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British Journal of Obstetrics and GynaecologyJanuary 1996, Vol.
103, pp. 39-47
ECPPA: randomised trial of low dose aspirin for theprevention of
maternal and fetal complications in high
risk pregnant womenECP PA (Estudo Colaborativo para Preveno da
Pr-eclampsia com Aspirina) Collaborative Group*
* Collaborators and participating centres are Iisted on pages
45-46
Objective To determine the effectiveness of low dose aspirin in
women at high risk of adverseoutcomes associated with
pre-eclampsia.
Design A collaborative randomised trial comparing the effects of
low dose aspirin (60 mg) withplacebo on pre-eclampsia and other
materno-fetal complications associated with hypertension.
Setting Twelve teaching maternity hospitais and 182
obstetricians' offices in Brazil.
Subjects One thousand and nine women considered to be at high
risk for the development of pre-eclampsia, or its complications,
entered the study between 12 and 32 weeks of gestation. Theywere
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 ofproteinuric pre-eclarnpsia (6'7
% aspirin-allocated compared with 60 % placebo-allocatedwomen), 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 anysubgroup of women studied, including those who
had systolic blood pressures of 120 mmHgor 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 maternalor fetal bleeding.
ConcIusion The results of this study do not support the routine
prophylactic administration of lowdose aspirin in pregnancy to any
category of high risk women (even those who have
chronichypertension or who are considered to be especially liable
to ear1y onset pre-eclarnpsia).
INTRODUCTIONPre-eclampsia is a major cause of maternal andfetal
morbidity and mortality', and placentalischaemia is considered to
have a central role inthe pathogenesis of these complications".
Pre-eclampsia is associated with deficient intravascularproduction
of prostacyclin and with excessiveproduction of thrornboxane".
There is also evi-dence of activation of the clotting system and
earlyinvolvement of platelets". This has led to the use
ofantiplatelet regimens (usually low dose aspirin) inan attempt to
prevent ar delay the developmentand 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,
DClinica 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 \owdose aspirin
(sometimes with the addition ofdipyridamole''"). But these findings
have notgenerally been confirmed by more recent largerandomised
controlled trials'"!'. Despite this it hasbeen suggested, usually
after retrospective data-dependent subgroup analysis, that the
benefits ofantiplatelet prophylaxis may still be of use incertain
restricted groups of women. For example,the CLASP investigators
concluded that low doseaspirin might be beneficial for those at
especiallyhigh risk of early onset pre-eclampsiall.
Similarexploratory analyses in another study'" led to thesuggestion
that low dose aspirin was efficacious inprimigravid women
presenting with systolic bloodpressures of 120 mmHg ar more.
Pre-eclampsiaand its sequelae are relatively common in Brazil,and
an observational study conducted there foundthat about half of the
chronically hypertensive
39
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40 ECPPA COLLABORATIVE GROUP
pregnant women had severe materno-fetalcomplications
attributable to hypertension'". Thepresent report is of the Estudo
Colaborativo paraPreveno da Pr-eclampsia com Aspirina(ECPPA). This
multicentre randomised controlleddouble-blind trial was designed to
determinewhether low dose aspirin is effective in women
atparticularly high risk of adverse outcomes asso-ciated with
pre-eclampsia.
METHODSOne thousand and nine women were recruited intothe trial
from 12 university teaching hospitaIs and182 obstetricians' offices
throughout Brazil be-tween December 1989 and March 1993. The
studywas approved by the Ethics Committee Board ofEscola Paulista
de Medicina, So Paulo.
EligibilityWomen were eligible if they were between 12 and32
weeks of gestation and, in the opinion of theresponsible clinician,
were at sufficient risk of pre-eclampsia or its sequelae for the
use of low dose
aspmn to be contemplated, but without clearindications for or
against its use. Women might beconsidered at sufficient risk for a
number ofreasons, including chronic hypertension detectedbefore or
during pregnancy, primigravidity(especially with other risk
factors, such as young orold age), diabetes, renal disease, a
history of pre-eclampsia or intrauterine growth retardation(IUGR)
in a previous pregnancy or evidence oftheir presence in the current
pregnancy. Contra-indications included an increased risk of
bleeding,asthma, allergy to aspirin, gastric ulcer, andplacenta
praevia. Consent to participate was soughtfrom eligible women.
RandomisationEntry to the study was attained by telephoning
acentral 24 h service at Escola Paulista de Medicinain So Paulo.
Baseline details of the women (Table1) were recorded directly on
computer-generatedrandomisation lists prepared by the Clinical
TrialService Unit, Oxford University. Only after com-plete baseline
information had been provided was
Table 1. Pre-randomisation characteristics of women studied.
