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British Journal of Obstetrics and G y naecolog y

January

1 996 , Vo l . 1 03 , p p . 39 - 47

ECPPA: randomised t r ial o f l o w d o se aspirin for the prevention of maternal and fet al complications in high risk pregnant women

ECP P A (Estudo Co l aborat i vo para P revenção da Pr é -ec l amp s ia c om Aspiri na) Co llaborati ve Group*

* C ollaborator s and parti c ipatin g c e ntre s a r e Ii s t e d o n page s 45 - 4 6

Objecti v e

T o d ete rmin e th e ef f ec ti ve ne ss

o f l ow d os e as pirin in w om e n at h ig h ris k of adverse

o u tco m es assoc i a t e d w ith pr e - e cl a mp s i a .

trial comp a ring

pl acebo on pr e - e cl a mp s ia and other materno - fetal

Design A coll a bor a ti ve r a ndomi sed

the effe cts o f low do se

as pirin (60 m g) w ith

compli ca tions a ss ocia ted with h y p er t e n s i o n .

Setting

Twel ve t eac hin g maternit y ho s pitai s a nd 18 2 ob s t etric i a n s'

offi ces

in B raz il.

Subjects

On e t h o u sand

a nd nin e wo m e n con s id e r e d

t o be a t hi g h ris k fo r th e d eve l o pm e nt

of pre -

e c l am p sia , o r it s co mp l i ca ti o n s , e ntered th e s tud y b e t wee n 1 2 a nd 32 wee k s of ges t ati o n . T h ey

were rand o ml y

an d fo ll ow up was o bt a in e d

a ll oca t e d to r e c e i ve aspirin ( 49 8 wo m e n ) o r pl a c e b o (511 wo m e n ) u n til de liv e r y ,

fo r 9 6 % .

Re s u1t s

Th ere we r e no s i g nifi ca nt diff e r e n ces b etwee n th e trea tmen t

gro up s in the i n cidence

of

p r o teinur i c pre- ec l a rnp s ia (6 ' 7 % aspirin- a lloc a ted

wo m e n ), of p re t e rm deliver y ( 22 ' 3 % comp a r e d w i th 26 · 1 %), of intrauter in e

c ompa red w ith 6·0 % pl ace b o - a lloc a ted

g r owt h r e t ar d ati o n

(8'5 % comp a red

n o r w e r e th e r e s ignificant

s

or a b ove a t e nt ry (8'5 % c omp a r e d

( 1 0' 0 % co mp are d

or fetal bl ee d i n g .

with 10·1 % ) , or of stillbirth and neon a t a l

differences in the incidenc e

de a th (7'3 % co mp a r e d

with 6· 0 %),

in a n y

of proteinuri c pr e - e cla mp s i a

ub gro up

o f wo m e n studied , in c luding

tho se who h a d s y s t o lic blood pr essur es

of 1 20 m mH g h y p erte n sive

w ith 7 ·3 % ) or th ose w h o were c h ro n ica lly

w ith 7 · 1 % ). A s pirin was n o t a ss ocia t e d

w ith a s i gnificant exces s of m ater n a l

ConcIusion

Th e re s ult s of thi s s tud y d o n o t s upp o rt the r o ut ine p r o ph y l actic

administr a tio n

o f l ow

do s e as p i r i n

h y p e rt e n s i o n

in p reg nan cy t o a n y ca t egory

of hi g h ris k wo m e n (eve n th ose w h o h ave chro ni c

or w h o a r e co n s id e red

to b e es p ec i a lly l iabl e to ea r1 y o n set pr e - ec l ar n p s i a ) .

INTRODUCTION

Pre-ecl a mp s i a i s a m a j o r cause o f maternal and fe t a l m o rbidit y a nd m o rtalit y ' , and placenta l isc h aemi a i s c on s id e r e d to ha v e a central role in th e p at h oge n es i s of th ese c ompli ca tion s". Pre-

ec l a mp sia i s ass o c i a t e d w ith d e fici e n t intravascula r pr o du c ti on o f pr os t acyclin a nd w ith exce ss i v e pr o du c ti o n of thrornbo x ane " . Th e r e i s al s o e v i-

d e nc e o f act i va tion o f the c lottin g syst e m a nd e a rly in v olv e m e nt of platelet s " . This ha s led t o the use of

a ntipl a t e let regimen s (u s ually low dose a spirin) in

a n a ttempt to prev e nt a r delay the de v elopment

a nd pr og r ess ion of th e co ndition .

S o m e s m a ll tri a l s o f a ntiplat e let therap y in

p

r eg n a n cy h av e rep o rt e d l a rge r e du c tion s in th e

C

orre s pond e nc e: D r A. N. Atal l a h , D e p artme n t

of Me d i ci n e , D

C

li n i ca Med i c a , E s cola P au li s t a d e M e d ic in a , R ua B o tuc a tu 740 ,

C

E P 040 23 - 9 00 São P a ul o , B ra z i l .

© R C OG 1 996 Br i t is h J o urn a l of Ob s t e tr ics a n d G y n ae c o l og y

incidence of pre-ecl a mp s i a with th e u se of \ ow dose as pirin ( s ometime s with th e a dditi o n of dipyrid a mole ' ' " ) . But t h es e f indin gs h ave n ot

gener a lly been con f irme d b y m o r e r ece n t l a r ge randomise d controll e d tri a l s' " !' . D esp ite t hi s i t h as been s u gges ted , u s u a lly af t er r etros p ecti ve d ata- dependent s ubgroup a n a l ys i s , t h at t h e b e n ef i ts of

a ntipl a telet proph y l ax i s m ay st ill be of u se i n

certain r e s tricted gr o up s of wo m e n . For exa m p l e , the CLASP in v e s tiga to rs c o n c lud e d th a t l ow d ose aspirin might be beneficial for th ose a t es p ec i a ll y high ri s k of earl y o n se t pre- ec l a mp s ia ll . Simil ar

explor a tor y a nalys e s in a noth e r st ud y'" l e d to t h e

s ugge s tion th a t l ow d ose as pir i n was e ffic ac i o u s in

primi g r av id w om e n pr ese ntin g w i t h sys t o lic b l ood pre ss ur es o f 120 mmH g a r m o r e . Pr e - ec l a m ps i a and its se qu e l ae are r e l a t ivel y co m mon i n B raz il ,

a nd a n ob s er v ation a l s tud y c ondu cte d t h e r e fo u n d that a bout half o f the c hron ica lly h y p e r ten s i ve

39

4

0

ECPPA COLLA B O R ATIVE

G R OUP

pr eg n a nt w om e n had s e v ere materno - feta l

com pli cat i o n s a ttribut a bl e to h y p e rt e n s ion' ". T h e pr ese n t r e p o rt i s of the Es tudo Colaborativo para

Pr eve n ção d a Pr é -e c l a mp s ia com Aspirina

(EC PP A). Thi s multicentr e r a ndomised controlled d o ubl e -blind tri a l w a s de s igned to determine whet h er l ow d ose a s pirin i s effecti v e in women at p ar ti c ul arl y hi g h ri s k of a d ve r s e outcomes a sso - c i ate d w ith pr e - eclamp s ia .

METHODS

On e th o u sa nd a nd nine w omen we r e recruited into

th e tri a l fr o m 1 2 univer s it y teaching ho s pitaIs and

1 82 o b s t e tri c i a n s' office s throughout Brazi l be-

tw ee n D ece mb e r 1989 and March 1993 . The study

w as a pprov e d by the Ethics Committee B oard of Esco l a P a uli s ta de Medicina , São Pau l o .

E l igibi l ity

W o m e n we r e eligible if they were between 12 and

32 week s o f ges tation and , in the opinion of t h e r es p o n s ibl e c linician , w ere a t s ufficient ri s k of pre-

ec l a mp s i a o r it s s equ e lae for the u s e of low dose

a s pmn to be c ont e mplated , but without c l e a r

indic ati o n s for or a gain s t its u s e. Women might be

con s idered at sufficient risk for a number of

re as on s, in c luding chronic h y p e rten s ion detected

before or during pregn a nc y,

( e s pecial l y with other risk fac t or s, s u c h as y oun g or old a ge ), diabetes , renal di sease, a hi s tor y o f pr e -

e c l amp s ia or intrauterine g r ow th r e tard a tion

( IUGR ) in a previou s pre g n a nc y o r ev id e nc e of their pre s ence in the current pregnanc y . Contr a -

indications in c luded an incr eas ed ri s k of bleedin g,

a sthma , a llergy to a s pirin , g as tric ul c er , a nd

primi g ra v idit y

pla ce nta pra ev ia. Consent to p a rticipate w as sought from eligible women .

