duarte, H Gonzalez, A Pantoja, M
Mesquita.
Study Monitoring Committee: I Chalmers, R
Collins, O Delascio (late), J A Grisso, R Peto, M
Zugaib.
The Clinical Trial Service Unit (CTSU), Nuffield
Department of Medicine, University of Oxford,
UK provided technical support and encouragement throughout the duration of the study. The
study was principally funded by Sterling Drugs (P
Tribble, S Weisman), who also donated specially
packaged aspirin and matching placebo and
by Escola Paulista de Medicina, CNPQ and
INCLEN, Inc. The study was, however, designed,
conducted, analysed, and interpreted independently of the commercial sponsor.
References
I Davies AM. Epidemiology ofhypertensive disorders ofpregnancy.
Buli World Health Organ 1979; 57: 373.
2 Redman CWG. Current topic: pre-eclampsia and the placenta.
Placenta 1991; 12: 301-308.
3 Bussolino F, Benedetto C, Massobrio M, Camussi G. Maternal
vascular prostacyclin activity in pre-eclampsia. Lancet 1980; 2:
702.
4 Redman CWG, Bonnar J, Beilin L. Early platelet consumption in
pre-eclampsia. BM] 1978; I: 467-469.
5 Beaufils M, Uzan S, Donsimoni R, Colau .IC. Prevention of preeclampsia by early antiplatelet therapy. Lancet 1985; I: 840-842.
6 Wallenburg HCS, Dekker GA, Makovitz JW, Rotmans P. Lowdose aspirin prevents pregnancy-induced hypertension and preeclampsia in angiotensin-sensitive primigravidae. Lancet 1986; I:
1-3.
7 Schiff E, Peleg E, Goldenberg M el ai. The use of aspirin to
prevent pregnancy-induced hypertension and lower the ratio of
thromboxane A2 to prostacyclin in relatively high risk pregnancies.
N Engl J Med 1989; 321: 351-356.
8 McParland P, Pearce JM, Chamberlain GVP. Doppler ultrasound
and aspirin in recognition and prevention of pregnancy-induced
hypertension. Lancet 1990; 335: 1552-1555.
9 Italian Study of Aspirin in Pregnancy. Low-dose aspirin in
prevention and treatment of intrauterine growth retardation and
pregnancy-induced hypertension. Lancet 1993; 341: 396-400.
10 Sibai BM, Caritis SN, Thom E et ai. Prevention of pre-eclampsia
with low-dose aspirin in healthy, nulliparous pregnant women.
New Engl] Med 1993; 329: 1213-1218.
11 CLASP (Collaborative Low-dose Aspirin Study in Pregnancy)
Collaborative Group. CLASP: a randomised trial of low-dose
aspirin for the prevention and treatment of pre-eclampsia among
9364 pregnant women. Lancet 1994; 343: 619-629.
12 Atallah AN, de Souza Mesquita MR, Duarte ML et ai. Estudo
prospectivo "cohort ' de gestantes com hipertanso arterial
crnica.v
Bras Nefro11990;
12: 113-120.
13 Benigini A, Gregorini G, Frusca T et ai. Etfect oflow-dose aspirin
on fetal and maternal generation of thromboxane by platelets
in women at risk of pregnancy-induced hypertension. N Engl J
Med 1989; 321: 357-362.

RCOG 1996 Br J Obstet Gynaecol 103, 39-47

ECPPA:
14 Peto R, Pike MC, Armitage P et ai. Design and analysis of
randomized clinical trials requiring prolonged observation or each
patient l l. Analysis and examples. Br J Cancer 1977; 35: 1-39.
15 Antiplatelet
Trialists' Collaboration.
Collaborative
overview of
randomised trials of antiplatelet therapy-I:
Prevention of death,
myocardial
infarction,
and stroke by prolonged
antiplatelet
therapy in various categories ofpatients. BMJ 1994; 308: 81-106.

RCOG 1996 Br J Obstet Gynaecol103,

39-47

A RANDOMISED

TRIAL

OF LOW

DOSE ASPIRIN

47

16 Atallah AN, Shinar R. Pre-ec1ampsia and prostaglandins.

LanceI
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17 Beilin L. Aspirin and pre-ec1ampsia. BMJ 1994; 308: 1200-1251.