Figures in parentheses are percentages unless otherwise stated.
No. (%) in allocated treatment group
Aspirin(n = 498)
Placebo(n=511)
Woman's age (years)< 2020-2930-39~ 40
Estimated duration of gestation (weeks)< 12*12 ~ 20> 20 ~
28> 28
Systolic blood pressure (mmHg)< 120120-139~ 140
Diastolic blood pressure (mmHg)< 9090-109~ 110
Other features of current pregnancyProteinuria andjor facial
oedemaEvidence of IUGR
Obstetric and medical historyPrimigravidMultiparous, no fetal
lossMultiparous, with fetal lossChronic hypertensionDiabetes or
hyperglycaemia
27-5 (SD 7-4) 27-5 (SD 7-4)79 (16) 84 (16)
218 (44) 228 (45)172 (35) 174 (34)29 (6) 25 (5)22-1 (SD 6-2)
22-4 (SD 6-0)18 (4) 20 (4)
186 (37) 161 (32)194 (39) 233 (46)100 (20) 97 ( 19)127-3 (SD
20-5) 126-8 (SD 20-5)153 (31) 159 (31)171 (34) 183 (36)174 (35) 169
(33)81-3 (SD 15-0) 80-3 (SD 14-8)
314 (63) 333 (65)155 (31) 159 (31)29 (6) 19 (4)
21 (4) 27 (5)34 (7) 28 (5)
221 (44) 250 (49)188 (38) 175 (34)89 (18) 86 (17)
242 (49) 231 (45)25 (5) 37 (7)
* Women randomised before 12 weeks of gestation were to start
treatment at 12 weeks,
RCOG 1996 Br J Obstet Gynaecol103, 39-47
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a specific numbered trial treatment pack allocated.Women could
be randomised before an estimatedgestational age of 12weeks, but in
such cases wereinstructed not to start taking the tablets before
the12th week. After randomisation, no woman wasexcluded from the
trial, irrespective of whethertreatment was dispensed ar taken. For
the pur-poses of analysis, women remained in the treatmentgroup to
which they had been originally allocated(i.e., intention to treat
analyses are reported).
TreatmentWomen were assigned calendar-packed treatmentwith
either one 60 mg film coated aspirin tabletdaily ar a placebo
tablet, identical in appearance,containing microcrystalline
cellulose and comstarch. The dose of aspirin was chosen to
besufficient to inhibit platelet aggregatiori'", and wasone that
had been reported to prevent pre-eclampsia" while keeping side
effects to a minimum.Women were asked to take the study
treatmentevery day until delivery, unless advised otherwise.Other
aspirin-containing preparations were to beavoided, with paracetamol
recommended whenanalgesia was necessary. The actual contents ofthe
allocated study treatment were not revealed,even after delivery,
unless there was a c1earmedicalreason for the treatment to be made
known. Drugstability was confirmed at intervals throughout thestudy
by testing a sample of the study treatmentpacks.
Follow upA very simple single page follow up form wascompleted
after hospital discharge of both motherand baby (ar at six weeks
postpartum, ifeither hadnot been discharged). Brief details were to
berecorded of proteinuria developing during thepregnancy, the
highest recorded blood pressure(other than during labour), 1UGR,
fetal loss orany maternal or neonatal bleeding. The mode
ofdelivery, birthweight, whether live birth, stillbirthar neonatal
death and any neonatal complicationswere also to be recorded. The
duration of tablettaking was assessed crudely by recording
theapproximate date when study treatment wasstopped and, in
addition, a small random sampleofwomen in the study were
interviewed about theircompliance. Efforts were made to check
andcorrect any incomplete and inconsistent datawherever
possible.
Outcome measuresThe main prespecified outcome measures
were:estimated duration of pregnancy; maximum
RCOG 1996 Br J Obstet Gynaecol103, 39-47
ECPPA: 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 tobleeding; blood transfusion. The study outcome
ofproteinuricpre-eclampsia required thedevelopmen tof hypertension
plus the detection of protein in theurine after randomisation.
Hypertension wasdefined for those with baseline diastolic
pressurebelow 90 mmHg as a rise of at least 25 mmHg to90 mmHg ar
higher; for those with initial diastolicpressure of 90 mmHg ar
above, an increment of15mmHg was required 11. Preterm delivery
wasdefined as delivery before 37 weeks of estimatedgestation and
1UGR as birthweight below thethird centile for sex and estimated
gestationalmaturity'". Stillbirths included ali deaths at arafter
24 weeks of gestation and neonatal deathsincluded all deaths after
birth, up to 28 days.
Comparisons and statistical methodsThe main comparison was to be
of all womenallocated aspirin against ali those allocatedplacebo.