Randomi s ation

Entry to the st u dy was att a ined by tel ephoning a central 24 h serv i ce at Escola P a u l i s t a de Medicin a in S ã o Paulo . B a s e l ine detail s of the women (T a bl e 1) were recorded directly on computer- g en e r a ted

r a ndomi s ation lists prepared b y the Clinical Tri a l

Ser v ice Unit , Oxford Univ e r s ity. On l y aft er co m-

plete b as eline information h a d be e n pro v ided was

T abl e 1 . Pre-randomisat i o n c h aracte r is ti cs of wome n st udi e d . Fi g ur es in p a r e nth eses a r e p e r ce n tages unl ess o th erwise stated.

 

No. (%) i n a ll oca t e d treatment

gro u p

 
 

Asp irin (n = 498)

   

Pl ace b o

(n=511)

 

W

o man ' s age (yea r s)

27-5 ( SD

7 - 4 )

27-5 (S D

7 - 4)

 

<

20

79

( 1 6)

84

( 1 6)

20

- 29

2 ( 44 )

1

8

 

228

(45)

30

- 39

1 72

(35)

1 74

(3 4 )

 

~ 40

29

(6)

25 (5)

 

Es

t i mated d ur a t io n of ges t a ti o n ( w eeks)

2

2 -1 ( SD

6 -2)

22 - 4 (S D

6-0)

<

1 2*

1

8

( 4)

2 0

( 4 )

1

2 ~ 20

1

8

6

(37 )

1 6 1

(32)

> 20 ~ 28 > 28

1 9 4

(39)

233

( 4 6)

1 00

( 20)

97

( 1 9)

Sys t o li c b l ood press u re ( mmH g)

1 27 - 3 ( SD 2 0 -5)

1 26-8 (S D 2 0 -5)

 

<

1 20

1 53

(3 1 )

15 9

(3 1 )

 

1 20 - 1 39

1 7 1

(3 4 )

1 83

(36)

~ 1 40

1 7 4

(35)

1 69

(33)

Diasto l ic b l ood pressu r e ( mmH g)

8

1 -3 (S D 1 5- 0 )

80- 3 (S D 1 4-8)

 

<

90

3

1

4

(63)

333

(65)

90

- 109

1

55

(3 1 )

1 59

(3 1 )

~

1 10

29

(6)

1 9

( 4 )

O

th er features of curre nt p regna n cy Proteinuria and j or facia l oedema Evidence of IUG R

 

2

1

(4)

27

(5)

 

3

4

(7)

28

(5)

Obstetric and med i cal hi s t ory

 
 

Primigravid

22

1

( 44 )

250

(49)

Mul ti parous, n o fe t a l loss

1

88

(38)

1 75

(34)

Mul t iparou s , wit h fe t a l l oss

89

( 1 8)

86

( 1 7)

C

h ronic hype rt ens i o n

2

4

2

( 4 9)

23 1

( 4 5)

D

ia b e t es o r h y p erglycae mi a

25

(5)

37

(7)

*

W o m e n ra nd o mi se d bef o r e 1 2 wee k s of

ges t a ti o n were to s ta r t tr ea tm e nt

a t 1 2 w e e k s ,

 

E

C PPA :

a specific numbered trial treatment pack alloc a t e d .

Women c o uld be randomised befor e an estima ted ge s tati o nal age of 12 weeks, but in such cases were

in s tructed not to s tart taking the tablets before the

12th week . After randomisation , no woman was ex c luded from the trial , irrespective of whether

tr ea tment was dispensed ar taken . For the pur -

p os e s o f a n a l ys is , w omen remained in the treatment g r o up to which the y h a d been originally allocated ( i. e ., intention to treat analyses are reported).

Treat m e n t

Women were assigned calendar-packed treatment with either one 60 mg film coated aspirin tablet

d a il y ar a placebo tablet , identical in appearance ,

cont a ining microcrystalline cellulose and com s tarch . The dose of aspirin was chosen to be s ufficient to in h ibit platelet aggregatiori'" , and was one that had been reported to prevent pre-

ec l a mp s i a " while keeping side effects to a minimum . Women were a s ked to take the study treatment every day until delivery, unle s s advised otherwise . Other a s pirin-containing preparations were to be

avo ided , with paracetamol recommended when

a n a l g e s i a w a s nece s sar y . The actual contents of

th e a ll o c a t e d s tud y treatment were not revealed ,

eve n after deli v er y , unle ss there was a c1ear medical

rea s o n for the treatment to be made known . Drug

s t a bilit y w as confirmed a t interval s throughout the s t ud y b y testing a s a mple of the study treatment p ack s .

Follow up

A v ery s imple s ingle page follow up form w as

c ompl e ted after hospital discharge of both mother a nd baby (ar at six week s postpartum, ifeither had not been discharged). Brief details were to be r e corded of proteinuria developing during the pregn a ncy , the highe s t recorded blood pressure

(o th e r th a n during labour) , 1UGR, fetal loss or

a n y m a ternal or neon a tal bleeding. The mode of

A R AN DOMIS ED

TRI A L

O F L O W

D OS E AS PIRI N

41

maternal blood pre s sure recorded after entry ;

crude birthweig ht ; stillbirth a nd neon a tal de a th ;

m a ternal and fetal complication s related to

bleeding ; blood tran s fu s ion . The s tud y outcom e o f proteinuricpre-eclamp s i a req uired thed e velo pm e n t of h y pertension plu s the detection of protein in th e urine after randomisa tion . H y perten s ion was

defined for those with b as elin e di as tolic pre s s ur e below 90 mmHg as a ri s e of a t leas t 25 mmHg t o

90 mmHg ar higher ; for tho se with initia l dia s tolic

pre s sure of 90 mmHg ar a bo v e , a n increment o f 15 mmHg was required 1 1 . Preterm deli ve r y was defined as delivery before 3 7 week s of e s tim a ted

gestation and 1UGR as birthweight below the

third centile for sex a nd e s timated ge s tation a l maturity'" . Stillbirths in c luded ali death s at ar after 24 weeks of gestation and neonatal death s

in c luded all deaths after birth , up to 28 day s.

Com p ariso n s a nd statistical metho d s

The main comparison w as to be of a ll women allocated aspirin against a li tho s e allocated placebo . In addition , s ub s idia r y compariso n s we r e made of the result s s ubdi v id e d a c cordin g t o

gestational age , parity and th e e x i s t e n ce of c hr o ni c hypertension at randomisa tion . Furth e r ex pl o r a - tor y analyses were conducte d in re s pon s e t o so m e of the findings of CLASP l 1 a nd other s tudi es'". Statistical analy s e s involve s impl e c omparis on s of total number s affected . St a nd a rd m e thod s we re

u s ed to calculate the app a r e nt r a tio of th e odd s of

an outcome occurring in th e as pirin g roup co m- pared with the odd s in th e control g roup , a lon g with its confidence interv a l: 95 % for princip a l a n a l yses , and , to take account of th e number of com - parisons, 99 % for subgroup an a ly s e s 14 . 1 5 . Alter- natively , the reduc t ion (or increas e) in the odds of the event in the aspirin group and its st a nd a rd deviation (SD) are cited ; an odd s ratio of 0, 8 , for

example , correspond s to an odd s r e duction of

20 % (such odds reduction s a re s lightly l a r g er th a n

d e li v ery , birthweight , whether live birth , stillbirth

ar

n e on a t a l death and any neonatal complication s

the corresponding ri s k r e duction s). In the high ri s k wom e n t o b e s tudied in E C PPA ,

we

r e a l s o to be recorded . The duration of tablet

ta kin g wa s a ss e ssed crudel y b y recording the a ppro x imate date w hen s tud y treatment was

co mpli a nce. Effort s were made to check and

it s hould have been po ss ible to detect r e li a bl y a reduction in the incidenc e o f pr e - e cla rnp s i a of

about three quarter s ( a s s u gges t e d b y th e r e s ult s

a

v ailable when this s tud y w as d es i g ned ) in a s tud y

tud y wa s designed to detect s omew h a t s m a ll e r

s

benefits . Resource s were ava ila ble t o continu e

s t o pped a nd , in addition , a s mall random sample o fwomen in the stud y w ere interviewed about their

of about 600 women . Su c h a n e ffect see m e d , however , to be too much to hop e for a nd so th e

co rr e ct an y incomplete a nd inconsistent data

w h e r ever pos s ible .