Received 27 April 1995

Accepted 13 September 1995

British Journal of Obstetrics and Gynaecology

January 1996, Vol. 103, pp. 48-53

Detection of fetal fibronectin as a predictor of preterm

delivery in high risk asymptomatic pregnancies
* s. C. Leeson Senior Registrar, * M. J. A. Maresh Consultant, ** E. A. Martindale Registrar,
tT. Mahmood Registrar, * A. Muotune SHO, tt N. Hawkes SHO, * K. J. Baldwin Registrar
* Department of Obstetrics and Gynaeeology, Saint Mary's Hospital, Manehester, ** Department of Obstetrics and
Gynaeeology, Bolton General Hospital; t Department of Obstetrics and Gynaeeology, North Manehester General Hospital;
tt Department of Obstetrics and Gynaeeology, Gloueester Royal Hospital
Objective
The study was designed to determine whether fetal fibronectin
before 37 weeks in women at high risk of preterm delivery.

would predict delivery

Study methods
Forty-three women considered at risk ofpreterm delivery were recruited antenatally
into a blind longitudinal study. Quantitative
assays of fetal fibronectin were obtained from
sequential high vaginal swabs taken fortnightly from 24 to 34 weeks of gestation. Fibronectin
concentrations
of 005 Ilg/ml or more were considered as positive.
Results
Results were calculated by swab and by subject. The sensitivity of an individual fibronectin
swab in predicting preterrn delivery within 14 days of testing was 71 % and the specificity was
93 %. The overall positive predictive value was 31 % and the negative predictive value was
99 %. The sensitivity of the fibronectin swab in predicting delivery before 37 weeks was 17 %
and the specificity was 93 %. The positive predictive value was 50 % and the nega tive predictive
value was 73 %. For a woman who has had a positive swab the sensitivity in predicting preterm
delivery within 14 days of testing was 80 % and the specificity was 83 %; a woman was counted
as positive only if the final swab was positive and preceded delivery by not more than 14 days.
The positive predictive value was 36% and the negative predictive value was 97%. For a
woman who has had a positive swab the sensitivity in predicting delivery before 37 weeks was
54 %. The specificity, the positive predictive value and the nega tive predictive value were 85 %,
64 % and 79 %, respectively. Women were counted as positive if any swab in the sampling
sequence was positive. Fibronectin swabbing when calculated by patient did predict preterm
delivery within 14 days of testing (P = 0'01) and before 37 weeks (P = 0'01). Analysis of the
accuracy of predicting delivery from 7 to 28 days after sampling revealed that the best
prediction for delivery was within the following 14 days.
Conclusion
Serial fetal fibronectin assessment from 24 to 34 weeks of gestation anticipated preterm
delivery within 14 days oftesting and before 37 weeks for high risk asymptomatic women. Such
testing should be performed every two weeks.

INTRODUCTION
Preterm delivery is the leading cause of newborn
infant mortality in the developed world. Most of
these deaths occur in pregnancies ending before
29 weeks'. A substantial morbidity accompanies
preterm delivery as well as iatrogenic morbidity
associated with prolonged neonatal intensive care.
Long term neurological problems are more difficult
to evaluate. Apart from the human cost, the
financial cost of providing inpatient care for
preterm babies and providing support in cases of
lifelong handicap is great.
Correspondence: Dr S. C. Leeson, Department
of Obstetrics
and Gynaecology, Saint Mary's Hospital, Hathersage Road,
Manchester M 13 9PT, UK.

48

Prediction ofpreterm labour is unreliable. Using

a history of previous preterm delivery, twin
pregnancy, uterine abnormality, low socio-economic status and cervical incompetence predicts, at
best, 50 % of preterm deliveries". The use of serial
vaginal examination, screening for reduced fetal
breathing movements on ultrasound scanning or
screening for recurrent contractions with external
tocography provides little additional sensitivity".
Fetal fibronectin is part of a family ofubiquitous
dimeric glycoproteins present predominantly in
plasma and extracellular matrix and which
influence cell adhesion, motility, tissue repair and
coagulation+". There are more than 20 isoforms of
the molecule. Fetal fibronectin has a molecular
weight of about 450,000 daltons and is produced
RCOG 1996 Britisli Journal of Obstetrics and Gynaeeology