In addition, subsidiary comparisons weremade of the results
subdivided according togestational age, parity and the existence of
chronichypertension at randomisation. Further explora-tory analyses
were conducted in response to someof the findings of CLASPl1 and
other studies'".Statistical analyses involve simple comparisons
oftotal numbers affected. Standard methods wereused to calculate
the apparent ratio of the odds ofan outcome occurring in the
aspirin group com-pared with the odds in the control group, along
withits confidence interval: 95 % for principal analyses,and, to
take account of the number of com-parisons, 99% for subgroup
analyses14.15. Alter-natively, the reduction (or increase) in the
odds ofthe event in the aspirin group and its standarddeviation
(SD) are cited; an odds ratio of 0,8, forexample, corresponds to an
odds reduction of20% (such odds reductions are slightly larger
thanthe corresponding risk reductions).In the high risk women to be
studied in ECPPA,
it should have been possible to detect reliably areduction in
the incidence of pre-eclarnpsia ofabout three quarters (as
suggested by the resultsavailable when this study was designed) in
a studyof about 600 women. Such an effect seemed,however, to be too
much to hope for and so thestudy was designed to detect somewhat
smallerbenefits. Resources were available to continuerecruitment
until March 1993 (when the study wasstopped in ignorance of the
results), by which time1009 women had been randomised. No
interimanalyses of ECPPA were conducted during re-
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42 ECPPA COLLABORATIVE GROUP
cruitment and the results remained concealed untilafter data
collection had been completed. Thereassuring data monitoring
committee reports tothe steering committee of the larger CLASP
studywere, however, provided to the principal inves-tigator of
ECPPA during the study.
RESULTSOne thousand and nine women were randomised,with good
balance between the treatment groupsfor the main pre-randomisation
characteristics(Table I). Of the women enrolled, 16% wereunder 20
years of age, 38 % were at 20 weeks ofgestation or earlier, 47 %
were primigravidae,47 % had chronic hypertension and 6 % had
ahistory of diabetes mellitus or hyperglycaemia.Post-delivery
follow up forms were obtained for
96 % of the randomised women (476 allocatedaspirin and 494
allocated placebo), and thesewomen had 985 infants or fetallosses
(482 aspirincompared with 503 placebo). Reported compliancewith
study treatment was good, with no differencebetween the groups
allocated aspirin or placebo.Of the 967 randomised women for whom
the dateof stopping trial tablets was known, 90 % stopped
Entrycharacteristic
(a)PROTEINURIC PRE-ECLAMPSIAEvents/Women Odds ratio & CI
Aspirin Placebo (Aspirin: Placebo)
Gestation
,; 20 weeks 16/192 8/172
> 20weeks 16/284 22/322
Parity
nulliparae 8/210 10/241
multlparae 24/266 20/253
Chronic hypertension
yes 23/231 16/224
no 9/245 14/270
Ali women entered: 32/ 476(6.7%)
30/494(6.1%)
only after 75% ofthe time between randomisationand delivery had
been completed, and 69 %stopped after 95 % of this time. Interviews
with arandom sample of 88 women in the studysupported the overall
estimate of compliance, with88% of the sample confirming that they
had takenmore than 75 % of the scheduled study tablets.
Incidence of proteinuric pre-eclampsiaProteinuric pre-eclarnpsia
in ECPPA was recordedin 67 % of women allocated aspirin versus 61
%of those allocated placebo (Fig. Ia). Although thisrepresents an
11% (SD 28) increase in the odds ofdeveloping proteinuric
pre-eclampsia, this diff-erence is not conventionally significant
and is stillconsistent with a reduction of as much as one-quarter
(as well as with more than a doubling inrisk). There was an absence
of good evidence thatthe effect on proteinuric pre-eclampsia
differedamong the different subgroups of women studied,inc1uding
women with evidence of chronic hyper-tension (10'0% compared with
7'1%; Fig. Ia).or those who had systolic blood pressures of120 mmHg
or over at entry: 28 (8' 5 %) of 331 such
(b)PRETERM DELIVERYEventslWomen Odds ratio & CI
Aspirin Placebo (Aspirin: Placebo)
53/192 49/172
53/284 80/322
41/210 50/241
65/266 79/253
56/231 70/224
501245 59/270
106/476 129/494~
~ 19%501411%SO28 (22.3%) (26.1%) reductionincrease
(2p=0.2)(2p=0.7)
0.5 1.0 1.5 0.5 1.0 1.5Aspirin Asplrin Aspirin Aspirinbetter
worse better worse
Fig. 1. Effects of aspirin on (a) proteinuric pre-eclampsia
developing after randomisation and (b) preterm delivery. The
outcome ofproteinuric pre-eclampsia required the development of
hypertension and proteinuria after randomisation, and preterm
delivery wasdefined as delivery before 37 weeks of estimated
gestation (as in Cl.Af'!'). Odds ratios (. = area proportional to
amount ofinformation 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 theleft of the solid verticalline). The overall
results for ali women (and 95% Cl) are represented by diamonds,
with the observed reductionsor increases in the odds of the outcome
developing given to the right of the solid verticalline. X2 tests
for differences between the effectsobserved in the different
subgroups were ali nonsignificant.