recruitment until M a rch 1993 (w hen the s tud y wa s

O u tco m e m eas u res

The main prespecified outcome measures were:

es timated duration of pregnancy ; maximum

© R C OG

1996 Br J Ob s t e t G y na ec o l103,

39 - 47

s topped in ignorance of the re s ults ) , b y which time 1009 women had been randomis ed. No interim analyses of ECPPA were c onducted durin g re-

42

E C PPA C OLLAB O R ATIVE

G R OUP

cru i tment a nd t h e res ult s remain e d conc ea led until

onl y af ter 7 5 % oft h e time bet wee n r a nd o m isat i o n

after data co ll ect io n h a d be e n c ompleted .

The

and del iv er y

ha d

b ee n c o mpleted ,

 

a nd

69 %

r

ea s sur i ng d a t a m o nit o rin g

commi ttee r eports to

s

t oppe d af ter 9 5 % of

thi s tim e . Int e r v i ews

with a

t

h e s t eeri n g co mmitte e of the l a r g er CLASP st u dy

ra ndom

s ample

of

8 8 women

in

the

s tudy

were , h owever , pr o vi d e d

tiga tor of EC P PA durin g th e s tud y.

t

o the prin c ip a l

in ves-

RESULTS

One tho u sa nd a nd nin e wo m e n we re r a ndomi s ed ,

w i th goo d b a l a n ce b etwee n th e tr ea tment group s

fo r t h e m a in pr e -r a nd o mi s ati o n

(

un der 20 year s of age , 38 % we r e at 2 0 w eek s of

ges t ation or ear l ier , 47 % were primi grav id ae ,

47 % had c h ronic

hi story of di a b etes m e ll it u s or h y per g l ycae mi a.

a nd 6 % had a

ch a r a cteristics 16 % were

T ab l e

I ) . O f th e wo m e n

h

e n ro lled ,

ype r te n s i o n

P ost-d e li ve r y fo llo w up form s were obt a ined for

96 % of th e r a ndomi se d

aspirin

women h a d 985 in fant s o r fe t a ll oss e s

compared w i th 5 0 3 pl aceb o) . Rep or ted co mplian ce

with stu d y t reat m e nt was go od , w ith n o differenc e

between t h e gro up s a l loca ted

O f t h e 967 r a nd o mi se d

o

f s topp in g tri a l t a blet s was kn ow n , 90 % s topped

women (476 a llocated

pl ace bo ),

a nd th ese ( 4 82 as pirin

as pir i n o r p l acebo.

an d 4 9 4 a llo ca t e d

women for whom the date

( a ) PROTEINURIC PRE - ECLAMPSIA

supported the overall e s timat e of compli a nce , w ith

8 8 % of the sampl e c on f irmin g

mor e than 7 5 % of th e s chedul e d

th a t the y h a d t a k e n

s tud y t a bl ets.

I n c id e nc e o f prote in u ric pr e - ecla mp sia

Proteinuric pre-eclarnp s i a in EC PPA w as rec o rd e d

in 6 · 7 % of wo men a ll o cat e d

of tho s e alloc a ted pl ac ebo ( F ig . I a) . A lth o u g h

repre s ent s

de ve loping proteinuri c

er e nce i s n ot c on v en t ionall y

con s i s tent with a reduction

qu a rter ( as wel l a s with mor e th a n a d o ublin g in

ris k ). The r e was an a b senc e of goo d ev id e n ce th at

th e e ffec t o n proteinuri c

sig nif ica nt a nd i s still

aspirin

ve r s u s 6· 1 %

thi s

a n 11 % ( SD 28) i n crease in t h e o dd s of

pr e - ec l a mp sia,

t hi s d iff -

of as mu c h as o n e -

p re - ec l a mp s i a

di ffere d

a mon g the diff ere nt s ub g r o up s of wome n st udi e d ,

in c 1uding w om e n w ith e v id e n ce of c h ro ni c h yper -

ten s ion (10 ' 0 % comp a red wi th 7 ' 1 %; F i g . I a).

or t h ose who had systo l ic

120 mmHg or over at entry : 2 8 (8 ' 5 %) of 33 1 s u c h

blood pr ess ur es

of

( b)PRETERM DELIVERY

Entry

Eve nts/ Women

Odds ratio & CI

Events l Women

Odds ra ti o & CI

characte r istic

As pirin

P l aceb o

(Asp i rin : P l a c ebo )

Asp i r i n

Placebo

( Aspirin : P l acebo )

Ges t ation

,; 20 w e eks

16 / 192

8 / 172

53 / 1 9 2

49 / 172

> 20weeks

16 / 284

22 / 3 2 2

53 / 284

80 / 32 2

Par i t y

nu l l i parae

8 / 210

1 0 / 2 4 1

4 1 / 2 10

50 / 2 4 1

mult l parae

24 / 266

20 / 25 3

6 5 / 266

79 / 2 53

Chronic hypertension

ye s

23 / 231

16 / 2 2 4

5 6 / 2 3 1

70 / 224

no

9 / 245

14 / 270

5 0 1 245

59 / 270

Ali women entered :

32 / 476

30

/ 4 9 4

1 06 / 476

1 29 / 494

~ 19 % 50 1 4

(6.7%)

(

6 .1%)

 

1 1% SO 28

i

( 2 2 . 3 %)

( 26 . 1 % )

~

r

educt i on

 

nc r ease

 

(2p = 0.2 )

(

2p=0 . 7 )

 

0. 5

1. 0

1.5

 

0 . 5

1. 0

1 . 5

Asp i r i n bette r

Asp l r in wo r se

Asp irin bette r

Asp iri n worse

Fig . 1 . Ef f ec t s of as pirin on (a) proteinuric pre - e c l ampsia d eveloping after ra nd omi s ation

prot e inuri c pr e - e c l a mp s ia requ i red t h e d eve l o pm ent of h y p erte n sio n a nd p ro t e inu ria after randomisa t ion , a n d p reterm de l ivery wa s

defi n ed as de l iv e ry before 37 wee k s of esti m a t e d ges t a ti o n (as in C l . A âf ' !'). Od ds ra ti os ( . = area propo r tiona l

inform a tion contr i buted " ' ) a n d 99 % c onfi d e n ce int erva l s ( C l : h o ri zo nt a llin e) a r e pl o tt e d for c er t a in s ub g r o u p s of th e st u dy pop ul atio n .

A b l ack s q u ar e t o t h e lef t of the so li d ver t ica llin e

left o f th e s olid v e rtic a l line ). T h e ove r a ll re s ult s for a li wo m e n ( a n d 95 % C l ) are r epresente d b y d i a m o nd s , with t h e o b s erved reduction s

sugges t s a be n e f it ( but thi s i s s i g n ifica nt a t 2P < 0·01 on l y if t h e w h o l e C l i s to the

and (b) pre t e r m de l iver y . T h e o ut c om e o f

t

o a m ou n t

of

o

r in c r e a se s in th e o dds of th e o utcome deve l oping given to t h e right of the so l i d ve rti c a llin e . X 2 te s t s for d i fferences between t h e e ff e ct s

o

b serv e d i n th e diff e r e nt s ubgr o up s were ali n o n s ig n ificant .