ReOG 1996 Br J Obstet Gynaeco/103, 39-47
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Entrycharacteristic
(a)INTRAUTERINE GROWTH RETAROATIONEvents/Babies Odds ratio &
CI
Aspirin Placebo (Aspirin: Placebo)
Gestation
520 weeks 13/196 9/174
> 20 weeks 28/286 421329
Parity
nulllparae 14/214 19/249
mulliparae 27/268 321254
Chronic hypertension
yes 26/233 26/226
no 15/249 25/2n
Ali babies: 41/482 51/503 18%50 20(8.5%) (10.1%) reduction
(2p=0.4)
ECPPA: A RANDOMISED TRIAL OF LOW DOSE ASPIRIN 43
(b)STILLBIRTHS ANO NEONATAL OEATHSEvents/Babies Odds ratlo &
CI
Aspirin Placebo (Aspirin: Placebo)
121196 9/174
231286 21/329
10/214 11/249
25/268 19/254
221233 17/226
13/249 13/2n
35/482 30/503(7.3%) (6.0%) 23%5029
Increase(2p=0.4)
0.5 1.0 1.5 0.5 1.0 1.5Aspirin Aspirin Asplrln Asplrlnbetter
worse better worse
Fig. 2. Effects of aspirin on (a) intrauterine growth
retardation and (b) stillbirth and neonatal death. Intrauterine
growth retardationwas defined as birthweight below the third
centile for sex and estimated maturity, and stillbirths and
neonatal deaths as deaths at orafter 24 weeks gestation and up to
28 days after birth. Symbols and conventions as in Fig. 1. X2 tests
for differences between the effectsobserved 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 inearly onset
pre-eclampsia: among women whowere delivered before 32 weeks,
pre-eclampsiaoccurred in 3/28 patients in the aspirin group andin
3/27 patients in the placebo group; amongwomen who were delivered
between 32 and 37weeks, pre-eclampsia occurred in 10/78 patients
inthe aspirin group, compared with 13/102 patientsin the placebo
group. Among women who weredelivered after 37 weeks, pre-eclampsia
occurredin 19/370 patients in the aspirin group and in14/365 in the
placebo group (X2 test for trend =0,64, 2P = 0-4). Sixty women with
a history ofdiabetes or hyperglycaemia were followed up;proteinuric
pre-eclampsia developed in none of the24 women allocated aspirin
and in only 3 out of 36of those allocated placebo (NS).There was no
difference between the treatment
groups in the medians ofthe highest blood pressuresrecorded
after randomisation and before labour(140/90 mmHg among both those
allocated as-pirin and those allocated placebo). Proteinuriawithout
hypertension severe enough to be definedas pre-eclampsia was
slightly less common amongaspirin-allocated women (41 (8'6 %)
comparedwith 52 (10'5 %); 2P = 0'3), while hypertension
RCOG 1996 Br J Obstet Gynaecol103, 39-47
without associated proteinuria was slightly morecommon (68 (14'3
%) compared with 56 (l1'3 %);2P = 0'2).
Duration of pregnancyThe mean duration of pregnancy was about
twodays longer among aspirin-allocated women thanamong
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 before37
weeks of estimated gestation, was lower amongwomen allocated
aspirin (22'3 % compared with261 %: Fig. 1b). However, although the
odds ofdelivering preterm was 19% (SD 14) lower
amongaspirin-allocated women, this difference was notsignificant
(95 % CI: 40 % reduction to 9 %increase). As was the case for
proteinuric pre-eclampsia, the effects on preterm delivery did
notappear to differ significantly in the differentsubgroups
studied.
BirthweightThe mean birthweight of all babies bom to
womenallocated aspirin was 30218 g (SD 763'3) com-pared with 29650
g (SD 756'0) in the placebogroup, but this slight increase of 568 g
(SD 48'7)was not statistically significant. Aspirin was asso-
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44 ECPPAcaLLABaRATIVEGRaUp
Table 2. Effects of aspirin on delivery type, bleeding and
fetalloss after randomisation. Values are shown as n (%).