E

C P P A:

(a)INTRAUTERINE GROWTH RETAROATION

A R A N D O MIS E D

TRI A L

OF LO W

DOS E ASP I R I N

( b)ST I LLB I RT H S A NO NEON A TAL OEATHS

43

Ent r y

 

Events / Babies

Odds ratio & CI (Aspir i n : Placebo)

 

Eve nt s / Bab i es

Odds rat l o & CI ( Asp iri n : Placebo)

 

c

haract e ristic

Asp i r i n

Placebo

Aspir in

P l a c ebo

Gestation

 
 

5

20 weeks

13 / 1 9 6

9 / 174

1

2 1 196

9 / 1 74

> 20 weeks

28 / 2 8 6

42 1 32 9

2 3 1 2 86

21 / 32 9

Parity

   
 

nulllparae

14 / 214

19 / 2 49

1 0 / 21 4

1 1 / 24 9

mulliparae

27 / 2 68

3 2 1 25 4

2 5 / 268

19 / 254

Chronic h ype r te n s i o n

   
 

ye s

2 6 / 233

26 / 2 2 6

2

2 1 233

1 7 / 2 2 6

 

n

o

15 / 2 4 9

2 5 / 2 n

1

3 / 249

13 / 2n

Ali babies:

4 1 / 48 2 ( 8 . 5 %)

51 / 50 3 ( 1 0. 1% )

18 % 50 20 reduction (2p = 0 . 4)

3 5 / 482 ( 7 . 3 % )

30 / 503 (6 . 0% )

23 % 5029

   

I

n c rease

 

(

2p=0 . 4 )

 

0. 5 A s pir i n bette r

1. 0

1.5

0 . 5 Asp l r l n bette r

1. 0

1 . 5 Asp l r l n wo r se

 

Aspirin

worse

F i g. 2 . Effec t s o f as p irin on (a) intr a ut eri n e g r ow th re t a rdati o n

w as d e f i ned a s bir t h we i g h t b e l ow th e third c enti l e f o r s e x a nd e s tima t ed m a t u r i t y , a nd s t ill b i rth s a n d n eo n a t a l dea th s as dea th s at or after 2 4 week s ge s t a t i o n a nd up t o 2 8 d a y s af t e r bi r th . Sy mb o l s a n d co n ve nti o n s a s i n F ig . 1 . X 2 t es t s f o r dif f e rence s b e tw ee n th e e f f e c t s o b s erv e d i n t h e d i ff e r e nt su b g r o up s we re a ll n o n s ignifi c ant .

a n d (b ) s til l birth a nd n eo n a t a l d ea th . In tra u ter in e

g r ow th r e t a rd a tion

wome n a ll ocated as pir i n compared with 25 (7 ' 3 % )

o f 343 a ll ocated pl aceb o.

T

h e r e

was a l so

a la c k

of s upport

for t h e

h y p ot h ese s ge n e rated b y CLASP of a reduction in

women w h o

were d e li ve r e d

o c c u rre d i n 3 / 28 p a tient s in the as p i rin group and

i n 3 / 27 p a ti e n ts

wome n w h o were deli v ered

e a r ly o n se t pr e -ec l a mp s i a:

mong

before 32 week s , pre - ec l ampsia

a

in the pl a cebo group ; among

between

32 a n d 37

wee k s, pr e - ecl a mp s ia occurred in 10 / 78 patient s i n

t h e a s pirin g r o up , comp a red

i n th e pl ace b o g r o up. Among women

d e li ve r e d aft e r 3 7 week s , pr e -e c l ampsia occu r re d

i n 1 9 / 37 0 p a ti e nt s

with 13 / 102 patients

w h o were

and i n

in the a spirin

gro u p

1 4 / 365 in th e placebo g r o up (X 2 test for trend

=

0, 6 4 , 2 P = 0 - 4) . Si x t y women

with a hi s tory

of

d

ia b etes o r h y perg lyc a emia

were fo ll owed

up ;

pr

o t ei nuri c

24 wom e n

pr e - eclamp s ia developed in no n e of the a ll o c a t e d as pirin and in only 3 out of 36

of th ose a ll oca ted placebo (NS) . Th e r e was n o differ e n c e betwe e n the treatment

g r o up s i n th e median s ofthe highe s t blood pres s ures

r

ecor d e d aft er r a nd o mi sa tion

and b e for e l abo u r

(

140 / 9 0 mmH g

amon g both tho s e a ll oca t ed

as-

pi r in a nd th ose a lloc a ted

placebo). Protein u r i a

w as s li g h t l y m o r e

common (68 (14 ' 3 % ) comp a red with 56 ( l1 '3 % ) ; 2P = 0 ' 2).

wit h out a ssociated proteinuria

Duration of pr eg n a n cy

T h e mean dur a t i on of pre g n a nc y w as ab o u t t wo

da y s l onger among aspirin- a l loc a ted wom e n t h a n among p l acebo-allocated w om e n (38 '0 8 wee k s

3'7 1 )) ,

(SD 3 - 48) compared with 3 7· 78 week s ( SD

but this d i fference wa s n o t stati s tic a ll y s i g nifi ca nt .

The l ike l ihood of preterm

37 weeks of estim a ted gestation , w a s l o w e r a m o n g

w ith

women a l located a s pirin (22 ' 3 % c o mp a r e d

26 ·1 %: Fig. 1b). How e ver ,

de l iveri n g preterm was 19 % ( SD 14) l owe r a m o n g

wa s not

a

s ignif i cant (95 % CI: 40 % r e du c ti o n t o 9 %

i

pr e -

the effect s on preterm deli ve r y did not

e c l a m p s ia , ap p ear

deliver y , th a t i s b e f o r e

a

lthough

th e o dd s o f

thi s differ e nc e

s p iri n-al l ocated

n crease) .

women ,

As was t h e c ase for pr o t e inuri c

to differ s ignificantly

in th e

diff e r e nt

su b gro u p s s tudied .

Birthw e i g ht

T h e mean birthweight

of all babie s b o m t o w o m e n

w

i t h o ut h y pert e n s ion s evere e nough to be de f ined

a

ll ocated

a s pir i n

was 3021 · 8 g ( SD

7 63 '3 ) c o m -

as p re-e c l a mp s i a w as slightly less common among

p

are d with 2965 · 0 g ( SD 756 ' 0) in th e pl ace bo

asp irin- a ll oca t e d

w ith 52 ( 10 ' 5 % ) ; 2 P = 0 ' 3) , whi l e hypertension

w omen

(41 (8 ' 6 %) compa r ed

gro u p , bu t t h i s slight incre ase of 56 · 8 g (SD 4 8 ' 7)

signific a nt . A s pirin w as ass o-

was not sta ti sticall y

44 E C P PAc a LLAB a R AT I VEG R a U p

Tabl e 2 . E f fect s of as pi r i n o n del i v e ry t y p e , ble e din g a n d fe t a l

l

o ss a f t e r ra nd o m isa tion .

V a l u es a r e s h o w n a s n (%).

Pr eg n a n c i es w i t h d a ta

Fe t a l o ut co m e s

Lab o u r a n d d e li v e r y Caesa r ean s e c t i o n F o r ce p s d e l iv e ry

M a t e r n a l bl ee din g P l ace nta I abru pt i o n Oth e r a nt ep a r t u m b lee d P o s t p a rtum b l eed Tr a n s f u s i o n

F e t a l b l ee di n g I n t r a ve ntri c ul ar h a emo r r h a ge Oth e r n eo n a t a l bleeds

F e t a l l oss e s L o s ses < 2 4 week s

S t i l l bir th s ( ~ 2 4 w e e k s )

eo n a t a l d e a th s «

2 8 d ay s )

As pi r in

Pla ceb o

n = 4 7 6

n = 4 9 4

n = 4 82

n = 50 3

2 91 ( 61 ' 1 ) 3 6 ( 7 - 6)

3 0 1 (6 0' 9) 36 (7 ' 3)

5

( 1 ' 1 )

7 ( l A )

6 ( 1 ' 3 ) 3 ( 0 , 6) 7 ( 1 ' 5 )

8 ( 1 , 6 ) 6 ( 1 ' 2) 7 ( l A )

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

3 ( 0 '6) 2 (O A )

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

6 ( 1 ' 2 ) 23 ( 4 '6)

7 ( 1 '5)

7 ( I A )

ci a te d w ith a s li g h t l y s m a ll er pr a partian of b a bi es w i t h l U GR (8 ' 5 % c ompared with 10 · 1 %: Fi g . 2a) , but , again , thi s d i fference was not s ignific a nt , e i t h er ove r al l o r in a n y of th e s ubgr o up s s tudi e d .

Stillbirths and neonatal d eat h s

F a u r ( 0'8 %) fet a ll osse s oc c urr e d b e fore 2 4 week s

of g e s tatio n i n t h e a s pirin g r o up a nd

acc u r r e d in th e pl acebo graup (T a ble 2). Ther e

we r e 28 st illbirth s plu s 7 neonatal death s (35 tota l:

7'3% ) in t h e as pirin 6· 0 % ) i n t h e pl a c e b o

( S D 29) increas e w i t h aspirin i s nat s tati s tic a lly s i g n i f icant a nd th e 95 % co n f iden ce inter va l i s wi d e . Th ere was n o a ppar e nt differen c e in th e effect in t h e va riau s s ubgroup s of women studied , n o r w e r e th e r e an y s i g nifi ca nt differences in the n u m b er of st illbirth s a nd n e onatal death s a ss o- c i a t e d w i t h p r e - e c 1 a mp s i a , m a ternal h y perten s ion ar l U G R ( 2 1 ( 4 - 4 % ) co mp a r e d w ith 2 6 ( 5 ' 2 % » or in t h a s e a ss oc i a t e d w ith m a t e rn a l or neon a t a l

b l ee d i n g (50'04 % ) co mp a r e d w ith 80 ' 59 %» .

Other o u tcomes

T h e r e wer e n o s i g ni f ic a nt diff e r e nce s b e tween the tr ea t m e n t graup s i n d e li ve r y b y caesar ea n s ectio n a r forcep s , nor were t h e r e a n y s i g ni f ic a nt di f - f e rence s in p l ace n ta l a brup tio n s o r o ther ant e

p a rtum bl e e d s ( T a bl e 2). All bl e ed s a fter deli v er y we r e n o t ex plicitl y re c orded a nd were incomp l ete l y r epo rt e d (ove ral l r a te of 0 · 9 % compared with 26 % in C L A SP ) , but m a t e rn a l tran sf u s ion s were sys tema ti call y so u g ht , a nd th e r e w a s no diff e ren c e bet we e n t h e trea tm e nt g r o up s in the number s

6 ( 1 · 2 % )

g

roup a nd 23 plu s 7 ( 30:

gr oup ( Fig . 2b ) . Thi s 23 %

t ra n sf u se d . Two m a tern a l d e a t h s we r e re p o r t e d i n this s tud y : one in t h e as pi r in- a lloc a t e d g r o up was attri buted to t he HELLP s y ndrom e a nd t h e ot h e r in the pl a cebo group w as du e to a ca r c r as h a t 2 4 week s of pr eg nan cy . N o s i g ni f i ca nt di ffere n ce s in

th e incid e n ce o f in t r av en t ri c ul a r h ae m o rrh ag e s or

oth e r bl ee d s in th e b a bi e s were ob s er v e d.

DISCUSSI O N

The incidence o f prot e inuric pr e - ec 1 a mp s i a in

ECPPA w as s imila r to t h a t r e p o rt e d in pr ev i o u s

st udies , but s tillbi r th s a nd n eo n a t a l d ea th s were

% c om p are d wit h 2 · 8 % i n

C LASp l l , 1 · 6 % in th e Ame ri c a n s t ud y'" a n d

2 · 3 % in t h e Itali a n st ud y"). C hr o n ic h y p erte n s i o n

w as pre se nt at e nt ry in 4 7% of t h e EC PPA

pati ents ( c o mpared w ith 2 0 % in C L A SP ) , a nd

4 7 % were primi g r av id ae (co mp a r e d w ith 2 8 % in

CLASP ). The perin a t a l morta lit y r a t e a m o n g t h e

l a r ge chronicall y h y p e r ten s i ve g r o u p in EC PPA

was 8 · 5 %, w hi c h m ay r ef l ect u ter in e vas c ul ar

l e s i o n s ca u se d b y c hroni c h y p e rt e n s i o n . De s pite the hi g h ri s k p o pul ation s tudie d i n

ECPPA , the e ffect s of a spirin o n a d ve r se o ut com es

a ppear t o be mu c h less pro m is in g th an those

m o r e c ommo n (6'6

s

u gg est e d b y the re s ults of th e first s m a ll tr i a l s , a nd

s

imila r t o tho se of t h e mo r e r ece n t l a r ger t ri a l s

(

Fi g. 3 : upd a t e d from C L A SP ll ). P o ss ible ex pl a n a -

tion s f o r t h e d iscre p a n c y b etwee n t h e r e s ul t s of the s mall trials a nd the l arge r tr i a l s h a ve b ee n

discussed in detai l in th e r e p o rt o f th e C L A SP

s tud y. In p a rticular , i t see m s lik e l y th a t this m ay

be due , a t lea st in p a rt , to publica tio n

s m a ll tr ial s wi th unp ro mis i n g re s ul t s b e in g l e ss

lik e l y t o b e publis h e d th a n th o s e w i t h p a r t i c ul a r l y

promisin g r es ults , a nd wit h so m e m eth o d o l o g i c a l problems!" in a t l ea s t one s m a ll t r i a \ . It wa s recently s u g gested " th a t th e r es ults o f th e

l arg er tria l s may h av e been dilut e d b y t h e ir br oa d

e ntr y c riteri a and b y the w id e va r i a t i o n s in care

betwe en t h e di f f ere n t p a r t icipa t in g co u ntri e s . Ho w e ve r , it h as n ot been p o s s ible , e i ther i n CLASP

o r in E C PPA , to id e ntify a n y p a r t i c ul a r cate g o r y of women - in c 1udin g th ose in a s ub s tud y of

C LASP who wer e a ngiote n s in II se n s iti ve (a s in

o ne partic ul ar l y pr o mis in g s m a ll s t ud y " ) , or th o s e

w ith e\e vate d bl oo d pre ss ur e a t entr y (a s i n a p os t

h o c s ub g r o up a n a l ys i s o f o n e of t h e r e cent l a r ger tria l s 1 0) - in w h o m t he r e du cti on i n p rote i n uri c pr e -e c 1 a mp s ia w as as g r ea t as th at r e p o rt e d in th e previou s s m a ll tria l s (Fig. 3a). M o r eove r , a lth o u g h it h a d been s uggested from ex pl o r a t o r y a n a l yses o f CLASP ll t h a t a s p ir in m ay b e ju s tif i e d for th o s e a t

e s p e cia lly high ri s k of e a r l y o n s et p r e - e c 1 a m p s ia ,

t hi s is n ot s uppor ted b y th e re s ults from EC PPA .

bi a s , w ith

( a ) PROTEINURIC PRE- ECLAMPSIA

EC P P A : A R A N DOM I S E D

TR I AL

O F LOW

D O S E AS PIRI N

4 5

( b ) ST I L L B I R T HS ANO NEONATA L OEATHS

Trial categories

N o 0 1 A nt l p lat e l e t

Con tr o l

 

Odds r a t lo & 95 ° , 4 C I

 

No 0 1 Antlpl a t e l e t

Cont r ol

 

Odds n.t l o & 95 % C I

ortrial

trlals

th e r ap y

therapy

( An tl p l atele t :

P l

aceb o)

 

trl a ls

th e r a py

 

t he r ap y

 

( A ntl plate l e t

: P l acebo )

 

Small trlals

 

W

l t h data

1 1

10 /

3 1 9

5 0 /

284

1 2

5 1 306

 

10 /

289

 

( 3 . 1 %)

( 17 . 6 % )

 

(

2.0%)

 

(

3 . 5% )

W

l tho ut d ata

7

- /

3 08

- /

228

6

-

I

320

- /

22 3

Larger trials

 

B

ef or e CLASP

5

t OO / 2697

139 / 25 2 4

 

5

48 / 2697

38 / 2524

 

CLASP

 

313 / 4659

352 1 465 0

 

129 / 4810

136

1 4821

ECPPA

 

32 /

476

3 0 /

494

 

35 / 482

30 /

503

Al i larger trlals

7

445 / 7832

52 1 / 7668

   

1 7 % 506

7

2 1 2 / 7989

2

04 1 7 8 4 8

 