Aspirin Placebo
Pregnancies with data n = 476 n = 494Fetal outcomes n = 482 n =
503
Labour and deliveryCaesarean section 291 (61'1) 301
(60'9)Forceps delivery 36 (7-6) 36 (7'3)
Maternal bleedingPlacenta I abruption 5 (1'1 ) 7 (l A)Other
antepartum bleed 6 (1'3) 8 ( 1,6)Postpartum bleed 3 (0,6) 6 (
1'2)Transfusion 7 ( 1'5) 7 (l A)
Fetal bleedingIntraventricular haemorrhage 6 (1'2) 3 (0'6)Other
neonatal bleeds 3 (0'6) 2 (OA)
Fetal lossesLosses < 24 weeks 4 (0'8) 6 (1'2)Stillbirths (~
24 weeks) 28 (5'8) 23 (4'6)eonatal deaths 28 days) 7 (1'5) 7 (I
A)
ciated with a slightly smaller prapartian of babieswith 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 deathsFaur (0'8 %) fetallosses occurred
before 24 weeksof gestation in the aspirin group and 6
(12%)accurred in the placebo graup (Table 2). Therewere 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 statisticallysignificant
and the 95% confidence interval iswide. There was no apparent
difference in theeffect in the variaus subgroups of women
studied,nor were there any significant differences in thenumber of
stillbirths and neonatal deaths asso-ciated with pre-ec1ampsia,
maternal hypertensionar lUGR (21 (4-4%) compared with 26 (5'2 %
orin thase associated with maternal or neonatalbleeding (50'04%)
compared with 80'59%.
Other outcomesThere were no significant differences between
thetreatment graups in delivery by caesarean sectionar forceps, nor
were there any significant dif-ferences in placental abruptions or
other antepartum bleeds (Table 2). All bleeds after deliverywere
not explicitly recorded and were incompletelyreported (overall rate
of 09% compared with26% in CLASP), but maternal transfusions
weresystematically sought, and there was no differencebetween the
treatment groups in the numbers
transfused. Two maternal deaths were reported inthis study: one
in the aspirin-allocated group wasattributed to the HELLP syndrome
and the otherin the placebo group was due to a car crash at 24weeks
of pregnancy. No significant differences inthe incidence of
intraventricular haemorrhages orother bleeds in the babies were
observed.
DISCUSSIONThe incidence of proteinuric pre-ec1ampsia inECPPA was
similar to that reported in previousstudies, but stillbirths and
neonatal deaths weremore common (6'6 % compared with 28% inCLASpll,
16% in the American study'" and23% in the Italian study"). Chronic
hypertensionwas present at entry in 47% of the ECPPApatients
(compared with 20% in CLASP), and47 % were primigravidae (compared
with 28% inCLASP). The perinatal mortality rate among thelarge
chronically hypertensive group in ECPPAwas 85%, which may reflect
uterine vascularlesions caused by chronic hypertension.Despite the
high risk population studied in
ECPPA, the effects of aspirin on adverse outcomesappear to be
much less promising than thosesuggested by the results of the first
small trials, andsimilar to those of the more recent larger
trials(Fig. 3: updated from CLASPll). Possible explana-tions for
the discrepancy between the results ofthe small trials and the
larger trials have beendiscussed in detail in the report of the
CLASPstudy. In particular, it seems likely that this maybe due, at
least in part, to publication bias, withsmall trials with
unpromising results being lesslikely to be published than those
with particularlypromising results, and with some
methodologicalproblems!" in at least one small tria\.It was
recently suggested " that the results of the
larger trials may have been diluted by their broadentry criteria
and by the wide variations in carebetween the different
participating countries.However, it has not been possible, either
in CLASPor in ECPPA, to identify any particular categoryof
women-inc1uding those in a substudy ofCLASP who were angiotensin II
sensitive (as inone particularly promising small study"), or
thosewith e\evated blood pressure at entry (as in a posthoc
subgroup analysis of one of the recent largertrials10)-in whom the
reduction in proteinuricpre-ec1ampsia was as great as that reported
in theprevious small trials (Fig. 3a). Moreover, althoughit had
been suggested from exploratory analyses ofCLASPll that aspirin may
be justified for those atespecially high risk of early onset
pre-ec1ampsia,this is not supported by the results from ECPPA.
RCOG 1996 Br J Obstei Gynaecol103, 39-47
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Trial categoriesortrial
(a)PROTEINURIC PRE-ECLAMPSIANo 01 Antlplatelet Control Odds
ratlo & 95,4 CItrlals therapy therapy (Antlplatelet:
Placebo)
Small trlals
Wlth data 11 10/ 319 50/ 284(3.1%) (17.6%)
7 -/ 308 -/ 228
5 tOO/2697 139/2524
313/4659 3521 4650
32/ 476 30/ 494
7 445/7832 521/7668( 5.7%) ( 6.8%)
18 455/8151 571/7952( 5.6%) ( 7.2%)
Wlthout data
Larger trials
Before CLASPCLASPECPPA tAli larger trlalsAli trlals wlth
data
ECPPA: A RANDOMISED TRIAL OF LOW DOSE ASPIRIN 45
(b)STILLBIRTHS ANO NEONATAL OEATHSNo 01 Antlplatelet Control
Odds n.tlo & 95% CItrlals therapy therapy (Antlplatelet :
Placebo)
12 51 306(2.0%)
-I 3206
10/ 289(3.5%)
-/ 223
5 48/ 2697
129/4810
35/ 482
38/2524
1361 4821
30/ 503
1%5010Inc .(2p:O.9)
1%5010reduct10n(2p:O.9)
17%506 7reductlon(2p=0.006)
23%506 19reductlon(2p=0.00006)
212/ 7989( 2.7%)
20417848( 2.6%)
218/ 8295( 2.6%)
214/ 8137( 2.6%)
o o 1.5Antlplatelettherapyworse
0.5Antlplatelettherapybatter
Test lor heterogenelty batween:
- ali trlals wlth data: X'" = 40.2 (p = 0.0004)X', = 25.7 (p
< 0.000001)X'. = 11.8 (p = 0.07)
- smaller trials versus largar trials:
- alllarger trials:
0.5 1.0Antlplatelettherapybatter
1.0 1.5Antlpletelettherapyworse
X~, = 10.3 (p = 0.6)
X~ = 1.3 (p = 0.3)
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 includedfewer 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 thesegenerally higher risk
Brazilian women, in whomclear effects on lUGR, stillbirths or
neonataldeaths could be demonstrated. Consequently, theECPPA
results support the conclusion!' that ifsome special category of
women exists that maybenefit substantially from aspirin, it must
composea much smaller and more select group than hadpreviously been
thought to be the case.As in the previous trials, the results of
ECPPA
are generally reassuring as regards maternal andneonatal
complications, with no significantexcesses of placental abruption,
other antepartumhaemorrhage, transfusion, or mortality due
tobleeding. Prior to ECPPA, a systematic overviewof the available
results from alI randomised trialsof antiplatelet therapy indicated
a 25 % reductionin the incidence of pre-eclampsia'", in
contrastwith the reduction of about three-quarters sug-gested by
the first small trials. The addition ofECPPA reduces still further
the apparent size ofthis benefit (Fig. 3a), and if the small
'hypothesisgenerating' trials are excluded, the apparentreduction
in the larger trials combined is only17% (SD 6). ln absolute terms,
these more modestproportional reductions imply that
antiplatelettherapy would typically prevent proteinuric
pre-ec1ampsia in about 1 woman per 100 treated (withconfidence
interval ranging from about zero to
RCOG 1996 Br J Obstet Gynaecol103, 39-47
about 2 per 100). ECPPA and some previous largescale trials!' do
suggest that aspirin may prevent afew preterm deliveries per 100
women treated. But,overall, there is no evidence of an effect of
aspirinon 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 placebo-controlled study in
1009 women, with very goodfollow up and compliance, does not
support thewidespread routine use of aspirin for the pre-vention of
pre-eclampsia or other hypertensivecomplications, even in the very
high risk pregnantwomen of a developing country.
AcknowledgementsThe most important acknowledgement is to
thehundreds of women who took part in ECPPA andto the doctors who
collaborated throughout Brazil.The following investigators
participated in thestudy.
Data management, analysis and writing committee:A N Atallah, R
Collins, B Farrell, H Handoll.