1% 50 10

 

(

5 . 7%)

( 6 . 8 % )

r

educt

l

on

(

2 . 7 %)

(

2 . 6 %)

I nc •. ••••

 

t

 

(

2p=0 . 006 )

 

(

2p : O . 9 )

Ali trlals wlth data

18

4 55 / 8151

571 / 79 52

 

23 % 506

1 9

218 / 8295

21 4 / 8 137

 

1% 50 1 0

 

(

5. 6 %)

( 7 . 2 %)

r

educt

l

on

(

2 . 6 %)

(

2 . 6 %)

 

r

educt 1 0n

 

(

2p = 0 . 00006 )

 

(

2p : O . 9 )

 

o

0

. 5

1 . 0

1 . 5

o

0 .5

1 . 0

1.5

Ant l platele t

 

An tl ple t ele t

 

Ant l platele t

An t lplatele t

therapy

t

herapy

 

t

herapy

 

therapy

batter

 

worse

 

batter

worse

Test l or h eter o genelty

b a t w een

:

- ali trlals wlth da ta :

 

X'" = 40 . 2 (p

= 0 . 0004 )

 

X~ , = 1 0 .3 ( p = 0 . 6)

- lar g ar trials :

smaller tria l s versus

 

X',

= 25 . 7 (p

< 0 . 0 0000 1)

 

X~ = 1 . 3 ( p = 0 . 3 )

- alllarger trials :

 

X'. = 11 . 8 (p = 0 . 0 7)

 

X~ = 6.3 ( p = 0 . 4 )

F ig . 3. O ve r v i ew of e ffec t s r e p o rt e d

( b ) s t i l l birt h s a nd n e o n a t a l d ea t h s.

fewer th an 200 wo m e n ) a n d f r o m l a rger t ri a l s w e r e c o m bin e d u s i n g s t a nd a rd ov er v ie w m e th o d s'" D e t a i l s of th e t r i a l s in c lud e d a r e g i v e n in C LAS p l l

fro m a li r a n do mi s e d t ri a l s of a n t ip l a t e l e t th erap y i n pr eg n a n cy o n ( a ) pr ot e i nu r i c pr e - ec l amp s i a an d

S y m b o l s a nd co n v en t io n s as i n Fig . 1 . A va i l a b le re s ult s fro m s m a ll e r tr i a l s ( i .e. t h ose th a t in c l ud ed

a n d s tr a t i fi e d o d d s r at i os p l o t t e d .

S

ge nerall y high e r risk Brazi l ian women , in whom

c l ea r e ff ect s on lUGR ,

d e aths could be demon s trated .

EC PPA r es ult s support

s o m e s p eci a l category

imilarly ,

th e re

were

no s ubgroup s

m these

stillbirth s or neonatal

Con s equently , the

the conclu s ion ! '

that if

of w omen e x ists that ma y

about 2 per 100) . ECPPA and some previou s l a r g e

sca l e trials!' do suggest that aspirin m a y prevent a

few preterm deliverie s per 100 women treated . But , overall , there is no e v idence of a n e ffect of as pirin

d ea th s w ith 2 14

(

on the incidence of s tillbirths and n e on a tal

218 ( 2 ' 6 %) a s pirin- a llo c ated

c o mp a r e d

 

be

n e fit s ub s t a ntiall y from a s pirin , it must compo s e

(2 ' 6 % ) pl a cebo-alloc a t e d death s: Fi g.

3 b ) .

a

much s m a ller and more select group than h a d

ln con c 1u s ion ,

as w a s s ugge s t e d

b y th e o th e r

p

re v i o u s l y b een thought

to be the ca s e .

large trial s , the pre s ent randomi sed pl ace b o -

A s in th e pr e viou s trial s , the result s of ECPPA

control l ed

s tudy in 1009 women , w ith v er y goo d

a

r e g e ner a ll y reassurin g as regards maternal

and

fo ll ow up and comp l iance , doe s not s upport the

n

ex c esses of placental a bruption , other antepartum

h

bl

of t h e ava il a ble re s ult s f rom alI r a ndomi s ed

of a n t ipl ate l et ther a p y

i

e onat a l

complication s ,

tran sf u s ion ,

with

no signific a nt

due to o v er v iew

tri a l s

ae morrh age,

or mortalit y

ee din g . Prior to ECPPA , a sys tem a tic

n t h e in c id e n c e

of pr e -eclamp s ia '" ,

indi c ated a 2 5 % reduction

in contra s t

wide s pread

vention of pre - ec l ampsia

complications, even in the v er y hi g h ri s k pre g n a n t women o f a developin g c ountr y.

routine

u s e of aspirin

for th e pr e -

or other h y pert e n s i v e

Ac kno w l e d ge men ts

The most important ac kno w l e d ge m e nt

i s t o th e

w

ith th e r e duction

o f a bout three-qu a rters

s ug-

hundred s of women who took p a rt in ECPPA a nd

ges ted b y th e first s mall trials. The addition

of

to

the doctors who collaborated

thr o u g h o ut Br az il.

E CPPA reduce s s till further the apparent

thi s benefit (Fig . 3a) , and if the sma ll ' h ypothesi s

g eneratin g'

r

size of

trials are exc l u d ed , the apparent

i s onl y

e du c ti o n

in the l arger trials combined

1 7 % ( SD

6 ). ln ab s olute term s , the s e more mode s t

pr

th e r a p y wo uld t y pi c all y pre v ent proteinuric

e c 1 a mp s i a in a bout 1 w oman per 100 treated ( with

co nfiden ce inter va l r a n g ing from abo u t zero to

o port i on a l

redu c tion s

impl y th a t a ntipl a telet

pre-

T h e following investigator s study .

Data m a n age m e n t, a nal ys i s and w ritin g c ommittee:

A N At a llah ,

A

Freitas Jr , L Kin s uÍ , O Fuku s him a , A ndr a din a: M Amorim , A ra ç atub a: R Edu a rd o , Arara qua ra: A Durante , C Vieir a , J Filho , A r a r aras: L D avol o s,

Princ ip a l In vest i g ato r:

p

a rti c ip a ted

in the

R Collin s , B Farr e ll ,

H H a nd o ll .

A N At a ll a h , A m e ri ca n a :

46

E C PPA C OLLAB ORA

TIV E G R OUP

As i s : R Zambott i , Bariri: C N e g r ão , Batatais: O

B evil áqua , I Wulkan , G P aramo , J Motto l a Jr , M

Al

v e s, Bauru : P ' Tobia s, Belo Horizonte: C Fr eire ,

Scott, Se rt ãozinho: A Só d e , R C l emente , S oro-

C

Almeida, Birigui: J Neto , L B ertechini , Botu-

c

ab a : L Neto , So ro c aba : C B arro s, S orocaba: N

ca

tu: I Mae s t , J P er a çoli , Mari l za V R udge , I

B

ressan , T aubaté: M de Assis , X Mazzini.

Sil v a , S Fi l ho , I Ca l deron , O Abujamra Jr , Brag-

a n ça : A Neto , W M un i z , José Car l os Pin to n , M

A Ferre ir a J r ,

de Me ll o , C achoeir a Paulista:

C ampinas : C Nog u e i ra , A Sanc h es, A Maria n o, C

Ferraz Costa , R de Lacerda , A E l ias, R Y os h iass u ,

Lustre, S Ximenes , P de Godoy , Campinas: A de Meio , C anguçu : D de Campos, Carapicuiba: D

S

B

ezerra , C atagua s e s : F Cesário , Cax ia s do S ul : D

T

e ss ari , C ru zeiro: M Kisse , W Sória, E rechim

- R S : A Teixeira , Fe rnandopóli s : A F l umignan ,

F r a nca: M Marcolini , Guarujá : E Ri mi , Guar-

u

lho s: C Simões , V de Aráujo ,

Itatiba:

C

Pavanelri , Jaboticabal :

L M art i ns , Jacareí:

J

Neto, C Bi anco , C Antoná l ia, Jundiaí: E G e nn ari ,

Limeira : Z Vin h al , Lin s : J Leão , Londrina:

F

Sobrinho , M arília :

J Prado , Mirandopóli s:

Z

Souza , Mo g i: J Maga lh ães, R Esteves, N atal-R N :

H

de O l iveira, N o v o Hamburgo -- R S : L J aeger ,

N

o v o Hori z ont e: R Melc h iori , Olimpia: J Mi nari ,

O

s a s co :

E Santana ,

I Mac h i d a,

Ourinhos: F

Ce s me , H de Carvalho , Pejuçara-RS :

Silva , Pind a monhangab a : A Wo l ff , Piracicaba: C Negretti , Porto Alegre: I B e ll i , L Napp, A M e n e-

L da

ghetti, E C h aves , S Costa, C d e Qu a dr os K r o e ff , S

Espinosa, Pre s idente Prudente :

T s ello , Rib e irão Preto: A M a tth es, C d os S a n tos

J

D Campo s,

J r , G Duarte, Rio Claro: G Neto , W d e M atos

P Gonçal ves, H

Ri v oire , S. B e rnardo : LC J oão , A Gra d el l a , S.