Principal Investigator: A N Atallah, Americana: AFreitas Jr, L
Kinsu, O Fukushima, Andradina: MAmorim, Araatuba: R Eduardo,
Araraquara: ADurante, C Vieira, J Filho, Arararas: L Davolos,
-
46 ECPPA COLLABORA TIVE GROUP
Asis: R Zambotti, Bariri: C Negro, Batatais: OAlves, Bauru:
P'Tobias, Belo Horizonte: C Freire,C Almeida, Birigui: J Neto, L
Bertechini, Botu-catu: I Maest, J Peraoli, Marilza V Rudge, ISilva,
S Filho, I Calderon, O Abujamra Jr, Brag-ana: A Neto, W Muniz, Jos
Carlos Pinton, Mde Mello, Cachoeira Paulista: A Ferreira
Jr,Campinas: C Nogueira, A Sanches, A Mariano, CFerraz Costa, R de
Lacerda, A Elias, R Yoshiassu,S Lustre, S Ximenes, P de Godoy,
Campinas: A deMeio, Canguu: D de Campos, Carapicuiba: DBezerra,
Cataguases: F Cesrio, Caxias do Sul: DTessari, Cruzeiro: M Kisse, W
Sria, Erechim-RS: A Teixeira, Fernandoplis: A Flumignan,Franca: M
Marcolini, Guaruj: E Rimi, Guar-ulhos: C Simes, V de Arujo,
Itatiba: CPavanelri, Jaboticabal: L Martins, Jacare: JNeto, C
Bianco, C Antonlia, Jundia: E Gennari,Limeira: Z Vinhal, Lins: J
Leo, Londrina: FSobrinho, Marlia: J Prado, Mirandoplis: ZSouza,
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: FCesme, H de
Carvalho, Pejuara-RS: L daSilva, Pindamonhangaba: A Wolff,
Piracicaba: CNegretti, Porto Alegre: I Belli, L Napp, A
Mene-ghetti, E Chaves, S Costa, C de Quadros Kroeff, SEspinosa,
Presidente Prudente: D Campos, JTsello, Ribeiro Preto: A Matthes, C
dos SantosJr, G Duarte, Rio Claro: G Neto, W de MatosRezende, Rio
Grande--RS: P Gonalves, HRivoire, 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 daSilva Ethur, F Jobim, Santo Andr: R
Serre, SSanforlin, J da Silva, J Neves, O Ferraro, Santos:Ma dos
Santos, A Ribeiro, R de Freitas, SoCaetano: A Adans, So
Leopoldo--RS: I Plentz,So Paulo: J de Andrade, H Nightingale,
JRebello, J Bencic, C da Costa Alves, C Camp-many, A Pereira, A
Kataguiri, L de Campos, JMasonetto, D Bentivegna, M de Oliveira,
MRusso, A Celestini, A Azevedo, H Lippi, FZanotto, F Simon, G
Frehse, H Halbe, L Primon,P David, P Franco, P Pirozzi, D Klotzel,
LAwoke, L de Figueiredo, R Theodozio, I Con-ceio, I Daniel, J
Kublikowski, J Adalaft Neto,G Kenji, S Guimares, S Leung, T Gollop,
VFreitas, B Carvalho, G Porto, J dos Santos, AAndrade, E
Cavalcante, A Henrich, W Arl, HAri, T de Oliveira, D Silvestrini, E
de Souza, A deArajo, A Allegrini, L Sakamoto, L Takano, RMattar, W
Taborda, H Paraventi, M Miyazawa,N Sass, R de Souza Mesquita, M
Lemos, M
Bevilqua, I Wulkan, G Paramo, J Mottola Jr, MScott, Sertozinho:
A Sde, R Clemente, Soro-caba: L Neto, Sorocaba: C Barros, Sorocaba:
NBressan, Taubat: M de Assis, X Mazzini.ECPPA Co-ordinating Centre:
A N Atallah, EClarizia, M L Duarte, H Gonzalez, A Pantoja,
MMesquita.Study Monitoring Committee: I Chalmers, RCollins, O
Delascio (late), J A Grisso, R Peto, MZugaib.The Clinical Trial
Service Unit (CTSU), NuffieldDepartment of Medicine, University of
Oxford,UK provided technical support and encourage-ment throughout
the duration of the study. Thestudy was principally funded by
Sterling Drugs (PTribble, S Weisman), who also donated
speciallypackaged aspirin and matching placebo andby Escola
Paulista de Medicina, CNPQ andINCLEN, Inc. The study was, however,
designed,conducted, analysed, and interpreted indepen-dently of the
commercial sponsor.
ReferencesI 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. Maternalvascular prostacyclin activity in
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4 Redman CWG, Bonnar J, Beilin L. Early platelet consumption
inpre-eclampsia. BM] 1978; I: 467-469.
5 Beaufils M, Uzan S, Donsimoni R, Colau .IC. Prevention of
pre-eclampsia by early antiplatelet therapy. Lancet 1985; I:
840-842.
6 Wallenburg HCS, Dekker GA, Makovitz JW, Rotmans P. Low-dose
aspirin prevents pregnancy-induced hypertension and pre-eclampsia
in angiotensin-sensitive primigravidae. Lancet 1986; I:1-3.
7 Schiff E, Peleg E, Goldenberg M el ai. The use of aspirin
toprevent pregnancy-induced hypertension and lower the ratio
ofthromboxane A2 to prostacyclin in relatively high risk
pregnancies.N Engl J Med 1989; 321: 351-356.
8 McParland P, Pearce JM, Chamberlain GVP. Doppler ultrasoundand
aspirin in recognition and prevention of
pregnancy-inducedhypertension. Lancet 1990; 335: 1552-1555.