Re z ende , Rio Grande-- R S:

José do R. Pr e to: R B ertazzo , I Moraes, J D ória ,

M

Trevisan , N Gabriel , Sa nta Maria-RS:

J d a

Sil

v a Ethur , F Jobim , S anto Andr é : R S e r re, S

Sanforlin , J da Silva, J Neves, O Ferra r o, Santo s :

M a dos Santos, A R ibe i ro, R d e F r e it a s , São

C a e tano : A Adans, S ão Leopoldo -- RS: I Pl e nt z ,

H Nig htin ga l e, J

Rebel l o , J Bencic , C da Costa A l ves, C Camp-

m a n y , A Pereira , A Kataguiri , L de Campos , J

Masonetto ,

Ru s so , A Celesti n i , A Azeve d o ,

Zanotto , F Simon , G Frehse , H Ha l be , L Pri mon ,

P David , P Franco ,

Awoke, L de Figueiredo, R Th eo d oz i o , I Con-

ceição, I Daniel, J Kub l ikowski , J A d a l a f t N e t o,

G Kenji , S Gui m arães ,

Freitas , B Carva lh o , G P orto, J d os S a nt os , A Andrade , E Cava l cante , A H e nri c h , W Ar l ê , H

Ariê , T de O l ive i ra, D Si l vestri n i , E d e So u za , A d e Araújo , A Al l egrini , L Saka m oto , L Ta k a n o , R Mattar , W Tabo rd a , H P a r ave n t i , M Miyazawa ,

N Sa s s , R de Souza Mes qu ita, M Le m os , M

V

L

F

o Paulo :

J de An dr a d e,

D B entivegna , M de O live ir a , M

P P irozzi ,

H Lippi ,

D K l otze l ,

S Le un g , T Gollop ,

ECPP A Co-ordinating C e ntr e: A N Ata llah , E

C l ariz i a , M L Du arte, H Go n za l ez , A Pantoja , M

M es qu ita.

S tud y Monitoring C ommitte e : I Cha l mers , R

Co lli n s , O D e l asc i o ( l ate) , J A Griss o , R P eto , M

Z u gaib .

The C l inical Trial Service Unit (CTSU) , Nuffield

D

epartment of Medicine , Univer s ity of Oxford ,

U

K provided tec h nical s upport and encourage-

m e n t throug h o u t the duration of the s tudy . The

st ud y was princip a lly funded by Ster l ing Drug s (P

Tribble, S W e i s m an) , who a l so donated

specia ll y

p a ck aged asp irin a n d matc h ing p l ace b o a nd

by Esco l a P a ulista

INCLEN, Inc. Th e study was , h owever , designed ,

de Me d icina ,

CN P Q and

co

ndu cte d , a n a l ysed , and interpreted indepen -

de

n t l y of the commercial sponsor .

R e fere n ces

I Davie s AM . Epidemiol ogy o fh y p e rten s i ve di s o rd e r s ofp r eg n a n c y.

Buli W o rld H e alth Organ 1 97 9 ; 57 : 3 73.

2

Redm a n C WG. Current topic: pre - ecl a mp s i a a nd the pl ace nt a .

Pla

c enta

1 99 1 ; 12 : 30 1 - 308.

 

3

B

u s so l in o F , Benedetto C , M ass obri o M , C a mu ss i G . Mat e rn a l

vascul a r pr os t a c yc l in a cti v it y in pr e - ec l a mp s i a . L an ce t 1 9 8 0 ; 2:

7

02 .

4

Redm a n C WG , Bonn a r J , B e ilin L . E a rl y pl a t e l et c o n s u mp t i o n

in

pre-

ec l a mp s i a . BM]

1 97 8; I : 4 6 7 - 4 69 .

5

Be a ufil s M , Uza n S , D o n s im o ni R , Co l a u . I C . Pr e v e nti o n of pr e-

e

cl a mp s i a b y e a rl y a n t ipl a t e l e t ther a p y . L an ce t 1 98 5 ; I : 8 4 0 - 8 4 2.

6

W

a ll e nbur g H C S , Dek ke r GA , M a k ov it z JW , R o tm a n s P . L o w-

do

s e as pirin pre v ent s pr eg n a n cy -indu ce d h y p e rt e n s i o n a nd p r e -

e

c l a mp s i a in a n g ioten s in - s e n s iti ve primi g r av id a e . L a n ce t 1 9 8 6 ; I:

1

- 3 .

7

Schiff E , Peleg E , Goldenb e r g M e l ai . Th e u s e o f a s pi r in t o

prevent pregn a n cy - in du c ed h y pertension a nd l o wer th e r a ti o of

t

hr ombox a ne A 2 t o pro s t a c yc l in in re l ati ve l y hi g h ri s k pr eg n a n c i e s.

N

En g l J M e d

1989 ; 3 2 1 : 3 51 - 356 .

 

8

McPar l and P , Pearce JM , C h a mberlain GVP . D o ppl e r ultr a so und

and a s pi r in in reco g niti o n a nd pr eve nti o n of p r eg n a n c y -indu c e d

h

y perten s ion . Lan c e t 19 9 0 ; 335 : 15 52 - 1 555 .

 

9

Itali a n Stud y of A s pirin in Pr e gn a n c y. L ow -d ose a s p i ri n in

pre ve nti o n a nd treatment o f i ntrauterin e g r o wt h r e t a rd a ti on a nd

pr

e gn a n c y -induced h y p e rt e n s i o n . L a n ce t 1 993 ; 34 1 : 396 - 400 .

 

10

Sib a i BM , Ca ritis SN , Th o m E e t a i . Pr eve nti o n of pr e - e c l a mp s i a

w ith lo w -d ose a spirin in h ea lth y, nullip a r o u s pr eg n a n t wom en .

Ne w Eng l]

M e d 199 3 ; 329 : 121 3 - 121 8 .

1 1 CLASP (Co l l a bo r ati ve Lo w - d ose A s pirin Stud y in Pr e g n a n c y ) Co ll a bor a ti v e Group. C LASP : a rand o mi s e d tri a l o f l o w-d o s e

as p i r in for t h e prevention a nd t r ea t ment of pr e - ec l amp s i a a m o n g

936 4 pre g n a nt women. Lan ce t 199 4 ; 3 4 3 : 6 1 9 - 629.

12

Atal l a h AN , de Sou za M e s quit a MR , Du a rt e ML e t ai . E s tud o

pro s p ec ti vo

" cohort ' de

ges t a nt es co m hip e r ta n são a r te ri a l

cr ô nica. v

Bra s Nefr o 11 990 ;

1 2 : 11 3 - 1 20 .

13

B

e nigini A , Gregorini G , Fru s c a T e t ai . Etf ec t o f l ow- d ose a s p i r i n

o n f e t a l a nd matern a l g e n e r a ti o n of t h r o m b o x a n e b y p l a t e l e t s

i n w o m e n a t ri s k of pr eg n a n c y -indu ce d h y p e rt e n s i o n . N En g l J

M e d 1 9 8 9 ; 32 1 : 35 7 - 362.

 

E CPPA : A RAND O MIS ED

TRIAL

OF LOW DOS E A S PIRI N

4 7

14 Pe t o

R , Pik e M C ,

Armit age

P e t ai. Design

and analysis

of

16 At a lla h

AN , S hin a r R . Pr e -e c 1 amp s i a

a nd pr ostag l a ndin s.