9 Italian Study of Aspirin in Pregnancy. Low-dose aspirin
inprevention and treatment of intrauterine growth retardation
andpregnancy-induced hypertension. Lancet 1993; 341: 396-400.
10 Sibai BM, Caritis SN, Thom E et ai. Prevention of
pre-eclampsiawith 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-doseaspirin for the prevention and treatment of pre-eclampsia
among9364 pregnant women. Lancet 1994; 343: 619-629.
12 Atallah AN, de Souza Mesquita MR, Duarte ML et ai.
Estudoprospectivo "cohort ' de gestantes com hipertanso
arterialcrnica.v Bras Nefro11990; 12: 113-120.
13 Benigini A, Gregorini G, Frusca T et ai. Etfect oflow-dose
aspirinon fetal and maternal generation of thromboxane by
plateletsin women at risk of pregnancy-induced hypertension. N Engl
JMed 1989; 321: 357-362.
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14 Peto R, Pike MC, Armitage P et ai. Design and analysis
ofrandomized clinical trials requiring prolonged observation or
eachpatient l l. Analysis and examples. Br J Cancer 1977; 35:
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15 Antiplatelet Trialists' Collaboration. Collaborative overview
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antiplatelettherapy in various categories ofpatients. BMJ 1994;
308: 81-106.
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ECPPA: A RANDOMISED TRIAL OF LOW DOSE ASPIRIN 47
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1200-1251.
Received 27 April 1995Accepted 13 September 1995
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British Journal of Obstetrics and GynaecologyJanuary 1996, Vol.
103, pp. 48-53
Detection of fetal fibronectin as a predictor of pretermdelivery
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 andGynaeeology,
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 would predict deliverybefore 37 weeks in women at high
risk of preterm delivery.
Study methods Forty-three women considered at risk ofpreterm
delivery were recruited antenatallyinto a blind longitudinal study.
Quantitative assays of fetal fibronectin were obtained
fromsequential high vaginal swabs taken fortnightly from 24 to 34
weeks of gestation. Fibronectinconcentrations of 005 Ilg/ml or more
were considered as positive.
Results Results were calculated by swab and by subject. The
sensitivity of an individual fibronectinswab in predicting preterrn
delivery within 14 days of testing was 71 % and the specificity
was93 %. The overall positive predictive value was 31 % and the
negative predictive value was99 %. 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 predictivevalue was 73 %. For a woman who has had a
positive swab the sensitivity in predicting pretermdelivery within
14 days of testing was 80 % and the specificity was 83 %; a woman
was countedas 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 awoman
who has had a positive swab the sensitivity in predicting delivery
before 37 weeks was54 %. 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
samplingsequence was positive. Fibronectin swabbing when calculated
by patient did predict pretermdelivery within 14 days of testing (P
= 0'01) and before 37 weeks (P = 0'01). Analysis of theaccuracy of
predicting delivery from 7 to 28 days after sampling revealed that
the bestprediction for delivery was within the following 14
days.
Conclusion Serial fetal fibronectin assessment from 24 to 34
weeks of gestation anticipated pretermdelivery within 14 days
oftesting and before 37 weeks for high risk asymptomatic women.
Suchtesting should be performed every two weeks.
INTRODUCTIONPreterm delivery is the leading cause of
newborninfant mortality in the developed world. Most ofthese deaths
occur in pregnancies ending before29 weeks'. A substantial
morbidity accompaniespreterm delivery as well as iatrogenic
morbidityassociated with prolonged neonatal intensive care.Long
term neurological problems are more difficultto evaluate. Apart
from the human cost, thefinancial cost of providing inpatient care
forpreterm babies and providing support in cases oflifelong
handicap is great.
Correspondence: Dr S. C. Leeson, Department of Obstetricsand
Gynaecology, Saint Mary's Hospital, Hathersage Road,Manchester M 13
9PT, UK.
48
Prediction ofpreterm labour is unreliable. Usinga history of
previous preterm delivery, twinpregnancy, uterine abnormality, low
socio-econ-omic status and cervical incompetence predicts, atbest,
50% of preterm deliveries". The use of serialvaginal examination,
screening for reduced fetalbreathing movements on ultrasound
scanning orscreening for recurrent contractions with
externaltocography provides little additional sensitivity".Fetal
fibronectin is part of a family ofubiquitous
dimeric glycoproteins present predominantly inplasma and
extracellular matrix and whichinfluence cell adhesion, motility,
tissue repair andcoagulation+". There are more than 20 isoforms
ofthe molecule. Fetal fibronectin has a molecularweight of about
450,000 daltons and is produced
RCOG 1996 Britisli Journal of Obstetrics and Gynaeeology