L a n c e I

ran d o mi ze d cl i nic a l tri a l s requiring

pat i e nt

a nd exa mpl es.

l l . A n a l ys i s

prolonged observation or each

B r J Ca nc e r 1977 ; 35: 1 - 39.

1 5 Ant ipl ate l e t

Tri a li s t s' C ollaboration.

C ollaborative

o verview of

ra

nd o mi sed tri a l s o f a n t iplat e let therap y -I:

Prev ention of death ,

m

yocardi a l

i nf a r c ti o n , a nd s troke by prolonged

a ntiplatelet

t h e r a p y in va ri o u s c a te g ories o f patient s.

BMJ 1994 ; 308 : 81 - 106.

© R C OG 1 996 Br J Ob s t e t G y na ec ol103 ,

39 - 47

1990 ; 1 : 12 67.

17 B e ilin L . A s pirin a nd pr e - ec 1 a mp s i a .

Re ce iv e d 27 April 1995 Ac ce pt e d 13 S e pt e mb e r 1995

BMJ 1 99 4 ; 308 : 1 2 00 - 1 25 1 .

B

r iti s h Jou rn al of O b stet ri cs a nd G y n aeco l og y

J

a nu a r y

1 996 , Vol . 10 3 , pp . 48 - 53

D e te c t ion o f fet a l fib r onectin as a predictor of preterm

d elivery i n h ig h risk a symptomatic pre g n an c i e s

* s . C . Lees on S e n ior R eg i s trar,

tT. Mahmood R e gistrar ,

* M. J. A . Maresh Consu l tant,

* * E . A . Martinda l e R eg i s tra r ,

S H O , tt N. Hawkes S HO , * K . J. Baldwin R e gi s tra r

* A . Muotune

* D e par t m e nt of Ob s t e trics and Gynaeeo l og y , Saint Mar y' s H ospit a l , Man e h e ster , ** D e partm e n t of Ob s t e tri c s and

G y n aeeo l ogy , B o lt o n G e n e ra l H o s pi t a l ; t D e partme n t of Ob s t e tri cs and G y na ee olog y, N orth Man e h es t e r G e n e r a l H os pita l ; tt D e partme nt of Ob ste tri cs and G y na eeo l ogy , G l o u ees t e r R oy al H os pita l

Objecti ve

The s tud y wa s de s ig n ed to determine

before 3 7 weeks in women at high risk of prete rm

w h eth er feta l fib ro n ecti n

delive r y.

wo u ld predict d e l iv e r y

S tudy methods

Forty-t h ree women consi der e d at r i s k o f pr e t e rm d e live r y were rec ru ite d a nt e n a t a lly

into a b l i n d long itud i n al

seq u entia l high vag i na l swa b s taken for t n i g h t l y

conc e ntration s

st ud y . Qu a ntit at i ve

assays o f fe tal

fib ro n ecti n were obtai ne d from

Fi b ronecti n

fro m 2 4 to 3 4 wee k s of ges t a t io n .

as positive .

of 0 · 05 I lg / ml or more were co n s id ered

R es u l t s

R e s ults w ere ca l c ul ated b y swab a nd by s ub ject . The sensitiv ity

of an individua l fibrone c tin

s

w a b in predicting p reterrn

d e l ivery w i t h in 1 4 d ays of tes tin g was 7 1 % a n d t h e s pecificit y

w as

93 % . T h e ove r a ll p ositive

p re di ctive valu e

was 3 1 % a nd t h e n ega t ive

p re d ict i ve

valu e

was

99 %. T h e sens i t i vity of t h e fibr o n ec tin

and the specific i ty was 93 %. Th e posit ive p re di c tive va lu e was 5 0 % an d t h e n ega t i ve pr e d ictive

preterm

v a lu e w a s 73 %. Fo r a woman who h as h a d a pos i tive s wa b the sensi tivity in predict in g

de l i v ery within 14 d a ys of tes ti ng was 80 % a nd t h e spec i ficity was 83 %; a woman wa s counted

as p os iti v e onl y if the fin a l swab was positiv e an d preced e d d e l ivery b y not more than 14 d ays.

The po s itive pred i c ti ve

woman w h o h as h a d a positive swab th e sensitiv i ty in pr e di ctin g

54 %. T h e s p ec i f i c it y, t h e p os it ive pre di c ti ve va lu e a nd t he n ega tive pr ed i c tive

6 4 % and 79 %, r esp ec ti ve l y.

sequence was posi ti ve. Fibro n ect in

deli ve ry within 14 d ays of testing (P = 0'0 1 ) an d before 37 weeks (P = 0 ' 0 1 ) . Ana l ysis of the

acc ur a c y of pr e dict i ng

valu e we r e 85 %,

d e livery be f ore 37 week s wa s

swa b in p re di c tin g

d e live r y b efore 37 weeks w as 1 7 %

v a l u e was 36 % and the negative

W o m e n w e r e c o un ted

delivery

pre d ict i ve

valu e wa s 97 %.

For a

as p os i t i ve if a n y

swa b in t h e sa m p l ing

swa bb ing w h en ca l c ul a t e d

by p a t ien t d i d predict preterm

reveal ed

th a t

the be s t

from 7 to 28 d ay s after samp l ing

predi c tion for deli v er y wa s within t h e fo llowing 1 4 days .

Co nc l u s ion

Seria l feta l fi b ronectin assessment fro m 2 4 to 3 4 weeks of gestation a n ticipated preterm

de l ivery wit h in 14 d ays oftes t ing a nd b efore 37 wee k s fo r hi g h r i sk asy m pto m ati c

te s ting s h o ul d be p erfo r me d

every t wo w ee k s.

wo m en . S u c h

I N TROD UCT IO N

P reterm delivery is the l eading cause of n ew b o r n infant morta l ity i n the d eve l ope d wo rl d . M ost of these death s occur in preg n anc i es ending be fore 29 wee k s' . A s ub s t a nti a l m or b i d i t y acco mp a ni es p r eterm d e l ivery as we ll as ia t roge n ic mo rbi dity a ss ociated with prol onge d n eo n a t a l in te n s i ve care . L o ng term neurolog i ca l pro bl ems a r e m ore diffic ult to eval uate. Apart from t h e hum a n cost , t h e

in p a ti e n t care f or

financia l co s t of provi din g

p reterm b a b ies a nd p rovi d i n g s uppor t in c a ses of li fe l ong h a n d i cap is g r ea t .

rres p o nd e n ce:

Co

a

M

nd Gynaeco l ogy ,

a n c h es t er

Dr S . C . L ees on ,

S a int M a r y ' s

M 1 3 9 PT , U K .

48

D e p a rtment

o f O b stetric s

R o a d ,

Ho s pit a l , Hather sa ge

P re di c t ion ofprete r m l abo u r is u n r eliab l e . U s i ng

a hi s tor y of p revious preter m de l ivery , twin

pr eg n a n cy , uterin e a bn o rm a lity , l ow soc i o - econ-

o mic s t a tu s a nd ce r v i ca l in co mp e t e n ce p re di cts , at

b es t , 50 % o f pret e rm de l i ver i es " . Th e u se of se ri a l vagin a l exa minatio n , sc re e nin g for re du ced feta l br eathin g movem ents o n ul t r aso u n d sca n ning or scree nin g for rec ur rent contractio n s wit h external tocog r a ph y p r ovi d es l ittle a dd iti onal se n s i tivit y".

F eta l f i br o n ec tin is p a r t of a fa m i l y of ubi q ui to u s

dime ric gl yc op r ot e in s pr ese n t pr e d o min a ntly in

p l a sma a nd extr ace l lular m a t r i x a nd w h ic h

i nf l u e nce ce ll a dh es i on , m o til ity , tissue repai r a nd coag ulati o n + ". Th ere a r e m ore th a n 20 i soforms of

t h e molec ul e . F eta l f ibr o n ectin h as a m o l ec ul ar

we i g ht of a b o ut 4 5 0 , 0 00 d a lto n s and is p r o du ced

© R C O G 1 996 Briti s l i J o urnal of Ob s t e tri cs an d G y na eeo l ogy